研究者総覧

山形 崇倫 (ヤマガタ タカノリ)

  • 小児科学講座(発達医学部門) 教授
Last Updated :2021/12/04

研究者情報

学位

  • 医学博士(自治医科大学(JMU))

ホームページURL

J-Global ID

研究キーワード

  • 発達障害   小児神経学   神経科学一般   人類遺伝学   小児科学   New Science in General   

研究分野

  • ライフサイエンス / 胎児医学、小児成育学
  • ライフサイエンス / 医化学
  • ライフサイエンス / 神経科学一般
  • ライフサイエンス / 神経科学一般

経歴

  • 2011年05月 - 現在  自治医科大学医学部小児科学教授
  • 1997年11月 - 2000年03月  ベイラー医科大学 人類遺伝学リサーチフェロー
  • 1997年 - 2000年  Research Associate, Department of Molecular
  • Medicine, USA
  • and Human Genetics, Baylor College of

学歴

  •         - 1986年   岐阜大学   医学部   医学科
  •         - 1986年   岐阜大学   Faculty of Medicine

所属学協会

  • アメリカ遺伝子細胞治療学会   日本遺伝子細胞治療学会   日本マススクリーニング学会   日本神経感染症学会   日本神経学会   日本小児遺伝学会   日本ADHD学会   日本先天代謝異常学会   アメリカ人類遺伝学会   日本てんかん学会   日本人類遺伝学会   日本小児神経学会   日本小児科学会   

研究活動情報

論文

  • Masahiro Hirai, Takeshi Sakurada, Jun Izawa, Takahiro Ikeda, Yukifumi Monden, Hideo Shimoizumi, Takanori Yamagata
    Scientific Reports 11 1 2021年12月 
    AbstractDifficulties with visual perspective-taking among individuals with autism spectrum disorders remain poorly understood. Many studies have presumed that first-person visual input can be mentally transformed to a third-person perspective during visual perspective-taking tasks; however, existing research has not fully revealed the computational strategy used by those with autism spectrum disorders for taking another person’s perspective. In this study, we designed a novel approach to test a strategy using the opposite-directional effect among children with autism spectrum disorders. This effect refers to how a third-person perspective as a visual input alters a cognitive process. We directly manipulated participants’ visual perspective by placing a camera at different positions; participants could watch themselves from a third-person perspective during a reaching task with no endpoint feedback. During a baseline task, endpoint bias (with endpoint feedback but no visual transformation) did not differ significantly between groups. However, the endpoint was affected by extrinsic coordinate information in the control group relative to the autism spectrum disorders group when the visual perspective was transformed. These results indicate an increased reliance on proprioception during the reaching task with perspective manipulation in the autism spectrum disorders group.
  • Takahiro Ikeda, Akari Inoue, Daisuke Tanaka, Tamao Hashimoto, Stephanie Sutoko, Tatsuya Tokuda, Yasushi Kyutoku, Atsushi Maki, Takanori Yamagata, Ippeita Dan, Yukifumi Monden
    Frontiers in Neuroergonomics 2 2021年07月 
    Objective: In the current study, we explored the neural substrate for acute effects of guanfacine extended release (GXR) on inhibitory control in school-aged children with attention deficit hyperactivity disorder (ADHD), using functional near-infrared spectroscopy (fNIRS). Methods: Following a GXR washout period, 12 AD HD children (6–10 years old) performed a go/no-go task before and 3 h after GXR or placebo administration, in a randomized, double-blind, placebo-controlled, crossover design study. In the primary analysis, fNIRS was used to monitor the right prefrontal cortical hemodynamics of the participants, where our former studies showed consistent dysfunction and osmotic release oral system-methylphenidate (OROS-MPH) and atomoxetine hydrochloride (ATX) elicited recovery. We examined the inter-medication contrast, comparing the effect of GXR against the placebo. In the exploratory analysis, we explored neural responses in regions other than the right prefrontal cortex (PFC). Results: In the primary analysis, we observed no significant main effects or interactions of medication type and age in month (two-way mixed ANCOVA, Fs < 0.20, all ps > .05). However, in the post-hoc analysis, we observed significant change in the oxy-Hb signal in the right angular gyrus (AG) for inter-medication (one sample t-test, p < 0.05, uncorrected, Cohen's d = 0.71). Conclusions: These results are different from the neuropharmacological effects of OROS-MPH and ATX, which, in an upregulated manner, reduced right PFC function in ADHD children during inhibitory tasks. This analysis, while limited by its secondary nature, suggested that the improved cognitive performance was associated with activation in the right AG, which might serve as a biological marker to monitor the effect of GXR in the ADHD children.
  • Saori Fukui, Mitsuru Seki, Takaomi Minami, Kazuhiko Kotani, Kensuke Oka, Akiko Yokomizo, Daisuke Matsubara, Tomoyuki Sato, Yasuyuki Nozaki, Mari Saito, Yutaka Kikuchi, Kenji Miyamoto, Yukifumi Monden, Takanori Yamagata
    Pediatric rheumatology online journal 19 1 107 - 107 2021年07月 
    BACKGROUND: High-dose intravenous immunoglobulin (IVIG) is the mainstay of treatment for Kawasaki disease (KD). Usually, 2 g/kg of IVIG is administered over 10-24 h, depending on the institution or physician, but the association between infusion speed and effectiveness has not been reported. In this study, we evaluated the differences in efficacy and safety between two different IVIG administration speeds. METHODS: This was a multicenter, unblinded, randomized controlled study. Patients newly diagnosed with KD were randomized into two groups: one who received IVIG over 12 h (12H group, double speed), and one that received IVIG over 24 h (24H group, reference speed). The endpoints included the duration of fever, incidence of coronary artery abnormalities (CAAs) and of adverse events. Laboratory data were evaluated before and after IVIG administration. RESULTS: A total of 39 patients were enrolled. There was no difference between groups in fever duration after the initiation of IVIG (21 h vs. 21.5 h, p = 0.325), and no patient experienced CAAs. Two adverse events were observed in the 12H group (elevation of aspartate aminotransferase and vomiting), however no severe adverse events requiring treatments or extension of hospital stay were observed in either group. After initial IVIG administration, the change ratio of inflammatory markers, such as white blood cell counts, neutrophils, C-reactive protein, and albumin, did not show significant differences between the two groups. On the other hand, a greater increase of serum immunoglobulin G from its baseline level was observed in the 24H group compared to the 12H group (3037 ± 648 mg/dl vs. 2414 ± 248 mg/dl, p < 0.01). CONCLUSION: The efficacy and safety of IVIG administered over 12 h (double speed) were similar to those administered over 24 h (reference speed). TRIAL REGISTRATION: University Hospital Medical Information Network ( UMIN000014665 ). Registered 27 July 2014 - Prospectively registered, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000017058.
  • Daisuke Tamura, Masanori Kurosaki, Masayoshi Shinjoh, Hidekazu Nishimura, Hirokazu Yamagishi, Takanori Yamagata
    Pediatric transplantation e14070  2021年06月 
    BACKGROUND: LAVV have historically been avoided in children after solid organ transplantation. However, it has been reported that post-transplant, children without severe immunosuppression can generate anti-varicella antibody after immunization but the duration of the response is not clear. Furthermore, the origin of the varicella virus in immunosuppressed patients who develop varicella after vaccination is often unclear. CLINICAL PROGRESS: A female child received LAVV 30 months after a living donor liver transplant at the age of 2 months. Varicella rash appeared on the trunk 16 days after vaccination and gradually spread over the body. The patient was treated with intravenous acyclovir followed by oral therapy and recovered fully. The virus detected in blisters was derived from the vaccine-type strain. Paired sera before and after the onset of varicella showed an increase in antibody titer. However, 2 years after onset, the antibody titer decreased to undetectable again. CONCLUSIONS: This was an informative case of varicella due to vaccine strain attenuated virus. Antibody levels were not maintained over many years. Although varicella was caused by the vaccine-type strain, repeated vaccinations may be necessary for post-transplant patients who develop varicella.
  • Daisuke Tamura, Yuta Kawahara, Masaaki Mori, Takanori Yamagata
    Pediatrics international : official journal of the Japan Pediatric Society 2021年06月
  • Ayumi Matsumoto, Karin Kojima, Fuyuki Miya, Akihiko Miyauchi, Kazuhisa Watanabe, Sadahiko Iwamoto, Kensuke Kawai, Mitsuhiro Kato, Yukitoshi Takahashi, Takanori Yamagata
    Brain & development 2021年06月 
    BACKGROUND: The DYNC1H1 gene encodes the heavy chain of cytoplasmic dynein 1, a core structure of the cytoplasmic dynein complex. Dominant DYNC1H1 mutations are implicated in Charcot-Marie-Tooth disease, axonal, type 20, spinal muscular atrophy, lower extremity-predominant 1, and autosomal dominant mental retardation 13 with neuronal migration defects. We report two patients with DYNC1H1 mutations who had intractable epilepsy and intellectual disability (ID), one with and one without pachygyria. CASE REPORTS: Patient 1 had severe ID. At the age of 2 months, she presented myoclonic seizures and tonic seizures, and later experienced atonic seizures and focal impaired-awareness seizures (FIAS). EEG showed slow waves in right central areas during myoclonic seizures. Brain MRI revealed pachygyria, predominantly in the occipital lobe. After callosal transection her atonic seizures disappeared, but FIAS remained. Patient 2 was diagnosed with autism spectrum disorder (ASD) and severe ID. At the age of 7 years, he presented generalized tonic-clonic seizures, myoclonic seizures, and FIAS. Interictal EEG showed generalized spike-and-wave complexes, predominantly in the left frontal area. Brain MRI was unremarkable. Exome sequencing revealed novel de novo mutations in DYNC1H1: c.4691A > T, p.(Glu1564Val) in Patient 1 and c.12536 T > C, p.(Leu4179Ser) in Patient 2. CONCLUSIONS: DYNC1H1 comprises a stem, stalk, and six AAA domains. Patient 2 is the second report of an AAA6 domain mutation without malformations of cortical development. The p.(Gly4072Ser) mutation in the AAA6 domain was also reported in a patient with ASD. It may be that the AAA6 domain has little effect on neuronal movement of DYNC1H1 along microtubules.
  • Sachie Nakamura, Hitoshi Osaka, Shin-Ichi Muramatsu, Naomi Takino, Mika Ito, Eriko F Jimbo, Chika Watanabe, Shuji Hishikawa, Takeshi Nakajima, Takanori Yamagata
    Gene therapy 28 6 329 - 338 2021年06月 
    Glucose transporter 1 deficiency syndrome (GLUT1DS) is caused by haplo-insufficiency of SLC2A1, which encodes GLUT1, resulting in impaired hexose transport into the brain. Previously, we generated a tyrosine-mutant AAV9/3 vector in which SLC2A1 was expressed under the control of the endogenous GLUT1 promoter (AAV-GLUT1), and confirmed the improved motor function and cerebrospinal fluid glucose levels of Glut1-deficient mice after cerebroventricular injection of AAV-GLUT1. In preparation for clinical application, we examined the expression of transgenes after intra-cisterna magna injection of AAV-GFP (tyrosine-mutant AAV9/3-GFP with the CMV promoter) and AAV-GLUT1. We injected AAV-GFP or AAV-GLUT1 (1.63 × 1012 vector genomes/kg) into the cisterna magna of pigs to compare differential promoter activity. After AAV-GFP injection, exogenous GFP was expressed in broad areas of the brain and peripheral organs. After AAV-GLUT1 injection, exogenous GLUT1 was expressed predominantly in the brain. At the cellular level, exogenous GLUT1 was mainly expressed in the endothelium, followed by glia and neurons, which was contrasted with the neuronal-predominant expression of GFP by the CMV promotor. We consider intra-cisterna magna injection of AAV-GLUT1 to be a feasible approach for gene therapy of GLUT1DS.
  • Yoshie Kurokawa, Hitoshi Osaka, Takeshi Kouga, Eriko Jimbo, Kazuhiro Muramatsu, Sachie Nakamura, Yuki Takayanagi, Tatsushi Onaka, Shin-Ichi Muramatsu, Takanori Yamagata
    Human gene therapy 32 11-12 589 - 598 2021年06月 
    Niemann-Pick disease type C1 (NPC1) is a fatal congenital neurodegenerative disorder caused by mutations in the NPC1 gene, which is involved in cholesterol transport in lysosomes. Broad clinical manifestations of NPC1 include liver failure, pulmonary disorder, neurological deficits, and psychiatric symptoms. The main cause of death in NPC1 patients involves central nervous system (CNS) dysfunction; there is no essential treatment. We generated a tyrosine-mutant adeno-associated virus (AAV) 9/3 vector that expresses human NPC1 under a cytomegalovirus (CMV) promoter (AAV-CMV-hNPC1) and injected it into the left lateral ventricle (5 μL) and cisterna magna (10 μL) of Npc1 homo-knockout (Npc1-/-) mice. Each mouse received total 1.35 × 1011 vector genome on days 4 or 5 of life. AAV-treated Npc1-/- mice (n = 11) had an average survival of >28 weeks, while all saline-treated Npc1-/- mice (n = 11) and untreated Npc1-/- mice (n = 6) died within 16 weeks. Saline-treated and untreated Npc1-/- mice lost body weight from 7 weeks until death. However, the average body weight of AAV-treated Npc1-/- mice increased until 15 weeks. AAV-treated Npc1-/- mice also showed a significant improvement in the rotarod test performance. A pathological analysis at 11 weeks showed that cerebellar Purkinje cells were preserved in AAV-treated Npc1-/- mice. In contrast, untreated Npc1-/- mice showed an almost total loss of cerebellar Purkinje cells. Combined injection into both the lateral ventricle and cisterna magna achieved broader delivery of the vector to the CNS, leading to better outcomes than noted in previous reports, with injection into the lateral ventricles or veins alone. In AAV-treated Npc1-/- mice, vector genome DNA was detected widely in the CNS and liver. Human NPC1 RNA was detected in the brain, liver, lung, and heart. Accumulated unesterified cholesterol in the liver was reduced in the AAV-treated Npc1-/- mice. Our results suggest the feasibility of gene therapy for patients with NPC1.
  • Hideki Kumagai, Koji Yokoyama, Keijiro Sunada, Takanori Yamagata
    Pediatrics international : official journal of the Japan Pediatric Society 63 6 739 - 740 2021年06月
  • Yoko Ono-Takiguchi, Kazuhiro Muramatsu, Kiri Koshu, Takanori Yamagata
    Brain & development 2021年05月 
    PURPOSE: Forced normalization (FN) indicates psychotic episodes associated with seizure remission and disappearance of epileptiform activity on EEG. FN is likely to occur when frequent seizures are abruptly terminated by anti-epileptic drugs (AEDs) or epilepsy surgery. METHODS: We describe an atypical case of a patient with FN induced by lacosamide (LCM). RESULTS: A 23-year-old female patient with Lennox-Gastaut syndrome (LGS) was administered AEDs for LGS and hospitalised with weight loss and abnormal behaviour. Her condition fulfilled the FN criteria, which was considered to be induced by LCM. After a reduction in LCM dose, her abnormal behaviour and appetite improved. During LCM use, the patient developed no seizures, and the high amplitude diffuse sharp and slow wave complexes that were frequently observed before LCM disappeared on EEG. The LCM dose was tapered to 150 mg per day, and she became calmer with socially appropriate behaviours, although a few mild focal seizures relapsed. CONCLUSION: LCM was effective for treating LGS in this patient and induced FN. Initially, it was difficult to recognise FN in cases of psychiatric disorders, especially in patients with intellectual disability. Patients with FN induced by LCM are rare, and only four patients have been previously reported who were treated by antipsychotic drug for psychosis.
  • 若江 恵三, 門田 行史, 井上 俊, 小太刀 豪, 俣野 美雪, 郡司 勇治, 山形 崇倫
    小児科臨床 74 3 277 - 281 (株)日本小児医事出版社 2021年03月 
    急性呼吸不全が原因で入院を繰り返す重症心身障害児に対し、在宅非侵襲的陽圧換気療法(noninvasive positive pressure ventilation;NPPV)を呼吸状態の安定時に使用する効果について検証した。重症心身障害児3例を対象に、在宅NPPV導入前後の入院回数を後方視的に比較した結果、在宅NPPV導入前の5年間で、全症例において呼吸障害を原因とする入院が5〜17回であったが、導入後は入院回数が0回となり、在宅NPPVの高い有効性を示した。また、全症例で在宅NPPV導入前に気管切開術の実施を家族と協議したが、気管切開術の高い侵襲性のため実施に至らなかったが、在宅NPPVは迅速に導入できた。本邦の重症心身障害児に対する在宅NPPV導入は、他の呼吸管理法と比べて途上であり、今後の普及が待たれる。(著者抄録)
  • Kei Wakabayashi, Hitoshi Osaka, Karin Kojima, Taichi Imaizumi, Toshiyuki Yamamoto, Takanori Yamagata
    Human genome variation 8 1 10 - 10 2021年02月 
    MCT8 deficiency is an X-linked recessive disorder. We report the case of a 2-year-old Japanese boy with MCT8 deficiency caused by a novel frameshift variant, NM_006517.5(SLC16A2_v001):c.966dup [p.(Ile323Hisfs*57)]. He presented no head control and spoke no meaningful words, indicating severe developmental delay. Although missense or in-frame mutations of SLC16A2 are usually related to milder phenotypes and later-onset pyramidal signs, loss-of-function mutations are expected to cause severe clinical symptoms.
  • Kei Ohashi, Satomi Fukuhara, Taishi Miyachi, Tomoko Asai, Masayuki Imaeda, Masahide Goto, Yoshie Kurokawa, Tatsuya Anzai, Yoshinori Tsurusaki, Noriko Miyake, Naomichi Matsumoto, Takanori Yamagata, Shinji Saitoh
    Journal of autism and developmental disorders 2021年02月 
    Although genetic factors are involved in the etiology of autism spectrum disorder (ASD), the significance of genetic analysis in clinical settings is unclear. Forty-nine subjects diagnosed with non-syndromic ASD were analyzed by microarray comparative genomic hybridization (CGH) analysis, whole-exome sequencing (WES) analysis, and panel sequencing analysis for 52 common causative genes of ASD to detect inherited rare variants. Genetic analysis by microarray CGH and WES analyses showed conclusive results in about 10% of patients, however, many inherited variants detected by panel sequencing analysis were difficult to interpret and apply in clinical practice in the majority of patients. Further improvement of interpretation of many variants detected would be necessary for combined genetic tests to be used in clinical settings.
  • Jun Aoyagi, Takahiro Kanai, Takane Ito, Jun Odaka, Takashi Saito, Hiroyuki Betsui, Masanori Kurosaki, Tomomi Maru, Takanori Yamagata
    Nephrology (Carlton, Vic.) 26 2 119 - 125 2021年02月 
    AIM: Glucocorticoids (GC) are essential medicines for idiopathic steroid-sensitive nephrotic syndrome (ISSNS) and IgA nephropathy (IgAN), with good clinical results. However, they cause bone fragility. The aim of this study was to elucidate GC effects on bone strength assessed as bone mineral density (BMD) and bone quality, using bone turnover markers (BTM), in children with ISSNS or IgAN. METHODS: Eleven children with ISSNS and 13 with IgAN were included. All the patients received GC treatment according to each protocol. The BMD and BTM-serum alkaline phosphatase (S-ALP), tartrate-resistant acid phosphatase 5b (S-TRACP-5b), and undercarboxylated osteocalcin (S-ucOC)-were measured from the initiation of steroid treatment (STx) to the end of STx in both groups. RESULTS: In ISSNS, S-ALP and S-ucOC levels were decreased significantly at 1 month. BMD and S-TRACP-5b levels showed no significant change through this observation period. In IgAN, BMD and S-ALP levels were decreased significantly at 1 and 3 months, respectively, and recovered to baseline at 10 months after the initiation of GC dosage reduction. S-TRACP-5b levels were decreased significantly at 3 months and remained lower than at baseline through the observation period. In both groups, S-ucOC levels did not directly reflect bone strength. CONCLUSION: This study clarified the following three points regarding GC effects on bone strength in children with ISSNS or IgAN: first, S-ALP is a more sensitive bone quality marker than S-TRACP-5b; second, BMD loss was observed only when both S-ALP and S-TRACP-5b levels decreased, and third, S-ucOC levels do not directly reflect bone strength.
  • Yoshiyuki Onuki, Sayaka Ono, Takeshi Nakajima, Karin Kojima, Naoyuki Taga, Takahiro Ikeda, Mari Kuwajima, Yoshie Kurokawa, Mitsuhiro Kato, Kensuke Kawai, Hitoshi Osaka, Toshihiko Sato, Shin-Ichi Muramatsu, Takanori Yamagata
    Brain communications 3 3 fcab078  2021年 
    Aromatic l-amino acid decarboxylase (AADC) is an essential dopamine-synthesizing enzyme. In children with AADC deficiency, the gene delivery of AADC into the putamen, which functionally interacts with cortical regions, was found to improve motor function and ameliorate dystonia. However, how the restoration of dopamine in the putamen in association with cortico-putaminal networks leads to therapeutic effects remains unclear. Here, we examined neuroimaging data of eight patients with AADC deficiency (five males and three females, age range 4-19 years) who received the AADC gene therapy of the bilateral putamen in an open-label phase 1/2 study. Using high-resolution positron emission tomography with a specific AADC tracer, 6-[18F]fluoro-l-m-tyrosine (FMT), we showed that FMT uptake increased in the broad area of the putamen over the years. Then, with the structural connectivity-based parcellation of the putaminal area, we found that motor improvement is associated with dopaminergic restoration of the putaminal area that belongs to the prefrontal cortico-putaminal network. The prefrontal area dominantly belongs to the frontoparietal control network, which contributes to cognitive-motor control function, including motor initiation and planning. The results suggest that putaminal dopamine promotes the development of an immature motor control system, particularly in the human prefrontal cortex that is primarily affected by AADC deficiency.
  • Masashi Mizuguchi, Takashi Ichiyama, George Imataka, Akihisa Okumura, Tomohide Goto, Hiroshi Sakuma, Jun-Ichi Takanashi, Kei Murayama, Takanori Yamagata, Hideo Yamanouchi, Tokiko Fukuda, Yoshihiro Maegaki
    Brain & development 43 1 2 - 31 2021年01月 
    The cardinal symptom of acute encephalopathy is impairment of consciousness of acute onset during the course of an infectious disease, with duration and severity meeting defined criteria. Acute encephalopathy consists of multiple syndromes such as acute necrotizing encephalopathy, acute encephalopathy with biphasic seizures and late reduced diffusion and clinically mild encephalitis/encephalopathy with reversible splenial lesion. Among these syndromes, there are both similarities and differences. In 2016, the Japanese Society of Child Neurology published 'Guidelines for the Diagnosis and Treatment of Acute Encephalopathy in Childhood', which made recommendations and comments on the general aspects of acute encephalopathy in the first half, and on individual syndromes in the latter half. Since the guidelines were written in Japanese, this review article describes extracts from the recommendations and comments in English, in order to introduce the essence of the guidelines to international clinicians and researchers.
  • Kiri Koshu, Takahiro Ikeda, Daisuke Tamura, Kazuhiro Muramatsu, Hitoshi Osaka, Shigeru Ono, Kaori Adachi, Eiji Nanba, Takero Nakajima, Takanori Yamagata
    Brain & development 43 1 140 - 143 2021年01月 
    INTRODUCTION: Metachromatic leukodystrophy (MLD) refers to leukodystrophy caused by the accumulation of sulfatide from arylsulfatase A (ARSA) gene mutations. Sulfatide also accumulates in various organs, including the peripheral nerves, kidney, and gallbladder. Proliferative changes in the gallbladder have been reported in several patients, while gallbladder cancer is reported in only two adult MLD cases. We report what is likely the first pediatric case of MLD with gallbladder cancer. CASE REPORT: The patient was a 5-year-old girl diagnosed with MLD using head magnetic resonance imaging and detecting a homozygous mutation of c.302G>A (p.Gly101Asp) in ARSA. Abdominal bloating was observed at the age of 4 years; CT revealed a giant tumor in the gallbladder and massive ascites. Cholecystectomy was performed and pathological examination revealed adenocarcinoma. Measurement of serum sulfatide revealed increased levels compared to the average healthy range. DISCUSSION: Rapidly increased ascites and large polyps which are reported as risk factors for cancer were characteristic in our MLD case. When such lesions are detected, they should be removed immediately because of the possibility of cancer, even in a pediatric patient.
  • Hideki Kumagai, Kazuto Kobayashi, Sachiko Yoshida, Koji Yokoyama, Norio Hirota, Takanori Yamagata
    Acoustics 3 1 3 - 10 2020年12月 
    Scanning acoustic microscopy reveals information on histology and acoustic impedance through tissues. The objective of the present study was to investigate whether acoustic impedance values in the liver over time reflect the progression of steatohepatitis through different grades and stages, and whether this approach can visualize histologic features of the disease. Mice were divided into two groups: a control group and a steatohepatitis group prepared by keeping the mice on a methionine and choline-deficient diet for 56 weeks. The hepatic lobe was excised for measurement of impedance and observation of microscopic structure using a commercially available scanning acoustic microscopy system with a central frequency of 320 MHz. Scanning acoustic microscopy revealed that acoustic impedance through liver tissue with steatohepatitis temporarily decreased with the degree of fat deposition and then increased in parallel with the progression of inflammation and fibrosis. However, the acoustic images obtained did not allow discrimination of detailed microstructures from those seen using light microscopy. In conclusion, estimation of acoustic impedance appears to have potential clinical applications, such as for monitoring or follow-up studies.
  • Yusuke Hashimoto, Koji Yokoyama, Hideki Kumagai, Yuko Okada, Takanori Yamagata
    Clinical journal of gastroenterology 13 6 1096 - 1101 2020年12月 
    Juvenile polyposis syndrome (JPS) and hereditary hemorrhagic telangiectasia (HHT) are both relatively rare hereditary disorders. Some patients with the SMAD4 gene mutation develop both JPS and HHT, a condition termed JPS-HHT. We herein report a case of childhood-onset JPS-HHT. At nine years old, the patient underwent colonoscopy under suspicion of Crohn's disease, which revealed multiple polyps. A genetic analysis for familial adenomatous polyposis and Peutz-Jeghers syndrome found no mutations. After several years, extraintestinal manifestations, such as repeated epistaxis and several telangiectasias in the upper palate and stomach, were identified, which led to the performance of gene mutation analysis for SMAD4. As a result, a missense mutation in exon 8, codon 361 from arginine to cysteine (c.1081 C>T) was found. Based on this finding, the patient underwent cerebral magnetic resonance angiography, pulmonary perfusion scintigraphy and thoracoabdominal contrast computed tomography. The examination revealed that she had pulmonary arteriovenous fistulas and arteriovenous malformations in both the liver and right mammary gland. Thus, continuous surveillance for vascular lesions and gastrointestinal cancer is scheduled. Making a precise diagnosis of JPS-HHT can lead to the detection of asymptomatic complications and enable appropriate future disease management.
  • Yasuyuki Fukuhara, Ai Miura, Narutoshi Yamazaki, Tetsumin So, Motomichi Kosuga, Kumiko Yanagi, Tadashi Kaname, Takanori Yamagata, Hitoshi Sakuraba, Torayuki Okuyama
    Molecular genetics and metabolism reports 25 100692 - 100692 2020年12月 
    We previously showed that the genotype-phenotype correlation in MPS II is well-conserved in Japan (Kosuga et al., 2016). Almost all of our patients with attenuated MPS II have missense variants, which is expected to result in residual activity of iduronate-2-sulfatase. In contrast, our patients with severe MPS II have so-called null-type disease-associated variants, such as nonsense variants, frame-shifts, gene insertions, gene deletions and rearrangement with pseudogene (IDS2), none of which are expected to result in residual activity. However, we recently encountered a patient with attenuated MPS II who had a presumable null-type disease-associated variant and 76-base deletion located in exon 1 that extended into intron 1. To investigate this discordance, we extracted RNA from the leukocytes of the patient and performed reverse transcription polymerase chain reaction. One of the bands of the cDNA analysis was found to include a nucleotide sequence whose transcript was expected to generate an almost full-length IDS mature peptide lacking only part of its signal peptide as well as only one amino acid at the end of the N-terminus. This suggests that an alternative splicing donor site is generated in exon 1 upstream of the deleted region. Based on these observations, we concluded that the phenotype-genotype discordance in this patient with MPS II was due to the decreased amount of IDS protein induced by the low level of the alternatively spliced mRNA, lacking part of the region coding for the signal peptide but including the region coding almost the full mature IDS protein. The first 25 amino acids at the N-terminus of IDS protein are a signal peptide. The alternative splice transcript has only 13 (1 M-13 L) of those 25 amino acids; 14G-25G are missing, suggesting that the exclusively hydrophobic 1 M-13 L of the signal peptide of IDS might have a crucial role in the signal peptide.
  • Koyuru Kurane, Yukifumi Monden, Daisuke Tanaka, Yuji Gunji, Takahiro Ikeda, Akihiko Miyauchi, Hitoshi Osaka, Toshiyuki Takahashi, Takanori Yamagata
    Multiple sclerosis and related disorders 45 102320 - 102320 2020年10月 [査読有り][通常論文]
     
    Intravenous corticosteroids have been regarded as the first-line therapy of anti-myelin-oligodendrocyte glycoprotein antibody (MOG-Ab)-positive acute disseminated encephalomyelitis (ADEM). While steroids are the first-choice therapy, MOG-Ab-positive ADEM has a high relapse rate. In some cases, MOG-Ab-positive ADEM relapses even in a low-MOG-Abs state. There is no evidence-based rule supporting steroid tapering. We herein report a case of MOG-Ab-positive ADEM in which recurrence was preventing by tapering steroids under MOG-Ab seronegativity confirmation. In some cases, the MOG-Ab titer may be an important index for tapering steroids to prevent relapse.
  • Mary Hanley, Deborah M Riby, Michael-John Derges, Anna Douligeri, Zackary Philyaw, Takahiro Ikeda, Yukifumi Monden, Hideo Shimoizumi, Takanori Yamagata, Masahiro Hirai
    Developmental science 23 5 e12942  2020年09月 [査読有り][通常論文]
     
    Autism spectrum disorders (ASD) are associated with face perception atypicalities, and atypical experience with faces has been proposed as an underlying explanation. Studying the own-race advantage (ORA) for face recognition can reveal the effect of experience on face perception in ASD, although the small number of studies in the area present mixed findings. This study probed the ORA in ASD by comparing two cultural groups simultaneously for the first time. Children with ASD in the UK (N = 16) and Japan (N = 26) were compared with age- and ability-matched typically developing (TD) children in the UK (N = 16) and Japan (N = 26). Participants completed a two-alternative forced-choice task, whereby they had to recognize a just seen face from a foil which was manipulated in one of four ways (IC: identity change; EE: easy eyes; HE: hard eyes; HM: hard mouth). Face stimuli were Asian and Caucasian, and thus the same stimuli were own and other race depending on the cultural group. The ASD groups in the UK and Japan did not show impaired face recognition abilities, or impairments with recognizing faces depending on manipulations to the eye region, and importantly they showed an ORA. There was considerable heterogeneity in the presence of the ORA in ASD and TD and also across cultures. Children in Japan had higher accuracy than children in the UK, and TD children in Japan did not show an ORA. This cross-cultural study challenges the view that atypical experiences with faces lead to a reduced/absent ORA in ASD.
  • 山下 莉奈, 山岸 裕和, 小坂 仁, 桑島 真理, 池田 尚広, 村松 一洋, 佐藤 智幸, 山形 崇倫
    脳と発達 52 Suppl. S248 - S248 (一社)日本小児神経学会 2020年08月
  • 山岸 裕和, 小坂 仁, 後藤 昌英, 桑島 真理, 池田 尚広, 小島 華林, 村松 一洋, 山形 崇倫
    脳と発達 52 Suppl. S252 - S252 (一社)日本小児神経学会 2020年08月
  • Mariko Kasai, Akiko Shibata, Ai Hoshino, Yoshihiro Maegaki, Hideo Yamanouchi, Jun-Ichi Takanashi, Takanori Yamagata, Hiroshi Sakuma, Akihisa Okumura, Hiroaki Nagase, Atsushi Ishii, Tomohide Goto, Akira Oka, Masashi Mizuguchi
    Brain & development 42 7 508 - 514 2020年08月 [査読有り][通常論文]
     
    BACKGROUND: We previously reported the nationwide, epidemiological data of acute encephalopathy in Japan during 2007-2010. Here we conducted the second national survey of acute encephalopathy during 2014-2017, and compared the results between the two studies to elucidate the trends in the seven years' interval as well as the influence of changes in pediatric viral infections and guidelines for acute encephalopathy in Japan. METHODS: The Research Committee on Acute Encephalopathy supported by the Japanese Government sent a questionnaire to 507 hospitals throughout Japan, and collected the responses by mail. RESULTS: A total of 1115 cases from 267 hospitals reportedly had acute encephalopathy during April 2014-June 2017. In this study, the age at onset was younger, the ratios of recently established syndromes, such as acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) and clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), were higher, and the ratio of influenza-associated encephalopathy was lower, than in the previous study. The age at onset of influenza-associated encephalopathy was lower, and that of HHV-6/7-associated encephalopathy higher, compared to the first survey. The outcomes of entire acute encephalopathy remained unchanged. CONCLUSION: Some of these changes reflected the recent trends of viral infectious diseases including 2009 influenza pandemic, and others the standardization of the diagnosis of acute encephalopathy in Japan.
  • 井上 俊, 小倉 一輝, 武田 昭, 俣野 美雪, 小太刀 豪, 沼崎 啓, 郡司 勇治, 高橋 和郎, 山岸 佑也, 森本 哲, 山形 崇倫, 門田 行史
    小児科臨床 73 7 1027 - 1030 (株)日本小児医事出版社 2020年07月 
    肢端紅痛症は、四肢末端の発赤・疼痛を特徴とする稀な疾患であるが、その臨床的特徴によって診断するため、同症状を訴える患者を見た際には念頭に置くべき病態である。しばしば難治性で、確立した治療法はない。今回、ステロイドによる早期治療が、慢性疼痛への移行を防ぐうえで有効であったと推測される小児例を経験したので報告する。症例は10歳女児。両手指の色調変化と疼痛を訴えて受診した。手指末端の灼熱痛、色調変化、熱感を認めた。疼痛は加温で増悪し、冷却で軽快した。これら臨床的特徴および他疾患の除外により、肢端紅痛症と診断した。続発性の肢端紅痛症を来す基礎疾患の存在は除外され、一次性肢端紅痛症と考えた。鎮痛薬(アセトアミノフェン)で疼痛は抑えられず、ステロイド薬治療を開始して軽減した。さらに、低用量アスピリンを加え、ステロイド薬の減量を進めながら、ガバペンチンの内服を併用し、疼痛は改善した。(著者抄録)
  • Sadahiro Furui, Mitsuru Seki, Takaomi Minami, Masahide Goto, Takanori Yamagata
    Pediatrics international : official journal of the Japan Pediatric Society 62 7 872 - 873 2020年07月
  • Kensuke Oka, Mitsuru Seki, Koichi Kataoka, Tomoyuki Sato, Yasushi Imai, Takanori Yamagata
    International heart journal 61 3 620 - 623 2020年05月 
    In Ebstein's anomaly, percutaneous atrial septal defect (ASD) closure for the treatment of hypoxemia due to a right-to-left interatrial shunt remains controversial. We report the case of a 40-year-old woman with Ebstein's anomaly who developed cyanosis and shortness of breath on exercise. Her symptoms improved after percutaneous ASD closure and her clinical course has been good during follow-up. The balloon ASD occlusion test, combined with dobutamine stimulation before the procedure, is useful to confirm treatment indication. A prior electrophysiological evaluation is also important because Ebstein's anomaly is often complicated by atrioventricular recurrent tachycardia.
  • 早期のステロイド治療が有効だった肢端紅痛症の1例
    井上 俊, 小倉 一輝, 武田 昭, 俣野 美雪, 小太刀 豪, 沼崎 啓, 郡司 勇治, 高橋 和郎, 森本 哲, 山形 崇倫, 門田 行史
    日本小児科学会雑誌 124 5 877 - 877 (公社)日本小児科学会 2020年05月
  • 副鼻腔炎から眼窩内及び硬膜外に波及したMRSA膿瘍の1例
    堀越 亜希子, 田村 大輔, 山岸 裕和, 田中 大輔, 苗加 真奈美, 山形 崇倫
    日本小児科学会雑誌 124 5 877 - 877 (公社)日本小児科学会 2020年05月
  • ファロー四徴症に合併した先天性門脈体循環シャントの1例
    奥村 一輝, 古井 貞浩, 鈴木 峻, 横溝 亜希子, 関 満, 佐藤 智幸, 片岡 功一, 眞田 幸弘, 大西 康晴, 佐久間 康成, 鵜垣 伸也, 吉積 功, 河田 政明, 山形 崇倫
    日本小児科学会雑誌 124 5 876 - 876 (公社)日本小児科学会 2020年05月
  • 早期のステロイド治療が有効だった肢端紅痛症の1例
    井上 俊, 小倉 一輝, 武田 昭, 俣野 美雪, 小太刀 豪, 沼崎 啓, 郡司 勇治, 高橋 和郎, 森本 哲, 山形 崇倫, 門田 行史
    日本小児科学会雑誌 124 5 877 - 877 (公社)日本小児科学会 2020年05月 [査読有り][通常論文]
  • Kohei Hamanaka, Eri Imagawa, Eriko Koshimizu, Satoko Miyatake, Jun Tohyama, Takanori Yamagata, Akihiko Miyauchi, Nina Ekhilevitch, Fumio Nakamura, Takeshi Kawashima, Yoshio Goshima, Ahmad Rithauddin Mohamed, Gaik-Siew Ch'ng, Atsushi Fujita, Yoshiteru Azuma, Ken Yasuda, Shintaro Imamura, Mitsuko Nakashima, Hirotomo Saitsu, Satomi Mitsuhashi, Takeshi Mizuguchi, Atsushi Takata, Noriko Miyake, Naomichi Matsumoto
    American journal of human genetics 106 4 549 - 558 2020年04月 [査読有り][通常論文]
     
    De novo variants (DNVs) cause many genetic diseases. When DNVs are examined in the whole coding regions of genes in next-generation sequencing analyses, pathogenic DNVs often cluster in a specific region. One such region is the last exon and the last 50 bp of the penultimate exon, where truncating DNVs cause escape from nonsense-mediated mRNA decay [NMD(-) region]. Such variants can have dominant-negative or gain-of-function effects. Here, we first developed a resource of rates of truncating DNVs in NMD(-) regions under the null model of DNVs. Utilizing this resource, we performed enrichment analysis of truncating DNVs in NMD(-) regions in 346 developmental and epileptic encephalopathy (DEE) trios. We observed statistically significant enrichment of truncating DNVs in semaphorin 6B (SEMA6B) (p value: 2.8 × 10-8; exome-wide threshold: 2.5 × 10-6). The initial analysis of the 346 individuals and additional screening of 1,406 and 4,293 independent individuals affected by DEE and developmental disorders collectively identified four truncating DNVs in the SEMA6B NMD(-) region in five individuals who came from unrelated families (p value: 1.9 × 10-13) and consistently showed progressive myoclonic epilepsy. RNA analysis of lymphoblastoid cells established from an affected individual showed that the mutant allele escaped NMD, indicating stable production of the truncated protein. Importantly, heterozygous truncating variants in the NMD(+) region of SEMA6B are observed in general populations, and SEMA6B is most likely loss-of-function tolerant. Zebrafish expressing truncating variants in the NMD(-) region of SEMA6B orthologs displayed defective development of brain neurons and enhanced pentylenetetrazole-induced seizure behavior. In summary, we show that truncating DNVs in the final exon of SEMA6B cause progressive myoclonic epilepsy.
  • Megumi Kobayashi, Takahiro Ikeda, Tatsuya Tokuda, Yukifumi Monden, Masako Nagashima, Sakae G Mizushima, Takeshi Inoue, Keiichi Shimamura, Yuta Ujiie, Akari Arakawa, Chie Kuroiwa, Mayuko Ishijima, Yuki Kishimoto, So Kanazawa, Takanori Yamagata, Masami K Yamaguchi, Ryoichi Sakuta, Ippeita Dan
    Neurophotonics 7 2 025003 - 025003 2020年04月 [査読有り][通常論文]
     
    Significance: It has been reported that children with attention-deficit hyperactivity disorder (ADHD) have impairment in the recognition of angry but not of happy facial expressions, and they show atypical cortical activation patterns in response to facial expressions. However, little is known about neural mechanisms underlying the impaired recognition of facial expressions in school-aged children with ADHD and the effects of acute medication on their processing of facial expressions. Aim: We aimed to investigate the possibility that acute administration of methylphenidate (MPH) affects processing of facial expressions in ADHD children. Approach: We measured the hemodynamic changes in the bilateral temporo-occipital areas of ADHD children observing the happy and angry facial expressions before and 1.5 h after MPH or placebo administration in a randomized, double-blind, placebo-controlled, crossover design study. Results: We found that, regardless of medication, happy expressions induced increased oxyhemoglobin (oxy-Hb) responses in the right inferior occipital region but not in the superior temporal region. For angry expressions, oxy-Hb responses increased after MPH administration, but not after placebo administration, in the left inferior occipital area, whereas there was no significant activation before MPH administration. Conclusions: Our results suggest that (1) ADHD children consistently recruit the right inferior occipital regions to process happy expressions and (2) MPH administration to ADHD children enhances cortical activation in the left inferior occipital regions when they process angry expressions.
  • 岡田 優子, 横山 孝二, 熊谷 秀規, 齋藤 貴志, 蓮沼 もも, 大草 陽史, 田村 大輔, 山形 崇倫
    小児科臨床 73 3 303 - 306 (株)日本小児医事出版社 2020年03月 [査読有り][通常論文]
     
    腸管出血性大腸菌(enterohemorrhagic Escherichia coil:EHEC)感染症では、溶血性尿毒症症候群(hemolytic uremic syndorome;HUS)に併発する急性膵炎の報告はあるが、HUSを伴わない膵炎は非常に稀である。症例は8歳の男児。腹痛と下痢、血便が続き、感染性腸炎の診断で第4病日に入院した。入院後、志賀毒素(Shigatoxin;Stx)陽性のEHEC O26が同定された。下痢と血便は軽快傾向にあったが腹痛は持続し、第5病日に血清アミラーゼとリパーゼが上昇した。腹部造影CTで膵腫大と横行結腸間膜域の脂肪織濃度上昇があり急性膵炎と診断した。膵炎は軽症で、ウリナスタチン点滴静注で軽快し第13病日に退院した。経過中にHUSは発症しなかった。本症例では、Stxに起因する炎症性サイトカインによりVater乳頭を含む十二指腸に浮腫を来して膵液の排出が障害されたことが、膵炎発症の要因の一つと考えられた。EHEC感染症では、HUSがない場合も膵炎を併発する可能性があることを念頭に置く必要がある。(著者抄録)
  • 急性脳症を合併した川崎病2例
    松村 悠香, 山岸 裕和, 田村 大輔, 浅倉 佑太, 橋本 佑介, 関 満, 村松 一洋, 小坂 仁, 山形 崇倫
    日本小児科学会雑誌 124 2 222 - 222 (公社)日本小児科学会 2020年02月
  • Jun Aoyagi, Takahiro Kanai, Tomomi Maru, Jun Odaka, Takashi Saito, Hiroyuki Betsui, Takanori Yamagata
    CEN case reports 9 1 15 - 18 2020年02月 
    In individuals treated with immunosuppressive therapies, the varicella-zoster virus (VZV) infection can become disseminated and lead to a life-threatening condition. There is currently no established treatment strategy for this life-threatening condition. Here, we describe a case where plasma exchange (PE) with a high dose of acyclovir (ACV) ameliorated the severe effects, including VZV-hemophagocytic lymphohistiocytosis (VZV-HLH) and disseminated intravascular coagulation (DIC), in a 9-year-old girl with steroid-dependent nephrotic syndrome. This 9-year-old girl experienced frequent relapse steroid-dependent nephrotic syndrome. She had been treated with steroids, tacrolimus, mizoribine, and rituximab. She had not previously received a varicella vaccine. She was admitted with only one vesicular rash. At admission, a serum test revealed 1.6 × 106 copies/mL of VZV DNA. The patient rapidly developed VZV-HLH and DIC. A combination of a high dose of ACV, immunoglobulin, and steroid pulse therapy could not improve these severe complications. Therefore, PE was applied. PE with a high dose of ACV successfully reduced serum VZV DNA from 7.5 × 106 to 2.8 × 104 copies/mL. This reduction in the VZV DNA copy number suggested that the combination of PE and a high dose of ACV was effective in treating a disseminated VZV infection. To the best of our knowledge, this is the first report showing that PE with a high dose of ACV ameliorated the severe complications of disseminated VZV by reducing the VZV DNA copy number.
  • 皮膚線維芽細胞を用いた原発性コエンザイムQ10欠乏症の診断
    渡邉 知佳, 小坂 仁, 村山 圭, 大竹 明, 山形 崇倫
    日本小児科学会雑誌 124 2 403 - 403 (公社)日本小児科学会 2020年02月 [査読有り][通常論文]
  • 肝紫斑病を合併し肝動脈塞栓術,肝移植術で救命しえたミオチュブラーミオパチーの1例
    福田 真也, 岡田 優子, 小高 淳, 田村 大輔, 橘木 浩平, 多賀 直行, 桑嶋 真理, 横山 孝二, 熊谷 秀規, 山形 崇倫
    日本小児科学会雑誌 124 2 265 - 265 (公社)日本小児科学会 2020年02月 [査読有り][通常論文]
  • Yuta Kawahara, Akira Morimoto, Yukiko Oh, Rieko Furukawa, Kei Wakabayashi, Yukifumi Monden, Hitoshi Osaka, Takanori Yamagata
    Brain & development 42 2 185 - 191 2020年02月 [査読有り][通常論文]
     
    BACKGROUND: The pathogenesis of acute encephalopathy (AE) remains unclear, and a biomarker has not been identified. METHODS: Levels of 49 cytokines and chemokines, including osteopontin (OPN), were measured in serum and cerebrospinal fluid (CSF) of children with AE (n = 17) or febrile convulsion (FC; n = 8; control group). The AE group included acute necrotizing encephalopathy (n = 1), acute encephalopathy with biphasic seizures and late reduced diffusion (AESD; n = 3), clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS; n = 4), and unclassified acute encephalopathy (UCAE; n = 9) that does not meet the criteria of syndrome classification. Five individuals with AE had neurological sequelae or death (poor prognosis), whereas 12 were alive without neurological sequelae (good prognosis). RESULTS: The CSF:serum ratios of OPN, CC chemokine ligand (CCL)4, and interleukin (IL)-10 were significantly higher in AE than in FC. The CSF levels of macrophage inhibitory factor (MIF) and leukemia inhibitory factor (LIF) were significantly higher in the poor-prognosis group than in the good-prognosis group. The CSF:serum ratios of OPN were significantly higher in AESD and in MERS than in FC. The CSF:serum ratios of MIF and OPN were higher in MERS than in UCAE or FC. CONCLUSION: Our results suggest that microglia-related cytokines and chemokines such as OPN, MIF, and LIF could be novel biomarkers of AE, in addition to the previously reported IL-10 and CCL4, and that MIF and LIF may be markers of poor prognosis.
  • Tatsuya Anzai, Takanori Yamagata, Hideki Uosaki
    Frontiers in cell and developmental biology 8 268 - 268 2020年 [査読有り][通常論文]
     
    Transcriptome landscape of organs from mice and humans offers perspectives on the process of how organs develop and the similarity and diversity in each organ between the species. Among multi-species and multi-organ dataset, which was previously generated, we focused on the mouse and human dataset and performed a reanalysis to provide a more specific perspective on the maturation of human cardiomyocytes. First, we examined how organs diversify their transcriptome during development across and within two species. We unexpectedly identified that ribosomal genes were differentially expressed between mice and humans. Second, we examined the corresponding ages of organs in mice and humans and found that the corresponding developmental ages did not match throughout organs. Mouse hearts at P0-3 and human hearts at 18-19 wpc showed the most proximity in the regard of the transcriptome. Third, we identified a novel set of maturation marker genes that are more consistent between mice and humans. In contrast, conventionally used maturation marker genes only work well with mouse hearts. Finally, we compared human pluripotent stem cell-derived cardiomyocytes (PSC-CMs) in maturation-enhanced conditions to human fetal and adult hearts and revealed that human PSC-CMs only expressed low levels of the potential maturation marker genes. Our findings provide a novel foundation to study cardiomyocyte maturation and highlight the importance of studying human samples rather than relying on a mouse time-series dataset.
  • Stephanie Sutoko, Yukifumi Monden, Tatsuya Tokuda, Takahiro Ikeda, Masako Nagashima, Tsukasa Funane, Hirokazu Atsumori, Masashi Kiguchi, Atsushi Maki, Takanori Yamagata, Ippeita Dan
    Frontiers in human neuroscience 14 3 - 3 2020年 [査読有り][通常論文]
     
    Connectivity between brain regions has been redefined beyond a stationary state. Even when a person is in a resting state, brain connectivity dynamically shifts. However, shifted brain connectivity under externally evoked stimulus is still little understood. The current study, therefore, focuses on task-based dynamic functional-connectivity (FC) analysis of brain signals measured by functional near-infrared spectroscopy (fNIRS). We hypothesize that a stimulus may influence not only brain connectivity but also the occurrence probabilities of task-related and task-irrelevant connectivity states. fNIRS measurement (of the prefrontal-to-inferior parietal lobes) was conducted on 21 typically developing (TD) and 21 age-matched attention-deficit/hyperactivity disorder (ADHD) children performing an inhibitory control task, namely, the Go/No-Go (GNG) task. It has been reported that ADHD children lack inhibitory control; differences between TD and ADHD children in terms of task-based dynamic FC were also evaluated. Four connectivity states were found to occur during the temporal task course. Two dominant connectivity states (states 1 and 2) are characterized by strong connectivities within the frontoparietal network (occurrence probabilities of 40%-56% and 26%-29%), and presumptively interpreted as task-related states. A connectivity state (state 3) shows strong connectivities in the bilateral medial frontal-to-parietal cortices (occurrence probability of 7-15%). The strong connectivities were found at the overlapped regions related the default mode network (DMN). Another connectivity state (state 4) visualizes strong connectivities in all measured regions (occurrence probability of 10%-16%). A global effect coming from cerebral vascular may highly influence this connectivity state. During the GNG stimulus interval, the ADHD children tended to show decreased occurrence probability of the dominant connectivity state and increased occurrence probability of other connectivity states (states 3 and 4). Bringing a new perspective to explain neuropathophysiology, these findings suggest atypical dynamic network recruitment to accommodate task demands in ADHD children.
  • Koji Yokoyama, Takaomi Minami, Mitsuru Seki, Yuko Okada, Hideki Kumagai, Takanori Yamagata
    Journal of cardiology cases 21 1 28 - 31 2020年01月 [査読有り][通常論文]
     
    Background: Alagille syndrome (ALGS) is characterized by cholestasis due to paucity of intrahepatic bile ducts, cardiac anomalies, ophthalmologic abnormalities, skeletal abnormalities, and characteristic facies. Mid-aortic syndrome (MAS) is a rare entity characterized by segmental narrowing of the proximal abdominal aorta and ostial stenosis of its major branches. We report a case of ALGS with MAS involving severe renal artery stenosis (RAS). Case: A four-year-old Japanese boy was referred to our hospital because of cholestatic liver dysfunction. He was diagnosed with ALGS due to having all five characteristic hallmarks. He had high blood pressure (152/84 mmHg) at his first visit. 3D-CT angiography showed coarctation of the abdominal aortic trunk, severe ostial stenosis of the celiac artery, superior mesenteric artery, and bilateral RAs. He was diagnosed with MAS, and treated with metoprolol, cilnidipine, and aspirin. Discussions: While vascular abnormalities are reported to occur in 9% of ALGS patients, MAS with ALGS was only reported in 11 patients between 1951 and 2011. In Japan, there were no reports of ALGS coexisting with MAS with the exception of one case with RAS. In addition to the vessels of the heart, it is important to examine patients with ALGS for abnormalities of other vessels..
  • Yutaka Negishi, Daisuke Ieda, Ikumi Hori, Yasuyuki Nozaki, Takanori Yamagata, Hirofumi Komaki, Jun Tohyama, Keisuke Nagasaki, Hiroko Tada, Shinji Saitoh
    Orphanet journal of rare diseases 14 1 277 - 277 2019年12月 [査読有り][通常論文]
     
    BACKGROUND: Schaaf-Yang syndrome (SYS) is a newly recognized imprinting related syndrome, which is caused by a truncating variant in maternally imprinted MAGEL2 located in 15q11-q13. Yet, precise pathomechanism remains to be solved. We sequenced MAGEL2 in patients suspected Prader-Willi syndrome (PWS) to delineate clinical presentation of SYS. We examined 105 patients with clinically suspected PWS but without a specific PWS genetic alteration. Sanger sequencing of the entire MAGEL2 gene and methylation-specific restriction enzyme treatment to detect the parent of origin were performed. Clinical presentation was retrospectively assessed in detail. RESULTS: Truncating variants in MAGEL2 were detected in six patients (5.7%), including a pair of siblings. All truncating variants in affected patients were on the paternally derived chromosome, while the healthy father of the affected siblings inherited the variant from his mother. Patients with MAGEL2 variants shared several features with PWS, such as neonatal hypotonia, poor suck, and obesity; however, there were also unique features, including arthrogryposis and a failure to acquire meaningful words. Additionally, an episode of neurological deterioration following febrile illness was confirmed in four of the six patients, which caused severe neurological sequalae. CONCLUSIONS: SYS can be present in infants suspected with PWS but some unique features, such as arthrogryposis, can help discriminate between the two syndromes. An episode of neurological deterioration following febrile illness should be recognized as an important complication.
  • 熊谷 秀規, ジャネルケ・トゥレウ, 神保 恵理子, 渡邊 真弥, 幸喜 富, 横山 孝二, 小坂 仁, 山形 崇倫
    日本小児栄養消化器肝臓学会雑誌 33 2 134 - 134 (一社)日本小児栄養消化器肝臓学会 2019年12月 [査読有り][通常論文]
  • Futoshi Sekiguchi, Yoshinori Tsurusaki, Nobuhiko Okamoto, Keng Wee Teik, Seiji Mizuno, Hiroshi Suzumura, Bertrand Isidor, Winnie Peitee Ong, Muzhirah Haniffa, Susan M White, Mari Matsuo, Kayoko Saito, Shubha Phadke, Tomoki Kosho, Patrick Yap, Manisha Goyal, Lorne A Clarke, Rani Sachdev, George McGillivray, Richard J Leventer, Chirag Patel, Takanori Yamagata, Hitoshi Osaka, Yoshiya Hisaeda, Hirofumi Ohashi, Kenji Shimizu, Keisuke Nagasaki, Junpei Hamada, Sumito Dateki, Takashi Sato, Yasutsugu Chinen, Tomonari Awaya, Takeo Kato, Kougoro Iwanaga, Masahiko Kawai, Takashi Matsuoka, Yoshikazu Shimoji, Tiong Yang Tan, Seema Kapoor, Nerine Gregersen, Massimiliano Rossi, Mathieu Marie-Laure, Lesley McGregor, Kimihiko Oishi, Lakshmi Mehta, Greta Gillies, Paul J Lockhart, Kate Pope, Anju Shukla, Katta Mohan Girisha, Ghada M H Abdel-Salam, David Mowat, David Coman, Ok Hwa Kim, Marie-Pierre Cordier, Kate Gibson, Jeff Milunsky, Jan Liebelt, Helen Cox, Salima El Chehadeh, Annick Toutain, Ken Saida, Hiromi Aoi, Gaku Minase, Naomi Tsuchida, Kazuhiro Iwama, Yuri Uchiyama, Toshifumi Suzuki, Kohei Hamanaka, Yoshiteru Azuma, Atsushi Fujita, Eri Imagawa, Eriko Koshimizu, Atsushi Takata, Satomi Mitsuhashi, Satoko Miyatake, Takeshi Mizuguchi, Noriko Miyake, Naomichi Matsumoto
    Journal of human genetics 64 12 1173 - 1186 2019年12月 [査読有り][通常論文]
     
    Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.
  • Yuko Okada, Koji Yokoyama, Tomonori Yano, Hideki Kumagai, Takaaki Morikawa, Yasutoshi Kobayashi, Tomoyuki Imagawa, Takanori Yamagata
    Clinical journal of gastroenterology 12 6 566 - 570 2019年12月 [査読有り][通常論文]
     
    Duodenocolic fistula (DCF) is a rare disorder defined by the presence of an internal fistula between the duodenum and colon. Colon cancer, Crohn's disease, diverticulum and duodenal ulcer are common causes of DCF, and vomiting and diarrhea are its main symptoms. We report a 14-year-old boy with DCF who had been treated for a functional gastrointestinal disorder (FGID). The boy had often experienced episodes of vomiting and diarrhea since infancy, and had been diagnosed with FGID. He was referred to our hospital because of a 2-month exacerbation of persistent vomiting and diarrhea. Upper gastrointestinal contrast revealed no abnormalities. Eventually, esophagogastroduodenoscopy detected a duodenal fistula, and DCF was diagnosed by endoscopic fistulography. Colonoscopy showed a diverticulum in the ascending colon near the fistula. In addition, a C13 urea breath test for Helicobacter pylori infection was positive. One hypothetical pathogenesis of his DCF was perforated colonic diverticulitis. Adhesion between the fistula wall and colonic diverticulum near the fistula strongly suggested a relationship between the fistula and the diverticulum. However, he never presented with symptoms of colonic diverticulitis. Thus, a congenital origin was also suspected. After confirming temporary relief from the symptoms by endoscopic closure, surgical closure was performed.
  • Akihiko Miyauchi, Takeshi Kouga, Eriko F Jimbo, Tetsuro Matsuhashi, Takaaki Abe, Takanori Yamagata, Hitoshi Osaka
    Mitochondrion 49 111 - 120 2019年11月 
    Mitochondrial disease is a genetic disorder in which individuals suffer from energy insufficiency. The various clinical phenotypes of mitochondrial disease include Leigh syndrome (LS), myopathy encephalopathy lactic acidosis and stroke-like episodes (MELAS). Thus far, no curative treatment is available, and effective treatment options are eagerly awaited. We examined the cell protective effect of an existing commercially available chemical library on fibroblasts from four patients with LS and MELAS and identified apomorphine as a potential therapeutic drug for mitochondrial disease. We conducted a cell viability assay under oxidative stress induced by L-butionine (S, R)-sulfoximine (BSO), a glutathione synthesis inhibitor. Among the chemicals of library, 4 compounds (apomorphine, olanzapine, phenothiazine and ethopropazine) rescued cells from death induced by oxidative stress much more effectively than idebenone, which was used as a positive control. The EC50 value showed that apomorphine was the most effective compound. Apomorphine also significantly improved all of the assessed oxygen consumption rate values by the extracellular flux analyzer for fibroblasts from LS patients with complex I deficiency. In addition, the elevation of the Growth Differentiation Factor-15 (GDF-15), a biomarker of mitochondrial disease, was significantly reduced by apomorphine. Among 441 apomorphine-responsive genes identified by the microarray, apomorphine induced the expression of genes that inhibit the mammalian target of rapamycin (mTOR) activity and inflammatory responses, suggesting that apomorphine induced cell survival via a new potential pathway. In conclusion, apomorphine rescued fibroblasts from cell death under oxidative stress and improved the mitochondrial respiratory activity and appears to be potentially useful for treating mitochondrial disease.
  • Daisuke Matsubara, Takaomi Minami, Mitsuru Seki, Daisuke Tamura, Takanori Yamagata
    Pediatrics international : official journal of the Japan Pediatric Society 61 11 1171 - 1173 2019年11月
  • Akiko Shibata, Mariko Kasai, Ai Hoshino, Taku Miyagawa, Hiroshi Matsumoto, Gaku Yamanaka, Kenjiro Kikuchi, Ichiro Kuki, Akira Kumakura, Shinya Hara, Takashi Shiihara, Sawako Yamazaki, Masayasu Ohta, Takanori Yamagata, Jun-Ichi Takanashi, Masaya Kubota, Akira Oka, Masashi Mizuguchi
    Brain & development 41 10 862 - 869 2019年11月 [査読有り][通常論文]
     
    OBJECTIVES: Acute encephalopathy is an acute brain dysfunction after preceding infection, consisting of multiple syndromes. Some syndromes, such as acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), are severe with poor outcome, whereas others, such as clinically mild encephalitis/encephalopathy with reversible splenial lesion (MERS), are mild with favorable outcome. Previous study reported the association of the thermolabile polymorphism in Carnitine Palmitoyltransferase 2 (CPT2) gene and severe syndromes of acute encephalopathy. To further explore the pathogenetic role of CPT2 in acute encephalopathy, we conducted a case-control association study of a typical thermolabile CPT2 polymorphism, rs2229291, in 416 patients of acute encephalopathy, including both severe and mild syndromes. METHODS: The case cohort consisted of 416 patients, including AESD, MERS, and other syndromes. The control subjects were 100 healthy Japanese. rs2229291 was genotyped by Sanger sequencing. Genetic distribution was compared between the patients and controls using Cochran-Armitage trend test. RESULTS: Minor allele frequency of rs2229291 was significantly higher in AESD (p = 0.044), MERS (p = 0.015) and entire acute encephalopathy (p = 0.044) compared to the controls. The polymorphism showed no significant association with influenza virus, or with outcome. CONCLUSIONS: This study provided evidence that CPT2 is a susceptibility gene for overall acute encephalopathy, including both severe and mild syndromes, and suggested that impairment of mitochondrial metabolism is common to various syndromes of acute encephalopathy.
  • Janyerkye Tulyeu, Hideki Kumagai, Eriko Jimbo, Shinya Watanabe, Koji Yokoyama, Longzhu Cui, Hitoshi Osaka, Makiko Mieno, Takanori Yamagata
    Microorganisms 7 10 463 - ; 2019年10月 [査読有り][通常論文]
     
    Increased intestinal permeability is thought to underlie the pathogenesis of food allergy. We explore the mechanism responsible for changes in the morphology and function of the intestinal barrier using a rat model of food allergy, focusing on the contribution of intestinal microbiota. Juvenile-young adult rats were sensitized with ovalbumin and treated with antibiotics or probiotics (Clostridium butyricum and Lactobacillus reuteri), respectively. The serum ovalbumin-IgE levels, intestinal permeability, histopathological features, tight junction (TJ)-associated proteins, Th2 cytokines, and gut microbiota in feces were analyzed in each group. Sensitized rats showed an increase in ovalbumin-IgE levels and intestinal permeability with gut mucosal inflammation, whereas rats that received probiotics were only mildly affected. Rats given ovalbumin, but not those given probiotics, showed a reduction in both TJ-related protein expression and localization. Th2 cytokine levels were increased in the sensitized rats, but not in those given probiotics. TJs in rats treated with ovalbumin and antibiotics were disrupted, but those in rats administered probiotics were undamaged. Clostridiaceae were increased in the probiotics groups, especially Alkaliphilus, relative to the ovalbumin-sensitized group. Gut microbiota appears to play a role in regulating epithelial barrier function, and probiotics may help to prevent food sensitization through the up-regulation of TJ proteins.
  • Stephanie Sutoko, Yukifumi Monden, Tatsuya Tokuda, Takahiro Ikeda, Masako Nagashima, Tsukasa Funane, Hiroki Sato, Masashi Kiguchi, Atsushi Maki, Takanori Yamagata, Ippeita Dan
    Neurophotonics 6 4 045013 - 045013 2019年10月 [査読有り][通常論文]
     
    Connectivity impairment has frequently been associated with the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). Although the connectivity of the resting state has mainly been studied, we expect the transition between baseline and task may also be impaired in ADHD children. Twenty-three typically developing (i.e., control) and 36 disordered (ADHD and autism-comorbid ADHD) children were subjected to connectivity analysis. Specifically, they performed an attention task, visual oddball, while their brains were measured by functional near-infrared spectroscopy. The results of the measurements revealed three key findings. First, the control group maintained attentive connectivity, even in the baseline interval. Meanwhile, the disordered group showed enhanced bilateral intra- and interhemispheric connectivities while performing the task. However, right intrahemispheric connectivity was found to be weaker than those for the control group. Second, connectivity and activation characteristics might not be positively correlated with each other. In our previous results, disordered children lacked activation in the right middle frontal gyrus. However, within region connectivity of the right middle frontal gyrus was relatively strong in the baseline interval and significantly increased in the task interval. Third, the connectivity-based biomarker performed better than the activation-based biomarker in terms of screening. Activation and connectivity features were independently optimized and cross validated to obtain the best performing threshold-based classifier. The effectiveness of connectivity features, which brought significantly higher training accuracy than the optimum activation features, was confirmed (88% versus 76%). The optimum screening features were characterized by two trends: (1) strong connectivities of right frontal, left frontal, and left parietal lobes and (2) weak connectivities of left frontal, left parietal, and right parietal lobes in the control group. We conclude that the attentive task-based connectivity effectively shows the difference between control and disordered children and may represent pathological characteristics to be feasibly implemented as a supporting tool for clinical screening.
  • 小俣 佳菜子, 岡田 憲樹, 宮原 豪, 眞田 幸弘, 大西 康晴, 福田 真也, 小高 淳, 桑島 真理, 山形 崇倫, 笠原 群生, 佐久間 康成, 佐田 尚宏
    移植 54 総会臨時 269 - 269 (一社)日本移植学会 2019年09月
  • Ayumi Matsumoto, Masako Nagashima, Kazuhiro Iwama, Takeshi Mizuguchi, Shinji Makino, Takahiro Ikeda, Kazuhiro Muramatsu, Naomichi Matsumoto, Takanori Yamagata, Hitoshi Osaka
    Brain & development 41 8 726 - 730 2019年09月 [査読有り][通常論文]
     
    INTRODUCTION: Neuronal ceroid lipofuscinoses (NCLs; CLN) are mainly autosomal recessive neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigments in neuronal and other cells. Symptoms include visual disabilities, motor decline, and epilepsy. Causative genes are CLN1, CLN2, CLN3, CLN5, CLN6, CLN7, CLN8, CLN10, CLN11, CLN12, CLN13, and CLN14. We present the fourth Japanese case with a CLN6 mutation. CASE PRESENTATION: At 3 years of age, our patient became clumsy and fell down easily. He developed focal seizures with impaired consciousness and was started on carbamazepine. He showed ataxic walking and dysarthria with increased deep tendon reflexes. Interictal electroencephalogram revealed slow waves in the left temporal and occipital areas. Brain magnetic resonance imaging showed cerebellar atrophy and ventriculomegaly. In optical coherence tomography (OCT), the inner layer of the retina was thick and highly reflective. Exome sequencing revealed a known homozygous mutation, C.794_976del, p. (Ser265del) in CLN6. DISCUSSION: A total of 130 cases of NCL with CLN6 mutations have been reported globally, of which only four were from Japan including the current patient. The deletion of serine at position 265 has been reported in six cases. Ser265 is located in a region of short repeated sequences that is susceptible to mutation. Clinical trials of gene therapy using adeno-associated virus serotype 9 have started for NCL6, making early diagnosis crucial. OCT examination might be helpful in achieving a diagnosis.
  • Takeshi Kouga, Shiro Koizume, Shiho Aoki, Eriko Jimbo, Takanori Yamagata, Ken Inoue, Hitoshi Osaka
    Molecular genetics and metabolism reports 20 100474 - 100474 2019年09月 [査読有り][通常論文]
     
    Background: Pelizaeus-Merzbacher disease (PMD) is caused by point mutations or copy number changes in the proteolipid protein 1 gene (PLP1). PLP1 is exclusively localized in the myelin sheath of oligodendrocytes. Amino acid-substituted PLP1 protein is unable to fold properly and is subsequently degraded and/or restrictedly translated, resulting in a decrease in the PLP1 protein level and a failure to localize to the membrane. Furthermore, misfolded proteins increase the burden on the intracellular quality control system and trafficking, finally resulting in cell apoptosis. The objective of this study was to identify therapeutic chemicals for PMD by quantifying the total levels and membrane localization of PLP1. Method: We established a cell line stably expressing PLP1A243V fused with green fluorescent protein in oligodendrocyte-derived MO3.13 cells. We screened a chemical library composed of drugs approved for central nervous system disorders that increased both the total intensity of PLP1A243V in the whole cell and the cell membrane localization. We analyzed the change in the endoplasmic reticulum (ER) stress and the gene expression of candidate chemicals using a micro-array analysis. Finally, we tested the in vivo effectiveness using myelin synthesis deficient (msd) mice with Plp A243V . Results and conclusion: Piracetam significantly increased the PLP1A243V intensity and membrane localization and decreased the ER stress. It was also shown to reverse the gene expression changes induced by PLP1A243V in a micro-array analysis. However, in vivo treatment of piracetam did not improve the survival of msd mice (Plp1A243V).
  • Hideki Kumagai, Nobuyuki Taniguchi, Koji Yokoyama, Kimito Katsuyama, Hiroaki Yamamoto, Shoji Hara, Norio Hirota, Kouichi Itoh, Takanori Yamagata
    Ultrasound in medicine & biology 45 8 2258 - 2265 2019年08月 [査読有り][通常論文]
     
    We have previously reported a non-invasive method that would be clinically applicable for measurement of speed of sound (SOS) in the liver. The objective of the present study was to confirm the utility of this new method for assessing over time the SOS in liver with progressive steatohepatitis of different grades and stages. Rats were divided into two groups-a control group and a steatohepatitis group-prepared by keeping the rats on a methionine and choline-deficient diet for 43 wk. The SOS through the liver tissue was measured using the new method in comparison with a pulse-receiver as the standard. The SOS through liver with steatohepatitis temporarily decreased with the fat deposition level and then increased in parallel with the progression of inflammation and fibrosis. Monitoring the change in SOS through liver tissue in individual patients with fatty liver would have considerable potential for assisting the non-invasive detection of early-stage steatohepatitis.
  • Takane Ito, Takahiro Kanai, Norio Hirota, Kouichi Itoh, Takanori Yamagata
    Clinical and experimental nephrology 23 6 867 - 869 2019年06月
  • 山岸 裕和, 小坂 仁, 後藤 昌英, 桑島 真理, 池田 尚広, 小島 華林, 村松 一洋, 山形 崇倫
    脳と発達 51 Suppl. S272 - S272 (一社)日本小児神経学会 2019年05月 [査読有り][通常論文]
  • Kuwajima M, Goto M, Kurane K, Shimbo H, Omika N, Jimbo EF, Muramatsu K, Tajika M, Shimura M, Murayama K, Kurosawa K, Yamagata T, Osaka H
    Brain & development 41 5 465 - 469 2019年05月 [査読有り][通常論文]
     
    Mutations in the mitochondrial tRNAMet gene have been reported in only five patients to date, all of whom presented with muscle weakness and exercise intolerance as signs of myopathy. We herein report the case of a 12-year-old girl with focal epilepsy since the age of eight years. At age 11, the patient developed sudden visual disturbances and headaches accompanied by recurrent, stroke-like episodes with lactic acidosis (pH 7.279, lactic acid 11.6 mmol/L). The patient frequently developed a delirious state, exhibited regression of intellectual ability. Brain magnetic resonance imaging revealed high-intensity signals on T2-weighted images of the left occipital lobe. Mitochondrial gene analysis revealed a heteroplasmic m.4450G > A mutation in the mitochondrial tRNAMet. The heteroplasmic rate of the m.4450G > A mutation in blood, skin, urinary sediment, hair, saliva, and nail samples were 20, 38, 59, 41, 27, and 35%, respectively. The patient's fibroblast showed an approximately 53% reduction in the oxygen consumption rate, compared to a control, and decreased complex I and IV activities. Stroke-like episodes, lactic acidosis, encephalopathy with brain magnetic resonance imaging findings, and declined mitochondrial function were consistent with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. To our knowledge, the findings associated with this first patient with MELAS syndrome harboring the m.4450G > A mutation in mitochondrial tRNAMet expand the phenotypic spectrum of tRNAMet gene.
  • Mariko Noda, Ikuko Iwamoto, Hidenori Tabata, Takanori Yamagata, Hidenori Ito, Koh-Ichi Nagata
    Scientific reports 9 1 5874 - 5874 2019年04月 [査読有り][通常論文]
     
    Per3 is one of the primary components of circadian clock system. While circadian dysregulation is known to be involved in the pathogenesis of several neuropsychiatric diseases. It remains largely unknown whether they participate in embryonic brain development. Here, we examined the role of clock gene Per3 in the development of mouse cerebral cortex. In situ hybridization analysis revealed that Per3 is expressed in the developing mouse cortex. Acute knockdown of Per3 with in utero electroporation caused abnormal positioning of cortical neurons, which was rescued by RNAi-resistant Per3. Per3-deficient cells showed abnormal migration phenotypes, impaired axon extension and dendritic arbor formation. Taken together, Per3 was found to play a pivotal role in corticogenesis via regulation of excitatory neuron migration and synaptic network formation.
  • Masahide Goto, Shinji Makino, Takanori Yamagata
    Pediatric neurology 93 59 - 60 2019年04月
  • Noriko Nishikura, Takanori Yamagata, Takao Morimune, Jun Matsui, Tatsuyuki Sokoda, Chihiro Sawai, Yuko Sakaue, Yujiro Higuchi, Akihiro Hashiguchi, Hiroshi Takashima, Yoshihiro Takeuchi, Yoshihiro Maruo
    Brain & development 41 2 201 - 204 2019年02月 [査読有り][通常論文]
     
    X-linked Charcot-Marie-Tooth disease type 5 (CMTX5) is an X-linked disorder characterized by early-onset sensorineural hearing impairment, peripheral neuropathy, and progressive optic atrophy. It is caused by a loss-of-function mutation in the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1), which encodes isoform I of phosphoribosyl pyrophosphate synthetase (PRS-I). A decreased activity leads to nonsyndromic sensorineural deafness (DFN2), CMTX5, and Arts syndrome depending upon residual PRS-I activity. Clinical and neurophysiological features of pediatric CMTX5 are poorly defined. We report two male siblings with peripheral neuropathy and prelingual sensorineural hearing loss who carried a novel c.319A>G (p.Ile107Val) PRPS1 missense mutation. They exhibited recurrent episodes of transient proximal muscle weakness, showing Gowers' sign and waddling gait after suffering from febrile illness. This transient weakness has not been previously reported in CMTX5. A patient with Arts syndrome was reported to have transient proximal weakness after febrile illness. The transient weakness presenting in both CMTX5 and Arts syndrome suggests an overlap of signs and a continuous spectrum of PRS-I hypoactivity disease. Children presenting with transient neurological signs should be evaluated for peripheral neuropathy and consider genetic analysis for PRPS1.
  • Janyerkye Tulyeu, Moe Tamaura, Eriko Jimbo, Hiroko Shimbo, Kyoko Takano, Mizue Iai, Sumimasa Yamashita, Tomohide Goto, Noriko Aida, Etsuro Tokuhiro, Takanori Yamagata, Hitoshi Osaka
    Brain & development 41 2 195 - 200 2019年02月 [査読有り][通常論文]
     
    Alexander disease (AxD) is a neurodegenerative disease in astrocytes caused by a mutation in the gene encoding glial fibrillary acidic protein, GFAP. We herein present the case of a 12-year-old girl who showed intermittent exotropia at 3 years of age and central precocious puberty at 7 years of age. The periventricular and medulla oblongata showed high signal intensity on T2-weighted magnetic resonance imaging. The patient was diagnosed with AxD after direct sequencing revealing a de novo recurrent mutation, c.1246C>T (p.R416W) in GFAP. The transient expression of GFAPR416W in cells resulted in the significant formation of aggregates, which recapitulated the hallmark of AxD. We firstly utilized In Cell analyzer to prove the tendency of aggregate formation by mutants of GFAP.
  • Karin Kojima, Takeshi Nakajima, Naoyuki Taga, Akihiko Miyauchi, Mitsuhiro Kato, Ayumi Matsumoto, Takahiro Ikeda, Kazuyuki Nakamura, Tetsuo Kubota, Hiroaki Mizukami, Sayaka Ono, Yoshiyuki Onuki, Toshihiko Sato, Hitoshi Osaka, Shin-Ichi Muramatsu, Takanori Yamagata
    Brain : a journal of neurology 142 2 322 - 333 2019年02月 [査読有り][通常論文]
     
    In patients with aromatic l-amino acid decarboxylase (AADC) deficiency, a decrease in catecholamines and serotonin levels in the brain leads to developmental delay and movement disorders. The beneficial effects of gene therapy in patients from 1 to 8 years of age with homogeneous severity of disease have been reported from Taiwan. We conducted an open-label phase 1/2 study of population including adolescent patients with different degrees of severity. Six patients were enrolled: four males (ages 4, 10, 15 and 19 years) and one female (age 12 years) with a severe phenotype who were not capable of voluntary movement or speech, and one female (age 5 years) with a moderate phenotype who could walk with support. The patients received a total of 2 × 1011 vector genomes of adeno-associated virus vector harbouring DDC via bilateral intraputaminal infusions. At up to 2 years after gene therapy, the motor function was remarkably improved in all patients. Three patients with the severe phenotype were able to stand with support, and one patient could walk with a walker, while the patient with the moderate phenotype could run and ride a bicycle. This moderate-phenotype patient also showed improvement in her mental function, being able to converse fluently and perform simple arithmetic. Dystonia disappeared and oculogyric crisis was markedly decreased in all patients. The patients exhibited transient choreic dyskinesia for a couple of months, but no adverse events caused by vector were observed. PET with 6-[18F]fluoro-l-m-tyrosine, a specific tracer for AADC, showed a persistently increased uptake in the broad areas of the putamen. In our study, older patients (>8 years of age) also showed improvement, although treatment was more effective in younger patients. The genetic background of our patients was heterogeneous, and some patients suspected of having remnant enzyme activity showed better improvement than the Taiwanese patients. In addition to the alleviation of motor symptoms, the cognitive and verbal functions were improved in a patient with the moderate phenotype. The restoration of dopamine synthesis in the putamen via gene transfer provides transformative medical benefit across all patient ages, genotypes, and disease severities included in this study, with the most pronounced improvements noted in moderate patients.10.1093/brain/awy331_video1awy331media15991361892001.
  • Daisuke Matsubara, Koichi Kataoka, Hironori Takahashi, Takaomi Minami, Takanori Yamagata
    International heart journal 60 1 100 - 107 2019年01月 [査読有り][通常論文]
     
    Percutaneous catheter closure of patent ductus arteriosus (PDA) is difficult when the ductus is large and long or shows calcification. We created a patient-specific 3-dimensional (3D) model for PDA, with which we simulated device deployment, thereby selecting the device/size in a patient-by-patient manner. We assessed whether this 3D model is effective for catheter PDA closure.The 3D model was created in this institute, requiring 3 days and 90 US dollars. After its introduction, 7 consecutive patients (the study group) with severe PDA underwent closure with the aid of the 3D model. The control group consisted of 4 patients before 3D-model introduction, with all having severe PDA: the requirement of computed tomography was considered a criterion of severe or difficult-procedure-requiring PDA.In all study group patients, the devices/sizes could be pre-selected based on the simulation, whereas devices were changed during the procedure in 2 of 4 in the control group. In the study group, compared with the control group, the fluoroscopic (median 31 [interquartile range of 16-42] versus 39 [19-71] minutes, respectively) and total procedural times (median 107 [interquartile range 67-114] versus 124 [78-184] minutes, respectively) were shorter. A questionnaire confirmed the doctors' understanding of the procedure.This 3D model may be effective for percutaneous catheter closure of PDA. This may be especially true in cases of severe or difficult-procedure-requiring PDA.
  • Stephanie Sutoko, Yukifumi Monden, Tatsuya Tokuda, Takahiro Ikeda, Masako Nagashima, Masashi Kiguchi, Atsushi Maki, Takanori Yamagata, Ippeita Dan
    Frontiers in human neuroscience 13 7 - 7 2019年 [査読有り][通常論文]
     
    Attention deficit/hyperactivity disorder (ADHD) has been frequently reported as co-occurring with autism spectrum disorder (ASD). However, ASD-comorbid ADHD is difficult to diagnose since clinically significant symptoms are similar in both disorders. Therefore, we propose a classification method of differentially recognizing the ASD-comorbid condition in ADHD children. The classification method was investigated based on functional brain imaging measured by near-infrared spectroscopy (NIRS) during a go/no-go task. Optimization and cross-validation of the classification method was carried out in medicated-naïve and methylphenidate (MPH) administered ADHD and ASD-comorbid ADHD children (randomized, double-blind, placebo-controlled, and crossover design) to select robust parameters and cut-off thresholds. The parameters could be defined as either single or averaged multi-channel task-evoked activations under an administration condition (i.e., pre-medication, post-MPH, and post-placebo). The ADHD children were distinguished by significantly high MPH-evoked activation in the right hemisphere near the midline vertex. The ASD-comorbid ADHD children tended to have low activation responses in all regions. High specificity (86 ± 4.1%; mean ± SD), sensitivity (93 ± 7.3%), and accuracy (82 ± 1.6%) were obtained using the activation of oxygenated-hemoglobin concentration change in right middle frontal, angular, and precentral gyri under MPH medication. Therefore, the significantly differing MPH-evoked responses are potentially effective features and as supporting differential diagnostic tools.
  • Koyuru Kurane, Masahide Goto, Kazumi Sano, Kumiko Noguchi, Daisuke Tamura, Takanori Yamagata
    Internal medicine (Tokyo, Japan) 57 23 3501 - 3502 2018年12月 [査読有り][通常論文]
  • Takahiro Kanai, Kazuhiro Shiizaki, Hiroyuki Betsui, Jun Aoyagi, Takanori Yamagata
    CEN case reports 7 2 259 - 263 2018年11月 [査読有り][通常論文]
     
    Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder. ADPKD is characterized clinically by the presence of multiple bilateral renal cysts that lead to chronic renal failure. The cysts evolve from renal tubular epithelial cells that express the Klotho gene. Notably, Klotho acts as a co-receptor for fibroblast growth factor 23 (FGF23); in this context, it induces phosphaturia and maintains serum phosphate at a normal level. Many reports have shown that decreases in the soluble Klotho level and increases in the FGF23 level are associated with glomerular filtration rate (GFR) decline, but a recent study observed these changes in patient with normal eGFR. It remains unclear whether the decrease in the Klotho level precedes the increase in FGF23. Here, we present an ADPKD patient with enlarged kidneys due to multiple cysts who had a decreased soluble Klotho level but a normal eGFR and a normal FGF23 level. The patient's serum phosphate level was normal, as was the fractional excretion of phosphate (FEP). This appears to be the first reported case to show a decreased soluble Klotho level plus normal eGFR, FGF23, and FEP. These results suggest that Klotho decreases before FGF23 increases and further suggest that Klotho is not required to maintain normal serum phosphate levels in ADPKD if the FEP and serum phosphate levels are normal.
  • Yuri Matsubara, Hitoshi Osaka, Takanori Yamagata, Ryusuke Ae, Jun Shimizu, Noriko Oguro
    Brain & development 40 9 807 - 812 2018年10月 [査読有り][通常論文]
     
    BACKGROUND: Acute encephalopathy causes various sequelae, including motor disabilities and intellectual delays. Previous studies reported that cognitive impairments can also occur after acute encephalitis. Although the incidence of acute encephalopathy is high in Japan, there have been few reports on its sequelae. OBJECTIVE: To characterize the neurological outcomes of pediatric patients who sought motor rehabilitation for motor dysfunction after acute encephalopathy. METHOD: Subjects were 26 children who were healthy before suffering from motor dysfunction following acute encephalopathy and were referred to our pediatric rehabilitation institute during a 9-year period (August 2007-April 2017). We examined subjects' neurological status and followed sequelae for at least 8 months. RESULTS: Of 26 individuals, 21 became ambulatory after several months or years during the observation period. Patients who could sit without support within 5 months after the onset of acute encephalopathy were able to walk within several months or years. Patients showing high intensity on T2-weighted sequences or "bright tree appearance" in the frontal region took an average of 7 months to develop walking, which was longer than other patients. Among ambulatory subjects, 16(76%) exhibited mild to moderate intellectual delay with a developmental quotient (DQ) under 70, and 20 (95%) exhibited cognitive impairment. There was a significant correlation between DQ scores and motor disability (p = 0.013, r = -0.481). CONCLUSIONS: Although 80% of patients who had motor dysfunction caused by acute encephalopathy and visited out motor rehabilitation outpatient clinic were eventually able to walk, the time taken to develop walking ability depended on which region exhibited magnetic resonance imaging abnormalities. DQ scores and motor disability were significantly correlated.
  • Sutoko S, Monden Y, Funane T, Tokuda T, Katura T, Sato H, Nagashima M, Kiguchi M, Maki A, Yamagata T, Dand I
    Neurophotonics 5 4 049801  2018年10月 [査読有り][通常論文]
  • Ikeda Takahiro, Tokuda Tatsuya, Monden Yukifumi, Hirai Masahiro, Mizushima Sakae G, Nagashima Masako, Kyutoku Yasushi, Taniguchi Takamichi, Shimoizumi Hideo, Dan Ippeita, Yamagata Takanori
    JAPANESE PSYCHOLOGICAL RESEARCH 60 4 251 - 264 2018年10月 [査読有り][通常論文]
     
    Autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) are believed to share the symptom of neurocognitive dysfunction in executive functions. Regarding the components of executive functions, however, dysfunction of motor-response inhibitory control in children with ASD remains unclear. Thus, using functional near-infrared spectroscopy (fNIRS), we investigated whether putative inhibitory brain dysfunctions are applicable to children with ASD by adopting a go/no-go task, which has robustly evoked activation in typically developing (TD) children but not in ADHD children. Twenty-four ASD and 24 TD children underwent a go/no-go task, and their cortical hemodynamics were assessed using fNIRS. Relative to TD participants, ASD participants showed reduced activation in the right inferior frontal gyrus and middle frontal gyrus (IFG/MFG) during go/no-go tasks. The current finding suggests that hypoactivation in the right IFG/MFG during a go/no-go task would serve as a potential biomarker for identifying children with ASD.
  • Stephanie Sutoko, Yukifumi Monden, Tsukasa Funane, Tatsuya Tokuda, Takusige Katura, Hiroki Sato, Masako Nagashima, Masashi Kiguchi, Atsushi Maki, Takanori Yamagata, Ippeita Dan
    Neurophotonics 5 4 045001 - 045001 2018年10月 [査読有り][通常論文]
     
    Functional near-infrared spectroscopy (fNIRS) signals are prone to problems caused by motion artifacts and physiological noises. These noises unfortunately reduce the fNIRS sensitivity in detecting the evoked brain activation while increasing the risk of statistical error. In fNIRS measurements, the repetitive resting-stimulus cycle (so-called block-design analysis) is commonly adapted to increase the sample number. However, these blocks are often affected by noises. Therefore, we developed an adaptive algorithm to identify, reject, and select the noise-free and/or least noisy blocks in accordance with the preset acceptance rate. The main features of this algorithm are personalized evaluation for individual data and controlled rejection to maintain the sample number. Three typical noise criteria (sudden amplitude change, shifted baseline, and minimum intertrial correlation) were adopted. Depending on the quality of the dataset used, the algorithm may require some or all noise criteria with distinct parameters. Aiming for real applications in a pediatric study, we applied this algorithm to fNIRS datasets obtained from attention deficit/hyperactivity disorder (ADHD) children as had been studied previously. These datasets were divided for training and validation purposes. A validation process was done to examine the feasibility of the algorithm regardless of the types of datasets, including those obtained under sample population (ADHD or typical developing children), intervention (nonmedication and drug/placebo administration), and measurement (task paradigm) conditions. The algorithm was optimized so as to enhance reproducibility of previous inferences. The optimum algorithm design involved all criteria ordered sequentially (0.047 mM mm of amplitude change, 0.029    mM    mm / s of baseline slope, and 0.6 × interquartile range of outlier threshold for each criterion, respectively) and presented complete reproducibility in both training and validation datasets. Compared to the visual-based rejection as done in the previous studies, the algorithm achieved 71.8% rejection accuracy. This suggests that the algorithm has robustness and potential to substitute for visual artifact-detection.
  • Daisuke Tamura, Shun Inoue, Yuta Kawahara, Masaaki Mori, Takanori Yamagata
    Pediatrics international : official journal of the Japan Pediatric Society 60 10 974 - 976 2018年10月 [査読有り][通常論文]
  • ECHS1欠乏症の一例における食事療法(Dietary Therapy in a patient with ECHS1 deficiency)
    Kuwajima Mari, Kojima Karin, Ikeda Takahiro, Goto Masahide, Hushimi Takuya, Murayama Kei, Kishita Yoshihito, Yamada Kenichirou, Osaka Hitoshi, Yamagata Takanori
    日本先天代謝異常学会雑誌 34 188 - 188 2018年09月
  • PCDH19関連てんかんにおけるトピラマートとスチリペントール併用の有用性
    山岸 裕和, 後藤 昌英, 小坂 仁, 桑島 真理, 村松 一洋, 山形 崇倫
    てんかん研究 36 2 590 - 590 (一社)日本てんかん学会 2018年09月 [査読有り][通常論文]
  • Matsumoto A, Tulyeu J, Furukawa R, Watanabe C, Monden Y, Nozaki Y, Mori M, Namekawa M, Jimbo EF, Aihara T, Yamagata T, Osaka H
    Brain & development 40 7 587 - 591 2018年08月 [査読有り][通常論文]
     
    Alexander disease (AxD) is a progressive neurodegenerative disease caused by a mutation in the glial fibrillary acid protein (GFAP) gene. A 4-year-old boy presented several times with hemiclonic seizures with eye deviation for a few minutes at 28 days after birth. Electroencephalogram showed independent sharp waves in the right and left temporal area. Magnetic resonance imaging showed high intensity T1-weighted images in the white matter of the frontal lobe and basal ganglia. He showed no head control at 4 years of age, and his weight gain was insufficient. He did not show macrocephaly. At 4 years of age, he died of bacterial pneumonia and septic shock. He was diagnosed with AxD, and direct sequencing revealed a de novo known mutation, c. 239 T > C, p.(F80S), in GFAP. Hela and U2-OS cells transfected with GFAP cDNA with c. 239 T > C showed dot-like cytoplasmic aggregation, similar to R239C, a common mutation found in severe infantile AxD. Aggregation in the cytoplasm caused by a GFAP mutation is a hallmark of AxD. Although there is only one previous report of a patient with an F80S mutation, our data support that F80S can cause the severe, infantile form of AxD.
  • Masako Nagashima, Hitoshi Osaka, Takahiro Ikeda, Ayumi Matsumoto, Akihiko Miyauchi, Kimihiko Kaneko, Ichiro Nakashima, Yuko Nakano, Kei Wakabayashi, Yukifumi Monden, Takanori Yamagata
    Brain & development 40 7 607 - 611 2018年08月 [査読有り][通常論文]
     
    BACKGROUND: The effect of rituximab on acute disseminated encephalomyelitis (ADEM) followed by recurrent optic neuritis (ON) is not yet known. PATIENT: We are reporting the case of a 4-year-old Japanese girl who was diagnosed with anti-myelin oligodendrocyte glycoprotein (MOG) antibody positive ADEM followed by recurrent ON. She developed altered mental status, left facial paralysis, left paresis, and experienced three episodes of ON. She was treated with rituximab and azathioprine (AZA) as prevention for recurrent ON. She relapsed under treatment with AZA when CD19 cells reappeared 6 months after the first rituximab infusion. However, she has not relapsed since her CD19 count was reduced and kept low with rituximab infusion. CONCLUSIONS: It is conceivable that anti-MOG antibodies are involved in the pathology of "ADEM followed by recurrent ON," and that the early introduction of rituximab, which is involved in the suppression of antibody production and has effects on CD20 T lymphocytes, may be a feasible treatment for ON. Due to the small number of patients, additional reports on prospectively followed patients are needed.
  • Takahiro Ikeda, Masahiro Hirai, Takeshi Sakurada, Yukifumi Monden, Tatsuya Tokuda, Masako Nagashima, Hideo Shimoizumi, Ippeita Dan, Takanori Yamagata
    Neurophotonics 5 3 035008 - 035008 2018年07月 [査読有り][通常論文]
     
    Autism spectrum disorder (ASD) is characterized by impairment in social communication and the presence of restricted and repetitive behaviors and interests. Executive function impairment is reportedly partially responsible for these symptoms. Executive function includes planning, flexibility, and inhibitory control. Although planning and flexibility in ASD have been consistently reported as atypical, the atypicality of inhibitory control remains controversial. As most previous studies have used nonsocial stimuli to investigate inhibitory control in ASD, the effects of socially relevant information on the inhibitory control system in individuals with ASD remain unclear. Therefore, we developed a go/no-go task with gaze stimuli and measured hemodynamic responses in the right prefrontal cortex (PFC), involved in inhibitory processing in both typically developing (TD) children and children with ASD, using functional near-infrared spectroscopy. Direct gaze induced commission errors to similar extents in both groups. Contrary to the behavioral responses, neural activation in the right PFC was modulated by gaze direction only in the TD group. These findings suggest that the gaze-processing mechanisms in the prefrontal region may be affected by atypical gaze processing in other brain regions during an inhibitory control task with socially relevant information in ASD.
  • Akihiko Miyauchi, Hitoshi Osaka, Masako Nagashima, Mari Kuwajima, Yukifumi Monden, Masakazu Kohda, Yoshihito Kishita, Yasushi Okazaki, Kei Murayama, Akira Ohtake, Takanori Yamagata
    Brain & development 40 6 498 - 502 2018年06月 [査読有り][通常論文]
     
    Leigh syndrome, which is a common phenotype of pediatric mitochondrial disease, is a progressive neurodegenerative disease. The typical neuroimaging findings of Leigh syndrome include bilateral symmetric lesions in the basal ganglia and/or the brainstem. However, there are a few reports on spinal cord involvement in patients with Leigh syndrome. In the present case, magnetic resonance imaging (MRI) obtained during infancy revealed symmetric lesions in the substantia nigra of a patient with Leigh syndrome with an NDUFA1 mutation; lesions of the bilateral putamen and brainstem were subsequently observed. Additionally, our patient presented large and extended spinal cord lesions. Therefore, this case is suggesting that we should consider the occurrence of spinal cord lesions as an atypical finding in Leigh syndrome.
  • Nakamura Sachie, Osaka Hitoshi, Muramatsu Shin-ichi, Takino Naomi, Ito Mika, Jimbo Eriko F, Shimazaki Kuniko, Onaka Tatsushi, Ohtsuki Sumio, Terasaki Tetsuya, Yamagata Takanori
    MOLECULAR THERAPY 26 5 130 - 131 2018年05月 [査読有り][通常論文]
  • Ayumi Matsumoto, Eri Imagawa, Noriko Miyake, Takahiro Ikeda, Mizuki Kobayashi, Masahide Goto, Naomichi Matsumoto, Takanori Yamagata, Hitoshi Osaka
    Brain and Development 40 4 325 - 329 2018年04月 [査読有り][通常論文]
     
    SOX9 is responsible for campomelic dysplasia (CMPD). Symptoms of CMPD include recurrent apnea, upper respiratory infection, facial features, and shortening of the lower extremities. The variant acampomelic CMPD (ACMPD) lacks long bone curvature. A patient showed macrocephaly (+3.9 standard deviations [SD]) and minor anomalies, such as hypertelorism, palpebronasal fold, small mandible, and a cleft of soft palate without long bone curvature. From three months of age, he required tracheal intubation and artificial respiration under sedation because of tracheomalacia. Cranial magnetic resonance imaging was normal at one month of age but showed ventriculomegaly, hydrocephaly, and the corpus callosum thinning at two years of age. Exome sequencing revealed a de novo novel mutation, c. 236A > C, p (Q79P), in SOX9. Sox9 is thought to be crucial in neural stem cell development in the central and peripheral nervous system along with Sox8 and Sox10 in mice. In humans, neuronal abnormalities have been reported in cases of CMPD and ACMPD, including relative macrocephaly in 11 out of 22 and mild lateral ventriculomegaly in 2 out of 22 patients. We encountered a two-year old boy with ACMPD presenting with tracheomalacia and macrocephaly with a SOX9 mutation. We described for the first time an ACMPD patient with acquired diminished white matter and corpus callosal thinning, indicating the failure of oligodendrocyte/astrocyte development postnatally. This phenotype suggests that SOX9 plays a crucial role in human central nervous system development. Further cases are needed to clarify the relationship between human neural development and SOX9 mutations.
  • Sachie Nakamura, Shin-Ichi Muramatsu, Naomi Takino, Mika Ito, Eriko F Jimbo, Kuniko Shimazaki, Tatsushi Onaka, Sumio Ohtsuki, Tetsuya Terasaki, Takanori Yamagata, Hitoshi Osaka
    The journal of gene medicine 20 4 e3013  2018年04月 [査読有り][通常論文]
     
    BACKGROUND: We generated an adeno-associated virus (AAV) vector in which the human SLC2A1 gene, encoding glucose transporter type 1 (GLUT1), was expressed under the human endogenous GLUT1 promoter (AAV-GLUT1). We examined whether AAV-GLUT1 administration could lead to functional improvement in GLUT1-deficient mice. METHODS: We extrapolated human endogenous GLUT1 promoter sequences from rat minimal Glut1 promoter sequences. We generated a tyrosine-mutant AAV9/3 vector in which human SLC2A1-myc-DDK was expressed under the human GLUT1 promoter (AAV-GLUT1). AAV-GLUT1 was administered to GLUT1-deficient mice (GLUT1+/- mice) via intracerebroventricular injection (1.85 × 1010 vg/mouse or 6.5 × 1010 vg/mouse). We analyzed exogenous GLUT1 mRNA and protein expression in the brain and other major organs. We also examined improvements of cerebral microvasculature, motor function using rota-rod and footprint tests, as well as blood and cerebrospinal fluid (CSF) glucose levels. Additionally, we confirmed exogenous GLUT1 protein distribution in the brain and other organs after intracardiac injection (7.8 × 1011 vg/mouse). RESULTS: Exogenous GLUT1 protein was strongly expressed in the cerebral cortex, hippocampus and thalamus. It was mainly expressed in endothelial cells, and partially expressed in neural cells and oligodendrocytes. Motor function and CSF glucose levels were significantly improved following intracerebroventricular injection. Exogenous GLUT1 expression was not detected in other organs after intracerebroventricular injection of AAV-GLUT1, whereas it was detected in the liver and muscle tissue after intracardiac injection. CONCLUSIONS: Exogenous GLUT1 expression after AAV-GLUT1 injection approximated that of physiological human GLUT1 expression. Local central nervous system administration of AAV-GLUT1 improved CSF glucose levels and motor function of GLUT1-deficient mice and minimized off-target effects.
  • Methylphenidate-Elicited Distinct Neuropharmacological Activation Patterns Between Medication-Naive Attention Deficit Hyperactivity Disorder Children With and Without Comorbid Autism Spectrum Disorder: A Functional NearInfrared Spectroscopy Study
    Tokuda, T, Ikeda, T, Monden, Y, Mizushima, S. G, Inoue, T, Nagashima, M, Shimamura, K, Arakawa, A, Kobayashi, M, Kuroiwa, C, Ujiie, Y, Dan, H, Kyutoku, Y, Taniguchi, T, Shimoizumi, H, Yamagata, T, Yamaguchi, M. K, Kanazawa, S, Sakuta, R, Dan, I
    Neuropsychiatry 8 2 739 - 744 2018年04月 [査読有り][通常論文]
  • Jun Aoyagi, Takahiro Kanai, Jun Odaka, Takane Ito, Takashi Saito, Hiroyuki Betsui, Rieko Furukawa, Waka Nakata, Takanori Yamagata
    Pediatrics International 60 2 200 - 203 2018年02月 [査読有り][通常論文]
     
    The utility of non-enhanced magnetic resonance imaging (MRI) has not been examined extensively for diagnosing acute pyelonephritis (APN) in children. The aims of this study were to compare non-enhanced MRI with technetium-99 m dimercaptosuccinic acid (99mTc-DMSA) renal scintigraphy in detecting APN. Six boys and one girl with temperature ≥38°C and positive urine culture received both non-enhanced MRI with whole body diffusion-weighted imaging (DWI) and 99mTc-DMSA scintigraphy ≤7 days from the fever onset. The sensitivity and specificity of MRI in detecting APN lesions diagnosed on 99mTc-DMSA scintigraphy were 80% and 100%, respectively. Non-enhanced MRI in children with suspected APN ≤7 days from fever onset might be a suitable replacement for 99mTc-DMSA scintigraphy for the detection of APN.
  • Tsuchida N, Nakashima M, Miyauchi A, Yoshitomi S, Kimizu T, Ganesan V, Teik K.W, Ch{'}ng G.-S, Kato M, Mizuguchi T, Takata A, Miyatake S, Miyake N, Osaka H, Yamagata T, Nakajima H, Saitsu H, Matsumoto N
    Clinical Genetics 93 2 266 - 274 2018年02月 [査読有り][通常論文]
  • Hirokazu Yamagishi, Hitoshi Osaka, Masako Nagashima, Mari Kuwajima, Akihiko Miyauchi, Takahiro Ikeda, Karin Kojima, Ayumi Matsumoto, Takanori Yamagata
    Journal of the Japan Epilepsy Society 35 3 693 - 701 2018年 [査読有り][通常論文]
     
    Perampanel (PER) is a novel class of anti-epileptic drug and a noncompetitive inhibitor of the AMPA receptor. Some reports have described the efficacy and side-effects of PER in Japan. We prescribed PER to 33 refractory epilepsy patients, including some with intellectual disabilities and/or an age under 12 years. A "Good response" was defined as more than 50% seizure reduction, and we investigated the responder rates for focal seizure (Fs) and generalized tonic clonic seizure (GTCS). The effective rate for Fs and GTCS were both 50%, and the overall seizure rate was 52%. The efficacy in patients < 12 years of age was similar to those > 12 years of age. Although there were no significant differences in the responder rates among the concomitant antiepileptic drugs (AEDs), two patients who received KBr combination treatment showed a good response. The responder rates with CYP3A4-inducing AEDs such as CBZ and PHT tended to be low (30% and 18%, respectively). Adverse events occurred in 55% of patients, including emotional and behavioral abnormalities in 30%, somnolence in 18%, and dizziness in 15%. We should therefore closely monitor young patients and those with intellectual disabilities, as emotional and behavioral abnormalities tend to occur with the administration of PER.
  • Karin Kojima, Kentaro Shirai, Mizuki Kobayashi, Akihiko Miyauchi, Hirotomo Saitsu, Naomichi Matsumoto, Hitoshi Osaka, Takanori Yamagata
    Brain and Development 40 1 69 - 73 2018年01月 [査読有り][通常論文]
     
    Background The potassium voltage-gated channel subfamily Q member 2 (KCNQ2) gene has been reported to be associated with various types of epilepsy, including benign familial neonatal seizure (BFNS), early infantile epileptic encephalopathy (EIEE), and unclassified early onset encephalopathies. We herein report a patient with early myoclonic encephalopathy (EME) caused by a KCNQ2 mutation. Case report A male infant started to exhibit erratic myoclonus several days after birth and apnea attacks lasting for seconds with desaturation. One month after birth, his myoclonuses worsened in frequency. Electroencephalogram (EEG) showed a burst and suppression pattern, and myoclonuses occurred in the burst phase with diffuse polyspikes on EEG. At five months, inter-ictal EEG revealed hypsarrhythmia, but his attacks were still only myoclonuses. ACTH treatment was effective and the myoclonus frequency markedly decreased. At one year of age, whole-exome sequencing revealed a heterozygous mutation of the KCNQ2 gene (NM_172107.2): c.601C > T p.(Arg201Cys), which was confirmed as de novo by Sanger sequencing. This mutation lies within the extracellular portion of the S4 voltage sensor. Conclusion Most patients with a KCNQ2 mutation present with seizures starting in the neonatal period with varying severity, ranging from BFNS to Ohtahara syndrome. Furthermore, KCNQ2 appears to be a causative gene for EME.
  • Ayako Ueda, Hiroko Shimbo, Yukari Yada, Yasunori Koike, Takanori Yamagata, Hitoshi Osaka
    Human genome variation 5 18013 - 18013 2018年 [査読有り][通常論文]
     
    Pelizaeus-Merzbacher disease (PMD; MIM #312080) is a rare X-linked recessive disorder. A male neonate presented with severe respiratory distress that required tracheostomy. After the appearance of nystagmus, PMD was suspected as a diagnosis for the patient, and a missense mutation, p.Phe51Val, was identified in PLP1, the gene responsible for PMD. PMD can be a differential diagnosis in a male neonate presenting severe respiratory distress.
  • Makiko Oguma, Mizuki Kobayashi, Masayo Yamazaki, Koji Yokoyama, Shuntaro Morikawa, Takeshi Yamaguchi, Takanori Yamagata, Toshihiro Tajima
    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 27 2 95 - 100 2018年 [査読有り][通常論文]
     
    Genetic defects in the immunoglobulin superfamily member 1(IGSF1) protein are the cause of congenital central hypothyroidism (C-CH). Here we report two Japanese siblings with C-CH due to a novel IGSF1 mutation. The youngest brother showed a failure to thrive, hypothermia, and neonatal icterus six days after birth. Further endocrine evaluations led to the diagnosis of C-CH. In addition, PRL deficiency was later detected. In contrast, the elder brother did not show symptoms of severe hypothyroidism during the neonatal period, but he had been followed up by doctors due to psychomotor developmental delays since the age of 1 yr. At the age of 3 yr, he had low thyroxine and PRL levels and was also diagnosed with C-CH. Because of the C-CH and PRL deficiency, an IGSF1 deficiency was suspected. Sequence analysis of the IGSF1 gene identified a novel hemizygous mutation of p.Trp1173GlyfsTer8 (NM_001170961.1:c.3517del) in both siblings. In conclusion, the phenotypic severity of C-CH is different, even in siblings. Importantly, an IGSF1 deficiency may result in severe hypothyroidism during the neonatal period.
  • Takahiro Ikeda, Hitoshi Osaka, Hiroko Shimbo, Makiko Tajika, Masayo Yamazaki, Ayako Ueda, Kei Murayama, Takanori Yamagata
    Human genome variation 5 25 - 25 2018年 [査読有り][通常論文]
     
    Approximately 80% of cases of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) harbor a heteroplasmic m.3243A>G transition in the tRNALeu (UUR) (MTTL1) gene. We report a MELAS case with a rare heteroplasmic m.3243A>T mutation found by direct sequencing of MTTL1. This mutation has been previously reported in 5 cases, of which 2 cases had the MELAS phenotype. Our case also strengthens the hypothesis that the m.3243A>T mutation can cause the MELAS phenotype.
  • Methylphenidate-Elicited Distinct Neuropharmacological Activation Patterns Between Medication-Naïve Attention Deficit Hyperactivity Disorder Children With and Without Comorbid Autism Spectrum Disorder: A Functional Near- Infrared Spectroscopy Study
    Tatsuya Tokuda, Takahiro Ikeda, Yukifumi Monden, Sakae G Mizushima, Takeshi Inoue, Masako Nagashima, Keiichi Shimamura, Akari Arakawa, Megumi Kobayashi, Chie Kuroiwa, Yuta Ujiie, Haruka Dan, Yasushi Kyutoku, Takamichi Taniguchi, Hideo Shimoizumi, Takanori Yamagata, Masami K Yamaguchi, So Kanazawa, Ryoichi Sakuta, Ippeita Dan
    Neuropsychiatry (London) 8 3 917 - 929 2018年 [査読有り][通常論文]
  • Miho Usui, Akihiko Miyauchi, Yuko Nakano, Sachie Nakamura, Eriko Jimbo, Shinji Itamura, Kaori Adachi, Eiji Nanba, Aya Narita, Takanori Yamagata, Hitoshi Osaka
    BRAIN & DEVELOPMENT 39 10 886 - 890 2017年11月 [査読有り][通常論文]
     
    Niemann-Pick disease type C (NPC) is a rare, progressive autosomal recessive disease. It is caused by mutations in either the NPCI or NPC2 genes, resulting in defective regulation of intracellular lipid trafficking. Miglustat, which reversibly inhibits glucosylceramide synthase, reportedly has beneficial effects on the progressive neurological symptoms of NPC and was approved in Japan in 2012. Some reports suggested that miglustat therapy delayed the onset or progression of NPC when treatment was initiated before the onset of neurological manifestation or at an early stage. We report here a patient with the early-infantile form of NPC who started on miglustat at 4 months of ages. To our knowledge, this patient is the youngest reported patient with NPC in which miglustat therapy was initiated. Our patient, who had hypotonia and developmental delay before treatment, remained stable and showed no new neurological symptoms. In addition, pulmonary involvement was improved during miglustat therapy. Our case and previous reports underscore the importance of early initiation of miglustat therapy for NPC. (C) 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
  • Tsuyoshi Kodachi, Shizuko Matsumoto, Masashi Mizuguchi, Hitoshi Osaka, Nobuyuki Kanai, Eiji Nanba, Kousaku Ohno, Takanori Yamagata
    NEUROPATHOLOGY 37 5 426 - 430 2017年10月 [査読有り][通常論文]
     
    Niemann-Pick disease type C (NPC) is a cholesterol storage disease caused by defective cellular cholesterol transportation. The onset and progression of NPC are variable, and autopsy findings have mainly been reported for the adult and juvenile forms of this disease. Here we report the clinical and pathological findings from a 9-year-old female patient with the late infantile form of NPC due to NPC1 gene mutation. She had notable splenomegaly at 4 months of age. She lost the ability to speak at 18months of age. She learned to walk, but often fell and could no longer walk after 30months. At 3 years of age, she was diagnosed with NPC. Sequence analysis of the NPC1 gene revealed compound heterozygous mutation of T2108C (F703S) and C2348G (S813X) (both novel). Thereafter, the patient suffered repeated respiratory infections and died of respiratory failure at 9 years of age. Pathological findings included cerebral atrophy (particularly of white matter), severe demyelination, and the loss of neurons from the cerebrum and from the nuclei of the brain stem. Remnant neuronal cells and microglia in the cerebrum, cerebellum, and brain stem had become swollen and foamy. Neurons of the hippocampal CA1 and Purkinje cells were relatively spared, and senile plaques and axonal spheroids were not present. Foamy cells were also observed in other organs, especially the spleen and bone marrow. The F703S mutation in this patient was localized in a sterol-sensing domain (SSD). Severe neurological phenotypes have been previously reported in patients with missense mutations in an SSD. It is considered that the combination of a nonsense mutation and missense mutation in an SSD was responsible for the severe neurological phenotype of our present patient. While pathological findings of adult/juvenile forms of NPC have included swollen neurons and glia, neuronal cell loss, and NFTs, demyelination may be a predominant finding in the infantile form of NPC.
  • Masahide Goto, Koji Y. okoyama, Yasuyuki Nozaki, Koichi Itoh, Ryou Kawamata, Shizuko Matsumoto, Takanori Yamagata
    BRAIN & DEVELOPMENT 39 9 791 - 798 2017年10月 [査読有り][通常論文]
     
    Purpose: Few studies have investigated pediatric headaches in Japan. Thus, we examined the lifetime prevalence and characteristics of headaches among elementary and junior high school students in Japan. Methods: In this school-based study, children aged 6-15 years completed a questionnaire based on the diagnostic criteria of the International Classification of Headache Disorders-3 beta to assess headache characteristics and related disability. Results: Of the 3285 respondents, 1623 (49.4%) experienced headaches. Migraine and tension-type headaches (TTH) were reported by 3.5% and 5.4% of elementary school students, respectively, and by 5.0% and 11.2% of junior high school students. Primary headaches increased with age. Compared with TTH sufferers, the dominant triggers in migraine sufferers were hunger (odds ratio = 4.7), sunny weather (3.3), and katakori (neck and shoulder pain) (2.5). Compared with TTH, migraine caused higher headache-related frustration (P = 0.010) as well as difficulty concentrating (P = 0.017). Migraine-related disability was greater among junior high school students (feeling fed up or irritated, P = 0.028; difficulty concentrating, P = 0.016). TTH-related disability was also greater among junior high school students (feeling fed up or irritated, P = 0.035). Approximately half of the students who complained of headache-related disability were not receiving medical treatment. Conclusion: This is the first detailed study of headaches in Japanese children to include elementary school students. Nearly 50% of the school children reported headaches and the disruption of daily activities caused by migraine was higher among junior high students than elementary school students. (C) 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
  • Koji Yokoyama, Hideki Kumagai, Masaharu Takahashi, Shigeo Nagashima, Hiroaki Okamoto, Takanori Yamagata
    PEDIATRICS INTERNATIONAL 59 9 1010 - 1016 2017年09月 [査読有り][通常論文]
     
    BackgroundThe prevalence of occult hepatitis B virus (HBV) infection (OBI) in children due to mother-to-child transmission (MTCT) despite immunoprophylaxis remains controversial and is still unknown in Japan. The aim of this study was to determine the OBI prevalence in such children in Japan and identify the genomic mutations that might be associated with the pathogenesis of OBI in children. MethodsThe data on 158 children born to HBV carrier mothers and who received complete passive-active immunoprophylaxis after birth in 2002-2014 were reviewed. HBV markers were detected using commercial enzyme-linked immunosorbent assay kits. HBV-DNA was detected using real-time and nested polymerase chain reaction. Complete genomic sequences were determined. ResultsAmong the 158 children studied, three had HBV MTCT: two had OBI, and one had resolved HBV infection (RBI). The prevalence of OBI and RBI was estimated to be 1.3% and 0.6%, respectively. The HBV genomes of the two OBI children were wild type and 100% identical to those of their mothers. Of these two children, one received repeated hepatitis B immunoglobulin (HBIG) and developed overt HBV infection. Her HBV genome had a G145R mutation in the S gene that might have been induced by HBIG treatment. The RBI child was persistently positive for antibody to HBV core antigen (10-12 signal/cut-off ratio; S/CO). ConclusionsA low prevalence of OBI was observed in children who received immunoprophylaxis for preventing MTCT in Japan. The development of overt HBV infection in infants with OBI indicates the necessity of close and long-term monitoring.
  • SMAD3新規遺伝子変異を有し側彎・骨格変形・大動脈解離家族歴を持つ若年女性の一例
    南 孝臣, 今井 靖, 松原 大輔, 武田 憲文, 岡 健介, 古井 貞浩, 鈴木 峻, 片岡 功一, 吉川 一郎, 河田 政明, 山形 崇倫
    日本小児循環器学会雑誌 33 Suppl.1 s1 - 335 (NPO)日本小児循環器学会 2017年07月
  • Daisuke Matsubara, Yu Suzuki, Yukari Yada, Takaomi Minami, Takanori Yamagata
    INTERNATIONAL JOURNAL OF CARDIOLOGY 239 7 - 7 2017年07月 [査読有り][通常論文]
  • Saori Sakamoto, Yukifumi Monden, Ryoko Fukai, Noriko Miyake, Hiroshi Saito, Akihiko Miyauchi, Ayumi Matsumoto, Masako Nagashima, Hitoshi Osaka, Naomichi Matsumoto, Takanori Yamagata
    Brain & development 39 5 439 - 443 2017年05月 [査読有り][通常論文]
     
    We report the case of a 19-year-old female patient who had progressive chorea associated with a GNAO1 mutation. Chorea was refractory to multiple anticonvulsants, and the patient suffered from tiapride-induced neuroleptic malignant syndrome. After identification of a GNAO1 missense mutation at the age of 18years, topiramate treatment was initiated and the frequency of chorea decreased dramatically. The efficacy of topiramate may have been related to the inhibitory modulation of voltage-activated Ca2+ channels. Given the side effects and complications associated with neuroleptics and deep brain stimulation, respectively, topiramate is recommended for the first-line management of severe chorea associated with a GNAO1 mutation.
  • Stickley A, Tachibana Y, Hashimoto K, Haraguchi H, Miyake A, Morokuma S, Nitta H, Oda M, Ohya Y, Senju A, Takahashi H, Yamagata T, Kamio Y
    Autism research : official journal of the International Society for Autism Research 10 5 852 - 865 2017年05月 [査読有り][通常論文]
     
    The recent development and use of autism measures for the general population has led to a growing body of evidence which suggests that autistic traits are distributed along a continuum. However, as most existing autism measures were designed for use in children older than age 4, to date, little is known about the autistic continuum in children younger than age 4. As autistic symptoms are evident in the first few years, to address this research gap, the current study tested the preschool version of the Social Responsiveness Scale (SRS-P) in children aged 2 to 41/2 years in clinical (N=74, average age 40 months, 26-51 months) and community settings (N=357, average age 39 months, 25-50 months) in Japan. Using information obtained from different raters (mothers, other caregivers, and teachers) it was found that the scale demonstrated a good degree of internal consistency, inter-rater reliability and test-retest reliability, and a satisfactory degree of convergent validity for the clinical sample when compared with scores from diagnostic "gold standard" autism measures. Receiver operating characteristic analyses and the group comparisons also showed that the SRS-P total score discriminated well between children with autism spectrum disorder (ASD) and those without ASD. Importantly, this scale could identify autistic symptoms or traits distributed continually across the child population at this age irrespective of the presence of an ASD diagnosis. These findings suggest that the SRS-P might be a sensitive instrument for case identification including subthreshold ASD, as well as a potentially useful research tool for exploring ASD endophenotypes. (C) VC 2016 International Society for Autism Research, Wiley Periodicals, Inc.
  • Sachie Nakamura, Hitoshi Osaka, Shin-Ichi Muramatsu, Naomi Takino, Mika Ito, Shiho Aoki, Eriko F Jimbo, Kuniko Shimazaki, Tatsushi Onaka, Sumio Ohtsuki, Tetsuya Terasaki, Takanori Yamagata
    Molecular genetics and metabolism reports 10 67 - 74 2017年03月 [査読有り][通常論文]
     
    OBJECTIVE: We generated an adeno-associated virus (AAV) vector in which the human SLC2A1 gene was expressed under the synapsin I promoter (AAV-hSLC2A1) and examined if AAV-hSLC2A1 administration can lead to functional improvement in GLUT1-deficient mice. METHODS: AAV-hSLC2A1 was injected into heterozygous knock-out murine Glut1 (GLUT1+/-) mice intraperitoneally (systemic; 1.85 × 1011 vg/mouse) or intra-cerebroventricularly (local; 1.85 × 1010 vg/mouse). We analyzed GLUT1 mRNA and protein expression, motor function using rota-rod and footprint tests, and blood and cerebrospinal fluid (CSF) glucose levels. RESULTS: Vector-derived RNA was detected in the cerebrum for both injection routes. In the intra-cerebroventricular injection group, exogenous GLUT1 protein was strongly expressed in the cerebral cortex and hippocampus near the injection site. In the intraperitoneal injection group, exogenous GLUT1 protein was mildly expressed in neural cells throughout the entire central nervous system. The motor function test and CSF/blood glucose ratio were significantly improved following intra-cerebroventricular injection. CONCLUSIONS: AAV-hSLC2A1 administration produced exogenous GLUT1 in neural cells and improved CSF glucose levels and motor function of heterozygous knock-out murine Glut1 mice.
  • Masahide Goto, Makoto Mizuno, Ayumi Matsumoto, Zhiliang Yang, Eriko F. Jimbo, Hidenori Tabata, Takanori Yamagata, Koh-ichi Nagata
    SCIENTIFIC REPORTS 7 43945  2017年03月 [査読有り][通常論文]
     
    In our previous study, we screened autism spectrum disorder (ASD) patients with and without sleep disorders for mutations in the coding regions of circadian-relevant genes, and detected mutations in several clock genes including NR1D1. Here, we further screened ASD patients for NR1D1 mutations and identified three novel mutations including a de novo heterozygous one c. 1499 G > A (p. R500H). We then analyzed the role of Nr1d1 in the development of the cerebral cortex in mice. Acute knockdown of mouse Nr1d1 with in utero electroporation caused abnormal positioning of cortical neurons during corticogenesis. This aberrant phenotype was rescued by wild type Nr1d1, but not by the c. 1499 G > A mutant. Time-lapse imaging revealed characteristic abnormal migration phenotypes in Nr1d1-deficient cortical neurons. When Nr1d1 was knocked down, axon extension and dendritic arbor formation of cortical neurons were also suppressed while proliferation of neuronal progenitors and stem cells at the ventricular zone was not affected. Taken together, Nr1d1 was found to play a pivotal role in corticogenesis via regulation of excitatory neuron migration and synaptic network formation. These results suggest that functional defects in NR1D1 may be related to ASD etiology and pathophysiology.
  • Yuki Takayanagi, Masahide Yoshida, Akihide Takashima, Keiko Takanami, Shoma Yoshida, Katsuhiko Nishimori, Ichiko Nishijima, Hirotaka Sakamoto, Takanori Yamagata, Tatsushi Onaka
    Biological psychiatry 81 3 243 - 251 2017年02月 [査読有り][通常論文]
     
    BACKGROUND: Social recognition underlies social behavior in animals, and patients with psychiatric disorders associated with social deficits show abnormalities in social recognition. Oxytocin is implicated in social behavior and has received attention as an effective treatment for sociobehavioral deficits. Secretin receptor-deficient mice show deficits in social behavior. The relationship between oxytocin and secretin concerning social behavior remains to be determined. METHODS: Expression of c-Fos in oxytocin neurons and release of oxytocin from their dendrites after secretin application were investigated. Social recognition was examined after intracerebroventricular or local injection of secretin, oxytocin, or an oxytocin receptor antagonist in rats, oxytocin receptor-deficient mice, and secretin receptor-deficient mice. Electron and light microscopic immunohistochemical analysis was also performed to determine whether oxytocin neurons extend their dendrites into the medial amygdala. RESULTS: Supraoptic oxytocin neurons expressed the secretin receptor. Secretin activated supraoptic oxytocin neurons and facilitated oxytocin release from dendrites. Secretin increased acquisition of social recognition in an oxytocin receptor-dependent manner. Local application of secretin into the supraoptic nucleus facilitated social recognition, and this facilitation was blocked by an oxytocin receptor antagonist injected into, but not outside of, the medial amygdala. In the medial amygdala, dendrite-like thick oxytocin processes were found to extend from the supraoptic nucleus. Furthermore, oxytocin treatment restored deficits of social recognition in secretin receptor-deficient mice. CONCLUSIONS: The results of our study demonstrate that secretin-induced dendritic oxytocin release from supraoptic neurons enhances social recognition. The newly defined secretin-oxytocin system may lead to a possible treatment for social deficits.
  • Jun Odaka, Takahiro Kanai, Takane Ito, Takashi Saito, Jun Aoyagi, Hiroyuki Betsui, Takanori Yamagata
    International Journal of Nephrology 2017 6392843  2017年 [査読有り][通常論文]
     
    Humoral factors may cause idiopathic steroid-sensitive nephrotic syndrome (ISSNS). In the present study, we analyzed serum proteins using mass spectrometry (MS) to identify proteins associated with the pathophysiology of pediatric ISSNS. We collected serial serum samples from 33 children during each ISSNS phase Phase A1 is the acute phase prior to steroid treatment (STx), Phase A2 represents the remission period with STx, and Phase A3 represents the remission period after completion of STx. Children with normal urinalyses (Group B) and children with a nephrotic syndrome other than ISSNS (Group C) served as controls. No significant differences in urinary protein/urinary creatinine (UP/UCr) ratios were observed between the children with phase A1 ISSNS and Group C. We used surface-enhanced laser desorption/ionization time of flight MS for sample analysis. Four ion peaks with a mass-To-charge ratio (m/z) of 6,444, 6,626, 8,695, and 8,915 were significantly elevated during ISSNS Phase A1 compared to Phase A2, Phase A3, and Group C. The intensity of an m/z of 6,626 significantly correlated with the UP/UCr ratio and an m/z of 6,626 was identified as apolipoprotein C-I (Apo C-I). Apo C-I levels correlate with the UP/UCr ratio in pediatric ISSNS. Our findings provide new insights into the pathophysiology of ISSNS.
  • Masayo Yamazaki, Hideo Sugie, Makiko Oguma, Tohru Yorifuji, Toshihiro Tajima, Takanori Yamagata
    Clinical Pediatric Endocrinology 26 3 165 - 169 2017年 [査読有り][通常論文]
     
    Neonatal diabetes mellitus (NDM) is an insulin-requiring monogenic form of diabetes that generally presents before six months of age. The following two types of NDM are known: transient NDM (TNDM) and permanent NDM (PNDM). Here we report on an infant with TNDM caused by a mutation (p.Gly832Cys) of the gene for the ATP binding cassette subfamily C member 8 (ABCC8). The patient exhibited hyperglycemia (600 mg/dL) at five weeks of age and insulin treatment was initiated. As genetic analysis identified a missense mutation within ABCC8, the insulin was replaced by glibenclamide at five months of age. Thereafter, the insulin was successfully withdrawn and his glycemic condition was well controlled at a dose of 0.0375 mg/kg/d. Since the patient’s blood glucose was under control and serum C-peptide levels were measurable, glibenclamide was stopped at 1 yr, 10 mo of age. The lack of DM relapsed to date confirms the TNDM diagnosis. In conclusion, when insulin is replaced with a sulfonylurea-class medication (SU) in NDM patients, serum C-peptide levels should be closely monitored and fine adjustment of SU dose is recommended.
  • Matsubara D, Kataoka K, Matsubara T, Minami T, Yamagata T
    World journal of emergency medicine 8 4 308 - 309 2017年 [査読有り][通常論文]
  • Jun Ito, Takeo Fujiwara, Yukifumi Monden, Takanori Yamagata, Hideki Ohira
    Frontiers in pediatrics 5 271 - 271 2017年 [査読有り][通常論文]
     
    Although previous studies have revealed the role of oxytocin (OT) in parental behavior, the role of OT has not been investigated through the direct assessment of prefrontal brain activation during parenting. By using functional near-infrared spectroscopy, we aimed to show the relationship between parental [maternal (N = 15) and paternal (N = 21)] OT levels and the activation of the prefrontal cortex (PFC), while holding their infants after separation. Baseline OT levels were measured in the subjects' saliva samples before the experiment. Prefrontal brain activation was assessed in participants sitting alone on a chair (i.e., separation from their infant for 120 s) and during the target period (i.e., holding their infant for 45 s), which was done in triplicate. The oxygen hemoglobin (oxy-Hb) dissociation curve significantly increased in 9 out of 22 channels on the PFC when maternal and paternal samples were combined. However, only the fathers showed a correlation between salivary OT and oxy-Hb signal. Furthermore, while holding their infants, high-OT fathers showed left hemispheric dominance compared to low-OT fathers, while high-OT mothers showed right hemispheric dominance compared to low-OT mothers. This study showed that fathers with high-OT levels showed neural activation with left hemispheric dominance, while holding their infants, suggesting that increase of OT level might activate paternal PFC related to parenting behavior, although the same is not true for mothers.
  • Stephanie Sutoko, Tsukasa Funane, Takusige Katura, Hiroki Sato, Masashi Kiguchi, Atsushi Maki, Yukifumi Monden, Masako Nagashima, Takanori Yamagata, Ippeita Dan
    OPTICAL TOMOGRAPHY AND SPECTROSCOPY OF TISSUE XII 10059 2017年 [査読有り][通常論文]
     
    In pediatrics studies, the quality of functional near infrared spectroscopy (fNIRS) signals is often reduced by motion artifacts. These artifacts likely mislead brain functionality analysis, causing false discoveries. While noise correction methods and their performance have been investigated, these methods require several parameter assumptions that apparently result in noise overfitting. In contrast, the rejection of noisy signals serves as a preferable method because it maintains the originality of the signal waveform. Here, we describe a semi-learning algorithm to detect and eliminate noisy signals. The algorithm dynamically adjusts noise detection according to the predetermined noise criteria, which are spikes, unusual activation values (averaged amplitude signals within the brain activation period), and high activation variances (among trials). Criteria were sequentially organized in the algorithm and orderly assessed signals based on each criterion. By initially setting an acceptable rejection rate, particular criteria causing excessive data rejections are neglected, whereas others with tolerable rejections practically eliminate noises. fNIRS data measured during the attention response paradigm (oddball task) in children with attention deficit/hyperactivity disorder (ADHD) were utilized to evaluate and optimize the algorithm's performance. This algorithm successfully substituted the visual noise identification done in the previous studies and consistently found significantly lower activation of the right prefrontal and parietal cortices in ADHD patients than in typical developing children. Thus, we conclude that the semi-learning algorithm confers more objective and standardized judgment for noise rejection and presents a promising alternative to visual noise rejection.
  • KCNQ2 de novo変異をみとめた無呼吸発作が頻発するKCNQ2関連てんかん性脳症の1例
    中村 久美子, 小島 華林, 廣瀬 優子, 小林 瑞, 宮内 彰彦, 横山 孝二, 白井 謙太朗, 才津 浩智, 松本 直通, 小坂 仁, 山形 崇倫
    脳と発達 49 1 62  (一社)日本小児神経学会 2017年01月 [査読無し][通常論文]
  • Tatsuya Anzai, Takaomi Minami, Tomoyuki Sato, Sadahiro Furui, Takanori Yamagata
    TURKISH JOURNAL OF PEDIATRICS 58 6 666 - 668 2016年11月 [査読有り][通常論文]
     
    Intravenous immunoglobulin therapy is standard for Kawasaki disease (KD) treatment; however, anaphylactic reactions to immunoglobulins are a risk in KD patients with selective IgA deficiency (sIgAD). The therapy for KD associated with sIgAD has not been established. The IgA immune response is believed to play an important role in KD vasculitis. We report the case of a 5-year-old boy with KD and sIgAD treated with intravenous cyclosporine A (CsA, 3.0 mg/kg/day) instead of intravenous immunoglobulin (IVIG). The fever and inflammation immediately resolved without a coronary artery lesion. In KD patients with sIgAD, we believe that an IgA immune response is lacking, which is the reason for milder KD symptoms than in those without sIgAD. This case report aids in clarifying the role of IgA antibodies in KD and provides evidence that CsA is a potential candidate for first-line therapy for patients with KD with contraindications to IVIG.
  • Karin Kojima, Rie Anzai, Chihiro Ohba, Tomohide Goto, Akihiko Miyauchi, Beat Thony, Hirotomo Saitsu, Naomichi Matsumoto, Hitoshi Osaka, Takanori Yamagata
    BRAIN & DEVELOPMENT 38 10 959 - 963 2016年11月 [査読有り][通常論文]
     
    Background: Aromatic L-amino acid decarboxylase (AADC) deficiency is an autosomal recessive disorder, caused by defects in the DDC gene. AADC catalyzes the synthesis of the neurotransmitters dopamine and serotonin from L-dopa and 5-HT respectively. Most patients are bed ridden for life, with little response to treatment. We now report one female patient who improved her motor and cognitive function after being prescribed a MAO-B inhibitor. Case: A five years old female presented with the typical clinical features of AADC deficiency. She was floppy, with no head control, had intermittent limb dystonia, and an upward deviation of the eyes (oculogyric crisis). This patient possessed compound heterozygous mutations in DDC (p.Trp105Cys, p.Pro129Ser), with a CSF draw indicating abnormal patterns of biogenic amine metabolites, compatible with AADC deficiency. Results: After her diagnosis at 3 years of age, medication with levodopa and vitamin B6 failed to show any efficacy. Subsequent administration with a MAO-B inhibitor improved her psychomotor functions to the extent that at 5 years of age she could walk several meters with support. Conclusion: Our analyses of chemical findings, together with in silica structure predictions, lead us to hypothesize that this patient retained some AADC activity. In these cases, accurate diagnosis and early treatment should improve patient outcome. (C) 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
  • Noriko Miyake, Ghada Abdel-Salam, Takanori Yamagata, Maha M. Eid, Hitoshi Osaka, Nobuhiko Okamoto, Amal M. Mohamed, Takahiro Ikeda, Hanan H. Afifi, Juliette Piard, Lionel van Maldergem, Takeshi Mizuguchi, Satoko Miyatake, Yoshinori Tsurusaki, Naomichi Matsumoto
    AMERICAN JOURNAL OF MEDICAL GENETICS PART A 170 10 2662 - 2670 2016年10月 [査読有り][通常論文]
     
    Coffin-Siris syndrome is a rare congenital malformation and intellectual disability syndrome. Mutations in at least seven genes have been identified. Here, we performed copy number analysis in 37 patients with features of CSS in whom no causative mutations were identified by exome sequencing. We identified a patient with a 9p24.3-p22.2 duplication and another patient with the chromosome der(6)t(6;9)(p25;p21)mat. Both patients share a duplicated 15.8-Mb region containing 46 protein coding genes, including SMARCA2. Dominant negative effects of SMARCA2 mutations may contribute to Nicolaides-Baraitser syndrome. We conclude that their features better resemble Coffin-Siris syndrome, rather than Nicolaides-Baraitser syndrome and that these features likely arise from SMARCA2 over-dosage. Pure 9p duplications (not caused by unbalanced translocations) are rare. Copy number analysis in patients with features that overlap with Coffin-Siris syndrome is recommended to further determine their genetic aspects. (c) 2016 Wiley Periodicals, Inc.
  • Shoya Wada, Hideki Kumagai, Koji Yokoyama, Takane Ito, Akihiko Miyauchi, Saori Sakamoto, Tomoyuki Imagawa, Janyerkye Tulyeu, Masanori Tanaka, Takanori Yamagata
    Clinical journal of gastroenterology 9 5 302 - 5 2016年10月 [査読有り][通常論文]
     
    5-Aminosalicylic acid preparations have been used as first-line drugs for treatment of ulcerative colitis (UC). However, some patients with UC present with exacerbation of symptoms because of allergy to mesalazine. Diagnosis of mesalazine allergy in active UC may be challenging because its symptoms mimic those of UC. Here we describe a 13-year-old boy with mesalazine allergy who achieved remission when his medication was changed from mesalazine to salazosulfapyridine. During his clinical course mesalazine was prescribed twice, and on each occasion exacerbation of the symptoms occurred. We considered a diagnosis of mesalazine allergy, and this was confirmed by a drug lymphocyte stimulation test; the result for salazosulfapyridine was negative. On the basis of criteria involving simple mucosal biopsy combined with endoscopy for predicting patients with UC who would ultimately require surgery, we considered that the UC in this case might be susceptible to steroid treatment, and we therefore treated the patient with salazosulfapyridine and prednisolone. Shortly afterwards, remission was achieved and the patient has remained in good condition on salazosulfapyridine alone. When treating patients with mesalazine, the possibility of allergy should always be borne in mind, especially when the clinical course is inconsistent with the results of biopsy.
  • Yutaka Inaguma, Ayumi Matsumoto, Mariko Noda, Hidenori Tabata, Akihiko Maeda, Masahide Goto, Daisuke Usui, Eriko F. Jimbo, Kiyoshi Kikkawa, Mamitaro Ohtsuki, Mariko Y. Momoi, Hitoshi Osaka, Takanori Yamagata, Koh-ichi Nagata
    JOURNAL OF NEUROCHEMISTRY 139 2 245 - 255 2016年10月 [査読有り][通常論文]
     
    Class III phosphoinositide 3-kinase (PIK3C3 or mammalian vacuolar protein sorting 34 homolog, Vps34) regulates vesicular trafficking, autophagy, and nutrient sensing. Recently, we reported that PIK3C3 is expressed in mouse cerebral cortex throughout the developmental process, especially at early embryonic stage. We thus examined the role of PIK3C3 in the development of the mouse cerebral cortex. Acute silencing of PIK3C3 with in utero electroporation method caused positional defects of excitatory neurons during corticogenesis. Time-lapse imaging revealed that the abnormal positioning was at least partially because of the reduced migration velocity. When PIK3C3 was silenced in cortical neurons in one hemisphere, axon extension to the contralateral hemisphere was also delayed. These aberrant phenotypes were rescued by RNAiresistant PIK3C3. Notably, knockdown of PIK3C3 did not affect the cell cycle of neuronal progenitors and stem cells at the ventricular zone. Taken together, PIK3C3 was thought to play a crucial role in corticogenesis through the regulation of excitatory neuron migration and axon extension. Meanwhile, when we performed comparative genomic hybridization on a patient with specific learning disorders, a 107 Kb-deletion was identified on 18q12.3 (nt. 39554147-39661206) that encompasses exons 5-23 of PIK3C3. Notably, the above aberrant migration and axon growth phenotypes were not rescued by the disease-related truncation mutant (172 amino acids) lacking the C-terminal kinase domain. Thus, functional defects of PIK3C3 might impair corticogenesis and relate to the pathophysiology of specific learning disorders and other neurodevelopmental disorders.
  • Masahide Goto, Masayo Kagami, Gen Nishimura, Takanori Yamagata
    AMERICAN JOURNAL OF MEDICAL GENETICS PART A 170 9 2483 - 2485 2016年09月 [査読有り][通常論文]
  • Hideki Kumagai, Koji Yokoyama, Tomoyuki Imagawa, Takanori Yamagata
    PEDIATRICS INTERNATIONAL 58 8 714 - 720 2016年08月 [査読有り][通常論文]
     
    BackgroundOnly a handful of studies have investigated children with functional dyspepsia (FD) and irritable bowel syndrome (IBS) classified according to the Rome III criteria, and limited information is available on the lifestyle of affected patients. MethodsWe conducted an Internet questionnaire survey of 2060 parents among the general public in Japan who lived with their children aged 10-15, who were screened for FD and IBS. ResultsThe prevalence of FD and IBS was 2.8% and 6.1%, respectively, and 1.4% of the subjects met the criteria for both FD and IBS. The lifestyles of 155 subjects who met the criteria for FD, IBS, or both were compared with those of 1745 control subjects. In comparison with the controls, a significantly higher percentage of subjects with FD, IBS, or both thought that their sleep was insufficient, ate meals irregularly, were susceptible to stress and to dizziness on standing, had difficulty in getting out of bed or felt sluggish in the morning, had a tendency to faint when standing, and had migraine/chronic headache. ConclusionsChildren with FD and IBS are susceptible to stress, have impaired sleep and eating habits, and have more frequent symptoms of comorbid orthostatic dysregulation and headache.
  • Koji Yokoyama, Tomonori Yano, Hideki Kumagai, Koichi Mizuta, Shigeru Ono, Tomoyuki Imagawa, Hironori Yamamoto, Takanori Yamagata
    JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION 63 1 34 - 40 2016年07月 [査読有り][通常論文]
     
    Objectives: The safety and efficacy of double-balloon enteroscopy (DBE) in pediatric patients has not been well documented. We aimed to evaluate the clinical efficacy and safety of DBE in children, especially those under 10. Methods: We retrospectively analyzed our database of DBE procedures performed between September 2000 and September 2013. Procedures performed in pediatric patients (under 18) were selected from a total of 3980, including double-balloon endoscopic retrograde cholangioscopy (DBERC). Results: Two hundred fifty-seven DBE procedures were performed in 117 pediatric patients (median age 12.5 years). Antegrade (oral-route) DBE was performed in 166 procedures including 104 DBERC procedures (lowest body weight 13.5 kg, youngest age 3 years), and retrograde (anal-route) DBE in 91 (lowest body weight 12.0 kg, youngest age 2 years). The overall diagnostic yield for obscure gastrointestinal bleeding and abdominal pain was 58.8%. The purpose of DBERC was achieved in 76.9% of procedures. The overall complication rate in our series was 5.4% (1.9% with the DBERC cases removed); in patients under 10, it was 10.4% (7/67). No severe complications associated with enteroscope insertion and sedation were observed. Serum amylase levels tended to be elevated in patients who underwent oral-route DBE. Conclusions: DBE is safe and feasible for diagnostic evaluation of small bowel disorders in pediatric patients, even those younger than 10 years. Special attention for possible complications must, however, be paid during therapeutic DBE procedures, including DBERC, especially for patients under 10.
  • Akihiko Miyauchi, Yukifumi Monden, Hitoshi Osaka, Yukitoshi Takahashi, Takanori Yamagata
    Brain & development 38 4 427 - 30 2016年04月 [査読有り][通常論文]
     
    We are reporting on a case of pediatric anti-NMDAR encephalitis with autonomic instability. The patient showed little response to first-line treatment of steroid and IVIG. We initiated plasma exchange, also a first-line treatment. This worsened his autonomic instability, resulting in hypotensive shock. He responded well to rituximab and cyclophosphamide, second-line therapies. Anti-NMDAR encephalitis is often accompanied by autonomic instability. Our and other reported cases, raise the question of plasma exchange as a first-line therapy for pediatric NMDAR encephalitis, which is frequently accompanied by autonomic instability. Plasma exchange should be performed cautiously in such patients.
  • Yutaka Inaguma, Hidenori Ito, Ikuko Iwamoto, Ayumi Matsumoto, Takanori Yamagata, Hidenori Tabata, Koh-ichi Nagata
    MEDICAL MOLECULAR MORPHOLOGY 49 1 28 - 33 2016年03月 [査読有り][通常論文]
     
    The mammalian Class III phosphoinositide 3-kinase (PIK3C3, also known as mammalian vacuolar protein sorting 34 homologue, Vps34) is a regulator of vesicular trafficking, autophagy, and nutrient sensing. In this study, we generated a specific antibody against PIK3C3, and carried out expression and morphological analyses of PIK3C3 during mouse brain development. In Western blotting, PIK3C3 was detected throughout the developmental process with higher expression in the early embryonic stage. In immunohistochemical analyses with embryonic day 16 mouse brain, PIK3C3 was detected strongly in the axon of cortical neurons. While PIK3C3 was distributed at the soma, nucleus, axon, and dendrites in primary cultured mouse hippocampal neurons at 3 days in vitro (div), it was also found in a punctate distribution with partial colocalization with synaptic marker, synaptophysin, at 21 div. The obtained results indicate that PIK3C3 is expressed and may have a physiological role in central nervous system during corticogenesis.
  • Takahiro Kanai, Takane Ito, Jun Odaka, Takashi Saito, Jun Aoyagi, Hiroyuki Betsui, Takanori Yamagata
    EUROPEAN JOURNAL OF PEDIATRICS 175 3 427 - 431 2016年03月 [査読有り][通常論文]
     
    Fabry disease is an X-linked glycosphingolipidosis caused by deficient synthesis of the enzyme alpha-galactosidase A, which results in accumulations of globotriaosylceramide (GL-3) in systemic tissues. Nephropathy is a dominant feature of Fabry disease. It still remains unclear how the nephropathy progresses. Recombinant agalsidase replacement therapy is currently the only approved, specific therapy for Fabry disease. The optimal dose of replacement enzyme also still remains unclear. The worldwide shortage of agalsidase-beta in 2009 forced dose reduction of administration. It showed that the proteinuria emerged like surges, followed by temporary plasma GL-3 elevations in the early stages of classic Fabry disease. Additionally, it also showed that 1 mg/kg of agalsidase-beta every other week could clear the GL-3 accumulations from podocytes and was required to maintain negative proteinuria and normal plasma GL-3 levels. Conclusion: This observation of a young patient with classic Fabry disease about 5 years reveals that the long-term, low-dose agalsidase-beta caused proteinuria surges, but not persistent proteinuria, followed by temporary plasma GL-3 elevations, and agalsidase-beta at 1 mg/kg every other week could clear accumulated GL-3 from podocytes and was required to maintain normal urinalysis and plasma GL-3 levels.
  • Jun Aoyagi, Takahiro Kanai, Takane Ito, Jun Odaka, Takashi Saito, Hiroyuki Betsui, Takanori Yamagata
    Journal of Comprehensive Pediatrics 7 4 2016年 [査読有り][通常論文]
     
    Background: We evaluated the effect of glucocorticoids (GCs) on bone strength via bone mineral density (BMD) scores and serum alkaline phosphatase (S-ALP) levels in children with idiopathic steroid-sensitive nephrotic syndrome (ISSNS) or IgA nephropathy (IgAN). Methods: Sixteen children with ISSNS and 13 with IgAN were eligible for this study. The BMD and S-ALP levels were measured before the initiation of steroid treatment (STx), one month after initiation of STx and one month after terminating STx (Phases 0, 1 and 2). For IgAN, scores and levels were measured before the initiation of STx (Phase 0) and 1, 3, 6, and 12 months after the initiation of STx (Phases 1, 2, 3, and 4). Results: In ISSNS, the BMD and S-ALP levels were significantly lower in Phase 1 than in Phase 0 however, scores and levels returned to baseline in Phase 2. In IgAN, BMD was significantly lower in Phase 2 than in Phase 0 while S-ALP levels were significantly lower in Phases 1, 2, and 3 compared to Phase 0. No significant difference was observed between Phase 0 and Phase 4. Conclusions: In ISSNS, bone strength recovered one month after terminating STx. In IgAN, bone strength recovered 10 months after tapering of STx.
  • Zhiliang Yang, Ayumi Matsumoto, Kazuhiro Nakayama, Eriko F. Jimbo, Karin Kojima, Koh-ichi Nagata, Sadahiko Iwamoto, Takanori Yamagata
    BRAIN & DEVELOPMENT 38 1 91 - 99 2016年01月 [査読有り][通常論文]
     
    Background: The genetic background of autism spectrum disorder (ASD) is considered a multi-genetic disorder with high heritability. Autistic children present with a higher prevalence of sleep disorders than has been observed in children with normal development. Some circadian-relevant genes have been associated with ASD (e.g., PER1, PER2, NPAS2, MTNR1A, and MTNR1B). Methods: We analyzed 28 ASD patients (14 with sleep disorders and 14 without) and 23 control subjects of Japanese descent. The coding regions of 18 canonical clock genes and clock-controlled genes were sequenced. Detected mutations were verified by direct sequencing analysis, and additional control individuals were screened. Results: Thirty-six base changes with amino acid changes were detected in 11 genes. Six missense changes were detected only in individuals with ASD with sleep disturbance: p.F498S in TIMELESS, p.S20R in NR1D1, p.R493C in PER3, p.H542R in CLOCK, p.L473S in ARNTL2; and p.A325V in MTNR1B. Six missense changes were detected only in individuals with ASD without sleep disturbance: p.S1241N in PER1, p.A325T in TIMELESS, p.S13T in ARNTL, p.G24E in MTNR1B, p.G24E in PER2, and p.T1177A in PER3. The p.R493C mutation in PER3 was detected in both groups. One missense change, p.P932L in PER2, was detected only in the control group. Mutations in NR1D1, CLOCK, and ARNTL2 were detected only in individuals with ASD with sleep disorder. The prevalence of the mutations detected only single time differed significantly among all ASD patients and controls (p = 0.003). Two kinds of mutations detected only in individuals with ASD with sleep disorder, p.F498S in TIMELESS and p.R366Q in PER3, were considered to affect gene function by three different methods: PolyPhen-2, scale-invariant feature transform (SIFT) prediction, and Mutation Taster (wwvv.mutationtaster.org). The mutations p.S20R in NR1D1, p.H542R in CLOCK, p.L473S in ARNTL2, p.A325T in TIMELESS, p.S13T in ARNTL, and p.G24E in PER2 were diagnosed to negatively affect gene function by more than one of these methods. Conclusion: Mutations in circadian-relevant genes affecting gene function are more frequent in patients with ASD than in controls. Circadian-relevant genes may be involved in the psychopathology of ASD. (c) 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
  • Hirotomo Saitsu, Ryoko Fukai, Bruria Ben-Zeev, Yasunari Sakai, Masakazu Mimaki, Nobuhiko Okamoto, Yasuhiro Suzuki, Yukifumi Monden, Hiroshi Saito, Barak Tziperman, Michiko Torio, Satoshi Akamine, Nagahisa Takahashi, Hitoshi Osaka, Takanori Yamagata, Kazuyuki Nakamura, Yoshinori Tsurusaki, Mitsuko Nakashima, Noriko Miyake, Masaaki Shiina, Kazuhiro Ogata, Naomichi Matsumoto
    European journal of human genetics : EJHG 24 1 129 - 34 2016年01月 [査読有り][通常論文]
     
    De novo GNAO1 variants have been found in four patients including three patients with Ohtahara syndrome and one patient with childhood epilepsy. In addition, two patients showed involuntary movements, suggesting that GNAO1 variants can cause various neurological phenotypes. Here we report an additional four patients with de novo missense GNAO1 variants, one of which was identical to that of the previously reported. All the three novel variants were predicted to impair Gαo function by structural evaluation. Two patients showed early-onset epileptic encephalopathy, presenting with migrating or multifocal partial seizures in their clinical course, but the remaining two patients showed no or a few seizures. All the four patients showed severe intellectual disability, motor developmental delay, and involuntary movements. Progressive cerebral atrophy and thin corpus callosum were common features in brain images. Our study demonstrated that GNAO1 variants can cause involuntary movements and severe developmental delay with/without seizures, including various types of early-onset epileptic encephalopathy.
  • Hideki Kumagai, Koji Yokoyama, Tomoyuki Imagawa, Shun Inoue, Janyerkye Tulyeu, Mamoru Tanaka, Takanori Yamagata
    Pediatric Gastroenterology, Hepatology and Nutrition 19 3 214 - 220 2016年 [査読有り][通常論文]
     
    Fecal microbiota transplantation (FMT) is a treatment designed to correct gut dysbiosis by administration of feces from a healthy volunteer. It is still unclear whether FMT for children with ulcerative colitis (UC) is effective or hazardous. Here we describe a young patient to have received FMT for UC. A three-year-old girl was admitted to our hospital with severe active UC, and treated with aminosalicylates and various immunosuppressive drugs. As remission was not achieved, we decided to try FMT before colectomy. We administered donor fecal material a total of six times by retention enema (×2) and via a nasoduodenal tube (×4) within 10 days. The patient developed abdominal pain and pyrexia after each FMT session. Analyses revealed the transferred donor fecal microbiota had not been retained by the patient, who ultimately underwent colectomy. The severity of the UC and/or timing of FMT may have partly accounted for the poor outcome.
  • Hironori Shimozawa, Yumi Kono, Miyuki Matano, Yume Suzuki, Yasunori Koike, Yukari Yada, Takanori Yamagata, Naoto Takahashi
    PEDIATRICS INTERNATIONAL 57 6 1211 - 1214 2015年12月 [査読有り][通常論文]
     
    We studied the cytokine profile of two siblings with neonatal lupus erythematosus (NLE) born to a mother positive for serum anti-Ro and -La antibodies, who did not receive any medication during the two pregnancies. The first sibling was found to have complete atrioventricular block in utero and became severely ill after birth. He fulfilled the diagnostic criteria for hemophagocytic lymphohistiocytosis on day 2. The second sibling did not have any fetal symptoms. He was generally stable after birth, but with typical skin rash. Laboratory data suggested that they both had hypercytokinemia during the neonatal period, requiring corticosteroid treatment. Interleukin (IL)-6, interferon-gamma, IL-8 and monocyte chemotactic protein-1 were elevated in both cases, while IL-12, IL-13 and IL-17 were elevated only in the second sibling. Comparison of the cytokine profiles suggests the potential roles of different cytokines in the onset and clinical manifestations of NLE.
  • Ryou Kawamata, Koji Yokoyama, Miori Sato, Masahide Goto, Yasuyuki Nozaki, Takeshi Takagi, Hideki Kumagai, Takanori Yamagata
    JOURNAL OF INFECTION AND CHEMOTHERAPY 21 11 783 - 789 2015年11月 [査読有り][通常論文]
     
    Introduction: Patients with severe mycoplasma pneumonia having very high serum interleukin-18 levels may require systemic corticosteroid treatment. However, we know of no laboratory markers that have been identified to assess the precise severity of Mycoplasma pneumoniae pneumonia. Thus, we investigated the usefulness of four clinical laboratory tests as severity indicators and surrogate markers for initiation of steroid therapy in these patients. Patients and methods: For 22 Japanese children (including 3 patients who needed systemic corticosteroid therapy) diagnosed with Mycoplasma pneumoniae pneumonia, white blood cell counts and serum concentrations of interleukin-18, C-reactive protein, lactate dehydrogenase, and ferritin were determined in the acute and recovery phases. Results: In total, 8 and 14 patients were classified as moderate and mild pneumonia, respectively, according to clinical manifestations. The serum interleukin-18 level in the acute phase of the pneumonia group was significantly higher than that of age-matched controls. Furthermore, serum interleukin-18, lactate dehydrogenase and ferritin levels in the acute phase increased in parallel with the severity of the pneumonia. The serum ferritin level was also higher in the acute phase than in the recovery phase. Positive correlations between the levels of serum interleukin-18, lactate dehydrogenase and ferritin were observed in the acute phase. Conclusions: Serum lactate dehydrogenase and ferritin levels may be useful as indicators of the severity of pediatric Mycoplasma pneumoniae pneumonia for initiation of corticosteroid therapy. (C) 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
  • Sachie Nakamura, Hitoshi Osaka, Shinichi Muramatsu, Shiho Aoki, Eriko F. Jimbo, Takanori Yamagata
    MOLECULAR GENETICS AND METABOLISM 116 3 157 - 162 2015年11月 [査読有り][通常論文]
     
    Objective: We investigated a correlation between a mutation in the SLC2A1 gene and functional disorders in Glucose transporter I deficiency syndrome (GLUT1DS). Methods: We performed direct sequence analysis of SLC2A1 in a severe GLUT1DS patient and identified a novel frame shift mutation, c.906_907insG, p.V303fs. We created a plasmid vector carrying the c.906_907insG mutation, as well as A405D or R333W in the SLC2A1, which are found in patients with mild and moderate GLUT1DS severity, respectively. We transiently expressed these mutants and wild type SLC2A1 plasmids in a human embryonic kidney cell line (HEK293), and performed immunoblotting, immunofluorescence, and enzymatic photometric 2-deoxyglucose (2DG) uptake assays. Results: GLUT1 was not detected after transient expression of the SLC2A1 plasmid carrying c.906_907insG by either immunoblotting or immunofluorescence. The degree of glucose transport reduction as determined by enzymatic photometric 2DG assay uptake correlated with disease severity. Conclusions: Enzymatic photometric 2DG uptake study appears to be a suitable functional assay to predict the effect of SLC2A1 mutations on GLUT1 transport. (C) 2015 Elsevier Inc. All rights reserved.
  • Hiroko Tada, Jun-ichi Takanashi, Hideo Okuno, Masaya Kubota, Takanori Yamagata, Gou Kawano, Takashi Shiihara, Shin-ichiro Hamano, Shinichi Hirose, Takuya Hayashi, Hitoshi Osaka, Masashi Mizuguchi
    JOURNAL OF THE NEUROLOGICAL SCIENCES 358 1-2 62 - 65 2015年11月 [査読有り][通常論文]
     
    Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) at onset manifests an early seizure (ES) usually lasting more than 30 min. Following ES, some patients exhibit almost clear consciousness with no neurological symptoms, and no MRI abnormality for a few days, which may lead to an initial misdiagnosis of prolonged febrile seizures (PFS). To allow an early diagnosis of AESD, we retrospectively analyzed clinical manifestations, laboratory data, and radiologic and EEG findings in patients with AESD (n = 62) having ES of over 30 min, and ones with PFS (n = 54), using logistic regression analyses. Multivariate logistic regression analysis revealed that an age below 1.5 years and a Glasgow Coma Scale score of 14 or less than 14 (Japan Coma Scale score of 1 or higher) were high risk factors of developing AESD. We proposed an AESD prediction score system consisting of consciousness level, age, duration of convulsions, enforcement of mechanical intubation, and aspartate aminotransferase, blood glucose and creatinine levels (full score: 9), the mean scores in AESD and PFS being 5.9 and 1.8, which were significantly different (p < 0.001). We herein propose a scoring system for differentiating patients with AESD and PFS around the time of ES (score of 4 or more than 4 suggesting AESD), which may contribute to early therapeutic intervention and an improved neurologic outcome. (C) 2015 Elsevier B.V. All rights reserved.
  • Matsumoto A, Yamagata T
    No to hattatsu = Brain and development 47 6 413 - 414 2015年11月 [査読有り][通常論文]
  • Jun Odaka, Takahiro Kanai, Takane Ito, Takashi Saito, Jun Aoyagi, Yoshihiko Ueda, Takanori Yamagata
    PEDIATRICS INTERNATIONAL 57 4 777 - 780 2015年08月 [査読有り][通常論文]
     
    A 10-year-old girl presented with mild proteinuria and hypertension. Laboratory data indicated slightly elevated serum creatinine (0.67mg/dL) and elevated serum IgG (2111mg/dL). On renal arteriography mild stenosis over the entire length of the right renal artery and irregular stenosis of the interlobar arteries in the right kidney were seen. She was diagnosed with renovascular hypertension, and received conventional anti-hypertensive therapy, but did not respond to them. The right kidney had atrophy and dysfunction on technetium-99m-labeled dimercaptosuccinic acid renal scintigraphy, and was therefore resected. Histopathology of the kidney indicated severe necrotizing granulomatous vasculitis affecting the arteries from the renal hilus to the interlobar area. After nephrectomy plus steroid pulse therapy, blood pressure and urinary protein returned to normal. To our knowledge, this is the first report of necrotizing granulomatous vasculitis limited to the medium-sized renal arteries.
  • Makiko Saitoh, Mayu Shinohara, Atsushi Ishii, Yukiko Ihara, Shinichi Hirose, Masashi Shiomi, Hisashi Kawawaki, Masaya Kubota, Takanori Yamagata, Akie Miyamoto, Gaku Yamanaka, Kaoru Amemiya, Kenjiro Kikuchi, Atsushi Kamei, Manami Akasaka, Yuki Anzai, Masashi Mizuguchi
    BRAIN & DEVELOPMENT 37 5 463 - 470 2015年05月 [査読有り][通常論文]
     
    Background: Theophylline has recently been suspected as a risk factor of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), although there has been no systematic study on the relationship between acute encephalopathy in children taking theophylline (AET) and AESD. Methods: We recruited 16 Japanese patients (11 male and 5 female, median age of 2 years and 7 months) with AET from 2008 to 2013. We evaluated their clinical features, such as the duration of first seizure, biphasic clinical course and cranial CT/MRI imaging and compared them with those of AESD. We analyzed the polymorphisms or mutations of genes which are associated with AESD. Results: Clinically, 12 patients had neurological and/or radiological features of AESD. Only one patient died, whereas all 15 surviving patients were left with motor and/or intellectual deficits. Genetically, 14 patients had at least one of the following polymorphisms or mutations associated with AESD: thennolabile variation of the carnitine palmitoyltransferase 2 (CPT2) gene, polymorphism causing high expression of the adenosine receptor A2A (ADORA2A) gene, and heterozygous missense mutation of the voltage gated sodium channel 1A (SCN1A) and 2A (SCN2A) gene. Conclusions: Our results demonstrate that AET overlaps with AESD, and that AET is a multifactorial disorder sharing a genetic background with AESD. (C) 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
  • Odaka J, Kanai T, Ito T, Saito T, Aoyagi J, Betsui H, Oda T, Ueda Y, Yamagata T
    CEN case reports 4 1 112 - 116 2015年05月 [査読有り][通常論文]
  • Yutaka Inaguma, Hidenori Ito, Akira Hara, Ikuko Iwamoto, Ayumi Matsumoto, Takanori Yamagata, Hidenori Tabata, Koh-ichi Nagata
    NEUROSCIENCE RESEARCH 92 21 - 28 2015年03月 [査読有り][通常論文]
     
    Timeless was originally identified in Drosophila as an essential component of circadian cycle regulation. In mammals, the ortholog of Timeless (Tim) has also implicated in cell cycle control and embryonic development. In this study, we generated a specific antibody against Tim, and carried out expression and localization analyses of Tim during mouse brain development. In Western blotting, Tim was detected throughout the developmental stage. In immunohistochemical analyses, Tim was detected strongly in neurons in the ventricular zone/subventricular zone and moderately in cortical neurons during corticogenesis. In adult mouse brain, Tim was observed moderately in cortical neurons. Notably, Tim was enriched in the nucleus of cortical neurons from embryonic to early postnatal stages while it was distributed in the cytoplasm in the adult stage. Similar distribution change from nucleus to cytoplasm was observed in the hippocampal neurons between PO and P30. In situ hybridization revealed that the tissue expression profile of Tim-mRNA was similar to that of the protein. In differentiated primary cultured mouse hippocampal neurons, Tim was detected in cell body, axon and dendrites. The obtained results suggest that Tim is expressed in neuronal tissues in a spatiotemporally regulated manner and involved in developmental stage-specific neuronal functions. (C) 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
  • Eriko Fujita-Jimbo, Yuko Tanabe, Zhiling Yu, Karin Kojima, Masato Mori, Hong Li, Sadahiko Iwamoto, Takanori Yamagata, Mariko Y. Momoi, Takashi Momoi
    MOLECULAR AUTISM 6 17  2015年03月 [査読有り][通常論文]
     
    Background: Autism spectrum disorder (ASD) has a complex genetic etiology. Some symptoms and mutated genes, including neuroligin (NLGN), neurexin (NRXN), and SH3 and multiple ankyrin repeat domains protein (SHANK), are shared by schizophrenia and ASD. Little is known about the molecular pathogenesis of ASD. One of the possible molecular pathogenesis is an imbalance of excitatory and inhibitory receptors linked with the NLGN-PSD-95-SHANK complex via postsynaptic density protein/Drosophila disc large tumor suppressor/zonula occludens-1 protein (PDZ) binding. In the present study, we focused on GPR85 as a candidate gene for ASD because the C-terminal amino acid sequence of GPR85 [Thr-Cys-Val-Ile (YCVI)] is classified as a type II PDZ-binding motif, and GPR85 is a risk factor for schizophrenia. GPR85 is an orphan receptor that regulates neural and synaptic plasticity and modulates diverse behaviors, including learning and memory. While searching for molecules that associate with GPR85, we found that GPR85 was associated with postsynaptic density protein (PSD)-95 linked with NLGN in the brain. Methods: We examined the proteins that associate with the C-terminal sequence of GPR85 by pull-down assay and immunoblot analysis and searched for a mutation of the GPR85 gene in patients with ASD. We used immunostaining to examine the intracellular localization of mutated GPR85 and its influence on the morphology of cells and neurons. Results: The C-terminal sequence of GPR85 interacted with PSD-95 at PDZ1, while NLGN interacted with PSD-95 at PDZ3. Two male patients with ASD from independent Japanese families possessed inherited missense mutations at conserved sites in GPR85: one had T1033C (M152T) and the other had G1239T (V221L). These mutations were located in a domain related to G protein interaction and signal transduction. In contrast to wild-type GPR85, mutated GPR85 was more preferentially accumulated, causing endoplasmic reticulum stress, and disturbed the dendrite formation of hippocampal neurons. Conclusions: GPR85 associated with the PSD-95 linked with NLGN, which is related to ASD. GPR85 carrying the mutations detected in ASD patients disturbed dendrite formation that could be the candidate for molecular pathogenesis of ASD through the associated NLGN-PSD-95 receptor complex.
  • Acute encephalopathy with callosal, subcortical and thalamic lesions
    Yuko Nakano, Yukifumi Monden, Masashi Mizuguchi, Masako Nagashima, Yasunori Koike, Yuji Gunji, Naoto Takahashi, Hideo Sugie, MarikoY. Momoi, Takanori Yamagata
    Neurology Asia 20 1 85 - 89 2015年03月 [査読有り][通常論文]
  • Takahiro Kanai, Takanori Yamagata, Takane Ito, Jun Odaka, Takashi Saito, Jun Aoyagi, Mariko Y. Momoi
    CLINICAL AND EXPERIMENTAL NEPHROLOGY 19 1 107 - 113 2015年02月 [査読有り][通常論文]
     
    Various humoral factors have been proposed as causal agents of idiopathic steroid-sensitive nephrotic syndrome (ISSNS), resulting in varying data. We used mass spectrometry (MS) to analyze serum proteins in a search for proteins that might be involved in ISSNS pathophysiology. Serial serum samples were obtained from 33 children with ISSNS. Samples were collected during Phase A1 [the acute phase prior to steroid treatment (STx)], Phase A2 (remission with STx), and Phase A3 (remission without any medication). We also included age- and sex-matched two control groups comprising children with normal urinalysis (Group B) and children with a nephrotic syndrome other than ISSNS (Group C). The urinary protein/urinary creatinine (UP/UCr) ratios were not statistically different between Phase A1 and Group C. Samples were analyzed using surface-enhanced laser desorption/ionization time of flight MS. A total of 207 peptide ion peaks were detected in the range of m/z 2000-10000. Four peptide ions (m/z 6444, 6626, 8695, and 8915) were detected at significant elevation during Phase A1 compared with Phase A2, Phase A3, and Group C. The intensities of m/z 6444 and 8695 were higher in Phase A3 than in Group B. There were significant correlations between the intensities of m/z 6626, 8695, and 8915 and UP/UCr levels. The m/z 8695 was identified as apolipoprotein AII. Apolipoprotein AII was detected as a protein associated with the UP/UCr levels in pediatric ISSNS. Our findings present an interesting starting point for further investigation into the pathophysiology of ISSNS.
  • Jun Odaka, Takahiro Kanai, Ritei Uehara, Eiji Kusano, Takanori Yamagata
    CLINICAL AND EXPERIMENTAL NEPHROLOGY 19 1 146 - 147 2015年02月 [査読有り][通常論文]
  • Makoto Mizuno, Ayumi Matsumoto, Nanako Hamada, Hidenori Ito, Akihiko Miyauchi, Eriko F. Jimbo, Mariko Y. Momoi, Hidenori Tabata, Takanori Yamagata, Koh-ichi Nagata
    JOURNAL OF NEUROCHEMISTRY 132 1 61 - 69 2015年01月 [査読有り][通常論文]
     
    Using comparative genomic hybridization analysis for an autism spectrum disorder (ASD) patient, a 73-Kb duplication at 19q13.33 (nt. 49562755-49635956) including LIN7B and 5 other genes was detected. We then identified a novel frameshift mutation in LIN7B in another ASD patient. Since LIN7B encodes a scaffold protein essential for neuronal function, we analyzed the role of Lin-7B in the development of cerebral cortex. Acute knockdown of Lin-7B with in utero electroporation caused a delay in neuronal migration during corticogenesis. When Lin-7B was knocked down in cortical neurons in one hemisphere, their axons failed to extend efficiently into the contralateral hemisphere after leaving the corpus callosum. Meanwhile, enhanced expression of Lin-7B had no effects on both cortical neuron migration and axon growth. Notably, silencing of Lin-7B did not affect the proliferation of neuronal progenitors and stem cells. Taken together, Lin-7B was found to play a pivotal role in corticogenesis through the regulation of excitatory neuron migration and interhemispheric axon growth, while further analyses are required to directly link functional defects of Lin-7B to ASD pathophysiology.
  • Matsumoto A, Nozaki Y, Minami T, Jimbo EF, Shiraishi H, Yamagata T
    Human genome variation 2 15015  2015年 [査読有り][通常論文]
  • Yukifumi Monden, Ippeita Dan, Masako Nagashima, Haruka Dan, Minako Uga, Takahiro Ikeda, Daisuke Tsuzuki, Yasushi Kyutoku, Yuji Gunji, Daisuke Hirano, Takamichi Taniguchi, Hideo Shimoizumi, Eiju Watanabe, Takanori Yamagata
    NeuroImage. Clinical 9 1 - 12 2015年 [査読有り][通常論文]
     
    While a growing body of neurocognitive research has explored the neural substrates associated with attention deficit hyperactive disorder (ADHD), an objective biomarker for diagnosis has not been established. The advent of functional near-infrared spectroscopy (fNIRS), which is a noninvasive and unrestrictive method of functional neuroimaging, raised the possibility of introducing functional neuroimaging diagnosis in young ADHD children. Previously, our fNIRS-based measurements successfully visualized the hypoactivation pattern in the right prefrontal cortex during a go/no-go task in ADHD children compared with typically developing control children at a group level. The current study aimed to explore a method of individual differentiation between ADHD and typically developing control children using multichannel fNIRS, emphasizing how spatial distribution and amplitude of hemodynamic response are associated with inhibition-related right prefrontal dysfunction. Thirty ADHD and thirty typically developing control children underwent a go/no-go task, and their cortical hemodynamics were assessed using fNIRS. We explored specific regions of interest (ROIs) and cut-off amplitudes for cortical activation to distinguish ADHD children from control children. The ROI located on the border of inferior and middle frontal gyri yielded the most accurate discrimination. Furthermore, we adapted well-formed formulae for the constituent channels of the optimized ROI, leading to improved classification accuracy with an area under the curve value of 85% and with 90% sensitivity. Thus, the right prefrontal hypoactivation assessed by fNIRS would serve as a potentially effective biomarker for classifying ADHD children at the individual level.
  • 木村 岳人, 横山 孝二, 熊谷 秀規, 今川 智之, 山形 崇倫
    日本小児栄養消化器肝臓学会雑誌 28 2 90 - 95 日本小児栄養消化器肝臓学会 2014年12月 [査読有り][通常論文]
     
    我々は、頻回に再発したステロイド依存性潰瘍性大腸炎(UC)の小児に対して、タクロリムス(TAC)による寛解導入を行い、引き続き同薬で約4年間にわたり寛解維持療法を継続している。本例は7歳時にUCと診断し、サラゾスルファピリジンで寛解導入後、維持治療を行った。8歳時に再燃したため顆粒球吸着療法を行い一旦軽快したが、間もなく再燃したためプレドニゾロン(PSL)を用いて再度寛解導入を行った。その後、アザチオプリンを併用したがPSL減量中に2回再燃したため、10歳時にはシクロスポリン持続静注を施行して寛解導入した。11歳時、PSLを減量中止後に6回目の再燃をした。この時点でステロイド総使用量はPSL換算で約10gとなったため、TACで寛解導入を行い、そのまま維持療法を施行している。TACの血中トラフ濃度は3〜5ng/ml程度で臨床的寛解及び大腸粘膜治癒が得られており、現在まで有害事象は認めない。TACは小児の難治性UCに対する寛解維持療法のひとつとして期待できる可能性がある。(著者抄録)
  • Hideki Kumagai, Koji Yokoyama, Kimito Katsuyama, Shoji Hara, Hiroaki Yamamoto, Takanori Yamagata, Nobuyuki Taniguchi, Norio Hirota, Kouichi Itoh
    ULTRASOUND IN MEDICINE AND BIOLOGY 40 10 2499 - 2507 2014年10月 [査読有り][通常論文]
     
    The speed of sound correlates well with the fat content of the liver. Therefore, non-invasive quantification of sound speed in the liver might be of diagnostic value. Here we describe a new non-invasive method that would be clinically applicable for measurement of sound speed in the liver. Sprague-Dawley rats were divided into two groups: a control group and a fatty liver group prepared by keeping the rats on a choline-deficient diet for 6 wk. The livers were subjected to pathologic and biochemical analysis; the speed of sound through the liver tissue was measured using our proposed method and a pulser-receiver as standard. Our results indicated that use of the proposed method makes it feasible to diagnose fatty liver with good accuracy on the basis of sound speed. This approach would have considerable potential for non-invasive diagnosis of fatty liver and would be a valuable adjunct to conventional liver diagnostic procedures. (C) 2014 World Federation for Ultrasound in Medicine & Biology.
  • Masako Nagashima, Yukifumi Monden, Ippeita Dan, Haruka Dan, Tsutomu Mizutani, Daisuke Tsuzuki, Yasushi Kyutoku, Yuji Gunji, Daisuke Hirano, Takamichi Taniguchi, Hideo Shimoizumi, Mariko Y Momoi, Takanori Yamagata, Eiju Watanabe
    Neurophotonics 1 2 025007 - 025007 2014年10月 [査読有り][通常論文]
     
    The current study aimed to explore the neural substrate for atomoxetine effects on attentional control in school-aged children with attention deficit hyperactivity disorder (ADHD) using functional near-infrared spectroscopy (fNIRS), which can be applied to young children with ADHD more easily than conventional neuroimaging modalities. Using fNIRS, we monitored the oxy-hemoglobin signal changes of 15 ADHD children (6 to 14 years old) performing an oddball task before and 1.5 h after atomoxetine or placebo administration, in a randomized, double-blind, placebo-controlled, crossover design. Fifteen age-, gender-, and intelligence quotient-matched normal controls without atomoxetine administration were also monitored. In the control subjects, the oddball task recruited the right prefrontal and inferior parietal cortices. The right prefrontal and parietal activation was normalized after atomoxetine administration in ADHD children. This was in contrast to our previous study using a similar protocol showing methylphenidate-induced normalization of only the right prefrontal function. fNIRS allows the detection of differential neuropharmacological profiles of both substances in the attentional network: the neuropharmacological effects of atomoxetine to upregulate the noradrenergic system reflected in the right prefrontal and inferior parietal activations and those of methylphenidate to upregulate the dopamine system reflected in the prefrontal cortex activation.
  • Hideki Kumagai, Koji Yokoyama, Wakamichi Shimamura, Yoshimasa Miura, Takanori Yamagata
    PEDIATRICS INTERNATIONAL 56 4 654 - 654 2014年08月 [査読有り][通常論文]
  • Masako Nagashima, Yukifumi Monden, Ippeita Dan, Haruka Dan, Daisuke Tsuzuki, Tsutomu Mizutani, Yasushi Kyutoku, Yuji Gunji, Mariko Y Momoi, Eiju Watanabe, Takanori Yamagata
    Neurophotonics 1 1 015001 - 015001 2014年07月 [査読有り][通常論文]
     
    The current study aimed to explore the neural substrate for methylphenidate effects on attentional control in school-aged children with attention deficit hyperactivity disorder (ADHD) using functional near-infrared spectroscopy (fNIRS), which can be applied to young children with ADHD more easily than conventional neuroimaging modalities. Using fNIRS, we monitored the oxy-hemoglobin signal changes of 22 ADHD children (6 to 14 years old) performing an oddball task before and 1.5 h after methylphenidate or placebo administration, in a randomized, double-blind, placebo-controlled, crossover design. Twenty-two age- and gender-matched normal controls without methylphenidate administration were also monitored. In the control subjects, the oddball task recruited the right prefrontal and inferior parietal cortices, and this activation was absent in premedicated ADHD children. The reduced right prefrontal activation was normalized after methylphenidate but not placebo administration in ADHD children. These results are consistent with the neuropharmacological effects of methylphenidate to upregulate the dopamine system in the prefrontal cortex innervating from the ventral tegmentum (mesocortical pathway), but not the noradrenergic system from the parietal cortex to the locus coeruleus. Thus, right prefrontal activation would serve as an objective neurofunctional biomarker to indicate the effectiveness of methylphenidate on ADHD children in attentional control. fNIRS monitoring enhances early clinical diagnosis and the treatment of ADHD children, especially those with an inattention phenotype.
  • 急性腎障害を合併した低力価寒冷凝集素症の小児例
    池田 貴江, 伊東 岳峰, 熊谷 秀規, 別井 広幸, 斉藤 洋, 川原 勇太, 小高 淳, 金井 孝裕, 森本 哲, 山形 崇倫
    日本小児腎不全学会雑誌 34 47 - 49 日本小児腎不全学会 2014年07月 [査読有り][通常論文]
     
    症例は4歳男児で、発熱、黄疸、腎機能障害を主訴に、精査加療目的で当科紹介転院となった。検査所見では溶血性貧血、血小板の軽度減少、FDPおよびD-dimerの著明高値、腎機能障害、肉眼的血尿、尿潜血3+、β2MG高値を認めた。直接クームス試験は抗C3d血清で陽性、間接クームス試験は陰性で、寒冷凝集素価は256倍であった。以上より、急性腎障害を合併した低力価寒冷凝集素症と診断し、保温と寒冷刺激回避で対応し、水溶性プレドニンの静注を3日間行い、漸減中止した。さらに輸血、ハプトグロビンの静注、輸液、フロセミド静注、炭酸水素ナトリウム静注などの保存的治療を行ったところ軽快が得られ、腎機能も正常化し、転院20日目に退院となった。
  • Noriko Okamoto, Takanori Yamagata, Yukari Yada, Ko Ichihashi, Naomichi Matsumoto, Mariko Y. Momoi, Takeshi Mizuguchi
    BRAIN & DEVELOPMENT 36 6 523 - 527 2014年06月 [査読有り][通常論文]
     
    Williams-Beuren syndrome (WBS) is a multisystemic genetic disorder caused by a contiguous gene deletion at 7q11.23. We report a severely affected WBS patient with cerebral and cerebellar dysplasia as well as hypertrophic cardiomyopathy. Microarray comparative genomic hybridization (aCGH) detected a deletion on 7q11.23 expanding from RP11-614D7 to RP11-137E8, which is a typical deletion in WBS. To the best of our knowledge, this is the first case report of a WBS patient with severe congenital central nervous system anomaly and progressive hypertrophic cardiomyopathy. The relationship between the genes deleted in WBS and a CNS anomaly plus hypertrophic cardiomyopathy requires further analysis. (C) 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
  • Akihiko Miyauchi, Yukifumi Monden, Meri Watanabe, Hideo Sugie, Mitsuya Morita, Takeshi Kezuka, Mariko Momoi, Takanori Yamagata
    NEUROPEDIATRICS 45 3 196 - 199 2014年06月 [査読有り][通常論文]
     
    We report the case of a 5-year-old Japanese girl who initially had acute disseminated encephalomyelitis (ADEM) and was positive for the myelin oligodendrocyte glycoprotein (MOG) antibodies and developed unilateral optic neuritis (ON) 71 days after ADEM onset. The patient's serum was positive for the anti-MOG antibodies from the onset of ADEM to the development of ON. This phenotype has been reported in only two previous articles, and the specific mechanism of action of the anti-MOG antibodies is not yet understood. Our case suggests that the anti-MOG antibody can be associated with the pathogenesis of ADEM followed by ON. Thus, patients with ADEM who test positive for the anti-MOG antibody may be at risk of developing subsequent ON.
  • Jun Aoyagi, Jun Odaka, Yuri Kuroiwa, Naomi Nakashima, Takane Ito, Takashi Saito, Takahiro Kanai, Takanori Yamagata, Mariko Y. Momoi
    PEDIATRICS INTERNATIONAL 56 3 e4 - e6 2014年06月 [査読有り][通常論文]
     
    It has been established that enhanced computed tomography (CT) and 99mTc-dimercaptosuccinic acid renal scintigraphy (99mTc-DMSA scintigraphy) used in conjunction with single-photon emission CT is a useful tool for the diagnosis of acute pyelonephritis (APN). The utility of non-enhanced magnetic resonance imaging (MRI), however, has not been investigated extensively for the diagnosis of APN or renal abscess in children. We describe the case of a 23-month-old boy with suspected APN who received non-enhanced MRI. Whole body diffusion-weighted imaging (DWI) was used, and a background body-signal suppression sequence was applied. High-intensity focal lesions were identified on DWI and low-intensity lesions on the apparent diffusion coefficient map in the acute phase. This case suggested that non-enhanced MRI could be a useful tool for the diagnosis of APN in children, because it can avoid the risks of not only radiation exposure but also nephrogenic systemic fibrosis associated with gadolinium-based contrast agents, especially in infants.
  • Natsumi Uehara, Masato Mori, Yoshimi Tokuzawa, Yosuke Mizuno, Shunsuke Tamaru, Masakazu Kohda, Yohsuke Moriyama, Yutaka Nakachi, Nana Matoba, Tetsuro Sakai, Taro Yamazaki, Hiroko Harashima, Kei Murayama, Keisuke Hattori, Jun-Ichi Hayashi, Takanori Yamagata, Yasunori Fujita, Masafumi Ito, Masashi Tanaka, Ken-ichi Nibu, Akira Ohtake, Yasushi Okazaki
    ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY 1 5 361 - 369 2014年05月 [査読有り][通常論文]
     
    Objective: Mitochondrial respiratory chain disorder (MRCD) is an intractable disease of infants with variable clinical symptoms. Our goal was to identify the causative mutations in MRCD patients. Methods: The subjects were 90 children diagnosed with MRCD by enzyme assay. We analyzed whole mitochondrial DNA (mtDNA) sequences. A cybrid study was performed in two patients. Whole exome sequencing was performed for one of these two patients whose mtDNA variant was confirmed as non-pathogenic. Results: Whole mtDNA sequences identified 29 mtDNA variants in 29 patients (13 were previously reported, the other 13 variants and three deletions were novel). The remaining 61 patients had no pathogenic mutations in their mtDNA. Of the 13 patients harboring unreported mtDNA variants, we excluded seven variants by manual curation. Of the remaining six variants, we selected two Leigh syndrome patients whose mitochondrial enzyme activity was decreased in their fibroblasts and performed a cybrid study. We confirmed that m.14439G>A (MT-ND6) was pathogenic, while m.1356A>G (mitochondrial 12S rRNA) was shown to be a non-pathogenic polymorphism. Exome sequencing and a complementation study of the latter patient identified a novel c.55C>T hemizygous missense mutation in the nuclear-encoded gene NDUFA1. Interpretation: Our results demonstrate that it is important to perform whole mtDNA sequencing rather than only typing reported mutations. Cybrid assays are also useful to diagnose the pathogenicity of mtDNA variants, and whole exome sequencing is a powerful tool to diagnose nuclear gene mutations as molecular diagnosis can provide a lead to appropriate genetic counseling.
  • Ayumi Matsumoto, Makoto Mizuno, Nanako Hamada, Yasuyuki Nozaki, Eriko F. Jimbo, Mariko Y. Momoi, Koh-ichi Nagata, Takanori Yamagata
    PLOS ONE 9 3 e92695  2014年03月 [査読有り][通常論文]
     
    Interstitial deletion of 12q21 has been reported in four cases, which share several common clinical features, including intellectual disability (ID), low-set ears, and minor cardiac abnormalities. Comparative genomic hybridization (CGH) analysis using the Agilent Human Genome CGH 180K array was performed with the genomic DNA from a two-year-old Japanese boy with these symptoms, as well as hypoplasia of the corpus callosum. Consequently, a 14 Mb deletion at 12q21.2-q21.33 (nt. 77 203 574-91 264 613 bp), which includes 72 genes, was detected. Of these, we focused on LIN7A, which encodes a scaffold protein that is important for synaptic function, as a possible responsible gene for ID, and we analyzed its role in cerebral cortex development. Western blotting analyses revealed that Lin-7A is expressed on embryonic day (E) 13.5, and gradually increases in the mouse brain during the embryonic stage. Biochemical fractionation resulted in the enrichment of Lin-7A in the presynaptic fraction. Suppression of Lin-7A expression by RNAi, using in utero electroporation on E14.5, delayed neuronal migration on postnatal day (P) 2, and Lin-7A-deficient neurons remained in the lower zone of the cortical plate and the intermediate zone. In addition, when Lin-7A was silenced in cortical neurons in one hemisphere, axonal growth in the contralateral hemisphere was delayed; development of these neurons was disrupted such that one half did not extend into the contralateral hemisphere after leaving the corpus callosum. Taken together, LIN7A is a candidate gene responsible for 12q21-deletion syndrome, and abnormal neuronal migration and interhemispheric axon development may contribute to ID and corpus callosum hypoplasia, respectively.
  • Yamagata T, Matsumoto A, Nagata K
    No to hattatsu = Brain and development 46 2 125 - 130 2014年03月 [査読有り][通常論文]
  • Mari Saito, Takanori Yamagata, Ayumi Matsumoto, Yusuke Shiba, Masako Nagashima, Shuhei Taniguchi, Eriko Jimbo, Mariko Y. Momoi
    BRAIN & DEVELOPMENT 36 1 64 - 69 2014年01月 [査読有り][通常論文]
     
    Deletion of the monoamine oxidase (MAO)-A and MAO-B was detected in two male siblings and in their mother. The approximately 800-kb deletion, extending from about 43.0 MB to 43.8 MB, was detected by array comparative genomic hybridization analysis. The MAOA and MAOB genes were included in the deletion, but the adjacent Norrie disease gene, NDP, was not deleted. The boys had short stature, hypotonia,,severe developmental delays, episodes of sudden loss of muscle tone, exiting behavior, lip-smacking and autistic features. The serotonin levels in their cerebrospinal fluid were extremely elevated. Another set of siblings with this deletion was reported previously. We propose recognition of MAOA/B deletion syndrome as a distinct disorder. (C) 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
  • Masako Nagashima, Yukifumi Monden, Ippeita Dan, Haruka Dan, Daisuke Tsuzuki, Tsutomu Mizutani, Yasushi Kyutoku, Yuji Gunji, Daisuke Hirano, Takamichi Taniguchi, Hideo Shimoizumi, Mariko Y Momoi, Eiju Watanabe, Takanori Yamagata
    NeuroImage. Clinical 6 192 - 201 2014年 [査読有り][通常論文]
     
    The object of the current study is to explore the neural substrate for effects of atomoxetine (ATX) on inhibitory control in school-aged children with attention deficit hyperactivity disorder (ADHD) using functional near-infrared spectroscopy (fNIRS). We monitored the oxy-hemoglobin signal changes of sixteen ADHD children (6-14 years old) performing a go/no-go task before and 1.5 h after ATX or placebo administration, in a randomized, double-blind, placebo-controlled, crossover design. Sixteen age- and gender-matched normal controls without ATX administration were also monitored. In the control subjects, the go/no-go task recruited the right inferior and middle prefrontal gyri (IFG/MFG), and this activation was absent in pre-medicated ADHD children. The reduction of right IFG/MFG activation was acutely normalized after ATX administration but not placebo administration in ADHD children. These results are reminiscent of the neuropharmacological effects of methylphenidate to up-regulate reduced right IFG/MFG function in ADHD children during inhibitory tasks. As with methylphenidate, activation in the IFG/MFG could serve as an objective neuro-functional biomarker to indicate the effects of ATX on inhibitory control in ADHD children. This promising technique will enhance early clinical diagnosis and treatment of ADHD in children, especially in those with a hyperactivity/impulsivity phenotype.
  • Ayumi Matsumoto, Mari Kuwajima, Kunio Miyake, Karin Kojima, Naomi Nakashima, Eriko F. Jimbo, Takeo Kubota, Mariko Y. Momoi, Takanori Yamagata
    JOURNAL OF HUMAN GENETICS 58 11 755 - 757 2013年11月 [査読有り][通常論文]
     
    The ribosomal protein S6 kinase, 90 kb, polypeptide 3 gene (RPS6KA3) is responsible for Coffin-Lowry syndrome (CLS), which is characterized by intellectual disability (ID) and facial and bony abnormalities. This gene also affects nonsyndromic X-linked ID and nonsyndromic X-linked ID without bony abnormalities. Two families have been previously reported to have genetic microduplication including RPS6KA3. In the present study, we used array-comparative genomic hybridization (CGH) analysis with Agilent Human genome CGH 180K and detected a 584-kb microduplication spanning 19.92-20.50 Mb of Xp22.12 (including RPS6KA3) in the members of one family, including three brothers, two sisters, and their mother. The 15-year-old male proband and one of his brothers had mild ID and localization-related epilepsy, whereas his other brother presented borderline intelligence quotient (IQ) and attention-deficit-hyperactivity disorder (ADHD). One sister presented pervasive development disorder (PDD). Analysis of this family suggests that RPS6KA3 duplication is responsible for mild ID, ADHD, and localization-related epilepsy, and possibly for PDD.
  • Mitsuhiro Kato, Takanori Yamagata, Masaya Kubota, Hiroshi Arai, Sumimasa Yamashita, Taku Nakagawa, Takanari Fujii, Kenji Sugai, Kaoru Imai, Tami Uster, David Chitayat, Shelly Weiss, Hirofumi Kashii, Ryosuke Kusano, Ayumi Matsumoto, Kazuyuki Nakamura, Yoshinobu Oyazato, Mari Maeno, Kiyomi Nishiyama, Hirofumi Kodera, Mitsuko Nakashima, Yoshinori Tsurusaki, Noriko Miyake, Kayoko Saito, Kiyoshi Hayasaka, Naomichi Matsumoto, Hirotomo Saitsu
    EPILEPSIA 54 7 1282 - 1287 2013年07月 [査読有り][通常論文]
     
    Purpose: KCNQ2 mutations have been found in patients with benign familial neonatal seizures, myokymia, or early onset epileptic encephalopathy (EOEE). In this study, we aimed to delineate the clinical spectrum of EOEE associated with KCNQ2 mutation. Methods: A total of 239 patients with EOEE, including 51 cases with Ohtahara syndrome and 104 cases with West syndrome, were analyzed by high-resolution melting (HRM) analysis or whole-exome sequencing. Detailed clinical information including electroencephalography (EEG) and brain magnetic resonance imaging (MRI) were collected from patients with KCNQ2 mutation. Key Findings: A total of nine de novo and one inherited mutations were identified (two mutations occurred recurrently). The initial seizures, which were mainly tonic seizures, occurred in the early neonatal period in all 12 patients. A suppression-burst pattern on EEG was found in most. Only three patients showed hypsarrhythmia on EEG; eight patients became seizure free when treated with carbamazepine, zonisamide, phenytoin, topiramate, or valproic acid. Although the seizures were relatively well controlled, moderate-to-profound intellectual disability was found in all except one patient who died at 3 months. Significance: De novo KCNQ2 mutations are involved in EOEE, most of which cases were diagnosed as Ohtahara syndrome. These cases showed distinct features with early neonatal onset, tonic seizures, a suppression-burst EEG pattern, infrequent evolution to West syndrome, and good response to sodium channel blockers, but poor developmental prognosis. Genetic testing for KCNQ2 should be considered for patients with EOEE.
  • Yukifumi Monden, Masato Mori, Mari Kuwajima, Tamako Goto, Takanori Yamagata, Mariko Y Momoi
    Brain & development 35 6 582 - 5 2013年06月 [査読有り][通常論文]
     
    We report the case of a boy with myoclonic epilepsy with ragged-red fibers (MERRF) who had astatic seizures since 2 years of age and later developed ataxia, absence seizures, and myoclonus. Almost homoplasmic A8344G mutation of mitochondrial DNA (m.8344A>G mutation) was detected in lymphocytes. He developed late-onset Leigh syndrome (LS) when he contracted pneumonia at 6 years. He developed bulbar palsy and deep coma. MRI demonstrated lesions in the brainstem, basal ganglia, and cerebral cortex. Three similar cases have been reported; two carried the almost-homoplasmic m.8344A>G mutation in muscle tissue. These suggested that almost homoplastic m.8344A>G mutation developed clinical phenotype of MERRF in the early stage and late-onset Leigh syndrome in the late course of the disease.
  • Mitsuaki Iwasa, Takanori Yamagata, Masashi Mizuguchi, Masayuki Itoh, Ayumi Matsumoto, Mitsugu Hironaka, Ayako Honda, Mariko Y. Momoi, Nobuyuki Shimozawa
    Neuropathology 33 3 292 - 298 2013年06月 [査読有り][通常論文]
     
    Contiguous ABCD1 DXS1357E deletion syndrome (CADDS) is a contiguous deletion syndrome involving the ABCD1 and DXS1357E/BAP31 genes on Xq28. Although ABCD1 is responsible for X-linked adrenoleukodystrophy (X-ALD), its phenotype differs from that of CADDS, which manifests with many features of Zellweger syndrome (ZS), including severe growth and developmental retardation, liver dysfunction, cholestasis and early infantile death. We report here the fourth case of CADDS, in which a boy had dysmorphic features, including a flat orbital edge, hypoplastic nose, micrognathia, inguinal hernia, micropenis, cryptorchidism and club feet, all of which are shared by ZS. The patient achieved no developmental milestones and died of pneumonia at 8 months. Biochemical studies demonstrated abnormal metabolism of very long chain fatty acids, which was higher than that seen in X-ALD. Immunocytochemistry and Western blot showed the absence of ALD protein (ALDP) despite the presence of other peroxisomal proteins. Pathological studies disclosed a small brain with hypomyelination and secondary hypoxic-ischemic changes. Neuronal heterotopia in the white matter and leptomeningeal glioneuronal heterotopia indicated a neuronal migration disorder. The liver showed fibrosis and cholestasis. The thymus and adrenal glands were hypoplastic. Array comparative genomic hybridization (CGH) analysis suggested that the deletion was a genomic rearrangement in the 90-kb span starting in DXS1357E/BACP31 exon 4 and included ABCD1, PLXNB3, SRPK3, IDH3G and SSR4, ending in PDZD4 exon 8. Thus, the absence of ALDP, when combined with defects in the B-cell antigen receptor associated protein 31 (BAP31) and other factors, severely affects VLCFA metabolism on peroxisomal functions and produces ZS-like pathology. © 2012 Japanese Society of Neuropathology.
  • 山形 崇倫, 杉江 秀夫
    脳と発達 45 3 223 - 226 The Japanese Society of Child Neurology 2013年05月
  • 小森 咲子, 南 孝臣, 谷口 祐子, 石井 朋之, 岡 健介, 高田 亜希子, 佐藤 智幸, 片岡 功一, 吉田 真, 山形 崇倫
    心臓 45 11 1452 - 1453 Japan Heart Foundation 2013年
  • Tomoki Kosho, Nobuhiko Okamoto, Hirofumi Ohashi, Yoshinori Tsurusaki, Yoko Imai, Yumiko Hibi-Ko, Hiroshi Kawame, Tomomi Homma, Saori Tanabe, Mitsuhiro Kato, Yoko Hiraki, Takanori Yamagata, Shoji Yano, Satoru Sakazume, Takuma Ishii, Toshiro Nagai, Tohru Ohta, Norio Niikawa, Seiji Mizuno, Tadashi Kaname, Kenji Naritomi, Yoko Narumi, Keiko Wakui, Yoshimitsu Fukushima, Satoko Miyatake, Takeshi Mizuguchi, Hirotomo Saitsu, Noriko Miyake, Naomichi Matsumoto
    American Journal of Medical Genetics, Part A 161 6 1221 - 1237 2013年 [査読有り][通常論文]
     
    Mutations in the components of the SWItch/sucrose nonfermentable (SWI/SNF)-like chromatin remodeling complex have recently been reported to cause Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NCBRS), and ARID1B-related intellectual disability (ID) syndrome. We detail here the genotype-phenotype correlations for 85 previously published and one additional patient with mutations in the SWI/SNF complex: four with SMARCB1 mutations, seven with SMARCA4 mutations, 37 with SMARCA2 mutations, one with an SMARCE1 mutation, three with ARID1A mutations, and 33 with ARID1B mutations. The mutations were associated with syndromic ID and speech impairment (severe/profound in SMARCB1, SMARCE1, and ARID1A mutations variable in SMARCA4, SMARCA2, and ARID1B mutations), which was frequently accompanied by agenesis or hypoplasia of the corpus callosum. SMARCB1 mutations caused "classical" CSS with typical facial "coarseness" and significant digital/nail hypoplasia. SMARCA4 mutations caused CSS without typical facial coarseness and with significant digital/nail hypoplasia. SMARCA2 mutations caused NCBRS, typically with short stature, sparse hair, a thin vermillion of the upper lip, an everted lower lip and prominent finger joints. A SMARCE1 mutation caused CSS without typical facial coarseness and with significant digital/nail hypoplasia. ARID1A mutations caused the most severe CSS with severe physical complications. ARID1B mutations caused CSS without typical facial coarseness and with mild digital/nail hypoplasia, or caused syndromic ID. Because of the common underlying mechanism and overlapping clinical features, we propose that these conditions be referred to collectively as "SWI/SNF-related ID syndromes". © 2013 Wiley Periodicals, Inc.
  • 長嶋雅子, 森雅人, 門田行史, 山形崇倫, 野崎靖之, 福田冬季子, 杉江秀夫, 桃井真里子
    脳と発達 45 1 62 - 63 2013年01月 [査読無し][通常論文]
  • fNIRSを用いたADHDの実行機能解析とMPHの薬理効果の検討-小児における早期診断を目指して
    門田行史, 檀はるか, 檀一平太, 長嶋雅子, 續木大介, 久徳康史, 山形崇倫, 郡司勇治, 渡辺英寿, 桃井真里子
    薬物脳波学会雑誌 (印刷中) 2013年 [査読無し][通常論文]
  • Michito Namekawa, Yoshihisa Takiyama, Junko Honda, Kumi Sakoe, Tametou Naoi, Haruo Shimazaki, Takanori Yamagata, Mariko Y. Momoi, Imaharu Nakano
    NEUROLOGICAL SCIENCES 33 6 1389 - 1392 2012年12月 [査読有り][通常論文]
     
    We present here a 25-year-old woman with genetically confirmed (p.R276L mutation in the GFAP gene) juvenile-onset AxD. Episodic vomiting appeared at age nine, causing anorexia and insufficient growth. Brain MRI at age 11 showed a small nodular lesion with contrast enhancement in the left dorsal portion of the cervicomedullary junction. Her episodic vomiting improved spontaneously at age 13, and she became neurologically asymptomatic. The enhancement of the lesion disappeared simultaneously, although the plaque remained. Longitudinal MRI observations, however, revealed insidiously progressive cervicomedullary atrophy without a signal change. This case broadens our knowledge of AxD: (1) molecular analysis of the GFAP gene is warranted in patients with MRI evidence of tumor-like lesions in the brainstem, particularly if they present with isolated episodic vomiting and/or anorexia; (2) the disease can be self-remitting for at least 12 years; (3) cervicomedullary atrophy, characteristic of the adult form, can be insidiously progressive without a signal change before the clinical symptoms appear.
  • Eriko Fujita-Jimbo, Zhi-Ling Yu, Hong Li, Takanori Yamagata, Masato Mori, Takashi Momoi, Mariko Y. Momoi
    PLOS ONE 7 12 e51155  2012年12月 [査読有り][通常論文]
     
    Little is known about the molecular pathogenesis of Autism spectrum disorder (ASD), a neurodevelopmental disorder. Here we identified two mutations in the G-protein-coupled receptor 37 gene (GPR37) localized on chromosome 7q31-33, called the AUTS1 region, of ASD patients; 1585-1587 ttc del (Del312F) in one Japanese patient and G2324A (R558Q) in one Caucasian patient. The Del312F was located in the conserved transmembrane domain, and the R558Q was located in a conserved region just distal to the last transmembrane domain. In addition, a potential ASD-related GPR37 variant, T589M, was found in 7 affected Caucasian men from five different families. Our results suggested that some alleles in GPR37 were related to the deleterious effect of ASD. GPR37 is associated with the dopamine transporter to modulate dopamine uptake, and regulates behavioral responses to dopaminergic drugs. Thus, dopaminergic neurons may be involved in the ASD. However, we also detected the Del321F mutation in the patient's unaffected father and R558Q in not only an affected brother but also an unaffected mother. The identification of unaffected parents that carried the mutated alleles suggested that the manifestation of ASD was also influenced by factors other than these mutations, including endoplasmic reticulum stress of the mutated proteins or gender. Our study will provide the new insight into the molecular pathogenesis of ASD.
  • Shimojima K, Okamoto N, Suzuki Y, Saito M, Mori M, Yamagata T, Momoi MY, Hattori H, Okano Y, Hisata K, Okumura A, Yamamoto T
    Journal of human genetics 57 9 593 - 600 2012年09月 [査読有り][通常論文]
     
    Subtelomeric deletions of 1q44 cause mental retardation, developmental delay and brain anomalies, including abnormalities of the corpus callosum (ACC) and microcephaly in most patients. We report the cases of six patients with 1q44 deletions; two patients with interstitial deletions of 1q44; and four patients with terminal deletions of 1q. One of the patients showed an unbalanced translocation between chromosome 5. All the deletion regions overlapped with previously reported critical regions for ACC, microcephaly and seizures, indicating the recurrent nature of the core phenotypic features of 1q44 deletions. The four patients with terminal deletions of 1q exhibited severe volume loss in the brain as compared with patients who harbored interstitial deletions of 1q44. This indicated that telomeric regions have a role in severe volume loss of the brain. In addition, two patients with terminal deletions of 1q43, beyond the critical region for 1q44 deletion syndrome exhibited delayed myelination. As the deletion regions identified in these patients extended toward centromere, we conclude that the genes responsible for delayed myelination may be located in the neighboring region of 1q43.
  • 門田行史, 檀はるか, 長嶋雅子, 檀一平太, 久徳康史, 岡本雅子, 山形崇倫, 桃井真里子, 渡辺英寿
    日本薬物脳波学会雑誌 13 1 57 - 66 2012年06月 [査読無し][通常論文]
  • Yukifumi Monden, Haruka Dan, Masako Nagashima, Ippeita Dan, Yasushi Kyutoku, Masako Okamoto, Takanori Yamagata, Mariko Y. Momoi, Eiju Watanabe
    CLINICAL NEUROPHYSIOLOGY 123 6 1147 - 1157 2012年06月 [査読有り][通常論文]
     
    Objective: Attention Deficit Hyperactivity Disorder (ADHD), a common developmental syndrome with inattention, hyperactivity, and impulsivity, is typically treated with the psychostimulant drug, methylphenidate (MPH). We explored the feasibility of using functional near-infrared spectroscopy (fNIRS) to search for a clinically implementable biological marker for the acute MPH effect on ADHD children. Methods: Following an MPH washout period, twelve ADHD children performed a go/no-go task before and 1.5 h after MPH intake. fNIRS was used to monitor the lateral prefrontal cortical hemodynamics of ADHD children performing a go/no-go task. Results: There was no significant activation in the lateral prefrontal cortices examined before MPH intake. However, after MPH intake, significant MPH-elicited activation (oxygenated hemoglobin signal increase) was detected in the right lateral prefrontal cortex (LPFC) implicated with response inhibition functions. There was a large significant correlation between increases in task performance and activation in the right LPFC. Conclusions: The improved cognitive performance was associated with activation in the right LPFC, which might serve as a biological marker to monitor the effect of MPH in ADHD children. Significance: MPH-effect assessment in ADHD children using fNIRS can be performed within a 3 h stay at a hospital during a single visit, and thus may be integrated into clinical practice. (C) 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
  • Yukifumi Monden, Takanori Yamagata, Yuri Kuroiwa, Toshiyuki Takahashi, Masato Mori, Tokiko Fukuda, Hideo Sugie, Mariko-Yoshida Momoi
    BRAIN & DEVELOPMENT 34 5 380 - 383 2012年05月 [査読有り][通常論文]
     
    The patient was a 14-year-old male diagnosed with acute disseminated encephalomyelitis (ADEM) with acute onset of multifocal central nervous system symptoms. He showed increased cerebrospinal fluid cell counts and high myelin basic protein levels, which responded well to steroid pulse therapy. Spinal MRI showed a centrally-located long spinal cord lesion (LCL) involving 17 vertebral bodies from C2 to T11 that later expanded into the white matter, and lesions on the ventral side of the medulla. The cause of LCL has been reported to be heterogeneous. In this case, LCL is considered to be associated with ADEM, an acute autoimmune response to myelin, and vascular inflammation of the gray matter of the spinal cord. (C) 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
  • Ai Hoshino, Makiko Saitoh, Akira Oka, Akihisa Okumura, Masaya Kubota, Yoshiaki Saito, Jun-ichi Takanashi, Shinichi Hirose, Takanori Yamagata, Hideo Yamanouchi, Masashi Mizuguchi
    BRAIN & DEVELOPMENT 34 5 337 - 343 2012年05月 [査読有り][通常論文]
     
    A research committee supported by the Japanese government conducted a nationwide survey on the epidemiology of acute encephalopathy in Japan using a questionnaire. A total of 983 cases reportedly had acute encephalopathy during the past 3 years, 2007-2010. Among the pathogens of the preceding infection, influenza virus was the most common, followed by human herpesvirus-6 (HHV-6) and rotavirus. Among syndromes of acute encephalopathy, acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) was the most frequent, followed by clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), acute necrotizing encephalopathy (ANE) and hemorrhagic shock and encephalopathy syndrome (HSES). Influenza virus was strongly associated with ANE and MERS, HHV-6 with AESD, and rotavirus with MERS. Mortality was high in ANE and HSES, but was low in AESD, MERS and HHV-6-associated encephalopathy. Neurologic sequelae were common in AESD and ANE, but were absent in MERS. (C) 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
  • Yoshinori Tsurusaki, Nobuhiko Okamoto, Hirofumi Ohashi, Tomoki Kosho, Yoko Imai, Yumiko Hibi-Ko, Tadashi Kaname, Kenji Naritomi, Hiroshi Kawame, Keiko Wakui, Yoshimitsu Fukushima, Tomomi Homma, Mitsuhiro Kato, Yoko Hiraki, Takanori Yamagata, Shoji Yano, Seiji Mizuno, Satoru Sakazume, Takuma Ishii, Toshiro Nagai, Masaaki Shiina, Kazuhiro Ogata, Tohru Ohta, Norio Niikawa, Satoko Miyatake, Ippei Okada, Takeshi Mizuguchi, Hiroshi Doi, Hirotomo Saitsu, Noriko Miyake, Naomichi Matsumoto
    NATURE GENETICS 44 4 376 - 378 2012年04月 [査読有り][通常論文]
     
    By exome sequencing, we found de novo SMARCB1 mutations in two of five individuals with typical Coffin-Siris syndrome (CSS), a rare autosomal dominant anomaly syndrome. As SMARCB1 encodes a subunit of the SWItch/Sucrose NonFermenting (SWI/SNF) complex, we screened 15 other genes encoding subunits of this complex in 23 individuals with CSS. Twenty affected individuals (87%) each had a germline mutation in one of six SWI/SNF subunit genes, including SMARCB1, SMARCA4, SMARCA2, SMARCE1, ARID1A and ARID1B.
  • Makiko Oguma, Akira Morimoto, Akiko Takada, Yoshifumi Kashii, Tokiko Fukuda, Masato Mori, Takanori Yamagata, Hideo Sugie, Mariko Y. Momoi
    BRAIN & DEVELOPMENT 34 3 251 - 254 2012年03月 [査読有り][通常論文]
     
    A one-year-old boy with neuroblastoma (NBoma)-associated opsoclonus-myoclonus syndrome (OMS) was treated by oral high-dose dexamethasone (DEX) pulses (20 mg/m(2)/day of DEX for three consecutive days) every 28 days for 6 months after resection of the tumor. All OMS symptoms improved after the first course of DEX pulse therapy and disappeared after the last course. No adverse effects were observed. Minor deterioration of his developmental quotient was noted 33 months after the onset of the disease. NBoma remission has been maintained since treatment. Before DEX pulse therapy, frequency of T lymphocyte, in particular CD4-positive cell decreased markedly resulted in low CD4/8 ratio in the peripheral blood (PB). The frequency of B lymphocyte increased, especially in cerebrospinal fluid. These aberrant values in PB were reversed by DEX pulse therapy and correlated well with the neurological symptoms. A prospective study that assesses the efficacy of this promising and inexpensive treatment for OMS is warranted. (C) 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
  • Yukifumi Monden, Haruka Dan, Masako Nagashima, Ippeita Dan, Daisuke Tsuzuki, Yasushi Kyutoku, Yuji Gunji, Takanori Yamagata, Eiju Watanabe, Mariko Y. Momoi
    NEUROIMAGE-CLINICAL 1 1 131 - 140 2012年 [査読有り][通常論文]
     
    An objective biomarker is a compelling need for the early diagnosis of attention deficit hyperactivity disorder (ADHD), as well as for themonitoring of pharmacological treatment effectiveness. The advent of fNIRS, which is relatively robust to the body movements of ADHD children, raised the possibility of introducing functional neuroimaging diagnosis in younger ADHD children. Using fNIRS, we monitored the oxy-hemoglobin signal changes of 16 ADHD children (6 to 13 years old) performing a go/no-go task before and 1.5 h after MPH or placebo administration, in a randomized, double-blind, placebo-controlled, crossover design. 16 age-and gender-matched normal controls without MPH administration were also monitored. Relative to control subjects, unmedicated ADHD children exhibited reduced activation in the right inferior frontal gyrus (IFG) and middle frontal gyrus (MFG) during go/no-go tasks. The reduced right IFG/MFG activation was acutely normalized after MPH administration, but not after placebo administration. The MPH-induced right IFG/MFG activation was significantly larger than the placebo-induced activation. Post-scan exclusion rate was 0% among 16 right-handed ADHD children with IQ>70. We revealed that the right IFG/MFG activation could serve as a neuro-functional biomarker for monitoring the acute effects of methylphenidate in ADHD children. fNIRS-based examinations were applicable to ADHD children as young as 6 years old, and thus would contribute to early clinical diagnosis and treatment of ADHD children. (C) 2012 The Authors. Published by Elsevier Inc. Open access under CC BY-NC-ND license.
  • Takahiro Kanai, Hirohiko Shiraishi, Takanori Yamagata, Takane Ito, Jun Odaka, Takashi Saito, Jun Aoyagi, Mariko Y. Momoi
    PEDIATRICS INTERNATIONAL 53 6 906 - 909 2011年12月 [査読有り][通常論文]
     
    Background: Several cytokines have a pathological association with idiopathic steroid-sensitive nephrotic syndrome (ISSNS) in inducing proteinuria or regulating T cells. Because interleukin (IL)-7 plays important roles in regulating T-cell proliferation and sustaining naive or memory T cells, IL-7 is one of the candidate cytokines in the pathogenesis of ISSNS. Very little is known, however, about the association of IL-7 with ISSNS. To clarify the IL-7 dynamics in children with ISSNS, serum IL-7 level was investigated, from the nephrotic phase before steroid treatment (STx; group A1) to the remission phase with STx (group A2) and without STx (group A3). Methods: Eighteen children with ISSNS were included in the present study. A total of 25 paired samples were analyzed for groups A1 and A2, and a total of 10 paired samples for groups A1, A2, and A3 due to recurrence. Two control groups ( with normal urinalysis, group B; or with nephrotic syndrome other than ISSNS, group C), matched for age and gender, were also included. Serum cytokine level was measured on bead-based assay. Results: Each serum IL-7 level in groups A1 and A3 was higher than each serum IL-7 level of groups C and B, respectively. The group A2 serum IL-7 level was higher than that of group A1. There was no statistical significance of serum IL-7 level between group A1 and group A3. Conclusion: Serum IL-7 level was elevated in children with ISSNS regardless of the status of the disease. This brings us one step closer to a better understanding of the pathophysiology of ISSNS in children.
  • Takahiro Kanai, Takanori Yamagata, Takane Ito, Jun Odaka, Takashi Saito, Jun Aoyagi, Masahisa Kobayashi, Toya Ohashi, Toya Ohashi, Yoshihiko Ueda, Mariko Y Momoi
    Journal of Inherited Metabolic Disease 1 39 - 42 2011年11月 [査読有り][通常論文]
     
    Fabry disease is an X-linked glycosphingolipidosiscaused by deficient synthesis of the enzymea-galactosidaseA, which results in glycosphingolipidosis,predominantly globotriaosylceramide, progressively accumulatingin systemic tissue. A dominant complication ofFabry disease is nephropathy. The average age for thedevelopment of clinical nephropathy is 27 years in malepatients, with up to half of all patients developing endstagerenal failure by their 50s. A recent study revealedpodocytes play important roles in antiproteinuria. Podocyteinjury leads to foot process effacement and proteinuria. Thefoot process effacement induces podocyte depletion from theglomerular wall, glomerulosclerosis, and results in end-stagerenal failure. We report on a 13-year-old boy with classicFabry disease, who developed foot process effacement andpodocyte depletion even before proteinuria appeared. Atthe time, his only symptom of Fabry disease was acroparesthesia.He was administered Agalsidase b (1 mg/kg/dosediv) every other week and 14 months after treatment, hisrenal function remained normal. This is the first report of apatient with classic Fabry disease, with only acroparesthesia,who had normal urinalysis but manifested foot processeffacement and podocyte depletion. Podocytes are highlydifferentiated cells with a limited capacity for cell divisionand replacement. The large individual variation and oftenprogressive nature of this disease raises concerns about theappropriate timing for initiating enzyme replacement therapy(ERT). Recent data have shown a limited effect of ERTon progressive organ damage. In our case, ERT was initiatedbefore proteinuria appeared, with good outcome.
  • Kanai T, Yamagata T, Ito T, Odaka J, Saito T, Aoyagi J, Kobayashi M, Ohashi T, Ueda Y, Momoi MY
    JIMD reports 1 39 - 42 2011年 [査読有り][通常論文]
  • 免疫グロブリン大量静注療法が奏効したフォスファチジン酸添加(ELISA法)による抗ガングリオシド抗体陽性Guillain-Barré症候群の幼児
    木村岳人, 熊谷秀規, 松本静子, 江橋正浩, 山形崇倫, 楠 進
    茨城県立病院医学雑誌 28 27 - 31 2011年 [査読有り][通常論文]
  • Takahiro Kanai, Hirohiko Shiraishi, Takanori Yamagata, Takane Ito, Jun Odaka, Takashi Saito, Jun Aoyagi, Mariko Y. Momoi
    CLINICAL AND EXPERIMENTAL NEPHROLOGY 14 6 578 - 583 2010年12月 [査読有り][通常論文]
     
    Various studies reported a higher incidence of allergic disorders, with an overreactivity of type 2 helper T-cell (Th2) immune mechanisms, in children with idiopathic steroid-sensitive nephrotic syndrome (ISSNS). However, Th2 predominance in ISSNS has not been definitively identified. To determine whether Th2 was predominant in children with ISSNS, we used paired samples to measure the type 1 helper T-cell (Th1)/Th2 ratios and serum cytokine levels secreted by Th1 and Th2. We measured the Th1/Th2 ratios and levels of Th1- or Th2-secreted cytokines in paired samples. Fourteen children met the inclusion criteria: (1) ISSNS; (2) selectivity index < 0.1; (3) sera obtained in at least two disease phases; (4) no infection; (5) no immunosuppressants. Two control groups (group B, normal urinalysis; group C, nephrotic syndrome other than ISSNS) were included for cytokine level comparisons. Th1 and Th2 numbers were counted by three-color flow cytometry. Cytokine levels were measured by bead-based assay. The Th1/Th2 ratio was lower in group A-1 [nephrotic-phase before steroid treatment (STx)] than in groups A-2 (remission-phase with STx) and A-3 (remission-phase without STx). Th2-secreted interleukin-5 (IL-5) levels were higher in group A-1 than in groups A-2 and A-3. There were no differences in IL-5 levels between groups A-1 and C and between groups A-3 and B. Our results suggest that Th2 played a predominant role both in the Th1/Th2 ratio and in the serum IL-5 level in children with ISSNS in the nephrotic phase.
  • Yuki Takayanagi, Eriko Fujita, Zhiling Yu, Takanori Yamagata, Mariko Y. Momoi, Takashi Momoi, Tatsushi Onaka
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 396 3 703 - 708 2010年06月 [査読有り][通常論文]
     
    Cell adhesion molecule 1 (CADM1), a member of the immunoglobulin superfamily, mediates synaptic cell adhesion. Missense mutations in the CADM1 gene have been identified in autism spectrum disorder (ASD) patients. In the present study, we examined emotional behaviors, social behaviors and motor performances in Cadm1-knockout (KO) mice. Cadm1-KO mice showed increased anxiety-related behavior in open-field and light-dark transition tests. Social behaviors of Cadm1-KO mice were impaired in social interaction, resident-intruder and social memory/recognition tests. Furthermore, motor coordination and gait of Cadm1-MO mice were impaired in rotarod and footprint tests. Our study demonstrates that CADM1 plays roles in regulating emotional behaviors, social behaviors and motor performances, and that CADM1 has important implications for psychiatric disorders with disruptions in social behavior, such as autism. (C) 2010 Elsevier Inc. All rights reserved.
  • Hirotomo Saitsu, Jun Tohyama, Tatsuro Kumada, Kiyoshi Egawa, Keisuke Hamada, Ippei Okada, Takeshi Mizuguchi, Hitoshi Osaka, Rie Miyata, Tomonori Furukawa, Kazuhiro Haginoya, Hideki Hoshino, Tomohide Goto, Yasuo Hachiya, Takanori Yamagata, Shinji Saitoh, Toshiro Nagai, Kiyomi Nishiyama, Akira Nishimura, Noriko Miyake, Masayuki Komada, Kenji Hayashi, Syu-ichi Hirai, Kazuhiro Ogata, Mitsuhiro Kato, Atsuo Fukuda, Naomichi Matsumoto
    AMERICAN JOURNAL OF HUMAN GENETICS 86 6 881 - 891 2010年06月 [査読有り][通常論文]
     
    A de novo 9q33.3-q34.11 microdeletion involving STX8P1 has been found in one of four individuals (group A) with early-onset West syndrome, severe hypomyelination, poor visual attention, and developmental delay. Although haploinsufficiency of STXBP1 was involved in early infantile epileptic encephalopathy in a previous different cohort study (group B), no mutations of SIXBP1 were found in two of the remaining three subjects of group A (one was unavailable), We assumed that another gene within the deletion might contribute to the phenotype of group A. SPTAN1 encoding alpha-II spectrin, which is essential for proper myelination in zebratish, turned out to be deleted. In two subjects, an in-frame 3 bp deletion and a 6 bp duplication in SHAN1 were found at the initial nucleation site of the alpha/beta spectrin heterodimer. SPTAN1 was further screened in six unrelated individuals with WS and hypomyelination, but no mutations were found. Recombinant mutant (mut) and wild-type (WT) alpha-II spectrin could assemble heterodimers with beta-II spectrin, but alpha-II (mut)/beta-II spectrin heterodimers were thermolabile compared with the alpha-II (WT)/beta-II heterodimers. Transient expression in mouse cortical neurons revealed aggregation of alpha-II (mut)/beta-II and alpha-II (mut)/beta-III spectrin heterodimers, which was also observed in lymphoblastoid cells from two subjects with in-frame mutations. Clustering of ankyrinG and voltage-gated sodium channels at axon initial segment (AIS) was disturbed in relation to the aggregates, together with an elevated action potential threshold. These findings suggest that pathological aggregation of alpha/beta spectrin heterodimers and abnormal AIS integrity resulting from SPTAN1 mutations were involved in pathogenesis of infantile epilepsy.
  • Tomomi Hayase, Jun Shimizu, Tamako Goto, Yasuyuki Nozaki, Masato Mori, Naoto Takahashi, Eiji Namba, Takanori Yamagata, Mariko Y. Momoi
    BRAIN & DEVELOPMENT 32 3 244 - 247 2010年03月 [査読有り][通常論文]
     
    We report the case of a girl with Tay-Sachs disease who had convulsions and deteriorated rapidly after an upper respiratory infection at the age of I I months. At the age of 16 months, her seizures became intractable and magnetic resonance imaging of the brain showed high signal intensity on T2-weighted images and marked swelling in the white matter and basal nucelei of the right hemisphere. Her seizures and right hemisphere lesion improved with glycerol and dexamethasone treatment. When dexamethasone was discontinued, her symptoms worsened and lesions later appeared in the left hemisphere. Her cerebrospinal fluid showed elevated levels of the cytokines TNF-alpha and IL-5. It is considered that inflammation contributes to disease progression in Tay-Sachs disease. (C) 2009 Elsevier B.V. All rights reserved.
  • Naomi Nakashima, Takanori Yamagata, Masato Mori, Mari Kuwajima, Kiyotaka Suwa, Mariko Y. Momoi
    BRAIN & DEVELOPMENT 32 2 98 - 104 2010年02月 [査読有り][通常論文]
     
    Linkage analysis has reported the chromosomal region 7q21 to be related with autism. This region contains an imprinting region with MECP2-binding sites, and DLX5 is reported to be modulated by MECP2. DLX5 and adjacent DLX6 are homeobox genes working in neurogenesis. From these points, DLX5 and DLX6 are candidate genes for autism. Therefore, we analyzed the expression of DLX5 and DLX6, and also PEG10 as a control in the lymphoblasts of autistic spectrum disorder (ASD) patients by real-time PCR to identify potential abnormality of expression. And we also analyzed DLX5 and DLX6 on ASD patients for mutation by direct sequence. The expression level of DLX5 was not different between ASD and controls but was higher in four ASD patients compared to controls. Clinical features of these four patients were variable. DLX5 expression was biallelic in two ASD patients and two controls, indicating that DLX5 was not imprinted. There was no mutation in DLX5 in ASD. Although DLX5 was not likely to play major role in ASD, genes relating to DLX5 expression and downstream of DLX5 are considered to be candidate genes for some of the ASD patients. In DLX6, we detected a G656A base change (R219H) in two ASD patients who were male siblings. DLX6 may contribute to the pathogenesis of ASD. (C) 2009 Elsevier B.V. All rights reserved.
  • Satoshi Narumi, Chikahiko Numakura, Takashi Shiihara, Chizuru Seiwa, Yasuyuki Nozaki, Takanori Yamagata, Mariko Y. Momoi, Yoriko Watanabe, Makoto Yoshino, Toyojiro Matsuishi, Eriko Nishi, Hiroshi Kawame, Tsutomu Akahane, Gen Nishimura, Mitsuru Emi, Tomonobu Hasegawa
    AMERICAN JOURNAL OF MEDICAL GENETICS PART A 152A 1 133 - 140 2010年01月 [査読有り][通常論文]
     
    Osteoporosis-pseudoglioma syndrome (OPS; OMIM 259770) is an autosomal-recessive genetic disorder characterized by severe osteoporosis and visual disturbance from childhood. Biallelic mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) have been frequently detected, while a subset of patients had only one or no detectable mutation. We report on the clinical and molecular findings of four unrelated Japanese patients with the syndrome. The four patients had typical skeletal and ocular phenotypes of OPS, namely severe juvenile osteoporosis and early-onset visual disturbance, with or without mental retardation. We undertook standard PCR-based sequencing for LRP5 and found four missense mutations (p.L145F, p.T244M, p.P382L, and p.T552M), one nonsense mutation (p.R1534X), and one splice site mutation (c.1584+1G>A) among four OPS patients. Although three patients had two heterozygous mutations, one had only one heterozygous splice site mutation. In this patient, RT-PCR from lymphocytic RNA demonstrated splice error resulting in 63-bp insertion between exons 7 and 8. Furthermore, the patient was found to have only mutated RT-PCR fragment, implying that a seemingly normal allele did not express LRP5 mRNA. We then conducted custom-designed oligonucleotide tiling microarray analyses targeted to a 600-kb genome region harboring LRP5 and discovered a 7.2-kb microdeletion encompassing exons 22 and 23 of LRP5. We found various types of LRP5 mutations, including an exon-level deletion that is undetectable by standard PCR-based mutation screening. Oligonucleotide tiling microarray seems to be a powerful tool in identifying cryptic structural mutations. (C) 2009 Wiley-Liss, Inc.
  • Takako Saito, Osamu Saito, Takao Maeda, Chiharu Ito, Yasuhiro Ando, Takanori Yamagata, Shigeaki Muto, Mariko Momoi, Eiji Kusano
    AMERICAN JOURNAL OF KIDNEY DISEASES 54 4 764 - 769 2009年10月 [査読有り][通常論文]
  • Takahiro Kanai, Takanori Yamagata, Mariko Y. Momoi
    PEDIATRICS INTERNATIONAL 51 4 443 - 447 2009年08月 [査読有り][通常論文]
     
    Background: The cytokines associated with idiopathic steroid-sensitive nephrotic syndrome (ISSNS) have not been identified definitively, because previous studies had variable sampling and population heterogeneity. To clarify the cytokines involved, serum cytokine levels were measured using uniform sampling in a homogeneous population. Methods: Five children meeting the following criteria were included: (i) ISSNS; (ii) selectivity index < 0.1; (iii) paired sera obtained in the nephrotic phase before steroid treatment (STx; group A) and in the remission phase under STx (group B); (iv) no infection; and (v) no immunosuppressant. Control groups were as follows: group C, four children with ISSNS in the remission phase without STx; group D, five with normal urinalysis; group E, five with symptomatic secondary nephrotic syndrome before STx. Cytokine levels were measured using bead-based assay. Results: Serum macrophage inflammatory protein-1 beta (MIP-1 beta) levels were higher in group B compared to group A, and group C was lower than groups A and B. Serum interleukin-8 (IL-8) levels were higher in group A than in groups B and C, and groups B and C did not differ. With regard to both cytokine levels, there were no differences between groups C and D, and groups A and E. Conclusion: Serum MIP-1 beta and IL-8 are associated with the clinical status of ISSNS in children. A relationship between MIP-1 beta and ISSNS has not been previously reported. The mechanism by which MIP-1 beta and IL-8 affect ISSNS is unclear. Nevertheless, the present findings are an interesting starting point for further investigations into the pathophysiology of ISSNS in children.
  • Akihide Ohkuchi, Shigeki Matsubara, Kayoko Takahashi, Soichiro Inoue, Tsutomu Saito, Takeshi Mitsuhashi, Takanori Yamagata, Naoto Takahashi, Atsushi Watanabe, Takashi Shimada, Mitsuaki Suzuki
    JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH 35 4 797 - 800 2009年08月 [査読有り][通常論文]
     
    Ehlers-Danlos syndrome (EDS) type IV is an autosomal dominantly inherited connective tissue disorder caused by abnormal type III collagen resulting from heterogenous mutations of the type III procollagen gene (COL3A1). The maternal mortality rate per pregnancy in EDS type IV has been reported as 11.5%, to 25%. A 30-year-old Japanese primiparous woman, with a brother who had suffered a bowel rupture due to EDS type IV, became pregnant. She also suffered from myocardial infarction due to coronary artery dissections at 24 years old, and underwent coronary artery bypass grafting. Due to uncontrollable uterine contractions, beta 2-stimulants were administered during 18 to 29 weeks of gestation. Therefore, we performed a cesarean section at 29 weeks of gestation to prevent uterine rupture. She and her baby were discharged without any complications. It was revealed that she had the same mutation as her brother, Gly220Trp, in the (Gly-X-Y)n repeat of the triple-helical domain of COL3A1.
  • Yu Zhiling, Eriko Fujita, Yuko Tanabe, Takanori Yamagata, Takashi Momoi, Mariko Y. Momoi
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 377 3 926 - 929 2008年12月 [査読有り][通常論文]
     
    The unified idea on the molecular pathogenesis of Autism Spectrum Disorder (ASD) is still unknown although mutations in genes encoding neuroligins and SHANK3 have been shown in a small part of the patients. RA175/SynCAM1/CADM1(CADM1), a member of immunoglobilin superfamily, is another synaptic cell adhesion molecule. To clarify the idea that impaired synaptogenesis underlies the pathogenesis of ASD, we examined the relationship between mutations in the CADM1 gene and ASD. We found two missense Mutations, C739A(H246N) and A755C(Y251S), in the CADM1 gene of male Caucasian ASD patients and their family members. Both mutations were located in the third immunoglobulin domain, which is essential for trans-active interaction. The mutated CADM1 exhibited less amount of high molecular weight with the Matured oligosaccharide, defective trafficking to the cell surface, and more susceptibility to the cleavage and or degradation. Our findings provide key support for the unified idea that impaired synaptogenesis underlies the pathogenesis of ASD. (C) 2008 Published by Elsevier Inc.
  • 早瀬 朋美, 後藤 珠子, 清水 純, 野崎 靖之, 森 雅人, 山形 崇倫, 桃井 真里子, 難波 栄二
    脳と発達 40 1 64 - 64 (一社)日本小児神経学会 2008年01月
  • Yuko Otake, Takanori Yamagata, Yasuko Morimoto, Mari Imi, Masato Mori, Toshinori Aihara, Takashi Lehiyama, Mariko Y. Momoi
    BRAIN & DEVELOPMENT 29 2 117 - 120 2007年03月 [査読有り][通常論文]
     
    The patient was an 11-month-old boy who developed encephalopathy associated with respiratory syncytial virus bronchiolitis. Right hemispheric encephalopathy was indicated by left hemiparesis and a diffuse right hemispheric lesion detected with magnetic resonance imaging. Elevated levels of interleukin-6 in the cerebrospinal fluid during the acute phase suggested the involvement of increased production of one or more cytokines in the pathogenesis of viral related encephalopathy, similarly to that proposed for influenza encephalopathy. (c) 2006 Elsevier B.V. All rights reserved.
  • Tamako Goto, Masato Mori, Takanori Yamagata, Masashi Mizuguchi, Mariko Y. Momoi
    No To Hattatsu 39 4 300 - 303 2007年 [査読有り][通常論文]
     
    A 7-year-old girl was diagnosed with generalized myasthenia gravis and became steroid-dependent. Dose of prednisolone could not be reduced to < 2 mg/kg/day on alternate days, despite adverse effects. Thymectomy was avoided. Oral tacrolimus was initiated at 1.0-1.3 mg/kg/day. Ptosis and weakness of the lingual and pharyngeal muscles began to ameliorate 2 weeks later, and disappeared within 2 months. Serum titer of anti-acetylcholine receptor antibody also declined. During the subsequent two years, remission was maintained although prednisolone was reduced to half the original dose. No adverse effects of tacrolimus were noted. This case suggests the usefulness of tacrolimus in the treatment of childhood myasthenia gravis.
  • Tamako Goto, Hirokazu Kimura, Kei Numazaki, Miho Akiyama, Masahiko Kato, Masahiro Noda, Yasuyuki Nozaki, Keiko Tanaka-Taya, Kiyosu Taniguchi, Takanori Yamagata, Osamu Nishio, Teruko Oogane, Mariko Y Momoi, Nobuhiko Okabe
    Scandinavian journal of infectious diseases 39 11-12 1067 - 70 2007年 [査読有り][通常論文]
     
    We report the case of a 2-y, 11-month-old boy with G1P[8] rotavirus infection accompanied by acute meningoencephalitis. Substitutions in both the VP4 and VP7 genes were found in the identified strain. A commonly circulating G1P[8] rotavirus with such mutations might be associated with the pathogenesis of CNS complications, including meningoencephalitis.
  • Ichiko Nishijima, Takanori Yamagata, Corinne M. Spencer, Edwin J. Weeber, Olga Alekseyenko, J. David Sweatt, Mariko Y. Momoi, Masayuki Ito, Dawna L. Armstrong, David L. Nelson, Richard Paylor, Allan Bradley
    HUMAN MOLECULAR GENETICS 15 21 3241 - 3250 2006年11月 [査読有り][通常論文]
     
    Secretin is a peptide hormone released from the duodenum to stimulate the secretion of digestive juice by the pancreas. Secretin also functions as a neuropeptide hormone in the brain, and exogenous administration has been reported to alleviate symptoms in some patients with autism. We have generated secretin receptor-deficient mice to explore the relationship between secretin signaling in the brain and behavioral phenotypes. Secretin receptor-deficient mice are overtly normal and fertile; however, synaptic plasticity in the hippocampus is impaired and there are slightly fewer dendritic spines in the CA1 hippocampal pyramidal cells. Furthermore, secretin receptor-deficient mice show abnormal social and cognitive behaviors. These findings suggest that the secretin receptor system has an important role in the central nervous system relating to social behavior.
  • N Miyake, O Shimokawa, N Harada, N Sosonkina, A Okubo, H Kawara, N Okamoto, K Kurosawa, H Kawame, M Iwakoshi, T Kosho, Y Fukushima, Y Makita, Y Yokoyama, T Yamagata, M Kato, Y Hiraki, M Nomura, K Yoshiura, T Kishino, T Ohta, T Mizuguchi, N Niikawa, N Matsumoto
    AMERICAN JOURNAL OF MEDICAL GENETICS PART A 140A 3 205 - 211 2006年02月 [査読有り][通常論文]
     
    Array using 2,173 BAC clones covering the whole human genome has been constructecl. All clones spottecl were confirmed to show a Unique signal at the predicted chromosomal location by FISH analysis in our laboratory. A total of 30 individuals with idiopathic mental retardation (MR) were analyzed by comparative genomic hybridization Using this array. Three deletions, one duplication, and one unbalanced translocation could be detected in five patients, which are likely to contribute to MR. The constructed array was shown to be an efficient tool for the detection of pathogenic genomic rearrangements in MR patients as well as copy number polymorphisms (CPN's). (c) 2006 Wiley-Liss, Inc.
  • Yamanouchi H, Kawaguchi N, Mori M, Imataka G, Yamagata T, Hashimoto T, Momoi MY, Eguchi M, Mizuguchi M
    Pediatric neurology 34 2 93 - 100 2006年02月 [査読有り][通常論文]
  • 大脳病変が半球性に急性発症、急性増悪を呈したTay-Sachs病の1幼児例
    清水 純, 野崎 靖之, 後藤 珠子, 森 雅人, 山形 崇倫, 桃井 真里子, 難波 栄二
    日本先天代謝異常学会雑誌 21 2 110 - 110 日本先天代謝異常学会 2005年11月
  • H Li, T Yamagata, M Mori, A Yasuhara, MY Momoi
    BRAIN & DEVELOPMENT 27 5 321 - 325 2005年08月 [査読有り][通常論文]
     
    Methyl-CpG binding protein 2 gene (MECP2), the gene implicated in Rett syndrome, was also reported to be involved in mental retardation and autism. MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a nuclear protein family sharing the methyl-CpG binding domain (MBD) and are related to transcriptional repression. In 65 Japanese autistic patients, all the exons of each gene were screened for mutations by DHPLC, and the results were confirmed by direct sequencing. An R269C mutation that resulted in the addition of cysteine near a cysteine rich region was found in the MBD1 gene in one patient. This mutation was also detected in the patient's father with some phenotypes of autism and his normal sister, but not in 151 controls. Two repeat length polymorphisms, (GGGGCC)2 to 3 and (GGC) 4 to 5, were detected in MBD2, and several polynnorphisms were detected in each gene. Although our findings could not confirm that the genes of this family are responsible for the etiology in the majority of autistic patients, the R269C mutation in the MBD1 gene may relate to autism. The potential association of the high-polymorphic gene variants with autism needs to be studied further. Furthermore, these polymorphisms are useful for linkage analysis. (c) 2004 Published by Elsevier B.V.
  • A Ito, T Yamagata, M Mori, MY Momoi
    PEDIATRIC NEUROLOGY 33 1 53 - 56 2005年07月 [査読有り][通常論文]
     
    Early-onset ataxia with oculomotor apraxia and hypoalbuminemia is an autosomal recessive cerebellar ataxia characterized by oculomotor apraxia, peripheral neuropathy, and hypoalbuminemia. Mutations in aprataxin gene located at chromosome 9q13 have been identified recently in Japanese and European patients. This study reports two cases of siblings with early-onset ataxia with oculomotor apraxia and hypoalbuminemia, which manifested early onset before 2 years of age with relatively rapid progression and severe dystonia. Both of the siblings were compound heterozygotes with aprataxin gene mutations, 689 insT and G692A, in exon 5 that encodes the histidine triad domain of the aprataxin protein. The novel missense mutation, G692A, was not present in 40 unrelated and unaffected individuals. (c) 2005 by Elsevier Inc. All rights reserved.
  • M Fujimoto, SN Leech, T Theron, M Mori, H Fawcett, E Botta, Y Nozaki, T Yamagata, SI Moriwaki, M Stefanini, MY Momoi, H Nakagawa, S Shuster, C Moss, AR Lehmann
    JOURNAL OF INVESTIGATIVE DERMATOLOGY 125 1 86 - 92 2005年07月 [査読有り][通常論文]
     
    Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are both rare autosomal recessive disorders with defects in DNA repair. They are usually distinct both clinically and genetically but in rare cases, patients exhibit the clinical characteristics of both diseases concurrently. We report two new phenotypically distinct cases of XP with additional features of CS (xeroderma pigmentosum and Cockayne syndrome crossover syndrome (XP/CS)) carrying an identical mutation (G47R) in the XPD gene within the N terminus of the protein. Both patients had clinical features of XP and CS but only one fulfilled most criteria for diagnosing CS. Unusually, patient I developed early skin cancer, in contrast to patient 2, who never developed any malignancies. Cells from both these patients have repair defects typical of xeroderma pigmentosum complementation group D (XPD) cells, but also had the phenotype of uncontrolled DNA breakage found specifically in XPD/CS cells and similarly reduced levels of TFIIH. Despite these similarities between our two patients, their clinical features are quite different and the clinical severity correlates with other cellular responses to ultraviolet irradiation.
  • H Li, T Yamagata, M Mori, MY Momoi
    BRAIN & DEVELOPMENT 27 3 207 - 210 2005年04月 [査読有り][通常論文]
     
    We analyzed the FOXP2 gene, which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, for a possible causative mutation in autism. FOXP2 was reported to be mutated in patients with a severe speech and language disorder. FOXP2 was located on chromosome 7q31, which is one of the loci involved in autism. Autism and specific language impairment share some of their clinical phenotypes. In addition, FOXP2 was expressed abundantly in the brain. We screened all of the exons of FOXP2 for causative mutations in 53 Japanese autistic patients using denaturing high-performance liquid chromatography and direct sequencing. A delCAA in exon 5 causing one glutamine deletion in the first polyglutamine tract was detected in four patients and in 2 of 50 control individuals. The frequency of the TT allele with the G to T base change in intron 15 was significantly high in the autistic population. The other base changes included one silent base change (A569G) in exon 5 and three in introns. Our results may suggest a relationship between autism and the FOXP2 gene or a gene located nearby. (c) 2004 Elsevier B.V. All rights reserved.
  • M Nakamura, T Yamagata, M Mori, MY Momoi
    BRAIN & DEVELOPMENT 27 2 114 - 117 2005年03月 [査読有り][通常論文]
     
    Coffin-Lowry syndrome is an X-linked mental retardation disorder with dysmorphism caused by mutation of the ribosomal S6 kinase (RSK2) gene. Coffin-Lowry syndrome patients can experience unusual drop episodes whereby an abrupt loss of muscle tone and falling down can be induced by sudden, unexpected tactile or auditory stimuli. We detected a C913T (R305X) mutation in a female Coffin-Lowry syndrome patient with drop episodes. All mutations in our patient and those previously reported in patients with drop episodes result in premature truncation of the RSK2 protein in the N-terminal kinase domain or upstream of this domain. (C) 2004 Elsevier B.V. All rights reserved.
  • M Mori, T Yamagata, T Goto, S Saito, MY Momoi
    BRAIN & DEVELOPMENT 26 7 453 - 458 2004年10月 [査読有り][通常論文]
     
    The long-term effects of the sodium salt of dichloroacetic acid (DCA) were evaluated in four patients with mitochondrial encephalomyelopathy with lactic acidosis and stroke-like episodes (MELAS) carrying A3243G mutation. Oral administration of DCA in MELAS patients was followed for an average of 5 years 4 months. Serum levels of lactate and pyruvate were maintained at around 10 and 0.6 mg/dl, respectively. Serum levels of DCA were 40-136 pLg/ml. Symptoms responding to treatment included persistent headache, abdominal pain, muscle weakness, and stroke-like episodes. In contrast, no improvements in mental status, deafness, short stature, or neuroelectrophysiological findings were observed. Adverse effects included mild liver dysfunction in all patients, hypocalcemia in three and peripheral neuropathy in one. None of these adverse events was severe enough to require discontinuation of treatment. To determine suitable indications for DCA therapy, analysis of many more patients who have undergone DCA administration is required. (C) 2004 Elsevier B.V. All rights reserved.
  • M Kubota, Y Sakakihara, M Mori, T Yamagata, M Momoi-Yoshida
    BRAIN & DEVELOPMENT 26 7 481 - 483 2004年10月 [査読有り][通常論文]
     
    We here reported the clinical course and therapeutic details of a 16-year-old girl with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) who had had five stroke-like episodes (two episodes were clinically mild, while the three subsequent episodes were severe). Among the three episodes, the symptoms improved earliest and magnetic resonance spectroscopy abnormality was minimal when given L-arginine in addition to prednisolone, glycerol and edalavone. L-arginine administration during the acute phase of MELAS might be a potential therapy to reduce brain damage due to mitochondrial dysfunction. (C) 2004 Elsevier B.V. All rights reserved.
  • Yozu A, Suwa K, Mori M, Yamagata T, Mizuguchi M, Momoi MY
    No to hattatsu = Brain and development 36 4 334 - 338 2004年07月 [査読有り][通常論文]
  • Saitoh M, Yamagata T, Mizuguchi M, Momoi MY
    No to hattatsu = Brain and development 35 6 515 - 520 2003年11月 [査読有り][通常論文]
  • 両側前頭葉の大脳皮質障害を示す乳幼児期発症の急性脳症
    山内 秀雄, 森 雅人, 河口 修子, 山形 崇倫, 中川 栄二, 桃井 真里子, 江口 光興, 水口 雅
    脳と発達 35 Suppl. S153 - S153 (一社)日本小児神経学会 2003年05月 [査読有り][通常論文]
  • T Yamagata, S Aradhya, M Mori, K Inoue, MY Momoi, DL Nelson
    GENOMICS 80 2 185 - 194 2002年08月 [査読無し][通常論文]
     
    Secretin is a peptide hormone involved in digestion that has been studied as a potential therapeutic agent in patients with autism. We characterized the human secretin locus to determine whether mutations in this gene might play a role in a fraction of autism patients. While the secretin gene (SCT) was not found to be mutated in the majority of autistic patients, rare heterozygous sequence variants were identified in three patients. We also investigated length variation in a variable number of tandem repeats (VNTR) immediately upstream of SCT and found no significant differences in length between patients with autism and normal controls. SCT is located on 11p15.5, adjacent to DRD4 and HRAS. This region has been reported to be associated with both autism and attention deficit hyperactivity disorder (ADHD). Although imprinting is a characteristic of some genes in the vicinity, we could find no evidence for methylation of SCT in lymphoblast cells from patients or control individuals.
  • Y Kouroku, E Fujita, A Jimbo, T Kikuchi, T Yamagata, MY Momoi, E Kominami, K Kuida, K Sakamaki, S Yonehara, T Momoi
    HUMAN MOLECULAR GENETICS 11 13 1505 - 1515 2002年06月 [査読有り][通常論文]
     
    Accumulation of unfolded and malfolded proteins causes endoplasmic reticulum (ER) stress, stimulating unfolded protein response (UPR) and c-Jun N-terminal kinase (JNK) activation and activating caspase-12 located on the ER. Little is known about the relationship between the ER stress and polyglutamine [poly(Q)] aggregates. Poly(Q)(72) repeats [poly(Q)(72)] induced the stimulation of ER stress signals such as JNK activation, upregulation of Grp78/Bip and caspase-12 activation in C2C5 cells. We prepared antiserum against the cleavage site of mouse caspase-12 at D(318) (anti-m12D318), and showed that poly(Q)(72) with perinuclear aggregates, cytoplasmic inclusions and nuclear inclusions stimulated JNK activation and anti-m12D318 immunoreactivity, but poly(Q)(72) with dispersed aggregates and small nuclear aggregates showed a significantly less effect. poly(Q)(72) and poly(Q)(11) dispersed in cytoplasm did not. Anti-m12D318-positive cells showed apoptotic features. Unlike anti-m8D387 immunoreactivity, the anti-m12D318 immunoreactivity was not coaggregated with poly(Q). Ac-IETD-fmk (caspase-8 inhibitor) and Ac-DEVD-CHO (caspase-3 inhibitor) did not prevent the anti-m12D318 immunoreactivity induced by poly(Q)(72) aggregates. Anti-m12D318 immunoreactivity was detected in caspase-8(-/-) and caspase-3(-/-) mouse embryonic fibroblasts expressing poly(Q)(72) aggregates. Thus, caspase-12 was activated by poly(0)72 aggregates via a pathway independent of caspase-8 and caspase-3 activation, and caspase-12 activation was closely associated with poly(Q) aggregate-mediated cell death. Stimulation of ER stress signals may be involved in the pathogenesis of neurodegenerative disorders with poly(Q) expansion.
  • YH Gu, KL McIlwain, EJ Weeber, T Yamagata, BS Xu, BA Antalffy, C Reyes, L Yuva-Paylor, D Armstrong, H Zoghbi, JD Sweatt, R Paylor, DL Nelson
    JOURNAL OF NEUROSCIENCE 22 7 2753 - 2763 2002年04月 [査読有り][通常論文]
     
    FRAXE mental retardation results from expansion and methylation of a CCG trinucleotide repeat located in exon 1 of the X-linked FMR2 gene, which results in transcriptional silencing. The product of FMR2 is a member of a family of proteins rich in serine and proline, members of which have been associated with transcriptional activation. We have developed a murine Fmr2 gene knock-out model by replacing a fragment containing parts of exon 1 and intron 1 with the Escherichia coli lacZ gene, placing lacZ under control of the Fmr2 promoter. Expression of lacZ in the knock-out animals indicates that Fmr2 is expressed in several tissues, including brain, bone, cartilage, hair follicles, lung, tongue, tendons, salivary glands, and major blood vessels. In the CNS, Fmr2 expression begins at the time that cells in the neuroepithelium differentiate into neuroblasts. Mice lacking Fmr2 showed a delay-dependent conditioned fear impairment. Long-term potentiation (LTP) was found to be enhanced in hippocampal slices of Fmr2 knock-out compared with wildtype littermates. To our knowledge, this mouse knock-out is the first example of an animal model of human mental retardation with impaired learning and memory performance and increased LTP. Thus, although a number of studies have suggested that diminished LTP is associated with memory impairment, our data suggest that increased LTP may be a mechanism that leads to impaired cognitive processing as well.
  • YH Gu, KL McIlwain, EJ Weeber, T Yamagata, BS Xu, BA Antalffy, C Reyes, L Yuva-Paylor, D Armstrong, H Zoghbi, JD Sweatt, R Paylor, DL Nelson
    JOURNAL OF NEUROSCIENCE 22 7 2753 - 2763 2002年04月 [査読有り][通常論文]
     
    FRAXE mental retardation results from expansion and methylation of a CCG trinucleotide repeat located in exon 1 of the X-linked FMR2 gene, which results in transcriptional silencing. The product of FMR2 is a member of a family of proteins rich in serine and proline, members of which have been associated with transcriptional activation. We have developed a murine Fmr2 gene knock-out model by replacing a fragment containing parts of exon 1 and intron 1 with the Escherichia coli lacZ gene, placing lacZ under control of the Fmr2 promoter. Expression of lacZ in the knock-out animals indicates that Fmr2 is expressed in several tissues, including brain, bone, cartilage, hair follicles, lung, tongue, tendons, salivary glands, and major blood vessels. In the CNS, Fmr2 expression begins at the time that cells in the neuroepithelium differentiate into neuroblasts. Mice lacking Fmr2 showed a delay-dependent conditioned fear impairment. Long-term potentiation (LTP) was found to be enhanced in hippocampal slices of Fmr2 knock-out compared with wildtype littermates. To our knowledge, this mouse knock-out is the first example of an animal model of human mental retardation with impaired learning and memory performance and increased LTP. Thus, although a number of studies have suggested that diminished LTP is associated with memory impairment, our data suggest that increased LTP may be a mechanism that leads to impaired cognitive processing as well.
  • L Hong, T Yamagata, M Mori, MY Momoi
    JOURNAL OF HUMAN GENETICS 47 5 262 - 265 2002年 [査読有り][通常論文]
     
    Two boys from separate families presented with hereditary multiple exostoses (EXT) and autism associated with mental retardation. Their fathers both expressed a clinical phenotype of hereditary multiple exostoses milder than those of the patients and without the associated mental disorder. The EXT1 and EXT2 genes from lymphocytes of the affected individuals were analyzed by using, denaturing high-performance liquid chromatography and direct sequencing. A novel deletion mutation, 1742delTGT-G in exon 9 of EXT1, causing a frameshift was detected in one boy and his father. Another novel deletion mutation, 2093delTT in exon 11 of EXT1, causing, transcription termination was detected in the other affected boy and his father. EXTI is expressed in the brain, and both EXTI and EXT2 proteins are associated with glycosyltransferase activities required for the biosynthesis of heparan sulfate, which also has activity in the brain. The coincidental association of mental disorders in the boys was not completely excluded. However, these results suggest the involvement of EXTI in the development of mental disorders, including mental retardation and autism.
  • S Aradhya, H Woffendin, P Bonnen, NS Heiss, T Yamagata, T Esposito, T Bardaro, A Poustka, M D'Urso, S Kenwrick, DL Nelson
    GENOMICS 79 1 31 - 40 2002年01月 [査読無し][通常論文]
     
    A large portion of human Xq28 has been completely characterized but the interval between G6PD and Xqter has remained poorly understood. Because of a lack of stable, high-density clone coverage in this region, we constructed a 1.6-Mb bacterial and P1 artificial chromosome (BAC and PAC, respectively) contig to expedite mapping, structural and evolutionary analysis, and sequencing. The contig helped to reposition previously mismapped genes and to characterize the XAP135 pseudogene near the int22h-2 repeat. BAC clones containing the distal int22h repeats also demonstrated spontaneous rearrangements and sparse coverage, which suggested that they were unstable. Because the int22h repeats are involved in genetic diseases, we examined them in great apes to see if they have always been unstable. Differences in copy number among the apes, due to duplications and deletions, indicated that they have been unstable throughout their evolution. Taking another approach toward understanding the genomic nature of distal Xq28, we examined the homologous mouse region and found an evolutionary junction near the distal int22h loci that separated the human distal Xq28 region into two segments on the mouse X chromosome. Finally, haplotype analysis showed that a segment within Xq28 has resisted excessive interchromosomal exchange through great ape evolution, potentially accounting for the linkage disequilibrium recently reported in this region. Collectively, these data highlight some interesting features of the genomic sequence in Xq28 and will be useful for positional cloning efforts, mouse mutagenesis studies, and further evolutionary analyses.
  • S Aradhya, H Woffendin, P Bonnen, NS Heiss, T Yamagata, T Esposito, T Bardaro, A Poustka, M D'Urso, S Kenwrick, DL Nelson
    GENOMICS 79 1 31 - 40 2002年01月 [査読有り][通常論文]
     
    A large portion of human Xq28 has been completely characterized but the interval between G6PD and Xqter has remained poorly understood. Because of a lack of stable, high-density clone coverage in this region, we constructed a 1.6-Mb bacterial and P1 artificial chromosome (BAC and PAC, respectively) contig to expedite mapping, structural and evolutionary analysis, and sequencing. The contig helped to reposition previously mismapped genes and to characterize the XAP135 pseudogene near the int22h-2 repeat. BAC clones containing the distal int22h repeats also demonstrated spontaneous rearrangements and sparse coverage, which suggested that they were unstable. Because the int22h repeats are involved in genetic diseases, we examined them in great apes to see if they have always been unstable. Differences in copy number among the apes, due to duplications and deletions, indicated that they have been unstable throughout their evolution. Taking another approach toward understanding the genomic nature of distal Xq28, we examined the homologous mouse region and found an evolutionary junction near the distal int22h loci that separated the human distal Xq28 region into two segments on the mouse X chromosome. Finally, haplotype analysis showed that a segment within Xq28 has resisted excessive interchromosomal exchange through great ape evolution, potentially accounting for the linkage disequilibrium recently reported in this region. Collectively, these data highlight some interesting features of the genomic sequence in Xq28 and will be useful for positional cloning efforts, mouse mutagenesis studies, and further evolutionary analyses.
  • S Aradhya, T Bardaro, P Galgoczy, T Yamagata, T Esposito, H Patlan, A Ciccodicola, A Munnich, S Kenwrick, M Platzer, M D'Urso, DL Nelson
    HUMAN MOLECULAR GENETICS 10 22 2557 - 2567 2001年10月 [査読有り][通常論文]
     
    The X-linked dominant and male-lethal disorder incontinentia pigmenti (IP) is caused by mutations in a gene called NEMO(IKK-gamma). We recently reported the structure of NEMO and demonstrated that most IP patients carry an identical deletion that arises due to misalignment between repeats. Affected male abortuses with the IP deletion had provided clues that a second, incomplete copy of NEMO was present in the genome. We have now identified clones containing this truncated copy (Delta NEMO) and incorporated them into a previously constructed physical contig in distal Xq28. Delta NEMO maps 22 kb distal to NEMO and only contains exons 3-10, confirming our proposed model. A sequence of 26 kb 3 of the NEMO coding sequence is also present in the same position relative to the Delta NEMO locus, bringing the total length of the duplication to 35.5 kb. The LAGE2 gene is also located within this duplicated region, and a similar but unique LAGE1 gene is located just distal to the duplicated loci. Mapping and sequence information indicated that the duplicated regions are in opposite orientation. Analysis of the great apes suggested that the NEMO/LAGE2 duplication occurred after divergence of the lineage leading to present day humans, chimpanzees and gorillas, similar to 10-15 million years ago. Intriguingly, despite this substantial evolutionary history, only 22 single nucleotide differences exist between the two copies over the entire 35.5 kb, making the duplications > 99% identical. This high sequence identity and the inverted orientations of the two copies, along with duplications of smaller internal sections within each copy, predispose this region to various genomic alterations. We detected four rearrangements that involved NEMO, Delta NEMO or LAGE1 and LAGE2. The high sequence similarity between the two NEMO/LAGE2 copies may be due to frequent gene conversion, as we have detected evidence of sequence transfer between them. Together, these data describe an unusual and complex genomic region that is susceptible to various types of pathogenic and polymorphic rearrangements, including the recurrent lethal deletion associated with IP.
  • T Matsuura, T Yamagata, DL Burgess', A Rasmussen, RP Grewal, K Watase, M Khajavi, AE McCall, CF Davis, L Zu, M Achari, SM Pulst, E Alonso, JL Noebels, DL Nelson, HY Zoghbi, T Ashizawa
    NATURE GENETICS 26 2 191 - 194 2000年10月 [査読無し][通常論文]
     
    Spinocerebellar ataxia type 10 (SCA10; MIM 603516; refs 1.2) is an autosomal dominant disorder characterized by cerebellar ataxia and seizures. The gene SCA10 maps to a 3.8-cM interval on human chromosome 22q13-qter (refs 1.2). Because several other SCA subtypes show trinucleotide repeat expansions, we examined microsatellites in this region. We found an expansion of a pentanucleotide (ATTCT) repeat in intron 9 of SCA10 in all patients in five Mexican SCA10 families. There was an inverse correlation between the expansion size, up to 22.5 kb larger than the normal allele, and the age of onset (r(2)=0.34, P=0.018). Analysis of 562 chromosomes from unaffected individuals of various ethnic origins (including 242 chromosomes from Mexican persons) showed a range of 10 to 22 ATTCT repeats with no evidence of expansions. Our data indicate that the new SCA10 intronic ATTCT pentanucleotide repeat in SCA10 patients is unstable and represents the largest microsatellite expansion found so far in the human genome.
  • MATSUURA T, YAMAGATA T, RASMUSSEN A, GREWAL R P, WATASE K, ZU L, ACHARI M, ZOGHBI H Y, ASHIZAWA T
    Nature Genetics 26 2 191 - 194 2000年10月 [査読有り][通常論文]
     
    Spinocerebellar ataxia type 10 (SCA10; MIM 603516; refs 1.2) is an autosomal dominant disorder characterized by cerebellar ataxia and seizures. The gene SCA10 maps to a 3.8-cM interval on human chromosome 22q13-qter (refs 1.2). Because several other SCA subtypes show trinucleotide repeat expansions, we examined microsatellites in this region. We found an expansion of a pentanucleotide (ATTCT) repeat in intron 9 of SCA10 in all patients in five Mexican SCA10 families. There was an inverse correlation between the expansion size, up to 22.5 kb larger than the normal allele, and the age of onset (r(2)=0.34, P=0.018). Analysis of 562 chromosomes from unaffected individuals of various ethnic origins (including 242 chromosomes from Mexican persons) showed a range of 10 to 22 ATTCT repeats with no evidence of expansions. Our data indicate that the new SCA10 intronic ATTCT pentanucleotide repeat in SCA10 patients is unstable and represents the largest microsatellite expansion found so far in the human genome.
  • K Suwa, T Yamagata, MY Momoi, A Kawakami, Y Kikuchi, M Miyao, H Hirokawa, T Oikawa
    BRAIN & DEVELOPMENT 21 8 554 - 558 1999年12月 [査読有り][通常論文]
     
    A 4-year-old boy showed two episodes of encephalitis/encephalopathy involving disturbed consciousness, convulsion, and paresis associated with the elevated levels of protein and myelin basic protein of the cerebrospinal fluid. MRI studies of the brain revealed symmetrical lesions in the brain stem and thalami at the first episode, and additional lesions were found in the cerebellum involving both the gray and white matter in the second episode. The intensities of MRI lesions were low in T1 and high in T2. These episodes were followed by an elevation of the anti-viral antibody titers, for influenza A virus during the first episode and for adenovirus during the second. In the second episode, intravenous methylprednisolone therapy resulted in rapid improvement of his neurological signs. (C) 1999 Elsevier Science B.V. All rights reserved.
  • T Tsuru, T Yamagata, MY Momoi, Okabe, I
    PRENATAL DIAGNOSIS 19 3 269 - 270 1999年03月 [査読有り][通常論文]
     
    Prenatal screening of oculo-cerebro-renal syndrome of Lowe (OCRL; McKusick 309000) was performed using cultured amniocytes. Following identification of defective mRNA expression in the OCRL1 gene of the proband's fibroblasts, the mRNA size and quantity of the cultured amniocytes were compared. Based on this analysis, the fetus was diagnosed as being normal and was subsequently delivered as a healthy boy. This is the first reported successful prenatal screening of OCRL using a comparison with defective mRNA of OCRL1 from affected subjects. Copyright (C) 1999 John Wiley & Sons, Ltd.
  • S. Saitoh, M. Y. Momoi, T. Yamagata, H. Nakauchi, K. Nihei, M. Fujii
    Journal of Inherited Metabolic Disease 22 5 608 - 614 1999年 [査読有り][通常論文]
     
    We examined heteroplasmy of mutated mitochondrial DNA in single peripheral lymphocytes derived from 4 individuals carrying the nt 3243 A-to-G mutation, including two patients with MELAS, a patient with cardiomyopathy, deafness and diabetes mellitus, and the asymptomatic mother of one of the MELAS patients. In these subjects, all lymphocytes examined were heteroplasmic to different degrees, with a wider range of heteroplasmy evident in the symptomatic patients than in the healthy carrier.
  • S Saitoh, MY Momoi, T Ohki, T Yamagata, T Tsuru, M Mizuguchi, K Arima
    JOURNAL OF CHILD NEUROLOGY 13 11 573 - 575 1998年11月 [査読有り][通常論文]
  • Takanori Yamagata, Mariko Y. Momoi, Kaori Murai, Kaori Ikematsu, Kiyotaka Suwa, Kouichi Sakamoto, Akio Fujimura
    Therapeutic Drug Monitoring 20 4 396 - 400 1998年08月 [査読有り][通常論文]
     
    Serum concentrations of valproic acid (VPA) were reduced to 0% to 40% of the original levels by concomitant use with panipenem-betamipron (PAM-BP) in three patients. The serum VPA level began to decrease 2 days after the administration of PAPM-BP, and it began to increase within 24 hours of the last dose. The rapid change in the serum VPA level suggests the existence of unique and as yet unknown mechanisms of interaction between VPA and PAPM-BP. Epileptic seizures developed in two of the three patients during PAPM-BP use, which signaled the dangers of PAPM-BP administration to patients concomitantly administered VPA. PAPM-BP should not be used in patients administered VPA.
  • M Nakamura, T Yamagata, MY Momoi, T Yamazaki
    PEDIATRIC NEUROLOGY 19 2 148 - 150 1998年08月 [査読有り][通常論文]
     
    A 16-year-old girl had fully manifested Coffin-Lowry syndrome and drop episodes. Her drop episodes were precipitated by sudden unexpected tactile or auditory stimuli associated with the electrostatic circumstances in her leg muscles immediately after the stimuli, Studies revealed that her drop episode symptom was an unusual type of startle response and that it map be associated with Coffin-Lowry syndrome, (C) 1998 by Elsevier Science Inc. All rights reserved.
  • Kiyotaka Suwa, Mariko Y. Momoi, Takanori Yamagata, Yuuko Mori
    American Journal of Medical Genetics 78 3 291 - 293 1998年07月 [査読有り][通常論文]
     
    We report on a boy with proximal interstitial deletion of chromosome 4, del(4)(q21. 22q23). The patient was born at term with a low birth weight, flat nasal bridge, micrognathia, wide-spaced nipples, clinodactyly of fifth fingers, overlapping fingers, postaxial polydactyly of the right foot, micropenis, hypospadias, a dermal sinus, and cardiac malformations. He developed psychomotor retardation, seizures, and a liver tumor with an increased serum α-fetoprotein level and rapid growth. The patient carried a deletion of chromosome 4 involving the 4q21-q22 region that was reported to form a unique syndrome. The absence of central nervous system overgrowth and the presence of a malignant liver tumor are unique to our patient, compared to others with the 4q21-q22 deletion syndrome. The clinical manifestations and relationship between the liver tumor and chromosomal anomaly are discussed.
  • Takanori Yamagata, Mariko Y. Momoi, Shigeko Saitoh, Kumiko Takadaya, Kenji Sato
    Pediatric Neurology 18 4 358 - 361 1998年04月 [査読有り][通常論文]
     
    A 12-year-old girl developed ataxia that gradually progressed. At age 18 the patient presented with mental retardation, cachectic dwarfism, microcephalus, and a progeroid appearance but no photosensitive skin lesions or deafness. On analysis of fibroblasts, unscheduled DNA synthesis was reduced to 50% of normal, but colony-forming ability after ultraviolet irradiation was normal. The symptoms and phenotype of the patient were distinguished from those in Cockayne syndrome and xeroderma pigmentosum. This case is interesting because the defect in DNA repair after ultraviolet irradiation was detected in a patient with neurologic disturbances but without photosensitive skin lesions.
  • H Igarashi, MY Momoi, T Yamagata, H Shiraishi, Eguchi, I
    PEDIATRIC NEUROLOGY 18 4 366 - 369 1998年04月 [査読有り][通常論文]
     
    Involvement of the cardiac conduction system is a common clinical feature in myotonic dystrophy, whereas the association of primary myocardial abnormalities has rarely been reported. A patient with a severe form of congenital myotonic dystrophy who developed fatal left ventricular hypertrophy at 3 months of age and died at 2 years of age is reported. Serial ultrasonographic studies revealed progressive left ventricular hypertrophy accompanied by outflow obstruction of the left ventricle. Southern analysis for the myotonin kinase gene revealed a 5.8 kb expansion of CTG repeats in addition to a fragment of normal length. The degree of expansion was much greater than those of other reported patients with congenital myotonic dystrophy. These findings suggest that left ventricular hypertrophy represents an extreme level of myocardial damage in myotonic dystrophy and that this damage may be related to the larger size of the CTG repeats. (C) 1998 by Elsevier Science Inc. All rights reserved.
  • S Saitoh, MY Momoi, T Yamagata, M Miyao, K Suwa
    PEDIATRIC NEUROLOGY 18 3 265 - 268 1998年03月 [査読有り][通常論文]
     
    We present five different types of dentatorubral-pallidoluysian atrophy in one Japanese family. Two siblings and their paternal uncle manifested the juvenile type dentatorubral-pallidoluysian atrophy, the siblings' father had the late-adult type, and another paternal uncle had the early-adult type, Gene analysis confirmed the diagnosis for the proband and her sibling. By following the clinical courses and electroencephalographic changes, we found that the types of epileptic seizures and the electroencephalograms of the juvenile dentatorubral-pallidoluysian atrophy patients changed as the illness progressed. The siblings exhibited different levels of clinical severity despite the similar deoxyribonucleic acid expansion detected in their lymphocytes. (C) 1998 by Elsevier Science Inc. All rights reserved.
  • T Yamagata, T Tsuru, MY Momoi, K Suwa, Y Nozaki, T Mukasa, H Ohashi, Y Fukushima, T Momoi
    GENOMICS 45 3 535 - 540 1997年11月 [査読有り][通常論文]
     
    The enzyme oligosaccharyltransferase (dolichyl-diphosphooligosaccharide-protein glycosyltransferase; EC 2.4.1.119) (DDOST) catalyzes the transfer of a high-mannose oligosaccharide (GlcNac(2)Man(9)Glc(3)) from a dolichol-linked oligosaccharide donor (dolichol-P-GlcNac(2)Man(9)Glc(3)) onto the asparagine acceptor site within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains across the membrane of the endoplasmic reticulum. We isolated mouse and human DDOST cDNAs from retinoic acid-treated mouse P19 EC cells and human NT-2 cells, respectively. DDOST mRNA is expressed intensely in heart and pancreas, but at lower levels in brain. Here we show that the human DDOST 48-kDa subunit gene (HGMW-approved symbol DDOST) is organized into 11 exons expanding about 9 kb. This DDOST subunit gene is localized on chromosome 1p36.1 by fluorescence in situ hybridization analysis. (C) 1997 Academic Press.
  • T Yamagata, MY Momoi, M Miyao, S Kobayashi
    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 63 4 528 - 530 1997年10月 [査読有り][通常論文]
     
    A 10 year old girl with benign childhood epilepsy with centrotemporal spikes showed centrotemporal spikes induced by blinking even in a dark room. Spikes could not be induced by photic stimulation, eye closure, eye movement, eye deviation, or passive blinks. There have been no previous reports of spikes induced by blinks in benign childhood epilepsy with centrotemporal spikes.
  • T Ohta, M Nakano, T Tsujita, K Abe, K Osoegawa, T Yamagata, K Yoshiura, Y Jinno, E Soeda, Y Nakamura, N Niikawa
    AMERICAN JOURNAL OF HUMAN GENETICS 58 3 544 - 550 1996年03月 [査読有り][通常論文]
     
    Transient abnormal myelopoiesis (TAM) is a leukemoid reaction occurring occasionally in Down syndrome (DS) newborn infants. It has been hypothesized that ''disomic homozygosity'' in 21-trisomic cells plays an important role in the genesis of TAM, and the putative TAM gene was suggested to be mapped at a 21q11 region. We encountered a DS-associated TAM infant with a 47,XY,inv(21)(q11.1q22.13), + inv(21)(q11.1q22.13) karyotype. On the basis of another presumption that in this patient the putative TAM gene is disrupted by the break, we tried to isolate a breakpoint DNA. FISH analysis with cosmid clones corresponding to various sequence-tagged-site (STS) markers mapped at around 21q11.1-q11.2, we confirmed that the proximal breakpoint of the inv(21) was located between two STSs, G51E07 and D21S215, the latter locus being consistent with the previous tentative mapping. After construction of a cosmid contig encompassing between the two markers, we have isolated a cosmid clone corresponding to the proximal breakpoint of the inversion. This breakpoint was located near a previously identified duplicated region that is homologous to the sequence at 21q22.1. The isolated cosmid clone is useful for analysis of other TAM patients and for a search for a transcript at or flanking the breakpoint.
  • Masato Mori, Takanori Yamagata, Yuuko Mori, Mitsuhiro Nokubi, Ken Saito, Yoshimitsu Fukushima, Mariko Y. Momoi
    American Journal of Medical Genetics 61 4 304 - 309 1996年02月 [査読無し][通常論文]
     
    Clinical and pathological observations of a 6-month-old-boy with Costello syndrome are reported. The main clinical findings were loose skin of the neck, hands, and feet, deep palmar and plantar creases, typical 'coarse' face with thick lips and macroglossia, relative macrocephaly, mental retardation, short stature, arrhythmia, large size for gestational age, and poor feeding. At age 6 months he died of rhabdomyolysis. The major pathological findings were fine, disrupted, and loosely-constructed elastic fibers in the skin, tongue, pharynx, larynx, and upper esophagus, but not in the bronchi, alveoli, aorta, or coronary arteries. Hyperplasia of collagen fibers in the skin, hyperplasia of the mucous glands in the bronchus, narrowing of the pulmonary artery, degeneration of the atrial conduction system, calcification and ballooning of skeletal muscle fibers with infiltration of macrophages, and myoglobin depositions in the collecting ducts in the kidney were also observed. The degeneration of elastic fibers was confirmed in the skin of a second Costello syndrome patient. Expression of elastin mRNA in the patient's fibroblasts was normal in size and amount. Given that elastic fiber degeneration was observed in the tissues with clinical symptoms, we speculate that a defect of elastic fibers, possibly relating to alternative splicing in the elastin gene or to defects in elastin microfibrils, might be involved in the pathogenesis of Costello syndrome.
  • MORI M, YAMAGATA T, MORI Y, NOKUBI M, SAITO K, FUKUSHIMA Y, MOMOI M Y
    Am. J. Med. Genet. 61 4 304 - 309 1996年02月 [査読有り][通常論文]
     
    Clinical and pathological observations of a 6-month-old-boy with Costello syndrome are reported. The main clinical findings were loose skin of the neck, hands, and feet, deep palmar and plantar creases, typical 'coarse' face with thick lips and macroglossia, relative macrocephaly, mental retardation, short stature, arrhythmia, large size for gestational age, and poor feeding. At age 6 months he died of rhabdomyolysis. The major pathological findings were fine, disrupted, and loosely-constructed elastic fibers in the skin, tongue, pharynx, larynx, and upper esophagus, but not in the bronchi, alveoli, aorta, or coronary arteries. Hyperplasia of collagen fibers in the skin, hyperplasia of the mucous glands in the bronchus, narrowing of the pulmonary artery, degeneration of the atrial conduction system, calcification and ballooning of skeletal muscle fibers with infiltration of macrophages, and myoglobin depositions in the collecting ducts in the kidney were also observed. The degeneration of elastic fibers was confirmed in the skin of a second Costello syndrome patient. Expression of elastin mRNA in the patient's fibroblasts was normal in size and amount. Given that elastic fiber degeneration was observed in the tissues with clinical symptoms, we speculate that a defect of elastic fibers, possibly relating to alternative splicing in the elastin gene or to defects in elastin microfibrils, might be involved in the pathogenesis of Costello syndrome.
  • S. Saitoh, M. Miyao, S. Kobayashi, T. Yamagata, M. Y. Momoi
    Journal of the Japan Epilepsy Society 14 3 192 - 197 1996年 [査読有り][通常論文]
     
    A seven year old boy presented non convulsive status epilepticus showing continuous diffuse high voltage slow waves in his ictal EEG. His interictal EEG studies revealed Rolandic discharges (RD) during sleep. After the first episodes, he presented occasional partial seizures showing right hemi-clonic convulsions of the face and upper extremity shortly after falling in sleep suggesting that he had benign epilepsy of childhood with centrotemporal spikes (BECCT). This is the first report of non convulsive status epilepticus in a patient with BECCT suggesting that the focal discharges of BECCT can cause non convulsive status epilepticus by the generalization of abnormal discharges.
  • K. Suwa, S. Kobayashi, M. Miyao, Y. Nozaki, Y. Mori, T. Yamagata, M. Y. Momoi
    No To Hattatsu 28 4 306 - 311 1996年 [査読有り][通常論文]
     
    The relationship between aphasia and electroencephalogram (EEG) findings was studied in 2 patients with Landau-Kleffner syndrome. The appearance of diffuse spike and wave complexes almost always preceded the exacerbation of aphasia. Prior to the improvement of aphasia, EEG abnormality localized into the temporal region, and subsequently disappeared.
  • T YAMAGATA, K MUROYA, T MUKASA, H IGARASHI, M MOMOI, T TSUKAHARA, K ARAHATA, H KUMAGAI, T MOMOI
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 210 1 231 - 237 1995年05月 [査読無し][通常論文]
     
    Hepatocyte growth factor (HGF) mRNA and its receptor (c-Met) mRNA were detected in the fetal and adult rat brain. Expression of c-Met mRNA was increased after birth. HGF mRNA was preferentially expressed in the microglia of the rat brain, while c-Met mRNA was expressed in neurons as well as astrocytes and microglia. Most of the neurons were c-Met positive, and HGF stimulated tyrosine phosphorylation of c-Met (140-kDa) in the neurons. HGF as well as bFGF also activated Ras in the neurons. These results suggest that HGF plays a biological role as one of the neurotrophic factors in the brain. (C) 1995 Academic Press, Inc.
  • T YAMAGATA, M NISHIE, H SHIOKAWA, S KOBAYASHI, M MIYAO, M YANAGISAWA
    JAPANESE JOURNAL OF PSYCHIATRY AND NEUROLOGY 48 2 302 - 303 1994年06月 [査読有り][通常論文]
  • T YAMAGATA, MY MOMOI, M YANAGISAWA, H KUMAGAI, M YAMAKADO, T MOMOI
    DEVELOPMENTAL BRAIN RESEARCH 77 2 163 - 176 1994年02月 [査読無し][通常論文]
     
    The expression and distribution of three retinoic acid receptors, alpha, beta and gamma, were investigated in the CNS of mouse embryos during development. mRNAs and proteins of RAR-beta that were expressed in the spinal cord of the 12.5-day mouse embryo decreased during development but they were not decreased in the brain. The RAR-beta-positive cells were already present in the ventral region of the spinal cord of 10.5-day mouse embryos, gradually appeared in the dorsal region during development and then disappeared from the spinal cord after birth. In the brain, RAR-beta-positive cells were detected in the mesencephalon and rhombencephalon but not in the telencephalon of the 12.5-day mouse embryos. RAR-beta-positive cells were present in the hippocampus and cingulum but not in the neocortex of 14.5-day mouse embryos. Most neurons in the hippocampus of 16.5-day mouse embryos and the cortex of newborn mice were RAR-beta-positive. In the spinal cord, RAR-alpha mRNAs and proteins also decreased during development but more gradually than RAR-beta mRNAs and proteins. During development, the distributions of RAR-alpha and -beta in the spinal cord and brain did not differ substantially. The main difference was the appearance of a subtypes of RAR-alpha, a 52-kDa protein, in the brain of newborn mice. On the other hand, RAR-gamma proteins were only faintly detected in the spinal cord and the brain of the mice during the embryonal stages but these increased after birth. The distribution of RAR-alpha- or -beta-positive cells were consistent with the neurogenesis during development in the spinal cord and brain.
  • T YAMAGATA, T MOMOI, H KUMAGAI, T NISHIKAWA, M YANAGISAWA, M MOMOI
    BIOMEDICAL RESEARCH-TOKYO 14 3 183 - 190 1993年06月 [査読無し][通常論文]
     
    While retinoic acid is known to be involved in the neurogenesis of embryos, little is known about its function in the adult brain despite the fact that many retinols and retinoic acid binding activities were detected in the extracts from mature rat brain. Furthermore, retinoic acid that was injected into peritoneal cavities was incorporated into the brain as well as into the testis and liver. By using immunoblot analyses with specific antisera against three retinoic acid receptors, alpha, beta and gamma, we demonstrated that the beta type is the main retinoic acid receptor expressed in the mature rat brain. Retinoic acid receptor beta proteins were expressed at a higher level in the cerebral cortex, striatum and cerebellum than in the other regions, and low levels were found in the limbic forebrain and hippocampus. In the cerebellum, granular cells were most strongly positive for retinoic acid receptor beta. The amount of retinoic acid receptor beta proteins in the cerebellum was reduced in rats fed with a vitamin A-deficient diet, and they were up-regulated at 12 h after the injection of retinoic acid into the peritoneal cavity. Immunohistochemical studies supported the immunoblot data; granular cells were negative for retinoic acid receptor beta in a vitamin A-deficient rat, but they became positive after the injection of retinoic acid. These findings suggest that retinoic acid receptor beta is involved in the physiological functions of the granular cells in the cerebellum and that these functions are regulated by the retinoic acid concentration in the adult brain.
  • K ICHIHASHI, M MOMOI, T YAMAGATA, M YANAGISAWA, T MOMOI
    BIOMEDICAL RESEARCH-TOKYO 12 2 105 - 112 1991年04月 [査読無し][通常論文]
     
    The expression of cellular retinoic acid binding protein (CRABP) was immunohistochemically analyzed in the muscle tissues of mouse embryos at various developmental stages. CRABP was expressed in cells in developing heart muscle and those in the vertebral primordia of 10.5- and 16.5-day embryos, and in cells of skeletal muscles of 16.5-day mouse embryos. The thickened ventricular wall of the heart and developed muscle fibers did not express CRABP. The temporal expression of CRABP in developing muscles suggests that retinoic acid is involved in the initial process of the muscle differentiation.
  • ステロイド療法が有効であった全身こむら返り病(里吉病)の一例.
    臨床神経 31 79 - 83 1991年 [査読有り][通常論文]
  • I. Eguchi, M. Miyao, T. Yamagata, H. Shimoizumi, S. Yano, M. Yanagisawa
    No To Hattatsu 23 4 355 - 361 1991年 [査読有り][通常論文]
  • T YAMAGATA, S YANO, OKABE, I, M MIYAO, MY MOMOI, M YANAGISAWA, H HIRATA, K KOMATSU
    PEDIATRIC NEUROLOGY 6 5 326 - 329 1990年09月 [査読無し][通常論文]
  • M MOMOI, T YAMAGATA, K ICHIHASHI, M YANAGISAWA, M YAMAKADO, T MOMOI
    DEVELOPMENTAL BRAIN RESEARCH 54 2 161 - 167 1990年07月 [査読無し][通常論文]
  • T YAMAGATA, M MOMOI, S MIYAMOTO, S KOBAYASHI, S KAMOSHITA
    BRAIN & DEVELOPMENT 12 6 760 - 765 1990年 [査読無し][通常論文]
     
    The first multi-institutional survey of the Aicardi syndrome in Japan was performed during 1985 and 1986. Among the 20 collected cases, 9 fulfilled the typical clinical triad; infantile spasms, agenesis of the corpus callosum and chorioretinal lacuna. Three cases had agenesis of corpus callosum and chorioretinal lacuna. Five cases had agenesis of the corpus callosum and infantile spasms. We classified 12 cases with both agenesis of the corpus callosum and a lacuna as typical cases, and the remaining 8 cases as atypical cases. No familial cases were found among either the typical or atypical cases. The presence of the vertebral anomalies or other anomalies in the atypical cases, which were frequently observed in the typical cases, suggested that unknown common processes were affected in both the typical and atypical groups.

MISC

  • Hirokazu Yamagishi, Masahide Goto, Hitoshi Osaka, Mari Kuwajima, Kazuhiro Muramatsu, Takanori Yamagata Epileptic disorders : international epilepsy journal with videotape 22 (2) 214 -218 2020年04月 [査読無し][通常論文]
     
    Ring chromosome 20 syndrome is an epileptic and neurodevelopmental encephalopathy that occurs in children, characterised by a triad of refractory frontal lobe seizures, recurrent non-convulsive status epilepticus and frontal lobe-dominant paroxysmal discharges. However, details of other clinical features associated with ring chromosome 20 syndrome remain unknown. Here, we report two patients with ring chromosome 20 syndrome who had praxis-induced reflex seizures. Case 1 was an 11-year-old girl who presented with seizures triggered by specific activities such as mental and written calculations, writing, decision-making, recall, sudden changes in routine or ambient temperature and bathing. During calculations, left frontal lobe-dominant, 3-Hz slow-wave bursts were observed on EEG. Lacosamide effectively suppressed her tonic seizures. Case 2 was a six-year-old boy who presented with seizures triggered by specific activities such as calculations, recall and bathing. During calculations, frontal lobe-dominant, 3-Hz spike and slow-wave bursts were observed on EEG. Although his epilepsy was refractory, gabapentin reduced the frequency of focal seizures. In both cases, the hyperexcitability in the frontal lobe may have spread to the motor cortex and precipitated praxis-induced seizures. Therefore, in addition to the known characteristic triad, praxis-induced reflex seizures may also be a feature of ring chromosome 20 syndrome.
  • 食物アレルギーにおいて腸内細菌叢が腸管上皮タイトジャンクションへ及ぼす影響
    熊谷 秀規, ジャネルケ・トゥレウ, 神保 恵理子, 渡邊 真弥, 幸喜 富, 横山 孝二, 小坂 仁, 山形 崇倫 日本小児栄養消化器肝臓学会雑誌 33 (2) 134 -134 2019年12月 [査読無し][通常論文]
  • 横山 孝二, 熊谷 秀規, 岡田 優子, 橋本 佑介, 山形 崇倫 日本小児栄養消化器肝臓学会雑誌 33 (Suppl.) 98 -98 2019年10月 [査読無し][通常論文]
  • 橋本 佑介, 横山 孝二, 熊谷 秀規, 岡田 優子, 山形 崇倫 日本小児栄養消化器肝臓学会雑誌 33 (Suppl.) 123 -123 2019年10月 [査読無し][通常論文]
  • Megumi Kobayashi, Masako Nagashima, Tatsuya Tokuda, Takahiro Ikeda, Yukifumi Monden, So Kanazawa, Masami K. Yamaguchi, Ryoichi Sakuta, Takanori Yamagata, Ippeita Dan I-PERCEPTION 10 169 -169 2019年09月
  • ADHD児童における表情認知の神経基盤 近赤外分光法による検討
    小林 恵, 池田 尚広, 徳田 竜也, 長嶋 雅子, 門田 行史, 金沢 創, 山口 真美, 作田 亮一, 山形 崇倫, 檀 一平太 日本心理学会大会発表論文集 83回 481 -481 2019年08月 [査読無し][通常論文]
  • 疫学と病態・PFAS 小児のモモ花粉-食物アレルギー症候群(pollen-food allergy syndrome: PFAS)発症に関連する花粉の検討
    渡邉 知佳, 加藤 正也, 宮本 学, 安藤 裕輔, 中山 元子, 福田 啓伸, 熊谷 秀規, 山形 崇倫, 吉原 重美 アレルギー 68 (4-5) 492 -492 2019年05月 [査読無し][通常論文]
  • 渡邉 知佳, 加藤 正也, 宮本 学, 安藤 裕輔, 中山 元子, 福田 啓伸, 熊谷 秀規, 山形 崇倫, 吉原 重美 アレルギー 68 (4-5) 492 -492 2019年05月 [査読無し][通常論文]
  • 若林慶, 若林慶, 水野晴夫, 田中大輔, 田中大輔, 久保達也, 高橋和郎, 山岸裕和, 山岸裕和, 渡辺浩史, 下泉秀夫, 山形崇倫, 沼崎啓, 郡司勇治, 門田行史, 門田行史 小児科臨床 72 (2) 199 -203 2019年02月 [査読無し][通常論文]
     
    症例は生来健康な11歳の女児。小学校2年次(7歳時)から不注意症状による学業成績の低下がみられた。8歳以降に体重増加不良、眼球突出、甲状腺腫大が出現し、11歳時にBasedow病と診断された。Basedow病の治療後に不注意症状が著しく改善した経過から、原因不明の学業成績の低下を初期症状とした低年齢の小児の場合には、学習障害や注意欠如多動症(attention deficit hyperactivity disorder:ADHD)のほかに身体疾患であるBasedow病を鑑別に挙げるべきである。(著者抄録)
  • 機能性胃腸障害として経過を観られていた十二指腸結腸瘻の1例
    横山 孝二, 矢野 智則, 熊谷 秀規, 今川 智之, 廣瀬 優子, 山形 崇倫 日本小児栄養消化器肝臓学会雑誌 32 (Suppl.) 94 -94 2018年09月 [査読無し][通常論文]
  • 蓮沼 もも, 廣瀬 優子, 齋藤 貴志, 川原 勇太, 横山 孝二, 熊谷 秀規, 森本 哲, 山形 崇倫 日本小児栄養消化器肝臓学会雑誌 32 (Suppl.) 90 -90 2018年09月 [査読無し][通常論文]
  • 横山 孝二, 矢野 智則, 熊谷 秀規, 今川 智之, 廣瀬 優子, 山形 崇倫 日本小児栄養消化器肝臓学会雑誌 32 (Suppl.) 94 -94 2018年09月 [査読無し][通常論文]
  • 松原 優里, 小黒 範子, 清水 純, 小坂 仁, 山形 崇倫 小児科臨床 71 (7) 1307 -1314 2018年07月 [査読無し][通常論文]
  • 自閉スペクトラム症児に対するアレイCGH解析によるMicroRNAの検討
    後藤 昌英, 松本 歩, 小島 華林, 神保 恵理子, 小坂 仁, 大橋 圭, 齋藤 伸治, 山形 崇倫 脳と発達 50 (Suppl.) S329 -S329 2018年05月 [査読無し][通常論文]
  • K. Kojima, A. Miyauchi, T. Nakajima, N. Taga, S. A. Ono, H. Mizukami, M. Kato, H. Osaka, S. Muramatsu, T. Yamagata HUMAN GENE THERAPY 28 (12) A4 -A4 2017年12月 [査読無し][通常論文]
  • 若林 慶, 水野 晴夫, 田中 大輔, 久保 達也, 高橋 和郎, 山岸 裕和, 渡辺 浩史, 下泉 秀夫, 山形 崇倫, 沼崎 啓, 郡司 勇治, 門田 行史 日本小児科学会雑誌 121 (12) 2034 -2035 2017年12月 [査読無し][通常論文]
  • ジャネルケ・トゥレウ, 熊谷 秀規, 神保 恵理子, 横山 孝二, 今川 智之, 加藤 耕平, 廣瀬 優子, 山形 崇倫 日本小児栄養消化器肝臓学会雑誌 31 (Suppl.) 107 -107 2017年09月 [査読無し][通常論文]
  • 横山 孝二, 熊谷 秀規, 今川 智之, 山形 崇倫, 岡本 宏明 日本小児栄養消化器肝臓学会雑誌 31 (Suppl.) 116 -116 2017年09月 [査読無し][通常論文]
  • 加藤 耕平, 熊谷 秀規, 今川 智之, 横山 孝二, 山形 崇倫 日本小児栄養消化器肝臓学会雑誌 31 (Suppl.) 138 -138 2017年09月 [査読無し][通常論文]
  • 廣瀬 優子, 熊谷 秀規, 田中 正則, 今川 智之, 横山 孝二, 山形 崇倫 日本小児栄養消化器肝臓学会雑誌 31 (Suppl.) 149 -149 2017年09月 [査読無し][通常論文]
  • 今川 智之, 加藤 耕平, 横山 孝二, 熊谷 秀規, 山形 崇倫, 戸川 貴夫 日本小児栄養消化器肝臓学会雑誌 31 (Suppl.) 157 -157 2017年09月 [査読無し][通常論文]
  • 安済 達也, 松本 歩, 別井 広幸, 小坂 仁, 山形 崇倫 小児科臨床 70 (8) 1257 -1262 2017年08月
  • 尾崎 理史, 宮内 彰彦, 松本 歩, 門田 行史, 保科 優, 菊池 豊, 古川 理恵子, 小坂 仁, 相原 敏則, 山形 崇倫 日本小児科学会雑誌 121 (8) 1391 -1396 2017年08月 [査読有り][通常論文]
     
    3ヵ月男児。父と入浴中に心肺停止状態となり、救急隊による蘇生後、小児集中治療室へ搬送された。受傷機転不明の急性硬膜下血腫、眼底出血を認めたため虐待関連頭部外傷を疑ったが、入院時の問診では虐待を疑うエピソードを確認できなかった。びまん性脳浮腫を認めたため頸椎MRIを撮影し、Short Tau Inversion Recovery矢状断像にて項靱帯や棘間靱帯などの椎体支持組織および頸髄内部が高信号を示し、頸髄損傷を示唆する所見であった。後日、父が本児を強く揺さぶったことが確認され、乳幼児揺さぶられ症候群による上位頸髄損傷から呼吸停止および心肺停止状態に至ったと判断した。入院経過中、各種治療への反応は乏しく徐々に多臓器不全の状態を呈し、第41病日に死亡した。
  • 若林 慶, 門田 行史, 小坂 仁, 尾崎 理史, 古井 麻衣, 宮島 有果, 川又 竜, 久保 達也, 小池 泰敬, 田中 惠子, 沼崎 啓, 高橋 和郎, 山形 崇倫, 郡司 勇治 日本小児科学会雑誌 121 (7) 1252 -1252 2017年07月 [査読無し][通常論文]
  • Sachie Nakamura, Hitoshi Osaka, Shin-ichi Muramatsu, Naomi Takino, Mika Ito, Shiho Aoki, Eriko F. Jimbo, Kuniko Shimazaki, Tatsushi Onaka, Sumio Ohtsuki, Tetsuya Terasaki, Takanori Yamagata MOLECULAR THERAPY 25 (5) 108 -108 2017年05月 [査読無し][通常論文]
  • Down症候群児に合併した自閉症スペクトラムの特徴
    松原 優里, 清水 純, 小黒 範子, 小坂 仁, 山形 崇倫 脳と発達 49 (Suppl.) S305 -S305 2017年05月 [査読無し][通常論文]
  • Down症候群児に合併した自閉症スペクトラムの特徴
    松原 優里, 清水 純, 小黒 範子, 小坂 仁, 山形 崇倫 脳と発達 49 (Suppl.) S305 -S305 2017年05月 [査読無し][通常論文]
  • 自閉症スペクトラム障害児に対するアレイCGH解析での検討
    後藤 昌英, 松本 歩, 神保 恵理子, 小坂 仁, 大橋 圭, 齋藤 伸治, 山形 崇倫 脳と発達 49 (Suppl.) S312 -S312 2017年05月 [査読無し][通常論文]
  • 肺炎球菌ワクチン接種後にワクチン非含有血清型による侵襲性肺炎球菌感染症を発症した1例
    尾崎 理史, 門田 行史, 高橋 和郎, 川又 竜, 若林 慶, 久保 達也, 宮島 有果, 小池 泰敬, 沼崎 啓, 山形 崇倫, 郡司 勇治 日本小児科学会雑誌 121 (4) 772 -772 2017年04月 [査読無し][通常論文]
  • 心房間での右左短絡を有する成人Ebstein奇形に対する治療戦略
    岡 健介, 片岡 功一, 鈴木 峻, 松原 大輔, 佐藤 智幸, 南 孝臣, 吉積 功, 河田 政明, 久保田 香菜, 今井 靖之, 山形 崇倫 日本成人先天性心疾患学会雑誌 6 (1) 134 -134 2017年01月 [査読無し][通常論文]
  • Stephanie Sutoko, Tsukasa Funane, Tsukasa Funane, Takusige Katura, Hiroki Sato, Masashi Kiguchi, Atsushi Maki, Yukifumi Monden, Masako Nagashima, Takanori Yamagata, Ippeita Dan, Ippeita Dan Progress in Biomedical Optics and Imaging - Proceedings of SPIE 10059 2017年01月 [査読無し][通常論文]
     
    © 2017 SPIE. In pediatrics studies, the quality of functional near infrared spectroscopy (fNIRS) signals is often reduced by motion artifacts. These artifacts likely mislead brain functionality analysis, causing false discoveries. While noise correction methods and their performance have been investigated, these methods require several parameter assumptions that apparently result in noise overfitting. In contrast, the rejection of noisy signals serves as a preferable method because it maintains the originality of the signal waveform. Here, we describe a semi-learning algorithm to detect and eliminate noisy signals. The algorithm dynamically adjusts noise detection according to the predetermined noise criteria, which are spikes, unusual activation values (averaged amplitude signals within the brain activation period), and high activation variances (among trials). Criteria were sequentially organized in the algorithm and orderly assessed signals based on each criterion. By initially setting an acceptable rejection rate, particular criteria causing excessive data rejections are neglected, whereas others with tolerable rejections practically eliminate noises. fNIRS data measured during the attention response paradigm (oddball task) in children with attention deficit/hyperactivity disorder (ADHD) were utilized to evaluate and optimize the algorithm's performance. This algorithm successfully substituted the visual noise identification done in the previous studies and consistently found significantly lower activation of the right prefrontal and parietal cortices in ADHD patients than in typical developing children. Thus, we conclude that the semi-learning algorithm confers more objective and standardized judgment for noise rejection and presents a promising alternative to visual noise rejection.
  • K. Kojima, A. Miyauchi, T. Nakajima, S. A. Ono, H. Mizukami, M. Kato, H. Osaka, S. Muramatsu, T. Yamagata HUMAN GENE THERAPY 27 (11) A146 -A147 2016年11月 [査読無し][通常論文]
  • T. Yamagata, K. Kojima, A. Miyauchi, T. Nakajima, S. A. Ono, H. Mizukami, K. Ozawa, T. Sato, M. Kato, H. Osaka, S. Muramatsu HUMAN GENE THERAPY 27 (11) A45 -A45 2016年11月 [査読無し][通常論文]
  • 自閉症スペクトラム児における視点変換時の運動プランニング方略
    平井真洋, 櫻田武, 井澤淳, 池田尚広, 門田行史, 下泉秀夫, 山形崇倫 発達神経科学学会 第5回大会 2016年11月 [査読無し][通常論文]
  • スチリペントールが著効したPCDH19関連てんかんの1例
    山岸 裕和, 小坂 仁, 日暮 憲道, 池田 尚広, 宮内 彰彦, 長嶋 雅子, 門田 行史, 桑島 真理, 廣瀬 伸一, 山形 崇倫 てんかん研究 34 (2) 533 -533 2016年09月 [査読無し][通常論文]
  • Veno-Venous Extracorporeal Membrane Oxygenation(V-V ECMO)管理で救命しえた重症呼吸不全の乳児例
    渡邉 知佳, 青柳 順, 今川 智之, 小高 淳, 中村 文人, 多賀 直行, 大宮 卓, 佐藤 光, 西村 秀一, 久保 亨, 森内 浩幸, 蒲地 一成, 田村 大輔, 山形 崇倫 日本小児呼吸器学会雑誌 27 (Suppl.) 150 -150 2016年09月 [査読無し][通常論文]
  • 熊谷 秀規, 横山 孝二, 今川 智之, 吉田 祥子, 小林 和人, 山形 崇倫 日本小児栄養消化器肝臓学会雑誌 30 (Suppl.) 90 -90 2016年08月 [査読無し][通常論文]
  • 横山 孝二, 熊谷 秀規, 南 孝臣, 今川 智之, 山形 崇倫 日本小児栄養消化器肝臓学会雑誌 30 (Suppl.) 103 -103 2016年08月 [査読無し][通常論文]
  • 今川 智之, 横山 孝二, 熊谷 秀規, 小野 滋, 山形 崇倫 日本小児栄養消化器肝臓学会雑誌 30 (Suppl.) 113 -113 2016年08月 [査読無し][通常論文]
  • 渡邉 知佳, 伊東 岳峰, 金井 孝裕, 甲賀 健史, 青柳 順, 小高 淳, 山形 崇倫 小児科臨床 69 (6) 1005 -1009 2016年06月
  • 抗MOG抗体陽性ADEMの一症例
    若林 慶, 桑島 真理, 宮内 彰彦, 高橋 利幸, 中島 一郎, 小坂 仁, 山形 崇倫 脳と発達 48 (Suppl.) S406 -S406 2016年05月 [査読無し][通常論文]
  • プロプラノロールが奏効した口唇および眼窩内血管腫の乳児例
    増田 卓哉, 川原 勇太, 和田 聖哉, 新島 瞳, 翁 由紀子, 早瀬 朋美, 森本 哲, 山形 崇倫 日本小児科学会雑誌 120 (3) 649 -649 2016年03月 [査読無し][通常論文]
  • 黒崎 雅典, 伊東 岳峰, 安済 達也, 小森 咲子, 別井 広幸, 青柳 順, 齋藤 貴志, 小高 淳, 金井 孝裕, 横山 孝二, 熊谷 秀規, 森本 哲, 山形 崇倫 日本小児科学会雑誌 120 (3) 649 -649 2016年03月 [査読無し][通常論文]
  • エベロリムスを投与した結節性硬化症に伴う腎血管筋脂肪腫の一例
    亀田 智弘, 黒川 真輔, 小松原 麻衣子, 久保 太郎, 中野 一彦, 藤崎 明, 鷲野 聡, 森川 愛, 貫井 昭徳, 中西 公司, 高山 達也, 森田 辰男, 山形 崇倫, 宮内 彰彦 泌尿器外科 29 (1) 94 -94 2016年01月 [査読無し][通常論文]
  • 尾崎 理史, 宮内 彰彦, 松本 歩, 門田 行史, 小坂 仁, 保科 優, 古川 理恵子, 相原 敏則, 山形 崇倫 脳と発達 47 (5) 375 -375 2015年09月 [査読無し][通常論文]
  • NIRS計測を用いた小児ADHD治療薬の効果判定法の開発
    門田 行史, 山形 崇倫 メディックス 63 8 -12 2015年09月 [査読無し][通常論文]
  • 難治性てんかんと退行を示したMECP2重複症候群兄弟例の発作型と脳波の経年的変化
    若林 慶, 長嶋 雅子, 宮内 彰彦, 小島 華林, 後藤 昌英, 安済 達也, 植田 綾子, 門田 行史, 小高 淳, 横山 孝二, 小坂 仁, 山形 崇倫 てんかん研究 33 (2) 599 -599 2015年09月 [査読無し][通常論文]
  • 井上 俊, 今川 智之, 横山 孝二, 熊谷 秀規, 山形 崇倫 日本小児栄養消化器肝臓学会雑誌 29 (Suppl.) 110 -110 2015年09月 [査読無し][通常論文]
  • 横山 孝二, 熊谷 秀規, 今川 智之, 岡本 宏明, 山形 崇倫 日本小児栄養消化器肝臓学会雑誌 29 (Suppl.) 129 -129 2015年09月 [査読無し][通常論文]
  • 熊谷 秀規, 横山 孝二, 今川 智之, 山形 崇倫 日本小児栄養消化器肝臓学会雑誌 29 (Suppl.) 150 -150 2015年09月 [査読無し][通常論文]
  • 田中 大輔, 門田 行史, 石井 朋之, 宮内 彰彦, 山形 崇倫 小児科臨床 68 (7) 1361 -1365 2015年07月 [査読無し][通常論文]
     
    片側顔面神経麻痺が先行し、両側顔面神経麻痺、さらに両側上下肢の感覚優位の末梢神経障害が出現した小児例を経験した。初発症状が片側顔面神経麻痺であり、Bell麻痺と診断され、近医でステロイド内服治療が開始された。5日後に感覚優位の両側末梢神経障害が出現し、髄液検査では細胞数6mm3、蛋白67mg/dLと蛋白細胞解離を認めた。Guillain-Barre症候群と診断しγグロブリン治療を実施した。約30日で右顔面神経麻痺は消失したが、左顔面神経麻痺は消失までに約400日を要した。通常、Guillain-Barre症候群の末梢神経障害は、下肢から上行性に障害が及ぶが、スペクトラムとして本症例のように顔面神経麻痺が先行する例がある。抗ガングリオシド抗体が陰性であり、ほかの自己抗体産生が誘因となりGuillain-Barre症候群様の病態を呈したと推測した。(著者抄録)
  • 中野 祐子, 池田 尚広, 宮内 彰彦, 長嶋 雅子, 門田 行史, 桑島 真理, 小坂 仁, 山形 崇倫 脳と発達 47 (Suppl.) S289 -S289 2015年05月 [査読無し][通常論文]
  • Kensuke Oka, Takaomi Minami, Tatsuya Anzai, Sadahiro Furui, Akiko Yokomizo, Tomoyuki Ishii, Tomoyuki Sato, Koichi Kataoka, Takanori Yamagata CIRCULATION 131 2015年04月 [査読無し][通常論文]
  • Kensuke Oka, Takaomi Minami, Tatsuya Anzai, Sadahiro Furui, Akiko Yokomizo, Tomoyuki Ishii, Tomoyuki Sato, Koichi Kataoka, Takanori Yamagata CIRCULATION 131 2015年04月 [査読無し][通常論文]
  • Anzai Tatsuya, Takaomi Minami, Sadahiro Furui, Kensuke Oka, Akiko Yokomizo, Tomoyuki Ishii, Tomoyuki Sato, Koichi Kataoka, Takanori Yamagata CIRCULATION 131 2015年04月 [査読無し][通常論文]
  • Anzai Tatsuya, Takaomi Minami, Sadahiro Furui, Kensuke Oka, Akiko Yokomizo, Tomoyuki Ishii, Tomoyuki Sato, Koichi Kataoka, Takanori Yamagata CIRCULATION 131 2015年04月 [査読無し][通常論文]
  • 結節性硬化症に伴う腎血管筋脂肪腫に対するエベロリムスの使用経験
    亀田 智弘, 黒川 真輔, 鷲野 聡, 藤崎 明, 小松原 麻衣子, 久保 太郎, 中野 一彦, 森川 愛, 中西 公司, 高山 達也, 森田 辰男, 山形 崇倫, 宮内 彰彦 日本泌尿器科学会総会 103回 778 -778 2015年04月 [査読無し][通常論文]
  • 佐藤 優子, 熊谷 秀規, 佐藤 未織, 吉原 重美, 山形 崇倫 アレルギー 64 (3-4) 493 -493 2015年04月 [査読無し][通常論文]
  • 宮内 彰彦, 門田 行史, 長嶋 雅子, 杉江 秀夫, 小黒 範子, 小坂 仁, 山形 崇倫 脳と発達 47 (1) 62 -62 2015年01月 [査読無し][通常論文]
  • 才津浩智, 深井綾子, 酒井康成, 三牧正和, 三牧正和, 岡本伸彦, 鈴木保宏, 門田行史, 齊藤洋, 鳥尾倫子, 赤峰哲, 高橋長久, 小坂仁, 山形崇倫, 中村和幸, 中島光子, 鶴崎美徳, 三宅紀子, 椎名政昭, 緒方一博, 松本直通 日本人類遺伝学会大会プログラム・抄録集 60th 296 2015年 [査読無し][通常論文]
  • 池田 尚広, 山崎 雅世, 鈴木 峻, 門田 行史, 小坂 仁, 杉江 秀夫, 新保 裕子, 山形 崇倫 脳と発達 46 (6) 454 -454 2014年11月 [査読無し][通常論文]
  • 臍帯血移植後に混合キメラを呈した副腎白質ジストロフィーの1例
    宮内 彰彦, 門田 行史, 池田 尚広, 川原 勇太, 長嶋 雅子, 杉江 秀夫, 小坂 仁, 森本 哲, 下澤 伸行, 山形 崇倫 日本先天代謝異常学会雑誌 30 127 -127 2014年10月 [査読無し][通常論文]
  • 長嶋 雅子, 森 雅人, 門田 行史, 福田 冬季子, 野崎 靖之, 杉江 秀夫, 山形 崇倫, 桃井 真里子 小児科臨床 67 (9) 1549 -1555 2014年09月 [査読無し][通常論文]
     
    目的:小児の在宅人工呼吸器管理(HMV)の背景と問題点を明らかにすることを目的とした。対象と方法:当院のHMV児(者)37例を対象に、HMVの現状を介護者への調査票により評価した(回収率68%)。結果:基礎疾患は、中枢神経疾患68%、神経筋疾患24%だった。89%が重症心身障害児(者)であり、数種類の専門的な医療的ケアや手技を必要としていた。在宅移行例は年々増加し、特に6歳未満で増加していた。HMVの利点として、家族が一緒にいられる(100%)、児の成長が得られる(79%)、介護者が納得するケアができる(74%)などが挙げられた。一方、療育費の自己負担が大きい(79%)、レスパイト施設利用が不便(68%)などの困難さが挙げられた。考察:HMVは、家族にとって利点が多い反面、金銭的、人的負担が大きいと考えられた。今後、レスパイト施設の拡充、療育費の補助拡大を検討する必要があると考えられた。(著者抄録)
  • 急性散在性脳脊髄炎治癒後に視神経炎を発症した3例
    宮内 彰彦, 中野 祐子, 長嶋 雅子, 門田 行史, 渡辺 芽里, 谷河 純平, 杉江 秀夫, 小坂 仁, 佐久間 啓, 山形 崇倫 神経免疫学 19 (1) 94 -94 2014年09月 [査読無し][通常論文]
  • 和田 聖哉, 熊谷 秀規, 横山 孝二, 湯田 貴江, 坂本 沙織, 伊東 岳峰, 宮内 彰彦, 山形 崇倫 日本小児栄養消化器肝臓学会雑誌 28 (Suppl.) 94 -94 2014年09月 [査読無し][通常論文]
  • 横山 孝二, 熊谷 秀規, 今川 智之, 岡本 宏明, 山形 崇倫 日本小児栄養消化器肝臓学会雑誌 28 (Suppl.) 99 -99 2014年09月 [査読無し][通常論文]
  • 小児ADHDの注意機能に関する脳機能障害部位と塩酸メチルフェニデートの効果 fNIRSを用いた検討
    長嶋 雅子, 門田 行史, 檀 一平太, 檀 はるか, 水谷 勉, 郡司 勇治, 桃井 真里子, 渡辺 英寿, 山形 崇倫 日本薬物脳波学会雑誌 15 (1) 33 -45 2014年08月 [査読無し][通常論文]
     
    小児注意欠陥多動障害(ADHD)の注意機能障害に関与する脳機能低下部位を明確にする事を目的に、注意機能課題(Oddball課題)遂行時にfNIRS計測を実施した。また、注意機能障害に対する塩酸メチルフェニデート徐放剤(MPH)の作用を脳機能学的に検討するためにプラセボ二重盲検試験を行った。IQが70以上の右利きのADHD(年齢6-14歳)児22人を対象とし、Oddball課題施行中にfNIRS計測を実施し、脳機能変化を酸素化ヘモグロビン(oxy-Hb)濃度の変化を用いて評価した。ADHD群と年齢、性別を統計学的に合致させた6-13歳の対照群22人の検討も行った。対照群において右前頭前野と右下頭頂葉に有意な活性を認めたが、MPH内服前とプラセボ内服後のADHD群では活性がなかった。一方、MPH内服後のADHD群において、右前頭前野にのみ活性を認めた。右前頭前野の脳機能変化は、ドパミントランスポーターに親和性が高いMPHが、ドパミン系回路であるmesocortical pathwayに作用したと考えられた。さらに、fNIRSにより認めた小児ADHDの右前頭前野機能不全は、ADHDの病態特性を示すバイオマーカーとなり、治療薬であるMPHの薬理効果の指標となりうると考えられた。(著者抄録)
  • 急性散在性脳脊髄炎治癒後に視神経炎を発症した3例
    宮内 彰彦, 中野 祐子, 長嶋 雅子, 門田 行史, 渡辺 芽里, 谷河 純平, 杉江 秀夫, 小坂 仁, 佐久間 啓, 山形 崇倫 NEUROINFECTION 19 (2) 172 -172 2014年08月 [査読無し][通常論文]
  • Akihiko Miyauchi, Yukifumi Monden, Meri Watanabe, Hideo Sugie, Mitsuya Morita, Takeshi Kezuka, Mariko Momoi, Takanori Yamagata NEUROPEDIATRICS 45 (3) E2 -E2 2014年06月 [査読無し][通常論文]
  • 臍帯血造血幹細胞移植を実施した1歳10ヵ月の副腎白質ジストロフィー例
    尾崎 理史, 宮内 彰彦, 門田 行史, 新島 瞳, 八木 正樹, 川原 勇太, 小坂 仁, 杉江 秀夫, 森本 哲, 下澤 伸行, 山形 崇倫 日本小児科学会雑誌 118 (6) 993 -994 2014年06月 [査読無し][通常論文]
  • 門田 行史, 檀 一平太, 山形 崇倫 脳と発達 46 (Suppl.) S208 -S208 2014年05月 [査読無し][通常論文]
  • 池田 尚広, 山形 崇倫, 谷口 祐子, 宮内 彰彦, 石井 朋之, 長嶋 雅子, 門田 行史, 小坂 仁, 杉江 秀夫 脳と発達 46 (Suppl.) S304 -S304 2014年05月 [査読無し][通常論文]
  • 当院における副腎白質ジストロフィー6例の臨床的検討
    宮内 彰彦, 門田 行史, 池田 尚広, 川原 勇太, 長嶋 雅子, 小坂 仁, 杉江 秀夫, 森本 哲, 渡辺 浩史, 下泉 秀夫, 下澤 伸行, 山形 崇倫 脳と発達 46 (Suppl.) S325 -S325 2014年05月 [査読無し][通常論文]
  • 門田 行史, 山形 崇倫 小児科診療 77 (増刊) 856 -858 2014年04月 [査読無し][通常論文]
     
    社会性の障害、コミュニケーション障害、常同的行動を特徴とする発達障害の一つである。脳機能の発達に関係する障害を原因として、症状が幼児期早期に出現し生涯続く。環境調整、構造化、行動療法的対応、意思伝達手段を作り、パニックなどに対し薬物療法を検討する。(著者抄録)
  • 植田 綾子, 池田 尚広, 英 雅世, 門田 行史, 森本 哲, 杉江 秀夫, 五味 玲, 古川 理恵子, 相原 敏則, 山形 崇倫 脳と発達 46 (1) 59 -60 2014年01月 [査読無し][通常論文]
  • 非ヘルペス性急性辺縁系脳炎後に脱力発作を来した1例
    池田 尚広, 門田 行史, 英 雅世, 宮内 彰彦, 石井 朋之, 森 雅人, 杉江 秀夫, 高橋 幸利, 山形 崇倫 てんかん研究 31 (3) 543 -543 2014年01月 [査読無し][通常論文]
  • 木村 岳人, 横山 孝二, 熊谷 秀規, 桃谷 孝之, 山形 崇倫 日本小児科学会雑誌 118 (1) 92 -92 2014年01月 [査読無し][通常論文]
  • 池田 貴江, 伊東 岳峰, 熊谷 秀規, 別井 広幸, 斉藤 洋, 川原 勇太, 森本 哲, 小高 淳, 金井 孝裕, 山形 崇倫, 鈴木 寿人 日本小児科学会雑誌 118 (1) 93 -93 2014年01月 [査読無し][通常論文]
  • 宮内 彰彦, 山形 崇倫, 渡辺 芽里, 英 雅代, 伊東 岳峰, 門田 行史, 森 雅人, 杉江 秀夫, 桃井 真里子 脳と発達 45 (5) 397 -397 2013年09月 [査読無し][通常論文]
  • トピラマートの難治性てんかん小児例に対する治療効果の検討
    宮内 彰彦, 池田 尚広, 長嶋 雅子, 門田 行史, 森 雅人, 杉江 秀夫, 山形 崇倫 てんかん研究 31 (2) 445 -445 2013年09月 [査読無し][通常論文]
  • 小児の在宅人工呼吸器管理の現状と問題点
    長嶋 雅子, 森 雅人, 門田 行史, 福田 冬季子, 野崎 靖之, 杉江 秀夫, 山形 崇倫 日本重症心身障害学会誌 38 (2) 252 -252 2013年08月 [査読無し][通常論文]
  • 勝部 奈都子, 長嶋 雅子, 門田 行史, 福田 冬季子, 野崎 靖之, 森 雅人, 杉江 秀夫, 山形 崇倫, 桃井 真里子 日本小児科学会雑誌 117 (6) 1008 -1013 2013年06月 [査読有り][通常論文]
     
    2000〜2010年の10年間に当科で入院加療したインフルエンザ菌髄膜炎22例について、臨床経過と治療効果を後方視的に検討した。BLPAR 2例とBLNAR 8例を耐性菌群、BLNAS 12例を非耐性菌群とした。その結果、耐性菌群では経過良好群が6例(60%)、難治群は4例(40%)であった。非耐性菌群では経過良好群が7例(58%)、難治群が5例(42%)であった。非耐性菌群では月齢が低いほど難治で、1歳未満は全例難治であった。診断時髄液糖値は、耐性菌難治群で血糖値の16%以下で、経過良好群より低値を示した。治療開始7日以内にCTXまたはMEPM単剤治療した14例中6例(42.9%)で後遺症を残し、2剤併用継続例の後遺症は8例中1例(12.5%)であった。合併症に関しては、難聴例で発症時髄液細胞数が有意に多く、知的障害例で月齢が有意に低かった。初期治療への反応性と後遺症との相関性はみられなかった。耐性菌難治群の硬膜下膿瘍1例でCPが著効した。
  • Facial Diplegia with Paresthesiaの4歳女児例
    田中 大輔, 石井 朋之, 勝部 奈都子, 宮内 彰彦, 門田 行史, 横山 孝二, 森 雅人, 山形 崇倫, 桃井 真里子 日本小児科学会雑誌 117 (5) 924 -925 2013年05月 [査読無し][通常論文]
  • 谷口 祐子, 山形 崇倫, 池田 尚広, 宮内 彰彦, 門田 行史, 森 雅人, 野崎 靖之, 杉江 秀夫, 高橋 幸利, 桃井 眞里子 脳と発達 45 (Suppl.) S318 -S318 2013年05月 [査読無し][通常論文]
  • 石井 朋之, 山形 崇倫, 宮内 彰彦, 池田 尚広, 門田 行史, 森 雅人, 桃井 眞里子 脳と発達 45 (Suppl.) S389 -S389 2013年05月 [査読無し][通常論文]
  • 池田 尚広, 門田 行史, 宮内 彰彦, 森 雅人, 山形 崇倫, 杉江 秀夫, 桃井 眞里子 脳と発達 45 (Suppl.) S410 -S410 2013年05月 [査読無し][通常論文]
  • 英 雅世, 山形 崇倫, 池田 尚広, 宮内 彰彦, 石井 朋之, 長嶋 雅子, 門田 行史, 森 雅人, 杉江 秀夫, 桃井 眞里子 脳と発達 45 (Suppl.) S412 -S412 2013年05月 [査読無し][通常論文]
  • 日齢7に感染を契機に副腎不全が増悪したX連鎖性先天性副腎低形成症の1例
    谷口 祐子, 門田 行史, 英 雅世, 醍醐 政樹, 嶋岡 鋼, 梅崎 光, 田中 吾朗, 沼崎 啓, 福田 冬季子, 山形 崇倫, 天野 直子, 長谷川 奉延, 桃井 真里子, 郡司 勇治 小児科臨床 66 (2) 247 -252 2013年02月 [査読無し][通常論文]
     
    新生児期に急性副腎不全を呈したX連鎖性先天性副腎低形成症の男児例を報告する。出生直後から全身に色素沈着があり、日齢7に急性腎盂腎炎を契機に副腎不全が増悪し、副腎皮質ステロイド投与により軽快した。新生児期の急性副腎不全は死亡率が高いため、色素沈着を呈する新生児で、マススクリーニング(17α-OHP)陰性の場合、本疾患を疑い、早期に副腎機能のスクリーニングを行う必要がある。(著者抄録)
  • 門田 行史, 山形 崇倫 小児科 53 (11) 1457 -1463 2012年10月 [査読無し][通常論文]
  • 長嶋 雅子, 門田 行史, 檀 はるか, 檀 一平太, 續木 大介, 久徳 康史, 山形 崇倫, 郡司 勇治, 渡辺 英寿, 桃井 真里子 臨床神経生理学 40 (5) 425 -425 2012年10月 [査読無し][通常論文]
  • Hunter症候群における酵素補充療法の経過
    長嶋 雅子, 山形 崇倫, 池田 尚弘, 宮内 彰彦, 南 孝臣, 門田 行史, 桃井 真理子 日本先天代謝異常学会雑誌 28 139 -139 2012年10月 [査読無し][通常論文]
  • 発症時にMRI上錐体路病変のみ呈した副腎白質ジストロフィーの1例
    宮内 彰彦, 山形 崇倫, 早瀬 朋美, 長嶋 雅子, 森本 哲, 稲垣 真澄, 加我 牧子, 下澤 伸行, 桃井 真里子 日本先天代謝異常学会雑誌 28 196 -196 2012年10月 [査読無し][通常論文]
  • 宮内 彰彦, 山形 崇倫, 門田 行史, 福田 冬季子, 長嶋 雅子, 杉江 秀夫, 桃井 真里子 小児科臨床 65 (7) 1693 -1698 2012年07月 [査読無し][通常論文]
     
    2000年4月から2011年4月までの11年間に経験したGBS髄膜炎7例を後方視的に検討した。髄液蛋白高値、髄液糖低値、人工呼吸や昇圧剤投与を要する例、急性期の難治性けいれんの合併が神経学的予後関連因子であると考えられた。検討症例の中で、児の髄膜炎症状が母体の乳腺炎症状に先行した。母乳感染による遅発性GBS髄膜炎の1症例を経験した。遅発型GBS感染症では母乳感染が感染経路の一つであり、GBS感染症と診断された場合は、母体の症状の有無にかかわらず、母乳の培養検査を行い、陽性例では母乳の中止、母体への抗生物質の投与を検討すべきである。(著者抄録)
  • テオフィリン関連急性脳症における遺伝的素因
    篠原 麻由, 齊藤 真木子, 山中 岳, 雨宮 馨, 久保田 雅也, 山形 崇倫, 菊池 健二郎, 川脇 寿, 亀井 淳, 赤坂 真奈美, 安西 有紀, 塩見 正司, 水口 雅 脳と発達 44 (Suppl.) S228 -S228 2012年05月 [査読無し][通常論文]
  • 難治てんかん患者におけるレベチラセタムの有効性
    松本 瞳, 山形 崇倫, 長嶋 雅子, 門田 行史, 野崎 靖之, 福田 冬季子, 森 雅人, 杉江 秀夫, 桃井 真里子 脳と発達 44 (Suppl.) S222 -S222 2012年05月 [査読無し][通常論文]
  • 多彩な画像所見を示したけいれん重積型脳症の1例
    谷口 祐子, 山形 崇倫, 門田 行史, 長嶋 雅子, 池田 尚広, 森 雅人, 英 雅世, 福田 冬季子, 郡司 勇治, 杉江 秀夫, 桃井 真里子 脳と発達 44 (Suppl.) S228 -S228 2012年05月 [査読無し][通常論文]
  • 小児の在宅人工呼吸器管理児の現状と問題点
    長嶋 雅子, 森 雅人, 門田 行史, 福田 冬季子, 野崎 靖之, 山形 崇倫, 杉江 秀夫, 桃井 真里子 脳と発達 44 (Suppl.) S363 -S363 2012年05月 [査読無し][通常論文]
  • 両側黒質、淡蒼球に病変を呈し、CoQ10投与後に改善があったミトコンドリア複合体I欠損の男児例
    門田 行史, 山形 崇倫, 森 雅人, 村山 圭, 大竹 明, 桃井 真里子 脳と発達 44 (2) 155 -155 2012年03月 [査読無し][通常論文]
  • 井上 元子, 山形 崇倫, 門田 行史, 英 雅世, 森 雅人, 福田 冬季子, 野崎 靖之, 長嶋 雅子, 水口 雅, 杉江 秀夫, 桃井 眞里子 小児科臨床 64 (10) 2215 -2223 2011年10月 [査読無し][通常論文]
     
    2006年〜2010年の4年間に経験した急性脳症の40例を、後方視的に検討した。症例数は40例で、年齢は8ヵ月〜14歳10ヵ月であった。疾患の内訳は出血性ショック脳症(HSES)1例、急性脳浮腫型(ABS)2例、けいれん重積型脳症(AESD)13例、可逆性の脳梁膨大部病変を有する脳炎脳症4例、けいれん後意識障害遷延例11例、意識障害/異常行動遷延例9例だった。原因と思われる疾患背景は突発性発疹12例、インフルエンザ13例、胃腸炎2例、テオフィリン1例であった。7例で大量メチルプレドニゾロン療法等を実施した。予後は2例が死亡、13例に後遺症があり、25例は後遺症なしであった。HSES、ABSは、積極的に治療しても、病勢の進行が速い例での治療は困難であった。初回けいれんの時間が長い、初回けいれん後の意識回復が悪い、脳波で異常所見がある、二峰目のけいれん時間が長い、等の例で後遺症を残す傾向があるが、短時間のけいれんでも後遺症がある例があり、早期診断、治療法確立が重要である。(著者抄録)
  • 難治てんかん患者におけるレベチラセタムの使用経験
    松本 瞳, 山形 崇倫, 森 雅人, 福田 冬季子, 野崎 靖之, 杉江 秀夫, 門田 行史, 長嶋 雅子, 桃井 真里子 てんかん研究 29 (2) 303 -303 2011年09月 [査読無し][通常論文]
  • 黒岩 祐梨, 門田 行史, 岡野 彩子, 福田 冬季子, 森 雅人, 山形 崇倫, 杉江 秀夫, 桃井 真里子 脳と発達 43 (3) 251 -251 2011年05月 [査読無し][通常論文]
  • 英 雅世, 山形 崇倫, 井上 元子, 門田 行史, 後藤 珠子, 桃井 真理子 脳と発達 43 (Suppl.) S218 -S218 2011年05月 [査読無し][通常論文]
  • 井上 元子, 山形 崇倫, 門田 行史, 英 雅世, 森 雅人, 福田 冬季子, 野崎 靖之, 長嶋 雅子, 杉江 秀夫, 桃井 真里子 脳と発達 43 (Suppl.) S289 -S289 2011年05月 [査読無し][通常論文]
  • 門田 行史, 檀 一平太, 長嶋 雅子, 渡辺 英寿, 山形 崇倫, 桃井 真里子 脳と発達 43 (Suppl.) S339 -S339 2011年05月 [査読無し][通常論文]
  • 日本人けいれん重積型急性脳症患者における遺伝的素因の検討
    篠原 麻由, Tin Le, Nguyen Nhut, 斎藤 真木子, 久保田 雅也, 菊池 健二郎, 山中 岳, 後藤 知英, 山内 秀雄, 高梨 潤一, 山形 崇倫, 豊島 光雄, 廣瀬 伸一, 水口 雅 脳と発達 43 (Suppl.) S213 -S213 2011年05月 [査読無し][通常論文]
  • 内包から延髄の錐体路病変で発症した副腎白質ジストロフィーの1例
    宮内 彰彦, 長嶋 雅子, 森本 哲, 稲垣 真澄, 加我 牧子, 下澤 伸行, 山形 崇倫, 桃井 真里子 脳と発達 43 (Suppl.) S246 -S246 2011年05月 [査読無し][通常論文]
  • 若年で発症したナルコレプシーの1例
    倉田 和美, 谷口 周平, 宮内 彰彦, 沼崎 啓, 下泉 秀夫, 山形 崇倫, 郡司 勇治 日本小児科学会雑誌 115 (3) 696 -697 2011年03月 [査読無し][通常論文]
  • 乳腺炎に起因したと考えられる遅発型B群溶連菌髄膜炎の1症例
    長嶋 雅子, 門田 行史, 宮内 彰彦, 勝部 奈都子, 福田 冬季子, 山形 崇倫, 桃井 真里子 日本小児科学会雑誌 114 (7) 1095 -1096 2010年07月 [査読無し][通常論文]
  • 門田 行史, 森 雅人, 山形 崇倫, 長嶋 雅子, 福田 冬季子, 杉江 秀夫, 桃井 真里子 脳と発達 42 (Suppl.) S226 -S226 2010年05月 [査読無し][通常論文]
  • 杉山 奈都子, 長嶋 雅子, 門田 行史, 野崎 靖之, 福田 冬季子, 森 雅人, 山形 崇倫, 杉江 秀夫, 桃井 真里子 脳と発達 42 (Suppl.) S291 -S291 2010年05月 [査読無し][通常論文]
  • 宮内 彰彦, 杉山 奈都子, 長嶋 雅子, 門田 行史, 野崎 靖之, 福田 冬季子, 森 雅人, 山形 崇倫, 杉江 秀夫, 桃井 真里子 脳と発達 42 (Suppl.) S291 -S291 2010年05月 [査読無し][通常論文]
  • 池田 尚広, 冨士根 明雄, 門田 行史, 福田 冬季子, 山形 崇倫, 杉江 秀夫, 桃井 真里子 脳と発達 42 (Suppl.) S292 -S292 2010年05月 [査読無し][通常論文]
  • 齋藤 真理, 山形 崇倫, 森 雅人, 門田 行史, 長嶋 雅子 脳と発達 42 (Suppl.) S299 -S299 2010年05月 [査読無し][通常論文]
  • 門田 行史, 山形 崇倫 小児科診療 73 (増刊) 792 -794 2010年04月 [査読無し][通常論文]
  • 門田 行史, 山形 崇倫, 福田 冬季子, 森 雅人, 杉江 秀夫, 桃井 真里子 小児科臨床 63 (2) 265 -270 2010年02月 [査読無し][通常論文]
     
    小児および若年性欠神てんかんは、特発性全般てんかんに分類されているが、欠神てんかんのなかに前頭葉欠神と呼ばれる、発作焦点が前頭領域に推定される一群が存在することが知られている。欠神てんかんに複雑部分発作を合併し、前頭葉欠神と考えられる男児例を経験した。本例は、2歳6ヵ月時に欠神発作が出現し、過呼吸で誘発される3Hzの全汎性棘徐波複合があり、9歳時に意識減損、姿勢発作を伴う複雑部分発作を示し、発作間歇期脳波では左右独立した前頭部棘波や前頭部を起始として急速に全汎化する3Hz棘徐波複合を認めた。前頭葉欠神は、年齢により発作型/病態が異なると考えられ、どの時期にどの治療薬を選択するか、治療法を検討する必要がある。(著者抄録)
  • Akihide Takashima, Yuki Takayanagi, Man Saito, Takanori Yamagata, Mariko Momoi, Tatsushi Onaka JOURNAL OF PHYSIOLOGICAL SCIENCES 60 S176 -S176 2010年 [査読無し][通常論文]
  • Eriko Fujita, Hongmei Dai, Yuko Tanabe, Yu Zhiling, Takanori Yamagata, Takuya Miyakawa, Masaru Tanokura, Mariko Momoi, Takashi Momoi NEUROSCIENCE RESEARCH 68 E145 -E145 2010年 [査読無し][通常論文]
  • 欠神てんかんに複雑部分発作を合併した男児例
    門田 行史, 山形 崇倫, 福田 冬季子, 森 雅人, 杉江 秀夫, 桃井 真里子 てんかん研究 27 (3) 442 -442 2010年01月 [査読無し][通常論文]
  • 冨士根 明雄, 森 雅人, 福田 冬季子, 山形 崇倫, 杉江 秀夫, 桃井 真里子 てんかん研究 26 (3) 468 -469 2009年01月 [査読無し][通常論文]
  • 星野英紀, 高橋寛, 三牧正和, 斉藤真木子, 山形崇倫, 桃井真里子, 水口雅 脳と発達 40 (1) 65 -65 2008年01月 [査読無し][通常論文]
  • 福田 冬季子, 山形 崇倫, 杉江 秀夫, 桃井 真里子, PLOTZ PAUL, RABEN NINA 日本先天代謝異常学会雑誌 23 (1) 2007年10月 [査読無し][通常論文]
  • 松本 歩, 山形 崇倫, 松本 静子, 藤田 ひとみ, 今井 真理, 後藤 珠子, 福田 冬季子, 諏訪 清隆, 森 雅人, 杉江 秀夫, 桃井 真里子 てんかん研究 25 (2) 2007年08月 [査読無し][通常論文]
  • 小宮山 真美, 森 雅人, 山形 崇倫 小児科臨床 59 (9) 2039 -2044 2006年09月
  • ステロイド投与を行ったインフルエンザ脳症のまとめ
    川又 竜, 柳下 恵子, 門田 行史, 大木 丈弘, 菊池 豊, 三浦 琢磨, 山形 崇倫, 桃井 真里子 日本小児科学会雑誌 110 (9) 1298 -1298 2006年09月 [査読無し][通常論文]
  • T Yamagata, K Suwa, M Mori, M Nakamura, MY Momoi AMERICAN JOURNAL OF HUMAN GENETICS 73 (5) 404 -404 2003年11月 [査読無し][通常論文]
  • M Mori, T Yamagata, H Li, T Goto, K Suwa, A Yasuhara, MY Momoi AMERICAN JOURNAL OF HUMAN GENETICS 73 (5) 511 -511 2003年11月 [査読無し][通常論文]
  • チョウセンアサガオによる精神・神経症候を呈した小児例
    田村 大輔, 山形 崇倫, 森 雅人, 水口 雅, 藤村 昭夫, 青木 康博, 桃井 真里子 小児科診療 66 (3) 529 -532 2003年03月 [査読無し][通常論文]
     
    8歳女児.庭に栽培していた植物の葉をハーブの一種と誤って妙め,15枚程度食べた.2時間程して,口が渇く,足がふらふらすると訴えた.食後3時間頃より,普段より早口,かつはっきりとした口調で「床に蛇がいる」,「みみずがいる」,「ねずみがいる」等と言い,何かをつかむような動作をはじめた.そのため,食後9時間頃,受診した.意識はJCS 1〜2で幻視と見当識障害を主としたせん妄状態,落ち着きなく,歩き回っていた.誤食から20時間後には対光反射が認められ,同時に興奮状態は徐々に落ち着き,室内を暗くすることにより入眠した.6時間睡眠し覚醒した後は,幻視や興奮状態は消失し,普段の状態に戻っていた.保健所による鑑定の結果,食べた植物はチョウセンアサガオと同定された
  • H Yamanouchi, M Mori, N Kawaguchi, T Yamagata, E Nakagawa, T Hashimoto, M Eguchi, M Momoi, M Mizuguchi ANNALS OF NEUROLOGY 54 S127 -S127 2003年 [査読無し][通常論文]
  • M Mori, M Komiyama, S Kato, L Hong, T Yamagata, M Mizuguchi, MY Momoi AMERICAN JOURNAL OF HUMAN GENETICS 71 (4) 258 -258 2002年10月 [査読無し][通常論文]
  • T Yamagata, H Li, M Mori, K Suwa, MY Momoi AMERICAN JOURNAL OF HUMAN GENETICS 71 (4) 489 -489 2002年10月 [査読無し][通常論文]
  • T Yamagata, H Li, M Mori, K Suwa, A Yasuhara, MY Momoi AMERICAN JOURNAL OF HUMAN GENETICS 69 (4) 551 -551 2001年10月 [査読無し][通常論文]
  • Y Gu, KL McILwain, EJ Weeber, T Yamagata, B Xu, BA Antalffy, D Armstrong, C Reye, H Zoghbi, JD Sweatt, RE Paylor, DL Nelson AMERICAN JOURNAL OF HUMAN GENETICS 69 (4) 362 -362 2001年10月 [査読無し][通常論文]
  • S Aradhya, T Yamagata, T Bardaro, P Galgoczy, T Esposito, S Kenwrick, M Platzer, M D'Urso, DL Nelson AMERICAN JOURNAL OF HUMAN GENETICS 69 (4) 454 -454 2001年10月 [査読無し][通常論文]
  • H Li, T Yamagata, M Mori, MY Momoi AMERICAN JOURNAL OF HUMAN GENETICS 69 (4) 632 -632 2001年10月 [査読無し][通常論文]
  • M Mori, S Saitoh, T Yamagata, MY Momoi AMERICAN JOURNAL OF HUMAN GENETICS 67 (4) 294 -294 2000年10月 [査読無し][通常論文]
  • Y Nozaki, T Kubota, Y Fukushima, T Yamagata, M Mizuguchi, MY Momoi, G Nishimura AMERICAN JOURNAL OF HUMAN GENETICS 67 (4) 109 -109 2000年10月 [査読無し][通常論文]
  • T Yamagata, S Aradhya, M Mori, MY Momoi, DL Nelson AMERICAN JOURNAL OF HUMAN GENETICS 65 (4) A473 -A473 1999年10月 [査読無し][通常論文]


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