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
374-
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(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.
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EPILEPSIA 57(1) E18-E23 2016年1月 査読有りDynamin 1 (DNM1) is a large guanosine triphosphatase involved in clathrin-mediated endocytosis. In recent studies, de novo mutations in DNM1 have been identified in five individuals with epileptic encephalopathy. In this study, we report two patients with early onset epileptic encephalopathy possessing de novo DNM1 mutations. Using whole exome sequencing, we detected the novel mutation c.127G>A (p.Gly43Ser) in a patient with Lennox-Gastaut syndrome, and a recurrent mutation c.709C>T (p.Arg237Trp) in a patient with West syndrome. Structural consideration of DNM1 mutations revealed that both mutations would destabilize the G domain structure and impair nucleotide binding, dimer formation, and/or GTPase activity of the G domain. These and previous cases of DNM1 mutations were reviewed to verify the phenotypic spectrum. The main clinical features of DNM1 mutations include intractable seizures, intellectual disability, developmental delay, and hypotonia. Most cases showed development delay before the onset of seizures. A patient carrying p.Arg237Trp in this report showed a different developmental status from that of a previously reported case, together with characteristic extrapyramidal movement.
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JOURNAL OF HUMAN GENETICS 60(12) 739-742 2015年12月 査読有りRecently, de novo KIF1A mutations were identified in patients with intellectual disability, spasticity and cerebellar atrophy and/or optic nerve atrophy. In this study, we analyzed a total of 62 families, including 68 patients with genetically unsolved childhood cerebellar atrophy, by whole-exome sequencing (WES). We identified five de novo missense KIF1A mutations, including only one previously reported mutation (p.Arg316Trp). All the mutations are located in the motor domain of KIF1A. In all patients, initial symptom onset was during the infantile period, and included developmental delay in three patients and gait disturbance in two. Thereafter, they showed gait disturbances, exaggerated deep tendon reflexes, cerebellar symptoms and cerebellar atrophy on brain magnetic resonance imaging. Four patients showed lower limb spasticity, upper limb clumsiness and visual disturbances. Nerve conduction study revealed peripheral neuropathy in three patients. This study further delineates clinical features of de novo KIF1A mutations. Genetic testing of KIF1A should be considered in children with developmental delay, cerebellar atrophy and pyramidal features.
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MOLECULAR GENETICS AND METABOLISM 116(3) 157-162 2015年11月 査読有り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.
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JOURNAL OF THE NEUROLOGICAL SCIENCES 358(1-2) 62-65 2015年11月 査読有り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.
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EPILEPSIA 56(9) E121-E128 2015年9月 査読有りKCNT1 mutations have been found in epilepsy of infancy with migrating focal seizures (EIMFS; also known as migrating partial seizures in infancy), autosomal dominant nocturnal frontal lobe epilepsy, and other types of early onset epileptic encephalopathies (EOEEs). We performed KCNT1-targeted next-generation sequencing (207 samples) and/or whole-exome sequencing (229 samples) in a total of 362 patients with Ohtahara syndrome, West syndrome, EIMFS, or unclassified EOEEs. We identified nine heterozygous KCNT1 mutations in 11 patients: nine of 18 EIMFS cases (50%) in whom migrating foci were observed, one of 180 West syndrome cases (0.56%), and one of 66 unclassified EOEE cases (1.52%). KCNT1 mutations occurred de novo in 10 patients, and one was transmitted from the patient's mother who carried a somatic mosaic mutation. The mutations accumulated in transmembrane segment 5 (2/9, 22.2%) and regulators of K+ conductance domains (7/9, 77.8%). Five of nine mutations were recurrent. Onset ages ranged from the neonatal period (<1month) in five patients (5/11, 45.5%) to 1-4months in six patients (6/11, 54.5%). A generalized attenuation of background activity on electroencephalography was seen in six patients (6/11, 54.5%). Our study demonstrates that the phenotypic spectrum of de novo KCNT1 mutations is largely restricted to EIMFS.
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NEUROMUSCULAR DISORDERS 25(8) 667-671 2015年8月 査読有りSchwartz-Jampel syndrome (SJS) type 1 is characterized by short stature, myotonia, and chondrodysplasia, and is caused by partial loss-of-function mutations in HSPG2 encoding perlecan. Six missense mutations have been reported in SJS to date and only one has been characterized using a recombinant protein. We report an 11-year-old Japanese boy with SJS, who shows "rigid" walking with less flexion of knees/ankles and protruded mouth. His intelligence is normal. We identified by whole genome resequencing a heterozygous missense p.Leu1088Pro in domain III-2 and a heterozygous nonsense p.G1n3061Ter in domain IV of perlecan. Expression studies revealed that p.Leu1088Pro markedly reduces the cellular expression of domain III-2 and almost nullifies its secretion into the culture medium. As five of the seven missense mutations in SJS affect domain III of perlecan, domain III is likely to be essential for secretion of perlecan into the extracellular space. (C) 2015 Elsevier B.A. All rights reserved.
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Epilepsy Research 113 90-97 2015年7月1日 査読有りWe evaluated outcomes of 56-week stiripentol use with valproate and clobazam for Dravet syndrome. Of 24 patients, 22 experienced stiripentol-related adverse events. No patients discontinued stiripentol due to adverse events. Seizure frequency decreased by ≥50% in 13 patients with 2 remaining seizure-free. Stiripentol adjunctive therapy has a favorable long-term risk-benefit profile. Background: We have previously shown the benefits of short-term add-on stiripentol therapy for Dravet syndrome inadequately controlled by clobazam and valproate in Japanese patients. We report here the outcomes of long-term stiripentol use. Methods: Patients with Dravet syndrome having ≥4 clonic/tonic-clonic seizures per 30 days while on clobazam and valproate (with or without bromide) received add-on stiripentol for 16 weeks. Those benefiting from stiripentol (50. mg/kg/day up to 2500. mg/day) continued the therapy for additional up to 40 weeks. Responders were defined as those whose clonic/tonic-clonic seizures became ≤50% frequent as compared to baseline. Results: Of 24 patients starting stiripentol, 21 received the drug for > 16 weeks and 19 completed the study. At the endpoint, the responder rate was 54%, with 2 patients remaining clonic/tonic-clonic seizure-free. Twenty-two patients experienced stiripentol-related adverse events, with two having severe ones. They included somnolence (79%), loss of appetite (67%), ataxia (58%), and elevated gamma-glutamyltransferase (38%). No adverse events led to study discontinuation, but 19 patients required dose reduction for stiripentol and/or either antiepileptic drug combined. Stiripentol dose reduction was done in 9 patients, mostly due to somnolence or loss of appetite. Conclusions: During adjunctive stiripentol use with clobazam and valproate, careful monitoring for adverse events such as somnolence and loss of appetite is recommended, and dose reduction may become needed for any of the antiepileptics. Despite the need for safety precautions, the durable responses to stiripentol for up to 56 weeks suggest that the drug is effective as an adjunct to clobazam and valproate for the treatment of Dravet syndrome.
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TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE 236(3) 225-232 2015年7月Mitochondria are key organelles implicated in a variety of processes related to energy and free radical generation, the regulation of apoptosis, and various signaling pathways. Mitochondrial dysfunction increases cellular oxidative stress and depletes ATP in a variety of inherited mitochondrial diseases and also in many other metabolic and neurodegenerative diseases. Mitochondrial diseases are characterized by the dysfunction of the mitochondrial respiratory chain, caused by mutations in the genes encoded by either nuclear DNA or mitochondrial DNA. We have hypothesized that chemicals that increase the cellular ATP levels may ameliorate the mitochondrial dysfunction seen in mitochondrial diseases. To search for the potential drugs for mitochondrial diseases, we screened an in-house chemical library of indole-3-acetic-acid analogs by measuring the cellular ATP levels in Hep3B human hepatocellular carcinoma cells. We have thus identified mitochonic acid 5 (MA-5), 4-(2,4-difluorophenyl)-2-(1H-indol-3-yl)-4-oxobutanoic acid, as a potential drug for enhancing ATP production. MA-5 is a newly synthesized derivative of the plant hormone, indole-3-acetic acid. Importantly, MA-5 improved the survival of fibroblasts established from patients with mitochondrial diseases under the stress-induced condition, including Leigh syndrome, MELAS (myopathy encephalopathy lactic acidosis and stroke-like episodes), Leber's hereditary optic neuropathy, and Kearns-Sayre syndrome. The improved survival was associated with the increased cellular ATP levels. Moreover, MA-5 increased the survival of mitochondrial disease fibroblasts even under the inhibition of the oxidative phosphorylation or the electron transport chain. These data suggest that MA-5 could be a therapeutic drug for mitochondrial diseases that exerts its effect in a manner different from anti-oxidant therapy.
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TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE 236(3) 225-232 2015年7月 査読有りMitochondria are key organelles implicated in a variety of processes related to energy and free radical generation, the regulation of apoptosis, and various signaling pathways. Mitochondrial dysfunction increases cellular oxidative stress and depletes ATP in a variety of inherited mitochondrial diseases and also in many other metabolic and neurodegenerative diseases. Mitochondrial diseases are characterized by the dysfunction of the mitochondrial respiratory chain, caused by mutations in the genes encoded by either nuclear DNA or mitochondrial DNA. We have hypothesized that chemicals that increase the cellular ATP levels may ameliorate the mitochondrial dysfunction seen in mitochondrial diseases. To search for the potential drugs for mitochondrial diseases, we screened an in-house chemical library of indole-3-acetic-acid analogs by measuring the cellular ATP levels in Hep3B human hepatocellular carcinoma cells. We have thus identified mitochonic acid 5 (MA-5), 4-(2,4-difluorophenyl)-2-(1H-indol-3-yl)-4-oxobutanoic acid, as a potential drug for enhancing ATP production. MA-5 is a newly synthesized derivative of the plant hormone, indole-3-acetic acid. Importantly, MA-5 improved the survival of fibroblasts established from patients with mitochondrial diseases under the stress-induced condition, including Leigh syndrome, MELAS (myopathy encephalopathy lactic acidosis and stroke-like episodes), Leber's hereditary optic neuropathy, and Kearns-Sayre syndrome. The improved survival was associated with the increased cellular ATP levels. Moreover, MA-5 increased the survival of mitochondrial disease fibroblasts even under the inhibition of the oxidative phosphorylation or the electron transport chain. These data suggest that MA-5 could be a therapeutic drug for mitochondrial diseases that exerts its effect in a manner different from anti-oxidant therapy.
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BRAIN & DEVELOPMENT 37(6) 638-642 2015年6月 査読有りVanishing white matter disease (VWM)/childhood ataxia with central hypomyelination (CACH) is an autosomal recessive leukoencephalopathy caused by mutations in one of five genes, EIF2B1-5, encoding the 5 subunits of eukaryotic translation initiation factor 2B (eIF2B). The classical phenotype is characterized by early childhood onset and chronic progressive neurological deterioration with cerebellar ataxia, spasticity, optic atrophy and epilepsy. However, the onset of disease varies from antenatal period to adulthood. Cree leukoencephalopathy (CLE) is a severe variant of VWM and caused by a homozygous mutation (R195H) in the EIF2B5 gene. The patient reported in this study developed lethargy, vomiting and seizure 3 days after an oral poliovirus vaccination at the age of 4 months. She presented with rapid neurological deterioration within a month of onset. Brain MRI showed abnormal white matter intensity. Whole-exome sequencing identified two heterozygous mutations in the EIF2B5 gene: a known mutation, c.584G>A (R195H, which is homozygous in CLE), and a novel mutation, c.1223T>C (I408T, which resides in the "I-patch"). Mutations in the "I-patch" encoded region of eIF2B epsilon may be related to an early-infantile onset phenotype. This patient exhibits an early-infantile onset and progressive disease course resembling CLE, suggesting a severe functional disruption of eIF2B epsilon caused by R195H as well as by I408T mutations. (C) 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
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脳と発達 47(Suppl.) S210-S210 2015年5月
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JOURNAL OF NEUROLOGY 262(5) 1278-1284 2015年5月 査読有りMutations in the inositol 1,4,5-triphosphate receptor type 1 gene (ITPR1) have been identified in families with early-onset spinocerebellar ataxia type 29 (SCA29) and late-onset SCA15, but have not been found in sporadic infantile-onset cerebellar ataxia. We examined if mutations of ITPR1 are also involved in sporadic infantile-onset SCA. Sixty patients with childhood-onset cerebellar atrophy of unknown etiology and their families were examined by whole-exome sequencing. We found de novo heterozygous ITPR1 missense mutations in four unrelated patients with sporadic infantile-onset, nonprogressive cerebellar ataxia. Patients displayed nystagmus, tremor, and hypotonia from very early infancy. Nonprogressive ataxia, motor delay, and mild cognitive deficits were common clinical findings. Brain magnetic resonance imaging revealed slowly progressive cerebellar atrophy. ITPR1 missense mutations cause infantile-onset cerebellar ataxia. ITPR1-related SCA includes sporadic infantile-onset cerebellar ataxia as well as SCA15 and SCA29.
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JOURNAL OF NIPPON MEDICAL SCHOOL 82(2) 74-75 2015年4月
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PEDIATRICS INTERNATIONAL 57(2) 324-326 2015年4月 査読有りMyoclonus-dystonia syndrome (MDS) is a rare autosomal-dominant movement disorder characterized by brief, frequently alcohol-responsive myoclonic jerks that begin in childhood or early adolescence, caused by mutations in the epsilon-sarcoglycan gene (SGCE). The patient was a 6-year-old boy. At 2 years 8 months, he had abnormal movement when he ran due to dystonia of his left leg. At 3 years 5 months, he exhibited dystonia and myoclonic movement of his arms when eating. Myoclonus was likely to develop when he felt anxiety or exhaustion. Genomic DNA showed a heterozygous mutation in SGCE (c.109 + 1 G > T). His father and uncle with the same mutation also experienced milder dystonia or myoclonic movements. SGCE mutation can cause a broad range of clinical symptoms between and within families. We should consider MDS as a differential diagnosis for patients with paroxysmal walking abnormalities and/or myoclonic movements.
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JOURNAL OF NIPPON MEDICAL SCHOOL 82(2) 74-75 2015年4月 査読有り
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BRAIN & DEVELOPMENT 37(4) 442-445 2015年4月 査読有りPyridoxine-dependent epilepsy (PDE) is an autosomal recessive disorder characterized by early onset and recurrent seizures that can be controlled by a high dose of pyridoxine. PDE is caused by mutations in ALDH7A1, which encodes antiquitin. Antiquitin converts a-aminoadipic semialdehyde to a-aminoadipic acid. Seizure recurrence after pyridoxine withdrawal is a criterion for diagnosis, but PDE can be diagnosed conclusively by genetic testing for mutations in the ALDH7A1 gene. In this case study, we report the long-term follow-up of a patient suspected with PDE. She experienced prolonged generalized tonic seizures and was hospitalized in an intensive care unit following pyridoxine withdrawal. Later, we identified a compound heterozygous mutation, c.1216G>A, p.Gly406Arg, and a novel splice donor site mutation, IVS9+5G>A. Confirmation of these mutations would have prevented an unsafe withdrawal test. This case suggests the importance of the genetic determination of PDE to avoid the diagnostic withdrawal of pyridoxine. (C) 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
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Clinical Genetics 87(2) 141-147 2015年2月1日 査読有りThe BCAP31 gene is located between SLC6A8, associated with X-linked creatine transporter deficiency, and ABCD1, associated with X-linked adrenoleukodystrophy. Recently, loss-of-function mutations in BCAP31 were reported in association with severe developmental delay, deafness and dystonia. We characterized the break points in eight patients with deletions of SLC6A8, BCAP31 and/or ABCD1 and studied the genotype-phenotype correlations. The phenotype in patients with contiguous gene deletions involving BCAP31 overlaps with the phenotype of isolated BCAP31 deficiency. Only deletions involving both BCAP31 and ABCD1 were associated with hepatic cholestasis and death before 1year, which might be explained by a synergistic effect. Remarkably, a patient with an isolated deletion at the 3′-end of SLC6A8 had a similar severe phenotype as seen in BCAP31 deficiency but without deafness. This might be caused by the disturbance of a regulatory element between SLC6A8 and BCAP31.
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BRAIN & DEVELOPMENT 37(2) 243-249 2015年2月 査読有りObjective: The objective of this study was to investigate stiripentol (STP) administration in cases of Dravet syndrome (DS) by comparing CYP2C19 allelic polymorphisms with the clinical effects of STP, including plasma concentrations of concomitant drugs and adverse effects of STP. Materials and methods: Eleven cases of DS cases were included. Demographic and clinical characteristics of the cases (age at the study period, body weight, mean dose and plasma concentration of valproate acid (VPA)/clobazam (CLB) off and on STP, mean plasma concentration of norclobazam (N-CLB) off and on STP, degree of seizure reduction, and adverse effects of STP) were examined with each CYP2C19 polymorphism. Results: There were 3 cases of DS with wild type, 6 with intermediate type, and 2 with poor type of CYP2C19 polymorphisms. The N-CLB coneentration/CLB dose ratio and N-CLB/CLB concentration ratio off STP were significantly higher in poor metabolizers. Three (37%) of 8 cases showed no effectiveness of STP regardless of the N-CLB concentration increase, and 1 (33%) of 3 cases showed effectiveness of STP regardless of N-CLB concentration decrease. In total, 6 (54%) of 11 cases with DS had >50% reduction in seizure frequency without significant differences in CYP2C19 polymorphisms. Conclusion: This study demonstrated an effect of CYP2C19 polymorphisms on STP administration in Japanese cases of DS. There were cases of seizure reduction regardless of N-CLB concentration decrease on STP, which suggests a significant anti-convulsant action of STP. N-CLB concentration decrease on STP was observed in 1 case with ketogenic diet and 2 cases with *3 allelic polymorphisms of CYP2C19. (C) 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
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JOURNAL OF HUMAN GENETICS 60(2) 97-101 2015年2月 査読有りAminoacylation is the process of attaching amino acids to their cognate tRNA, and thus is essential for the translation of mRNA into protein. This direct interaction of tRNA with amino acids is catalyzed by aminoacyl-tRNA synthetases. Using whole-exome sequencing, we identified compound heterozygous mutations [c.169T > C (p.Tyr57His) and c.1485dup (p.Lys496*)] in QARS, which encodes glutaminyl-tRNA synthetase, in two siblings with early-onset epileptic encephalopathy (EOEE). Recessive mutations in QARS, including the loss-of-function missense mutation p.Tyr57His, have been reported to cause intractable seizures with progressive microcephaly. The p.Lys496* mutation is novel and causes truncation of the QARS protein, leading to a deletion of part of the catalytic domain and the entire anticodon-binding domain. Transient expression of the p.Lys496* mutant in neuroblastoma 2A cells revealed diminished and aberrantly aggregated expression, indicating the loss-of-function nature of this mutant. Together with the previous report, our data suggest that abnormal aminoacylation is one of the underlying pathologies of EOEE.
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脳と発達 47(1) 49-52 2015年1月1日クレアチントランスポーター欠損症は, 筋緊張低下, 知的障害とけいれんを特徴とするX連鎖劣性遺伝性疾患である. 本邦3家系目を経験したので報告する. 発端者は8歳男児. 重度知的障害とけいれんを認めた. 2名の兄にてんかんと重度知的障害を認め, 長兄は17歳で突然死した. 尿中クレアチン/クレアチニン比上昇, 頭部MRスペクトロスコピーでクレアチンピーク低下, <i>SLC6A8</i>遺伝子解析でc.1661 C>T;p.Pro554Leuの既報告ミスセンス変異を認め, 確定診断した. 兄にも同じ変異があり, 母はヘテロ接合変異を認めた. 知的障害, けいれんや発達障害等を認め, X連鎖劣性遺伝を示唆する男児例では尿中クレアチン/クレアチニン比の測定をすることが重要である.
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Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine 14(3) 223-226 2015年 査読有り
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No To Hattatsu 47(1) 49-52 2015年1月1日 査読有りCreatine transporter deficiency (CRTR-D) is an X-hnked disorder characterized by hypotonia, developmental delay, and seizures. We report the third Japanese family with CRTR-D. The proband was an 8-year-old boy who presented with hypotonia, severe intellectual disability and two episodes of seizures associated with/without fever Among 7 siblings (4 males, 3 females), the eldest brother had severe intellectual disability, epilepsy, and sudden death at 17 years of age, while 18-year-old third elder brother had severe intellectual disability, autism, and drug-resistant epilepsy The proband's urinary creatine/creatinine ratio was increased A reduced creatine peak on brain magnetic resonance spectroscopy and a known pathogenic mutation in the SLC6A8 gene (c.1661 C> T,p.Pro554Leu) confirmed the diagnosis of CRTR-D The same mutation was found in the third elder brother. Their mother was a heterozygote. Symptoms of CRTR-D are non-specific. Urinary creatine/creatinine ratio should be measured in patients with hypotonia, developmental delay, seizure and autism whose family history indicates an X-linked inheritance.
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BRAIN & DEVELOPMENT 36(7) 630-633 2014年8月 査読有りCreatine transporter deficiency (CTD) is an example of X-linked intellectual disability syndromes, caused by mutations in SLC6A8 on Xq28. Although this is the second most frequent genetic cause of intellectual disabilities in Europe or America after Fragile X syndrome, information on the morbidity of this disease is limited in Japan. Using the HPLC screening method we have established recently, we examined samples of urine of 105 patients (73 males and 32 females) with developmental disabilities at our medical center. And we have found a family with three ID boys with a novel missense mutation in SLC6A8. This is the second report of a Japanese family case of CTD. A systematic diagnostic system of this syndrome should be established in Japan to enable us to estimate its frequency and treatment. (C) 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
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JOURNAL OF HUMAN GENETICS 59(8) 471-474 2014年8月 査読有りWe report on a 1-year-old boy with microcephaly with a simplified gyral pattern, early-onset seizures, congenital hearing loss and a severe developmental delay. Trio-based whole-exome sequencing identified candidate compound heterozygous mutations in two genes: c.163G > T (p.Ala55Ser) and c.874G > A (p.Gly292Arg) in polynucleotide kinase 30-phosphatase gene (PNKP), and c.195G > A (p.Met65Ile) and c.1210A > C (p.Ser404Arg) in PCDH15. PNKP and PCDH15 mutations have been reported in autosomal recessive microcephaly with early-onset seizures and developmental delay syndrome, and Usher syndrome type 1F, respectively. Our patient showed neurological features similar to reported cases of both syndromes that could be explained by the observed mutations in both PNKP and PCDH15, which therefore appear to be pathogenic in this case.
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NEUROLOGY 82(24) 2230-2237 2014年6月 査読有りObjective:We performed whole-exome sequencing analysis of patients with genetically unsolved hypomyelinating leukoencephalopathies, identifying 8 patients with TUBB4A mutations and allowing the phenotypic spectrum of TUBB4A mutations to be investigated.Methods:Fourteen patients with hypomyelinating leukoencephalopathies, 7 clinically diagnosed with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), and 7 with unclassified hypomyelinating leukoencephalopathy, were analyzed by whole-exome sequencing. The effect of the mutations on microtubule assembly was examined by mapping altered amino acids onto 3-dimensional models of the -tubulin heterodimer.Results:Six heterozygous missense mutations in TUBB4A, 5 of which are novel, were identified in 8 patients (6/7 patients with H-ABC [the remaining patient is an atypical case] and 2/7 patients with unclassified hypomyelinating leukoencephalopathy). In 4 cases with parental samples available, the mutations occurred de novo. Analysis of 3-dimensional models revealed that the p.Glu410Lys mutation, identified in patients with unclassified hypomyelinating leukoencephalopathy, directly impairs motor protein and/or microtubule-associated protein interactions with microtubules, whereas the other mutations affect longitudinal interactions for maintaining -tubulin structure, suggesting different mechanisms in tubulin function impairment. In patients with the p.Glu410Lys mutation, basal ganglia atrophy was unobserved or minimal although extrapyramidal features were detected, suggesting its functional impairment.Conclusions:TUBB4A mutations cause typical H-ABC. Furthermore, TUBB4A mutations associate cases of unclassified hypomyelinating leukoencephalopathies with morphologically retained but functionally impaired basal ganglia, suggesting that TUBB4A-related hypomyelinating leukoencephalopathies encompass a broader clinical spectrum than previously expected. Extrapyramidal findings may be a key for consideration of TUBB4A mutations in hypomyelinating leukoencephalopathies.
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PEDIATRIC RADIOLOGY 44(5) 597-604 2014年5月 査読有りKnowledge of MRI findings in pediatric cerebral infarction is limited. To determine whether cortical necrosis and network injury appear in the acute phase in post-stroke children and to identify anatomical location of acute network injury and the ages at which these phenomena are seen. Images from 12 children (age range: 0-9 years; neonates [< 1 month], n=5; infants [1 month-12 months], n=3; others [a parts per thousand yen1 year], n=4) with acute middle cerebral artery (MCA) cortical infarction were retrospectively analyzed. Cortical necrosis was defined as hyperintense cortical lesions on T1-weighted imaging that lacked evidence of hemorrhage. Acute network injury was defined as hyperintense lesions on diffusion-weighted imaging that were not in the MCA territory and had fiber connections with the affected cerebral cortex. MRI was performed within the first week after disease onset. Cortical necrosis was only found in three neonates. Acute network injury was seen in the corticospinal tract (CST), thalamus and corpus callosum. Acute network injury along the CST was found in five neonates and one 7-month-old infant. Acute network injury was evident in the thalamus of four neonates and two infants (ages 4 and 7 months) and in the corpus callosum of five neonates and two infants (ages 4 and 7 months). The entire thalamus was involved in three children when infarction of MCA was complete. In acute MCA cortical infarction, MRI findings indicating cortical necrosis or acute network injury was frequently found in neonates and early infants. Response to injury in a developing brain may be faster than that in a mature one.
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NEUROLOGY 82(18) 1587-1596 2014年5月 査読有りObjective:To investigate the clinical spectrum caused by mutations in PIGA at Xp22.2, which is involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor, among patients with early-onset epileptic encephalopathies (EOEEs).Methods:Whole-exome sequencing was performed as a comprehensive genetic analysis for a cohort of 172 patients with EOEEs including early myoclonic encephalopathy, Ohtahara syndrome, and West syndrome, and PIGA mutations were carefully investigated.Results:We identified 4 PIGA mutations in probands showing early myoclonic encephalopathy, West syndrome, or unclassified EOEE. Flow cytometry of blood granulocytes from patients demonstrated reduced expression of GPI-anchored proteins. Expression of GPI-anchored proteins in PIGA-deficient JY5 cells was only partially or hardly restored by transient expression of PIGA mutants with a weak TATA box promoter, indicating a variable loss of PIGA activity. The phenotypic consequences of PIGA mutations can be classified into 2 types, severe and less severe, which correlate with the degree of PIGA activity reduction caused by the mutations. Severe forms involved myoclonus and asymmetrical suppression bursts on EEG, multiple anomalies with a dysmorphic face, and delayed myelination with restricted diffusion patterns in specific areas. The less severe form presented with intellectual disability and treatable seizures without facial dysmorphism.Conclusions:Our study confirmed that PIGA mutations are one genetic cause of EOEE, suggesting that GPI-anchor deficiencies may be an underlying cause of EOEE.
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STEM CELL REPORTS 2(5) 648-661 2014年5月 査読有りPelizaeus-Merzbacher disease (PMD) is a form of X-linked leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene. Although PLP1 proteins with missense mutations have been shown to accumulate in the rough endoplasmic reticulum (ER) in disease model animals and cell lines transfected with mutant PLP1 genes, the exact pathogenetic mechanism of PMD has not previously been clarified. In this study, we established induced pluripotent stem cells (iPSCs) from two PMD patients carrying missense mutation and differentiated them into oligodendrocytes in vitro. In the PMD iPSC-derived oligodendrocytes, mislocalization of mutant PLP1 proteins to the ER and an association between increased susceptibility to ER stress and increased numbers of apoptotic oligodendrocytes were observed. Moreover, electron microscopic analysis demonstrated drastically reduced myelin formation accompanied by abnormal ER morphology. Thus, this study demonstrates the involvement of ER stress in pathogenic dysmyelination in the oligodendrocytes of PMD patients with the PLP1 missense mutation.
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JOURNAL OF NEUROLOGY 261(4) 752-758 2014年4月 査読有りTo determine the epidemiological, clinical, and genetic characteristics of congenital hypomyelinating leukodystrophies, including Pelizaeus-Merzbacher disease (PMD), we conducted a nationwide epidemiological survey in Japan. A two-step survey targeting all medical institutions specializing in pediatric neurology and childhood disability (919 institutes) in Japan was performed. Detailed information was collected for 101 patients (86 males and 15 females) with congenital hypomyelinating leukodystrophies. The prevalence of congenital hypomyelinating disorders was 0.78 per 100,000 people (0-19 years old), and the incidence was 1.40 per 100,000 live births. Molecular testing was performed in 75 % of patients, and PLP1 gene abnormalities were observed in 62 %. The incidence of PMD with PLP1 mutations was estimated to be 1.45 per 100,000 male live births and that for congenital hypomyelinating disorders with unknown cause to be 0.41 per 100,000 live births. Patients with PLP1 mutations showed a higher proportion of nystagmus and hypotonia, both of which tend to disappear over time. Our results constitute the first nationwide survey of congenital hypomyelinating disorders, and provide the epidemiological, clinical, and genetic landscapes of these disorders.
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PEDIATRIC NEUROLOGY 50(4) 417-420 2014年4月 査読有りBACKGROUND: Determining the relationship between clinical phenotype and genotype in genetic diseases is important in clinical practice. In general, frameshift mutations are expected to produce premature termination codons, leading to production of mutant transcripts destined for degradation by nonsense-mediated decay. In X-linked recessive diseases, male patients with frameshift mutations typically have a severe or even lethal phenotype. PATIENT: We report a case of a 17-month-old boy with Menkes disease (NIM #309400), an X-linked recessive copper metabolism disorder caused by mutations in the ATP7A copper transporter gene. He exhibited an unexpectedly late onset and experienced milder symptoms. STUDY AND RESULT: His genomic DNA showed a de novo two-nucleotide deletion in exon 4 of ATP7A, predicting a translational frameshift and premature stop codon, and a classic severe phenotype. Characterization of his ATP7A mRNA showed no abnormal splicing. CONCLUSION: We speculate that translation reinitiation could occur downstream to the premature termination codon and produce a partially functional ATP7A protein. Study of the child's fibroblasts found no evidence of translation reinitiation; however, the possibility remains that this phenomenon occurred in neural tissues and influenced the clinical phenotype.
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