基本情報
- 所属
- 自治医科大学 医学部小児科学講座 / 医学部小児科学講座 小児医学部門 教授
- 研究者番号
- 90426320
- J-GLOBAL ID
- 201401039803985369
- researchmap会員ID
- B000238601
- 外部リンク
経歴
10論文
354-
日本先天代謝異常学会雑誌 34 188-188 2018年9月
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Brain & development 40(7) 587-591 2018年8月 査読有り
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Brain & development 40(7) 607-611 2018年8月 査読有り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.
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Brain & development 40(6) 498-502 2018年6月 査読有り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.
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MOLECULAR THERAPY 26(5) 130-131 2018年5月 査読有り
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Brain & development 40(5) 444 2018年5月 査読有り
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The journal of gene medicine 20(4) e3013 2018年4月 査読有り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.
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Brain and Development 40(4) 325-329 2018年4月1日 査読有り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.
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Clinical Genetics 93(2) 266-274 2018年2月1日 査読有りThe seizure threshold 2 (SZT2) gene encodes a large, highly conserved protein that is associated with epileptogenesis. In mice, Szt2 is abundantly expressed in the central nervous system. Recently, biallelic SZT2 mutations were found in 7 patients (from 5 families) presenting with epileptic encephalopathy with dysmorphic features and/or non-syndromic intellectual disabilities. In this study, we identified by whole-exome sequencing compound heterozygous SZT2 mutations in 3 patients with early-onset epileptic encephalopathies. Six novel SZT2 mutations were found, including 3 truncating, 1 splice site and 2 missense mutations. The splice-site mutation resulted in skipping of exon 20 and was associated with a premature stop codon. All individuals presented with seizures, severe developmental delay and intellectual disabilities with high variability. Brain MRIs revealed a characteristic thick and short corpus callosum or a persistent cavum septum pellucidum in each of the 2 cases. Interestingly, in the third case, born to consanguineous parents, had unexpected compound heterozygous missense mutations. She showed microcephaly despite the other case and previous ones presenting with macrocephaly, suggesting that SZT2 mutations might affect head size.
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Brain and Development 40(2) 145-149 2018年2月1日 査読有りBackground Leigh syndrome is a mitochondrial disease caused by respiratory chain deficiency, and there are no proven effective therapies. EPI-743 is a potent cellular oxidative stress protectant and results of clinical trials for mitochondrial diseases are accumulating. Case At 5 months, a girl presented with the scarce eye movement and diminished muscle tone. She was diagnosed with Leigh encephalopathy from blood and cerebrospinal fluid lactate elevation and MRI findings. Sequence analysis for mitochondrial DNA revealed a T10158C mutation in the mitochondrial encoded ND3 gene in complex I. Results At 8 months, succinate was prescribed expected to restore the electron transport chain system. After that her condition got worse and succinate was discontinued. Subsequent administration of EPI-743 improved her eye movement, fine motor movements of the extremities, and bowel movement. She is now 5 years old. Although brain atrophy has progressed, she has still respiratory free time. Conclusion Our patient showed visible improvement with EPI-743 treatment and the only patient surviving after 4 years. There is a possibility that EPI-743 is modifying the natural course of the syndrome.
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Cell reports 22(3) 734-747 2018年1月16日 査読有りRecent studies have established important roles of de novo mutations (DNMs) in autism spectrum disorders (ASDs). Here, we analyze DNMs in 262 ASD probands of Japanese origin and confirm the "de novo paradigm" of ASDs across ethnicities. Based on this consistency, we combine the lists of damaging DNMs in our and published ASD cohorts (total number of trios, 4,244) and perform integrative bioinformatics analyses. Besides replicating the findings of previous studies, our analyses highlight ATP-binding genes and fetal cerebellar/striatal circuits. Analysis of individual genes identified 61 genes enriched for damaging DNMs, including ten genes for which our dataset now contributes to statistical significance. Screening of compounds altering the expression of genes hit by damaging DNMs reveals a global downregulating effect of valproic acid, a known risk factor for ASDs, whereas cardiac glycosides upregulate these genes. Collectively, our integrative approach provides deeper biological and potential medical insights into ASDs.
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Journal of the Japan Epilepsy Society 35(3) 693-701 2018年 査読有り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.
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Human genome variation 5 18013-18013 2018年 査読有り
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Brain and Development 40(9) 807-812 2018年 査読有り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.
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Human genome variation 5 25-25 2018年 査読有り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.
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Brain and Development 40(1) 69-73 2018年1月1日 査読有り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.
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BRAIN & DEVELOPMENT 39(10) 886-890 2017年11月 査読有り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.
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NEUROPATHOLOGY 37(5) 426-430 2017年10月 査読有り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.
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PLOS ONE 12(8) e0181791 2017年8月 査読有りThe CASK gene (Xp11.4) is highly expressed in the mammalian nervous system and plays several roles in neural development and synaptic function. Loss-of-function mutations of CASK are associated with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH), especially in females. Here, we present a comprehensive investigation of 41 MICPCH patients, analyzed by mutational search of CASK and screening of candidate genes using an SNP array, targeted resequencing and whole-exome sequencing (WES). In total, we identified causative or candidate genomic aberrations in 37 of the 41 cases (90.2%). CASK aberrations including a rare mosaic mutation in a male patient, were found in 32 cases, and a mutation in ITPR1, another known gene in which mutations are causative for MICPCH, was found in one case. We also found aberrations involving genes other than CASK, such as HDAC2, MARCKS, and possibly HS3ST5, which may be associated with MICPCH. Moreover, the targeted resequencing screening detected heterozygous variants in RELN in two cases, of uncertain pathogenicity, and WES analysis suggested that concurrent mutations of both DYNC1H1 and DCTN1 in one case could lead to MICPCH. Our results not only identified the etiology of MICPCH in nearly all the investigated patients but also suggest that MICPCH is a genetically heterogeneous condition, in which CASK inactivating mutations appear to account for the majority of cases.
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EBIOMEDICINE 20 27-38 2017年6月 査読有りMitochondrial dysfunction increases oxidative stress and depletes ATP in a variety of disorders. Several antioxidant therapies and drugs affecting mitochondrial biogenesis are undergoing investigation, although not all of them have demonstrated favorable effects in the clinic. We recently reported a therapeutic mitochondrial drug mitochonic acid MA-5 (Tohoku J. Exp. Med., 2015). MA-5 increased ATP, rescued mitochondrial disease fibroblasts and prolonged the life span of the disease model "Mitomouse" (JASN, 2016). To investigate the potential of MA-5 on various mitochondrial diseases, we collected 25 cases of fibroblasts from various genetic mutations and cell protective effect of MA-5 and the ATP producing mechanism was examined. 24 out of the 25 patient fibroblasts (96%) were responded to MA-5. Under oxidative stress condition, the GDF-15 was increased and this increase was significantly abrogated by MA-5. The serum GDF-15 elevated in Mitomouse was likewise reduced by MA-5. MA-5 facilitates mitochondrial ATP production and reduces ROS independent of ETC by facilitating ATP synthase oligomerization and supercomplex formation with mitofilin/Mic60. MA-5 reduced mitochondria fragmentation, restores crista shape and dynamics. MA-5 has potential as a drug for the treatment of various mitochondrial diseases. The diagnostic use of GDF-15 will be also useful in a forthcoming MA-5 clinical trial. (C) 2017 The Authors. Published by Elsevier B.V.
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脳と発達 49(Suppl.) S289-S289 2017年5月
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脳と発達 49(Suppl.) S289-S289 2017年5月
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脳と発達 49(Suppl.) S293-S293 2017年5月
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NEUROLOGY 88(20) 1919-1924 2017年5月 査読有りObjective: We report a case series of 10 patients with gamma-aminobutyric acid (GABA)-transaminase deficiency including a novel therapeutic trial and an expanded phenotype. Methods: Case ascertainment, literature review, comprehensive evaluations, and long-term treatment with flumazenil. Results: All patients presented with neonatal or early infantile-onset encephalopathy; other features were hypotonia, hypersomnolence, epilepsy, choreoathetosis, and accelerated linear growth. EEGs showed burst-suppression, modified hypsarrhythmia, multifocal spikes, and generalized spike-wave. Five of the 10 patients are currently alive with age at last follow-up between 18 months and 9.5 years. Treatment with continuous flumazenil was implemented in 2 patients. One patient, with a milder phenotype, began treatment at age 21 months and has continued for 20 months with improved alertness and less excessive adventitious movements. The second patient had a more severe phenotype and was 7 years of age at initiation of flumazenil, which was not continued. Conclusions: GABA-transaminase deficiency presents with neonatal or infantile-onset encephalopathy including hypersomnolence and choreoathetosis. A widened phenotypic spectrum is reported as opposed to lethality by 2 years of age. The GABA-A benzodiazepine receptor antagonist flumazenil may represent a therapeutic strategy.
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JOURNAL OF THE NEUROLOGICAL SCIENCES 376 7-12 2017年5月 査読有りPurpose: Little is known regarding neuroimaging-genotype correlations in Joubert syndrome (JBTS). To elucidate one of these correlations, we investigated the neuroimaging findings of JBTS patients with C5orf42 mutations. Materials and methods: Neuroimaging findings in five JBTS patients with C5orf42 mutations were retrospectively assessed with regard to the infratentorial and supratentorial structures on T1-magnetization prepared rapid gradient echo (MPRAGE), T2-weighted images, and color-coded fractional anisotropy (FA) maps; the findings were compared to those in four JBTS patients with mutations in other genes (including three with AHI1 and one with TMEM67 mutations). Results: In C5orf42-mutant patients, the infratentorial magnetic resonance (MR) images showed normal or minimally thickened and minimally elongated superior cerebellar peduncles (SCP), normal or minimally deepened interpeduncular fossa (IF), and mild vermian hypoplasia (VH). However, in other patients, all had severe abnormalities in the SCP and IF, and moderate to marked VH. Supratentorial abnormalities were found in one individual in other JBTS. In JBTS with all mutations, color-coded FA maps showed the absence of decussation of the SCP (DSCP). Conclusion: The morphological neuroimaging findings in C5orf42-mutant JBTS were distinctly mild and made diagnosis difficult. However, the absence of DSCP on color-coded FA maps may facilitate the diagnosis of JBTS. (C) 2017 Elsevier B.V. All rights reserved.
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Brain & development 39(5) 439-443 2017年5月 査読有り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.
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Molecular genetics and metabolism reports 10 67-74 2017年3月 査読有り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.
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BMC NEUROLOGY 17(1) 47 2017年2月 査読有りBackground: Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inborn error of metabolism inherited in autosomal recessive pattern and is associated with a wide spectrum of neurological abnormalities. Case presentation: We herein describe a 15-year-old boy with MTHFR deficiency who presented with a slowly progressive decline of school performance and a spastic gait. Rapidly deteriorating psychosis and repetitive seizures triggered by a febrile infection prompted neurological investigation. He had significantly elevated total plasma homocysteine and urinary homocystine levels, as well as a decreased plasma methionine level. Brain magnetic resonance imaging (MRI) revealed leukoencephalopathy. DNA gene sequencing showed c.446_447 del GC ins TT and c.137G > A, and c.665C > T heterozygous mutations in the MTHFR gene of the patient. Oral administration of betaine drastically improved his clinical symptoms within a few months. After 8 months of treatment, his total plasma homocysteine level moderately decreased; and the plasma methionine concentration became normalized. Furthermore, the white matter lesions on MRI had disappeared. Conclusion: This patient demonstrates the possibility that MTHFR deficiency should be considered in mentally retarded adolescents who display an abnormally elevated plasma level of homocysteine in association with progressive neurological dysfunction and leukoencephalopathy. Febrile infections may be an aggravating factor in patients with MTHFR deficiency.
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Human genome variation 4 17035-17035 2017年 査読有り
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Brain & Development 38(10) 959-963 2016年11月
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Brain & Development 38(10) 959-963 2016年11月
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BRAIN & DEVELOPMENT 38(9) 871-874 2016年10月 査読有りBackground: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder that affects the degradation of gamma-aminobutyric acid and leads to the accumulation of gamma-hydroxybutyric acid (GHB) in body fluids. Diagnosis of SSADH deficiency is challenging, since the neurological symptoms are non-specific. Case: The patient is a nine-year-old Japanese boy who presented with developmental delay, autism, epilepsy, and episodic gait disturbance. Brain magnetic resonance imaging showed hyperintense lesions in the bilateral thalami, globus pallidi, substantia nigra, and dentate nuclei. Urine metabolome analysis revealed elevated GHB, which led to a biochemical diagnosis of SSADH deficiency. Genetic analysis of the ALDH5A1 gene revealed a novel missense mutation c.1586G>A inherited from his father. It also demonstrated three single nucleotide polymorphisms (SNPs) (c.106G>C, c.538C>T, and c.545C>T), all of which were inherited from his mother and are known to reduce SSADH enzyme activity. There were no duplications or deletions in other exons in the patient or his parents. No variants in the upstream, intronic, or downstream regions of the ALDH5A1 gene were found in the patient. Enzymatic assay revealed a marked reduction of SSADH enzyme activity (approximate to 2% of the lower limit of the normal range). Conclusion: Although other mechanisms cannot be fully excluded, the clinical manifestation of SSADH deficiency in this patient may be attributed to the combined effect of the mutation and the three enzyme activity-reducing SNPs. Urine metabolome analysis effectively detected his elevated GHB and is thus considered to be a good screening method for this underdiagnosed and potentially manageable metabolic disorder. (C) 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
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AMERICAN JOURNAL OF MEDICAL GENETICS PART A 170(10) 2662-2670 2016年10月 査読有り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.
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JOURNAL OF NEUROCHEMISTRY 139(2) 245-255 2016年10月 査読有り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.
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Brain & Development 38(9) 871-874 2016年10月
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ACTA NEUROPATHOLOGICA COMMUNICATIONS 4(1) 101 2016年9月 査読有り
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JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 27(7) 1925-1932 2016年7月 査読有りMitochondrial dysfunction causes increased oxidative stress and depletion of ATP, which are involved in the etiology of a variety of renal diseases, such as CKD, AKI, and steroid resistant nephrotic syndrome. Antioxidant therapies are being investigated, but clinical outcomes have yet to be determined. Recently, we reported that a newly synthesized indole derivative, mitochonic acid 5 (MA-5), increases cellular ATP level and survival of fibroblasts from patients with mitochondrial disease. MA-5 modulates mitochondrial ATP synthesis independently of oxidative phosphorylation and the electron transport chain. Here, we further investigated the mechanism of action for MA-5. Administration of MA-5 to an ischemia-reperfusion injury model and a cisplatin-induced nephropathy model improved renal function. In in vitro bioenergetic studies, MA-5 facilitated ATP production and reduced the level of mitochondrial reactive oxygen species (ROS) without affecting activity of mitochondrial complexes I-IV. Additional assays revealed that MA-5 targets the mitochondrial protein mitofilin at the crista junction of the inner membrane. In Hep3B cells, overexpression of mitofilin increased the basal ATP level, and treatment with MA-5 amplified this effect. In a unique mitochondrial disease model (Mitomice with mitochondria) DNA deletion that mimics typical human mitochondrial disease phenotype), MA-5 improved the reduced cardiac and renal mitochondria respiration and seemed to prolong survival, although statistical analysis of survival times could not be conducted. These results suggest that MA-5 functions in a manner differing from that of antioxidant therapy and could be a novel therapeutic drug for the treatment of cardiac and renal diseases associated with mitochondrial dysfunction.
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JOURNAL OF HUMAN GENETICS 61(7) 653-661 2016年7月 査読有りWest syndrome is an early-onset epileptic encephalopathy characterized by clustered spasms with hypsarrhythmia seen on electroencephalogram (EEG). West syndrome is genetically heterogeneous, and its genetic causes have not been fully elucidated. WD Repeat Domain 45 (WDR45) resides on Xp11.23, and encodes a member of the WD repeat protein interacting with phosphoinositides (WIPI) family, which is crucial in the macroautophagy pathway. De novo mutations in WDR45 cause beta-propeller protein-associated neurodegeneration characterized by iron accumulation in the basal ganglia. In this study, we performed whole exome sequencing of individuals with West syndrome and identified three WDR45 mutations in three independent males (patients 1, 2 and 3). Two novel mutations occurred de novo (patients 1 and 2) and the remaining mutation detected in a male patient (patient 3) and his affected sister was inherited from the mother, harboring the somatic mutation. The three male patients showed early-onset intractable seizures, profound intellectual disability and developmental delay. Their brain magnetic resonance imaging scans showed cerebral atrophy. We found no evidence of somatic mosaicism in the three male patients. Our findings indicate that hemizygous WDR45 mutations in males lead to severe epileptic encephalopathy.
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Modeling Alexander disease with patient iPSCs reveals cellular and molecular pathology of astrocytesACTA NEUROPATHOLOGICA COMMUNICATIONS 4(1) 69 2016年7月 査読有りAlexander disease is a fatal neurological illness characterized by white-matter degeneration and formation of Rosenthal fibers, which contain glial fibrillary acidic protein as astrocytic inclusion. Alexander disease is mainly caused by a gene mutation encoding glial fibrillary acidic protein, although the underlying pathomechanism remains unclear. We established induced pluripotent stem cells from Alexander disease patients, and differentiated induced pluripotent stem cells into astrocytes. Alexander disease patient astrocytes exhibited Rosenthal fiber-like structures, a key Alexander disease pathology, and increased inflammatory cytokine release compared to healthy control. These results suggested that Alexander disease astrocytes contribute to leukodystrophy and a variety of symptoms as an inflammatory source in the Alexander disease patient brain. Astrocytes, differentiated from induced pluripotent stem cells of Alexander disease, could be a cellular model for future translational medicine.
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BRAIN & DEVELOPMENT 38(6) 581-584 2016年6月 査読有りA patient with an unusually mild form of Pelizaeus-Merzbacher disease was studied. Clinically, mild developmental delay with acquisition of assisted walking at 16 months and mild spastic tetraplegia were evident, but no nystagmus, cerebellar, or extra pyramidal signs were present. PLP1 mutation analysis revealed a nucleotide substitution adjacent to the acceptor site of intron 3, NM_000533.4:c.454-9T>G. Expression analysis using the patient's leukocytes demonstrated an additional abnormal transcript including the last 118 bp of intron 3. In silico prediction analysis suggested the reduction of wild-type acceptor activity, which presumably evokes the cryptic splicing variant. Putative cryptic transcript results in premature termination, which may explain the mild clinical phenotype observed in this patient. (c) 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
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BRAIN & DEVELOPMENT 38(6) 571-580 2016年6月 査読有りPurpose: We retrospectively evaluated the imaging spectrum of Pelizaeus Merzbacher disease (PMD) in correlation with the clinical course and genetic abnormality. Methods: We collected the magnetic resonance imaging (MRI) findings of 19 genetically proven PMD patients (all males, aged 0-29 years old) using our integrated web-based MRI data collection system from 14 hospitals. The patterns of hypomyelination were determined mainly by the signals of the cerebrum, corticospinal tract, and brainstem on T2-weighted images (T2WI). We assessed the degree of myelination age on T1-weighted images (T1WI) and T2WI independently, and we evaluated cerebellar and callosal atrophy. The clinical severity and genetic abnormalities (causal mutations of the proteolipid protein gene PLP1) were analyzed together with the imaging findings. Results: The clinical stage tended to be more severe when the whole brainstem, or corticospinal tract in the internal capsule showed abnormally high intensity on T2WI. Diffuse T2-high signal of brainstem was observed only in the patients with PLP1 point mutation. Myelination age "before birth" on T1WI is a second manifestation correlated with the clinically severe phenotypes. On the other hand, eight patients whose myelination ages were >4 months on T1WI were associated with mild clinical phenotypes. Four of them showed almost complete myelination on T1WI with a discrepancy in myelination age between T1WI and T2WI. A random and patchy pattern of myelination on T2WI was noted in one patient with PLP1 point mutation. Advanced myelination was observed in three of the seven followed-up patients. Four patients had atrophy of the cerebellum, and 17 patients had atrophy of the corpus callosum. Conclusion: Our multicenter study has demonstrated a wide variety of imaging findings of PMD. Signal intensity of brainstem and corticospinal tract of internal capsule would be the points to presume clinical severity in PMD patients. The spectrum of MRI findings should be kept in mind to diagnose PMD and to differentiate from other demyelinating leukodystrophies. (c) 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
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脳と発達 48(Suppl.) S238-S238 2016年5月
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Brain & development 38(4) 427-30 2016年4月 査読有り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.
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European journal of human genetics : EJHG 24(1) 129-34 2016年1月 査読有り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.
MISC
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Epileptic disorders : international epilepsy journal with videotape 22(2) 214-218 2020年4月16日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.
共同研究・競争的資金等の研究課題
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日本学術振興会 科学研究費助成事業 2022年4月 - 2025年3月
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日本学術振興会 科学研究費助成事業 2020年4月 - 2023年3月
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日本学術振興会 科学研究費助成事業 2016年4月 - 2019年3月
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日本学術振興会 科学研究費助成事業 2015年4月 - 2019年3月
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日本学術振興会 科学研究費助成事業 2014年4月 - 2018年3月