担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Recent studies have elucidated causative roles for genetic abnormalities in early-onset epileptic encephalopathies (EOEE). Accompanying characteristic features, in addition to seizures, have also been suggested to provide important clues for an early and accurate genetic diagnosis of affected patients. In this study, we investigated the underlying genetic causes in patients with EOEE associated with infantile movement disorders. METHODS: We examined 11 patients with EOEE and involuntary movements (nine with West syndrome and two with nonsyndromic epileptic encephalopathy). All showed severe developmental delay, cognitive impairment, and involuntary movements such as chorea, ballism, dyskinesia or myoclonus, and hand stereotypies. We performed whole-exome sequencing of 10 patients, while the other patient underwent high-resolution melting analysis of candidate EOEE genes. RESULTS: We identified mutations in CDKL5, SCN2A, SETD5, ALG13, and TBL1XR1 in seven patients with West syndrome, and in SCN1A and GRIN1 in the two patients with unclassified epileptic encephalopathy. All mutations were validated as de novo events. The genetic cause was undetermined in the remaining two patients. CONCLUSIONS: We found pathogenic mutations in seven genes, in nine of 11 patients with EOEE and involuntary movements. Although the results of our study are preliminary because of the small number of patients, they nevertheless suggest that specific accompanying phenotypes such as hyperkinetic movements or hand stereotypies could be important in narrowing the disease spectrum and identifying causative genetic abnormalities.

DOI： 10.1016/j.braindev.2015.09.011

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Focal cortical dysplasia (FCD) type IIb is a cortical malformation characterized by cortical architectural abnormalities, dysmorphic neurons, and balloon cells. It has been suggested that FCDs are caused by somatic mutations in cells in the developing brain. Here, we explore the possible involvement of somatic mutations in FCD type IIb. METHODS: We collected a total of 24 blood-brain paired samples with FCD, including 13 individuals with FCD type IIb, 5 with type IIa, and 6 with type I. We performed whole-exome sequencing using paired samples from 9 of the FCD type IIb subjects. Somatic MTOR mutations were identified and further investigated using all 24 paired samples by deep sequencing of the entire gene's coding region. Somatic MTOR mutations were confirmed by droplet digital polymerase chain reaction. The effect of MTOR mutations on mammalian target of rapamycin (mTOR) kinase signaling was evaluated by immunohistochemistry and Western blotting analyses of brain samples and by in vitro transfection experiments. RESULTS: We identified four lesion-specific somatic MTOR mutations in 6 of 13 (46%) individuals with FCD type IIb showing mutant allele rates of 1.11% to 9.31%. Functional analyses showed that phosphorylation of ribosomal protein S6 in FCD type IIb brain tissues with MTOR mutations was clearly elevated, compared to control samples. Transfection of any of the four MTOR mutants into HEK293T cells led to elevated phosphorylation of 4EBP, the direct target of mTOR kinase. INTERPRETATION: We found low-prevalence somatic mutations in MTOR in FCD type IIb, indicating that activating somatic mutations in MTOR cause FCD type IIb.

DOI： 10.1002/ana.24444

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recent progress in genetic analysis reveals that a significant proportion of cryptogenic epileptic encephalopathies are single-gene disorders. Mutations in numerous genes for early-onset epileptic encephalopathies have been rapidly identified, including in SPTAN1, which encodes α-II spectrin. The aim of this review is to delineate SPTAN1 encephalopathy as a distinct clinical syndrome. To date, a total of seven epileptic patients with four different in-frame SPTAN1 mutations have been identified. The major clinical features of SPTAN1 mutations include epileptic encephalopathy with hypsarrhythmia, no visual attention, acquired microcephaly, spastic quadriplegia and severe intellectual disability. Brainstem and cerebellar atrophy and cerebral hypomyelination, as observed by magnetic resonance imaging, are specific hallmarks of this condition. A milder variant is characterized by generalized epilepsy with pontocerebellar atrophy. Only in-frame SPTAN1 mutations in the last two spectrin repeats in the C-terminal region lead to dominant negative effects and these specific phenotypes. The last two spectrin repeats are required for α/β spectrin heterodimer associations and the mutations can alter heterodimer formation between the two spectrins. From these data we suggest that SPTAN1 encephalopathy is a distinct clinical syndrome owing to specific SPTAN1 mutations. It is important that this syndrome is recognized by pediatric neurologists to enable proper diagnostic work-up for patients.

DOI： 10.1038/jhg.2015.5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A de novo 9q33.3-q34.11 microdeletion involving STXBP1 has been found in one of four individuals (group A) with early-onset West syndrome, severe hypomyelination, poor visual attention, and developmental delay. Although haploinsufficiency of STXBP1 was involved in early infantile epileptic encephalopathy in a previous different cohort study (group B), no mutations of STXBP1 were found in two of the remaining three subjects of group A (one was unavailable). We assumed that another gene within the deletion might contribute to the phenotype of group A. SPTAN1 encoding alpha-II spectrin, which is essential for proper myelination in zebrafish, turned out to be deleted. In two subjects, an in-frame 3 bp deletion and a 6 bp duplication in SPTAN1 were found at the initial nucleation site of the alpha/beta spectrin heterodimer. SPTAN1 was further screened in six unrelated individuals with WS and hypomyelination, but no mutations were found. Recombinant mutant (mut) and wild-type (WT) alpha-II spectrin could assemble heterodimers with beta-II spectrin, but alpha-II (mut)/beta-II spectrin heterodimers were thermolabile compared with the alpha-II (WT)/beta-II heterodimers. Transient expression in mouse cortical neurons revealed aggregation of alpha-II (mut)/beta-II and alpha-II (mut)/beta-III spectrin heterodimers, which was also observed in lymphoblastoid cells from two subjects with in-frame mutations. Clustering of ankyrinG and voltage-gated sodium channels at axon initial segment (AIS) was disturbed in relation to the aggregates, together with an elevated action potential threshold. These findings suggest that pathological aggregation of alpha/beta spectrin heterodimers and abnormal AIS integrity resulting from SPTAN1 mutations were involved in pathogenesis of infantile epilepsy.

DOI： 10.1016/j.ajhg.2010.04.013

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Early infantile epileptic encephalopathy with suppression-burst (EIEE), also known as Ohtahara syndrome, is one of the most severe and earliest forms of epilepsy. Using array-based comparative genomic hybridization, we found a de novo 2.0-Mb microdeletion at 9q33.3-q34.11 in a girl with EIEE. Mutation analysis of candidate genes mapped to the deletion revealed that four unrelated individuals with EIEE had heterozygous missense mutations in the gene encoding syntaxin binding protein 1 (STXBP1). STXBP1 (also known as MUNC18-1) is an evolutionally conserved neuronal Sec1/Munc-18 (SM) protein that is essential in synaptic vesicle release in several species. Circular dichroism melting experiments revealed that a mutant form of the protein was significantly thermolabile compared to wild type. Furthermore, binding of the mutant protein to syntaxin was impaired. These findings suggest that haploinsufficiency of STXBP1 causes EIEE.

DOI： 10.1038/ng.150

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Numerous numbers of pre-, peri- and postnatal damages cause West syndrome in early infancy, however, etiology in many cases are not still elucidated despite intensive biochemical and neuroradiologic investigations. We described four patients having early onset epileptic encephalopathy with severe hypomyelination and reduction in cerebral white matter. The clinical symptoms of these patients are impaired visual attention, acquired microcephaly, spastic tetraplegia, profound psychomotor delay and infantile spasms since early infancy. All patients had striking hypomyelination of cerebrum, reduced volume of white matter and cortical atrophy on MRI. Serial MRI investigations in three patients showed absence of myelination of the white matter. On EEG, one patient revealed suppression-burst and other three had hypsarrhythmia. Despite having intractable seizures, no patient showed deterioration of neurological development. The group of these findings is mimicking to clinical manifestations of 3-phosphoglycerate dehydrogenase deficiency, and has some overlap with progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) like syndrome, however it is not compatible with these two conditions. The findings observed in our patients can be regarded as a new clinical condition associated with early onset West syndrome.

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）  

We have cross-bred twitcher mice (galactosylceramidase deficiency) and acid β-galactosidase knockout mice (G(M1) gangliosidosis) and found that the acid β-galactosidase gene dosage exerts an unexpected and paradoxical influence on the twitcher phenotype. Twitcher mice with an additional complete deficiency of acid β-galactosidase have the mildest phenotype with the longest lifespan and nearly rescued CNS pathology. In contrast, twitcher mice with a single functional acid β-galactosidase gene have the most severe disease with the shortest lifespan, despite the fact that G(M1) gangliosidosis carrier mice with an otherwise normal genetic background are phenotypically normal. A significant proportion of these galc(-/-), bgal(+/-) mice clinically develop additional extreme hyper-reactivity and generalized seizures not seen in any other genotypes. Consistent with the clinical seizures, widespread neuronal degeneration is present in the galc(-/-), bgal(+/-) mice, most prominently in the CA3 region of the hippocampus. The double knockout mice show a massive accumulation of lactosylceramide in all tissues. The brain inexplicably contains only a half-normal amount of galactosylceramide, which may account for the mild clinical and pathological phenotype. On the other hand, brain psychosine level is increased in all twitcher mice, but galc(-/-), bgal(+/-) mice show a significantly higher level than other genotypes. The reduced galactosylceramide in the brain of the double knockout mice and the significantly higher psychosine in the brain of the galc(-/-), bgal(+/-) mice cannot readily be explained from the genotypes of these mice. These observations are contrary to the expected outcome of Mendelian autosomal recessive single gene disorders and may also be interpreted as that the acid β-galactosidase gene functions as a modifier gene for the phenotypic expression of genetic galactosylceramidase deficiency.

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Focal cortical dysplasia is the most common malformation during cortical development, sometimes excised by epilepsy surgery and often caused by somatic variants of the mTOR pathway genes. In this study, we performed a genetic analysis of epileptogenic brain malformed lesions from 64 patients with focal cortical dysplasia, hemimegalencephy, brain tumors, or hippocampal sclerosis. Targeted sequencing, whole-exome sequencing, and single nucleotide polymorphism microarray detected four germline and 35 somatic variants, comprising three copy number variants and 36 single nucleotide variants and indels in 37 patients. One of the somatic variants in focal cortical dysplasia type IIB was an in-frame deletion in MTOR, in which only gain-of-function missense variants have been reported. In focal cortical dysplasia type I, somatic variants of MAP2K1 and PTPN11 involved in the RAS/MAPK pathway were detected. The in-frame deletions of MTOR and MAP2K1 in this study resulted in the activation of the mTOR pathway in transiently transfected cells. In addition, the PTPN11 missense variant tended to elongate activation of the mTOR or RAS/MAPK pathway, depending on culture conditions. We demonstrate that epileptogenic brain malformed lesions except for focal cortical dysplasia type II arose from somatic variants of diverse genes but were eventually linked to the mTOR pathway.

DOI： 10.1186/s40478-023-01532-x

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その他リンク： https://link.springer.com/article/10.1186/s40478-023-01532-x/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1684/epd.2022.1441

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1684/epd.2022.1441

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To determine whether sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, reduces epileptic seizures associated with focal cortical dysplasia (FCD) type II. METHODS: Sixteen patients (aged 6-57 years) with FCD type II received sirolimus at an initial dose of 1 or 2 mg/day based on body weight (FCDS-01). In 15 patients, the dose was adjusted to achieve target trough ranges of 5-15 ng/mL, followed by a 12-week maintenance therapy period. The primary endpoint was a lower focal seizure frequency during the maintenance therapy period. Further, we also conducted a prospective cohort study (RES-FCD) in which 60 patients with FCD type II were included as an external control group. RESULTS: The focal seizure frequency reduced by 25% in all patients during the maintenance therapy period and by a median value of 17%, 28%, and 23% during the 1-4-, 5-8-, and 9-12-week periods. The response rate was 33%. The focal seizure frequency in the external control group reduced by 0.5%. However, the background characteristics of external and sirolimus-treated groups differed. Adverse events were consistent with those of mTOR inhibitors reported previously. The blood KL-6 level was elevated over time. INTERPRETATION: The reduction of focal seizures did not meet the predetermined level of statistical significance. The safety profile of the drug was tolerable. The potential for a reduction of focal seizures over time merit further investigations.

DOI： 10.1002/acn3.51505

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

GRIA3 at Xq25 encodes glutamate ionotropic receptor AMPA type 3 (GluA3), a subunit of postsynaptic glutamate-gated ion channels mediating neurotransmission. Hemizygous loss-of-function (LOF) variants in GRIA3 cause a neurodevelopmental disorder (NDD) in male individuals. Here, we report a gain-of-function (GOF) variant at GRIA3 in a male patient. We identified a hemizygous de novo missense variant in GRIA3 in a boy with an NDD: c.1844C > T (p.Ala615Val) using whole-exome sequencing. His neurological signs, such as hypertonia and hyperreflexia, were opposite to those in previous cases having LOF GRIA3 variants. His seizures and hypertonia were ameliorated by carbamazepine, inhibiting glutamate release from presynapses. Patch-clamp recordings showed that the human GluA3 mutant (p.Ala615Val) had slower desensitization and deactivation kinetics. A fly line expressing a human GluA3 mutant possessing our variant and the Lurcher variant, which makes ion channels leaky, showed developmental defects, while one expressing a mutant possessing either of them did not. Collectively, these results suggest that p.Ala615Val has GOF effects. GRIA3 GOF variants may cause an NDD phenotype distinctive from that of LOF variants, and drugs suppressing glutamatergic neurotransmission may ameliorate this phenotype. This study should help in refining the clinical management of GRIA3-related NDDs.

DOI： 10.1007/s00439-021-02416-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Epileptic seizures are core symptoms in focal cortical dysplasia (FCD), a disease that often develops in infancy. Such seizures are refractory to conventional antiepileptic drugs (AED) and temporarily disappear in response to AED in only 17% of patients. Currently, surgical resection is an important option for the treatment of epileptic seizures in FCD. In 2015, Korean and Japanese groups independently reported that FCD is caused by somatic mosaic mutation of the MTOR gene in the brain tissue. Based on these results we decided to test a novel treatment using sirolimus, an mTOR inhibitor, for epileptic seizures in patients with FCD type II. A single arm open-label clinical trial for FCD type II patients is being conducted in order to evaluate the efficacy and safety of sirolimus. The dose of sirolimus is fixed for the first 4 weeks and dose adjustment is achieved to maintain a blood level of 5 to 15 ng/mL during 8 to 24 weeks after initiation of administration, and it is kept within this level during a maintenance therapy period of 12 weeks. Primary endpoint is a reduction in the rate of incidence of focal seizures (including focal to bilateral tonic-clonic seizures) per 28 days during the maintenance therapy period from the observation period. To evaluate the frequency of epileptic seizures, registry data will be used as an external control group. We hope that the results of this trial will lead to future innovative treatments for FCD type II patients.

DOI： 10.2739/kurumemedj.MS662007

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Vacuolar H+-ATPases (V-ATPases) transport protons across cellular membranes to acidify various organelles. ATP6V0A1 encodes the a1-subunit of the V0 domain of V-ATPases, which is strongly expressed in neurons. However, its role in brain development is unknown. Here we report four individuals with developmental and epileptic encephalopathy with ATP6V0A1 variants: two individuals with a de novo missense variant (R741Q) and the other two individuals with biallelic variants comprising one almost complete loss-of-function variant and one missense variant (A512P and N534D). Lysosomal acidification is significantly impaired in cell lines expressing three missense ATP6V0A1 mutants. Homozygous mutant mice harboring human R741Q (Atp6v0a1R741Q) and A512P (Atp6v0a1A512P) variants show embryonic lethality and early postnatal mortality, respectively, suggesting that R741Q affects V-ATPase function more severely. Lysosomal dysfunction resulting in cell death, accumulated autophagosomes and lysosomes, reduced mTORC1 signaling and synaptic connectivity, and lowered neurotransmitter contents of synaptic vesicles are observed in the brains of Atp6v0a1A512P/A512P mice. These findings demonstrate the essential roles of ATP6V0A1/Atp6v0a1 in neuronal development in terms of integrity and connectivity of neurons in both humans and mice.

DOI： 10.1038/s41467-021-22389-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSES: The purpose of the study was to investigate the positive and negative effects of perampanel (PER) treatment on the psychiatric and behavioral symptoms in patients with epilepsy and to evaluate factors associated with the psychiatric and behavioral changes caused by PER. METHODS: We retrospectively examined medical records of patients with epilepsy treated with PER in the Department of Psychiatry, Epilepsy Center, Nishiniigata Chuo National Hospital. Multiple regression analyses were performed with the psychiatric and behavioral prognoses as dependent variables and clinical characteristics of the patients as independent variables. RESULTS: Thirty-two of 135 patients (23.7%) had psychiatric and behavioral deterioration after the initiation of PER, whereas 22 patients (16.3%) showed improvement in psychiatric and behavioral symptoms after PER administration. Etiology of structural abnormalities, concomitant use of nitrazepam, and comorbidities of irritability and depression were significantly associated with increasing incidence of psychiatric and behavioral deterioration. Concomitant use of carbamazepine was significantly associated with decreasing incidence of psychiatric and behavioral deterioration. Suppression of awareness-impaired seizures by PER, concomitant use of carbamazepine, and comorbidities of insomnia, anxiety, and amnesia were significantly associated with an increasing incidence of psychiatric and behavioral improvement. Improvements in psychiatric symptoms by PER were associated with a reduction in the use of psychotropic drugs. In particular, about 1/4 of benzodiazepines had been discontinued. CONCLUSIONS: Perampanel therapy may aggravate or even ameliorate psychiatric and behavioral symptoms in patients with epilepsy. The psychiatric and behavioral prognoses after administration of PER vary depending on the type of psychiatric and behavioral comorbidities in patients with epilepsy. Psychiatric and behavioral symptoms may improve in patients with successful suppression of seizures by PER. Additionally, combination therapy consisting of PER and carbamazepine may be associated with good outcomes of psychiatric and behavioral symptoms in patients with epilepsy.

DOI： 10.1016/j.yebeh.2020.107515

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担当区分：責任著者   記述言語：英語  

BACKGROUND: Pallister-Killian syndrome (PKS) is a rare disorder caused by the mosaic tetrasomy of chromosome 12p, and is characterized by facial dysmorphism, developmental delay, hypotonia and seizures. RESULTS: We report a patient with PKS showing unique polymicrogyria with calcification. He had delayed development and dysmorphic facial features including frontal bossing, hypertelorism, and high arched palate at 6 months of age. Neuroimaging revealed unilateral polymicrogyria with spot calcifications, which predominantly affected the right perisylvian region. Chromosome G-banding showed the karyotype 46,XY, however, array-based comparative genomic hybridization analysis showed mosaic duplication of chromosome 12p, in which CCND2, which encodes cyclin D2 and is a downstream mediator of PI3K-AKT pathway, is located. Supernumerary chromosome of 12p was detected in 58% of buccal mucosa cells by the interphase fluorescence in situ hybridization analysis using chromosome 12 centromere-specific D12Z3 probe. The diagnosis of PKS was made based on distinctive clinical features of our patient and the results of cytogenetic analyses. CONCLUSION: This report is, to our knowledge, the first case of a patient with PKS who clearly demonstrates polymicrogyria colocalized with calcifications, as shown by CT scans and MRI, and suggests that a patient with PKS could show structural brain anomalies with calcification. We assume that somatic mosaicism of tetrasomy could cause asymmetrical polymicrogyria in our patient, and speculate that increased dosages of CCND2 at chromosome 12p might be involved in the abnormal neuronal migration in PKS.

DOI： 10.1016/j.braindev.2020.11.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: The present study evaluated whether patients with epilepsy who received both levetiracetam (LEV) and perampanel (PER) therapy showed side effects of irritability. The study also examined the relationship between patient characteristics and irritability when it occurred as a side effect. METHODS: We retrospectively examined medical records of 98 patients with epilepsy who were treated with both LEV and PER at the Department of Psychiatry in the Epilepsy Center of Nishiniigata Chuo National Hospital in Japan. We performed multiple regression analyses with the presence/absence of irritability due to LEV or PER as the dependent variables and clinical characteristics of the patients as independent variables. RESULTS: LEV and PER caused irritability in 7 and 17 of 98 patients, respectively. LEV- and PER-related irritability did not occur in the same patients. A logistic multiple regression analysis revealed that EEG findings of temporal focal epileptic discharge were significantly associated with increased incidence of irritability due to LEV. LEV-related irritability decreased significantly with higher dosages of LEV. Another logistic multiple regression analysis revealed that a psychiatric comorbidity of irritability and EEG findings of nontemporal focal epileptic discharge were significantly associated with increased incidence of irritability due to PER. CONCLUSIONS: LEV and PER cause irritability in different patient groups. Additionally, irritability as a side effect was present only at low dosages of LEV, but PER tended to cause irritability even at high dosages.

DOI： 10.1016/j.yebeh.2020.107644

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We report heterozygous CELF2 (NM_006561.3) variants in five unrelated individuals: Individuals 1-4 exhibited developmental and epileptic encephalopathy (DEE) and Individual 5 had intellectual disability and autistic features. CELF2 encodes a nucleocytoplasmic shuttling RNA-binding protein that has multiple roles in RNA processing and is involved in the embryonic development of the central nervous system and heart. Whole-exome sequencing identified the following CELF2 variants: two missense variants [c.1558C>T:p.(Pro520Ser) in unrelated Individuals 1 and 2, and c.1516C>G:p.(Arg506Gly) in Individual 3], one frameshift variant in Individual 4 that removed the last amino acid of CELF2 c.1562dup:p.(Tyr521Ter), possibly resulting in escape from nonsense-mediated mRNA decay (NMD), and one canonical splice site variant, c.272-1G>C in Individual 5, also probably leading to NMD. The identified variants in Individuals 1, 2, 4, and 5 were de novo, while the variant in Individual 3 was inherited from her mosaic mother. Notably, all identified variants, except for c.272-1G>C, were clustered within 20 amino acid residues of the C-terminus, which might be a nuclear localization signal. We demonstrated the extranuclear mislocalization of mutant CELF2 protein in cells transfected with mutant CELF2 complementary DNA plasmids. Our findings indicate that CELF2 variants that disrupt its nuclear localization are associated with DEE.

DOI： 10.1002/humu.24130

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

De novo variants (DNVs) cause many genetic diseases. When DNVs are examined in the whole coding regions of genes in next-generation sequencing analyses, pathogenic DNVs often cluster in a specific region. One such region is the last exon and the last 50 bp of the penultimate exon, where truncating DNVs cause escape from nonsense-mediated mRNA decay [NMD(-) region]. Such variants can have dominant-negative or gain-of-function effects. Here, we first developed a resource of rates of truncating DNVs in NMD(-) regions under the null model of DNVs. Utilizing this resource, we performed enrichment analysis of truncating DNVs in NMD(-) regions in 346 developmental and epileptic encephalopathy (DEE) trios. We observed statistically significant enrichment of truncating DNVs in semaphorin 6B (SEMA6B) (p value: 2.8 × 10-8; exome-wide threshold: 2.5 × 10-6). The initial analysis of the 346 individuals and additional screening of 1,406 and 4,293 independent individuals affected by DEE and developmental disorders collectively identified four truncating DNVs in the SEMA6B NMD(-) region in five individuals who came from unrelated families (p value: 1.9 × 10-13) and consistently showed progressive myoclonic epilepsy. RNA analysis of lymphoblastoid cells established from an affected individual showed that the mutant allele escaped NMD, indicating stable production of the truncated protein. Importantly, heterozygous truncating variants in the NMD(+) region of SEMA6B are observed in general populations, and SEMA6B is most likely loss-of-function tolerant. Zebrafish expressing truncating variants in the NMD(-) region of SEMA6B orthologs displayed defective development of brain neurons and enhanced pentylenetetrazole-induced seizure behavior. In summary, we show that truncating DNVs in the final exon of SEMA6B cause progressive myoclonic epilepsy.

DOI： 10.1016/j.ajhg.2020.02.011

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Schaaf-Yang syndrome (SYS) is a newly recognized imprinting related syndrome, which is caused by a truncating variant in maternally imprinted MAGEL2 located in 15q11-q13. Yet, precise pathomechanism remains to be solved. We sequenced MAGEL2 in patients suspected Prader-Willi syndrome (PWS) to delineate clinical presentation of SYS. We examined 105 patients with clinically suspected PWS but without a specific PWS genetic alteration. Sanger sequencing of the entire MAGEL2 gene and methylation-specific restriction enzyme treatment to detect the parent of origin were performed. Clinical presentation was retrospectively assessed in detail. RESULTS: Truncating variants in MAGEL2 were detected in six patients (5.7%), including a pair of siblings. All truncating variants in affected patients were on the paternally derived chromosome, while the healthy father of the affected siblings inherited the variant from his mother. Patients with MAGEL2 variants shared several features with PWS, such as neonatal hypotonia, poor suck, and obesity; however, there were also unique features, including arthrogryposis and a failure to acquire meaningful words. Additionally, an episode of neurological deterioration following febrile illness was confirmed in four of the six patients, which caused severe neurological sequalae. CONCLUSIONS: SYS can be present in infants suspected with PWS but some unique features, such as arthrogryposis, can help discriminate between the two syndromes. An episode of neurological deterioration following febrile illness should be recognized as an important complication.

DOI： 10.1186/s13023-019-1249-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: This study was performed to clarify the clinical features of Japanese patients with PRRT2 mutations. METHODS: The PRRT2 gene was analyzed in 135 patients with benign infantile epilepsy (BIE) or paroxysmal kinesigenic dyskinesia (PKD) using a direct sequencing method: 92 patients had BIE alone, 25 had both BIE and PKD, and 18 had PKD alone. Of the cases, 105 were familial, and 30 were sporadic. Clinical information was collected using a structured questionnaire. RESULTS: PRRT2 mutations were identified in 104 patients. Among the familial cases, PRRT2 mutations were found in at least one individual in 21 of 28 families with BIE alone, in 26 of 27 families with infantile convulsions and choreoathetosis, and in 2 of 3 families with PKD alone. Among the sporadic cases, PRRT2 mutations were observed in 7 of 25 patients with BIE alone, in 1 of 1 patient with BIE and PKD, and in 3 of 4 patients with PKD alone. The c.649dupC mutation was the most frequent, followed by the c.981C > G mutation. Among the patients with epilepsy, the median age at BIE onset was 5 months, the median age at the last seizure was 6 months, and the median number of seizures was 5. CONCLUSION: PRRT2 mutations were found in 68% of Japanese probands with BIE or PKD. The phenotypes of BIE associated with PRRT2 mutations were consistent with those of BIE diagnosed clinically.

DOI： 10.1016/j.seizure.2019.05.017

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Casein kinase 2 (CK2) is a serine threonine kinase ubiquitously expressed in eukaryotic cells and involved in various cellular processes. In recent studies, de novo variants in CSNK2A1 and CSNK2B, which encode the subunits of CK2, have been identified in individuals with intellectual disability syndrome. In this study, we describe four patients with neurodevelopmental disorders possessing de novo variants in CSNK2A1 or CSNK2B. Using whole-exome sequencing, we detected two de novo variants in CSNK2A1 in two unrelated Japanese patients, a novel variant c.571C>T, p.(Arg191*) and a recurrent variant c.593A>G, p.(Lys198Arg), and two novel de novo variants in CSNK2B in Japanese and Malaysian patients, c.494A>G, p.(His165Arg) and c.533_534insGT, p.(Pro179Tyrfs*49), respectively. All four patients showed mild to profound intellectual disabilities, developmental delays, and various types of seizures. This and previous studies have found a total of 20 CSNK2A1 variants in 28 individuals with syndromic intellectual disability. The hotspot variant c.593A>G, p.(Lys198Arg) was found in eight of 28 patients. Meanwhile, only five CSNK2B variants were identified in five individuals with neurodevelopmental disorders. We reviewed the previous literature to verify the phenotypic spectrum of CSNK2A1- and CSNK2B-related syndromes.

DOI： 10.1038/s10038-018-0559-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Epilepsy with continuous spikes and waves during slow sleep (ECSWS) is associated with cognitive deficits. The underlying mechanism is thought to relate to disturbance of functions of the foci by the persistent epileptic activity. However, the relationship between epileptic foci and cognitive deficits remains largely unknown, except for in Landau-Kleffner syndrome. The aim of this study was to evaluate the relationship of epileptic foci estimated from magnetoencephalography (MEG) with cognitive functions at the period of diagnosis in non-lesional ECSWS children, excluding those with Landau-Kleffner syndrome. METHODS: MEG data and the Wechsler intelligence scale for children-III scores at ECSWS diagnosis, and medical records, were reviewed. Multiple regression analysis was performed to examine the relationship of parameters of MEG spike dipole clusters, including anatomical location or laterality, with the Wechsler intelligence scale for children-III scores at ECSWS diagnosis. RESULTS: Sixteen patients were included, all of whom were right-handed. Epilepsy onset (first unprovoked seizure) ranged from 31 to 110 months (mean, 68.5). The age at ECSWS diagnosis ranged from 72 to 156 months (mean, 108.9). The dipole clusters were estimated on the right Rolandic area (RA) in 4 patients (25%), right supramarginal gyrus (SMG) in 3 (19%), left RA in 2 (13%), left SMG in 2 (13%), bilateral RA in 3 (19%), multiple anatomical locations in 2 (13%). The age at epilepsy onset had the strongest prognostic effect, and full-scale intelligence quotient was relatively less-affected if the cluster was found on the SMG (β = 14.7, p = 0.031). Cases with only a right side cluster exhibited reduced impairment of perceptual organization compared with those with only a left side cluster or bilateral clusters (β = 17.48, p = 0.02). In 12 patients, long-term intellectual prognosis was evaluated, and was associated with intellectual level at the period of ECSWS diagnosis. CONCLUSION: In non-lesional ECSWS, the relationship between epileptic focus and cognitive deficits differs from that observed in adults. Rather, it is similar to epilepsies associated with congenital or early infantile brain insults, in that the left epileptic foci in right-handed patients were associated with lower non-verbal functions. Future studies are required to determine the role of plasticity of the immature brain in driving these differences.

DOI： 10.1016/j.braindev.2018.09.005

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記述言語：日本語   出版者・発行元：(一社)日本てんかん学会  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Objetives: As the first step forward building a supporting system for the Parents of Children with Profound Intellectual and Multiple Disabilities (PIMD) at home, we developed a new resilience scale that can be used by multiple professionals to understand the situation of those parents and to provide the necessary support. METHODS: First, we collected scale items on the basis of our previous study as well as related reports in the literature. These items were then screened by the research team with knowledge and experience in supporting those parents, finally, 37 items were generated. Then, we asked the parents of children with PIMD who were of elementary school age and above in the Kanto-Shinetsu area to complete a questionnaire. Out of 477 questionnaires sent, 193 were refused, and the data were statistically analyzed. RESULTS: Exploratory factor analysis revealed that the scale was made up of the following seven factors. 1) Understanding and awareness of the child, 2) Empowerment by the child, 3) Use of specialists, 4) Interest and concern in something other than the child, 5) Emotional adjustment, 6) Maintenance of lifestyle balance, and 7) Request for assistances. Cronbach's alpha coefficient of each factor was calculated. The validity was also confirmed by determining the relationship of resilience with parents' well-being. CONCLUSIONS: The results suggest that the new resilience scale for parents of children with PIMD developed in this study can be a reliable instrument for assessing resilience in Japanese parents of a child with such disabilities.

DOI： 10.1265/jjh.18025

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

N-methyl-d-aspartate (NMDA) receptors are glutamate-activated ion channels that are widely distributed in the central nervous system and essential for brain development and function. Dysfunction of NMDA receptors has been associated with various neurodevelopmental disorders. Recently, a de novo recurrent GRIN2D missense variant was found in two unrelated patients with developmental and epileptic encephalopathy. In this study, we identified by whole exome sequencing novel heterozygous GRIN2D missense variants in three unrelated patients with severe developmental delay and intractable epilepsy. All altered residues were highly conserved across vertebrates and among the four GluN2 subunits. Structural consideration indicated that all three variants are probably to impair GluN2D function, either by affecting intersubunit interaction or altering channel gating activity. We assessed the clinical features of our three cases and compared them to those of the two previously reported GRIN2D variant cases, and found that they all show similar clinical features. This study provides further evidence of GRIN2D variants being causal for epilepsy. Genetic diagnosis for GluN2-related disorders may be clinically useful when considering drug therapy targeting NMDA receptors.

DOI： 10.1111/cge.13454

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記述言語：英語  

DOI： 10.1111/1346-8138.14151

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We first characterized PPT1 and TPP1 enzymes in dried blood spots (DBS), plasma/serum, and leukocytes/lymphocytes using neuronal ceroid lipofuscinosis (NCL) 1 and 2 patients and control subjects. PPT1 enzyme had only one acid form in control DBS, plasma/serum, and leukocytes/lymphocytes and showed deficient activities in these samples from NCL 1 patients. Conversely, TPP1 enzymes in control DBS and leukocytes/lymphocytes consisted of two forms, an acidic form and a neutral form, whereas serum TPP1 enzyme had only a neutral form. In control subjects, the optimal pH of PPT1 enzyme in DBS, plasma/serum, and leukocytes/lymphocytes was 4.5 to 5.0 in the acidic form, whereas TPP1 enzyme in control DBS and leukocytes/lymphocytes was pH 4.5 and 6.5, respectively. In NCL 1 and 2, both PPT1 and TPP1 enzyme activities in DBS, plasma, and leukocytes/lymphocytes were markedly reduced in acidic pH, whereas heterozygotes of NCL 1 and 2 in the acidic form showed intermediate activities between patients and control subjects. In neutral conditions, pH 6.0, the PPT1 enzyme activities in NCL 1 patients showed rather higher residual activities and intermediate activities in heterozygotes in NCL 1, which was probably caused by mutated proteins in three cases with NCL 1 patients. TPP1 enzyme activities at neutral pH 6.5 to 7.0 in DBS and leukocytes/lymphocytes showed higher enzyme activities in NCL 2 patients and heterozygotes. The reason for the increases of neutral TPP1 enzyme activities at pH 6.5 to 7.0 in NCL 2 DBS and leukocytes/lymphocytes, is obscure, but possibly caused by secondary activation of neutral TPP1 enzyme due to the absence of the acidic form. Interestingly, TPP1 activity in serum only consisted of a neutral form, no acidic form, and was not deficient in any NCL 2 patient. Therefore, we can diagnose NCL 1 patients by plasma/serum enzyme assay of PPT1, but not diagnose NCL 2 by serum TPP1 enzyme assay. A pilot study of newborn screening of NCL 1 and 2 has been established by more than 1000 newborn DBS assays. Using this assay system, we will be able to perform newborn screening of NCL 1 and 2 by DBS.

DOI： 10.1016/j.ymgme.2018.03.007

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: α (CAMK2A) and β (CAMK2B) isoforms of Calcium/calmodulin-dependent protein kinase II (CaMKII) play a pivotal role in neuronal plasticity and in learning and memory processes in the brain. Here, we explore the possible involvement of α- and β-CaMKII variants in neurodevelopmental disorders. Methods: Whole-exome sequencing was performed for 976 individuals with intellectual disability, developmental delay, and epilepsy. The effect of CAMK2A and CAMK2B variants on CaMKII structure and firing of neurons was evaluated by computational structural analysis, immunoblotting, and electrophysiological analysis. Results: We identified a total of five de novo CAMK2A and CAMK2B variants in three and two individuals, respectively. Seizures were common to three individuals with CAMK2A variants. Using a minigene splicing assay, we demonstrated that a splice site variant caused skipping of exon 11 leading to an in-frame deletion of the regulatory segment of CaMKII α. By structural analysis, four missense variants are predicted to impair the interaction between the kinase domain and the regulatory segment responsible for the autoinhibition of its kinase activity. The Thr286/Thr287 phosphorylation as a result of release from autoinhibition was increased in three mutants when the mutants were stably expressed in Neuro-2a neuroblastoma cells. Expression of a CaMKII α mutant in primary hippocampal neurons significantly increased A-type K+ currents, which facilitated spike repolarization of single action potentials. Interpretation: Our data highlight the importance of CaMKII α and CaMKII β and their autoinhibitory regulation in human brain function, and suggest the enhancement of A-type K+ currents as a possible pathophysiological basis.

DOI： 10.1002/acn3.528

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Misato 1, mitochondrial distribution and morphology regulator (encoded by the MSTO1 gene), is involved in mitochondrial distribution and morphology. Recently, MSTO1 mutations have been shown to cause clinical manifestations suggestive of mitochondrial dysfunction, such as muscle weakness, short stature, motor developmental delay, and cerebellar atrophy. Both autosomal dominant and recessive modes of inheritance have been suggested. We performed whole-exome sequencing in two unrelated patients showing cerebellar atrophy, intellectual disability, and pigmentary retinopathy. Three novel mutations were identified: c.836 G > A (p.Arg279His), c.1099-1 G > A (p.Val367Trpfs*2), and c.79 C > T (p.Gln27*). Both patients had compound heterozygous mutations with a combination of protein-truncation mutation and missense mutation, the latter shared by them both. This survey of two patients with recessive and novel MSTO1 mutations provides additional clinical and genetic information on the pathogenicity of MSTO1 in humans.

DOI： 10.1038/s10038-017-0405-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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.

DOI： 10.1016/j.celrep.2017.12.074

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記述言語：英語  

Immune-mediated central nervous system manifestations of group A β-hemolytic Streptococcus (GABHS) infection include Sydenham's chorea, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS)-which includes tic and obsessive compulsive disorders-and a variety of neurobehavioral disorders. We report a case of Streptococcus dysgalactiae subspecies equisimilis (group G Streptococcus) (GGS) infection associated with involuntary movements, complex tics, and emotional lability in an 11-year-old Japanese girl. Serum IgM and IgG antibodies to lysoganglioside were positive, and she responded rapidly to intravenous immunoglobulin treatment. Neuropsychiatric disorder associated with GGS infection was ultimately diagnosed. The present findings suggest that neuropsychiatric disorders can result from GGS infection and that the pathogenic mechanism is similar to that of GABHS infection. Future large-scale studies should examine the relation between GGS infection and onset of neuropsychiatric disorder.

DOI： 10.1155/2018/6047318

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記述言語：日本語   出版者・発行元：(一社)日本てんかん学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Vici syndrome (VICIS) is a rare, autosomal recessive neurodevelopmental disorder with multisystem involvement characterized by agenesis of the corpus callosum, cataracts, cardiomyopathy, combined immunodeficiency, developmental delay, and hypopigmentation. Mutations in EPG5, a gene that encodes a key autophagy regulator, have been shown to cause VICIS, however, the precise pathomechanism underlying VICIS is yet to be clarified. Here, we describe detailed clinical (including brain MRI and muscle biopsy) and genetic features of nine Japanese patients with VICIS. Genetic dissection of these nine patients from seven families identified 14 causative mutations in EPG5. These included five nonsense, two frameshift, three splicing, one missense, and one multi-exon deletion mutations, and two initiation codon variants. Furthermore, cultured skin fibroblasts (SFs) from two affected patients demonstrated partial autophagic dysfunction. To investigate the function of EPG5, siRNA based EPG5 knock-down, and CRISPR/Cas9 mediated EPG5 knock-out HeLa cells were generated. EPG5-depleted cells exhibited a complete block of autophagic flux caused by defective autophagosome-lysosome fusion. Unexpectedly, endocytic degradation was normal in both VICIS SFs and EPG5 depleted cells, suggesting that EPG5 function is limited to the regulation of autophagosome-lysosome fusion.

DOI： 10.1038/s41598-017-02840-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cerebral folate deficiency due to folate receptor 1 gene (FOLR1) mutations is an autosomal recessive disorder resulting from a brain-specific folate transport defect. It is characterized by late infantile onset, severe psychomotor regression, epilepsy, and leukodystrophy. We describe a consanguineous girl exhibiting severe developmental regression, intractable epilepsy, polyneuropathy, and profound hypomyelination with cortical involvement. Magnetic resonance imaging showed cortical disturbances in addition to profound hypomyelination and cerebellar atrophy. Nerve conduction studies revealed both axonal degeneration and demyelinating features. A diagnosis of cerebral folate deficiency was confirmed by a homozygous c.466T>G (p.W156G) mutation in FOLR1, coupled with extremely low cerebrospinal fluid levels of 5-methyltetrahydrofolate. Her symptoms, neuroradiological findings, and polyneuropathy were alleviated by oral folinic acid treatment in conjunction with intravenous and intramuscular administration therapy. Our patient shows that folinic acid therapy can ameliorate the clinical symptoms, white matter disturbances, cortical insults, and peripheral neuropathy of cerebral folate deficiency caused by FOLR1 mutation. It is important to recognize these clinical symptoms and make a precise diagnosis early on, because cerebral folate deficiency is treatable.

DOI： 10.1016/j.braindev.2016.09.011

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by surfactant accumulation, and is caused by disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling. Abnormalities in CSF2 receptor alpha (CSF2RA) were reported to cause pediatric hereditary PAP. We report here the first case of CSF2RA-mutated, elderly-onset hereditary (h) PAP. CASE PRESENTATION: The patient developed dyspnea on exertion, and was diagnosed with PAP at the age of 77 years, based on findings from chest computed tomography scan and bronchoalveolar lavage. She tested negative for GM-CSF autoantibodies, with no underlying disease. Her serum GM-CSF level was elevated (91.3 pg/mL), indicating GM-CSF signaling impairment and genetic defects in the GM-CSF receptor. GM-CSF-stimulated phosphorylation in signal transducer and activator of transcription 5 (STAT5) was not observed, and GM-CSF-Rα expression was defective in her blood cells. Genetic screening revealed a homozygous, single-base C > T mutation at nt 508-a nonsense mutation that yields a stop codon (Q170X)-in exon 7 of CSF2RA. High-resolution analysis of single nucleotide polymorphism array confirmed a 22.8-Mb loss of heterozygosity region in Xp22.33p22.11, encompassing the CSF2RA gene. She was successfully treated with whole lung lavage (WLL), which reduced the serum levels of interleukin (IL)-2, IL-5, and IL-17, although IL-3 and M-CSF levels remained high. CONCLUSIONS: This is the first known report of elderly-onset hPAP associated with a CSF2RA mutation, which caused defective GM-CSF-Rα expression and impaired signaling. The analyses of serum cytokine levels during WLL suggested that GM-CSF signaling might be compensated by other signaling pathways, leading to elderly-onset PAP.

DOI： 10.1186/s12890-017-0382-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 4-year-old boy with severe intellectual disability (ID) and characteristics of autism was found to have a de novo 1.9-Mb microdeletion in 7q31.33q32.1, in which LRRC4, GRM8, and 11 other genes were included. GRM8 is associated with attention deficit hyperactivity disorder. LRRC4 is related to synaptic cell adhesion molecules, some of which are associated with autism. The deletion of LRRC4 may be responsible for the severe ID and characteristics of autism observed in the present patient.

DOI： 10.1038/hgv.2017.1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

[This corrects the article DOI: 10.1155/2015/807591.].

DOI： 10.1155/2017/4120361

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Megalencephalic polymicrogyria syndromes include megalencephaly-capillary malformation and megalencephaly-polymicrogyria-polydactyly-hydrocephalus. Recent genetic studies have identified that genes in the PI3K-AKT pathway are involved in the pathogenesis of these disorders. Herein, we report a patient who presented with developmental delay, epilepsy and peculiar neuroimaging findings of megalencephaly, polymicrogyria, and symmetrical band heterotopia in the periventricular region. The heterotopias exhibited inhomogeneous signals with undulatory mixtures of gray and white matter, resembling ribbon-like heterotopia, with a predominance in the temporal to occipital regions. These neuroradiological findings were not consistent with those in known megalencephalic polymicrogyria syndromes. No genetic abnormality was identified through whole-exome sequencing. The neuroimaging findings of this patient may represent a novel cortical malformation involving megalencephaly with polymicrogyria and ribbon-like band heterotopia.

DOI： 10.1016/j.braindev.2016.06.004

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記述言語：英語  

Interstitial deletions of the 16q centromeric region are rarely reported. A microdeletion of the 16q12.2q21 region was identified in a patient with intellectual disability, epilepsy, short stature, and distinctive features; including up-slanting palpebral fissures, hypertelorism, epicanthic folds, anteverted nares, simple philtrum, thin upper lip vermilion, high arched palate, posteriorly rotated ears, and overlapping toes in his right foot. Although the deleted region includes the genes responsible for neurological impairments (GNOA1, GPR56, KATNB1, and BBS2), haploinsufficiency of these genes would not be associated with the patient's phenotype. When NDRG4, present in the deleted region, was knocked out in mice, these mice exhibited spatial learning deficits. Thus, we hypothesize that this gene could be a potential candidate underlying the neurological observations of the patient. Because RSPRY1 was been discovered as the cause of progressive skeletal dysplasia, a loss of this gene might explain the skeletal defects observed in the patient.

DOI： 10.1111/cga.12172

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To describe an assay of 5-methyltetrahydrofolate (5MTHF) in the cerebrospinal fluid (CSF) of children, to determine reference values, and to report the clinical significance of this assay in metabolic disorders affecting folate transport and metabolism. METHODS: CSF 5MTHF was determined by high-performance liquid chromatography with fluorescent detection in pediatric patients including one with FOLR1 gene mutation and one with methylenetetrahydrofolate reductase (MTHFR) deficiency. CSF total folate was measured using an automated analyzer. RESULTS: 5MTHF and total folate were determined in 188 and 93 CSF samples, respectively. CSF 5MTHF was high throughout the first six months of life and subsequently declined with age. Reference values of CSF 5MTHF and total folate were determined from 162 and 82 samples, respectively. The patient with FOLR1 gene mutation had extremely low CSF 5MTHF and total folate, though these values normalized after folinic acid supplementation. The patient with MTHFR deficiency had extremely low 5MTHF and moderately low total folate; these values were not associated and showed no significant change after folic acid supplementation. CONCLUSIONS: This 5MTHF assay is simple, rapid, sensitive, reliable, and cost-effective. It will aid in the diagnosis and therapeutic monitoring of metabolic disorders affecting folate transport and metabolism.

DOI： 10.1016/j.cca.2016.06.032

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Bilateral paramedian thalamic infarctions (BPTIs) due to artery of Percheron occlusion are known to cause hypersomnia. However, the role of hypocretin-1, a wake-promoting peptide that is located at the lateral hypothalamus, in hypersomnia in these patients remains unclear. METHODS: To clarify the role of hypocretin-1 in hypersomnia in patients with BPTIs, hypocretin-1 levels in the cerebrospinal fluid (CSF) were measured in 6 patients with BPTIs: 2 with rostral midbrain involvement (BPT+RMI) and 4 without midbrain involvement (BPT-MI). RESULTS: CSF hypocretin-1 levels were decreased in 2 patients with BPT+RMI and were within normal ranges in 4 patients with BPT-MI. Hypersomnia was noted in all the patients. In one BPT+RMI patient, hypersomnia was improved within 2 weeks and decreased CSF hypocretin-1 levels were reversed (acute phase (on day 9), 109.2 pg/mL; chronic phase (at 3 months), 323 pg/mL), whereas another BPT+RMI patient who displayed coma in the acute phase had decreased CSF orexin levels (107 pg/mL) at day 49 and exhibited severe disability. CONCLUSION: Hypocretin deficiency was not involved in hypersomnia observed in BPT-MI patients; however, CSF hypocretin-1 levels were reduced in BPT+RMI patients. Reduced CSF hypocretin-1 levels in the chronic phase may possibly predict a poor clinical outcome in patients with Percheron artery infarction.

DOI： 10.1097/MD.0000000000004281

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: To delineate the clinical and neuroimaging characteristics of localized megalencephaly involving the right frontal lobe. METHOD: Data from three patients aged 14-16 years at the last follow-up were retrospectively reviewed. RESULTS: All the patients were normal on neurological examination with no signs of hemiparesis. Enlargement of the right frontal lobe with increased volume of subcortical and deep white matter, as well as thickening of the ipsilateral genu of the corpus callosum was common. The onset of epilepsy was 4-7 years of age, with seizure types of massive myoclonus in two and generalized tonic-clonic in two, which could be eventually controlled by antiepileptics. Interictal electroencephalography showed frontal alpha-like activity in one, and abundant spike-wave complexes resulting in diffuse continuous spike-wave activity during sleep in two patients even after suppression of clinical seizures. Psychomotor development appeared unaffected or slightly delayed before the onset of epilepsy, but became mildly disturbed during follow-up period of 7-11 years. CONCLUSION: Certain patients with right frontal megalencephaly can present with a milder epileptic and intellectual phenotype among those with localized megalencephaly and holohemispheric hemimegalencephaly, whose characteristic as epileptic encephalopathy was assumed from this study.

DOI： 10.1016/j.braindev.2015.09.005

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The voltage-gated Kv2.1 potassium channel encoded by KCNB1 produces the major delayed rectifier potassium current in pyramidal neurons. Recently, de novo heterozygous missense KCNB1 mutations have been identified in three patients with epileptic encephalopathy and a patient with neurodevelopmental disorder. However, the frequency of KCNB1 mutations in infantile epileptic patients and their effects on neuronal activity are yet unknown. We searched whole exome sequencing data of a total of 437 patients with infantile epilepsy, and found novel de novo heterozygous missense KCNB1 mutations in two patients showing psychomotor developmental delay and severe infantile generalized seizures with high-amplitude spike-and-wave electroencephalogram discharges. The mutation located in the channel voltage sensor (p.R306C) disrupted sensitivity and cooperativity of the sensor, while the mutation in the channel pore domain (p.G401R) selectively abolished endogenous Kv2 currents in transfected pyramidal neurons, indicating a dominant-negative effect. Both mutants inhibited repetitive neuronal firing through preventing production of deep interspike voltages. Thus KCNB1 mutations can be a rare genetic cause of infantile epilepsy, and insufficient firing of pyramidal neurons would disturb both development and stability of neuronal circuits, leading to the disease phenotypes.

DOI： 10.1038/srep15199

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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 (<1 month) in five patients (5/11, 45.5%) to 1-4 months 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.

DOI： 10.1111/epi.13072

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We report a case of infantile refractory epilepsy associated with Turner syndrome (TS), showing very frequent, focal clonic seizures of the left upper extremity. Characteristically, in addition to spontaneous fits, her seizure was inducible by rubbing her left hand and forearm for a few seconds. Accordingly, she was diagnosed with a rare form of reflex epilepsy, "rub epilepsy". Neuroradiological investigation indicated the existence of cortical abnormalities, such as focal cortical dysplasia of the right parietal lobe. Patients with TS are reported to have neuroanatomical abnormalities, especially of the parietal lobe. Thus, our case may imply a causal relationship between potential cortical hyperexcitability of the parietal lobe and epilepsy in TS. This is the first reported infantile case of rub epilepsy, and more generally, reflex epilepsy associated with TS.

DOI： 10.1016/j.braindev.2014.11.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Recently, de novo mutations in GRIN1 have been identified in patients with nonsyndromic intellectual disability and epileptic encephalopathy. Whole exome sequencing (WES) analysis of patients with genetically unsolved epileptic encephalopathies identified four patients with GRIN1 mutations, allowing us to investigate the phenotypic spectrum of GRIN1 mutations. METHODS: Eighty-eight patients with unclassified early onset epileptic encephalopathies (EOEEs) with an age of onset <1 year were analyzed by WES. The effect of mutations on N-methyl-D-aspartate (NMDA) receptors was examined by mapping altered amino acids onto three-dimensional models. RESULTS: We identified four de novo missense GRIN1 mutations in 4 of 88 patients with unclassified EOEEs. In these four patients, initial symptoms appeared within 3 months of birth, including hyperkinetic movements in two patients (2/4, 50%), and seizures in two patients (2/4, 50%). Involuntary movements, severe developmental delay, and intellectual disability were recognized in all four patients. In addition, abnormal eye movements resembling oculogyric crises and stereotypic hand movements were observed in two and three patients, respectively. All the four patients exhibited only nonspecific focal and diffuse epileptiform abnormality, and never showed suppression-burst or hypsarrhythmia during infancy. A de novo mosaic mutation (c.1923G>A) with a mutant allele frequency of 16% (in DNA of blood leukocytes) was detected in one patient. Three mutations were located in the transmembrane domain (3/4, 75%), and one in the extracellular loop near transmembrane helix 1. All the mutations were predicted to impair the function of the NMDA receptor. SIGNIFICANCE: Clinical features of de novo GRIN1 mutations include infantile involuntary movements, seizures, and hand stereotypies, suggesting that GRIN1 mutations cause encephalopathy resulting in seizures and movement disorders.

DOI： 10.1111/epi.12987

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Eukaryotic elongation factor 1, alpha-2 (eEF1A2) protein is involved in protein synthesis, suppression of apoptosis, and regulation of actin function and cytoskeletal structure. EEF1A2 gene is highly expressed in the central nervous system and Eef1a2 knockout mice show the neuronal degeneration. Until now, only one missense mutation (c.208G&gt;A, p.Gly70Ser) in EEF1A2 has been reported in two independent patients with neurological disease. In this report, we described two patients with de novo mutations (c.754G&gt;C, p.Asp252His and c.364G&gt;A, p.Glu122Lys) in EEF1A2 found by whole-exome sequencing. Common clinical features are shared by all four individuals: severe intellectual disability, autistic behavior, absent speech, neonatal hypotonia, epilepsy and progressive microcephaly. Furthermore, the two patients share the similar characteristic facial features including a depressed nasal bridge, tented upper lip, everted lower lip and downturned corners of the mouth. These data strongly indicate that a new recognizable disorder is caused by EEF1A2 mutations.

DOI： 10.1111/cge.12394

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Gómez-López-Hernández syndrome (GLHS) is a rare neurocutaneous syndrome characterized by the triad of rhombencephalosynapsis, trigeminal anesthesia, and bilateral parieto-occipital alopecia. We herein describe the first Japanese patient with GLHS characterized by the standard triad with typical craniofacial anomaly including hypertelorism, brachyturricephaly and midface retrusion, and a short stature. This female patient had also exhibited fever-induced convulsive seizures and psychomotor developmental delay since infancy. Brain magnetic resonance imaging showed severe rhombencephalosynapsis, supratentorial abnormalities (aplasia of the septum pellucidum, severe ventricular enlargement, and hypoplasia of the corpus callosum), and hippocampus atrophy. Bilateral ectopic cerebellums were also observed. This report describes the long-term clinical outcome of GLHS and a new neuroradiological finding regarding rhombencephalosynapsis.

DOI： 10.1016/j.braindev.2014.05.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Niemann-Pick disease type C (NPC) is a rare progressive neurodegenerative disorder, often with onset after normal early childhood development. Juvenile onset NPC patients slowly develop cerebellar symptoms and cognitive impairment and often experience difficulties at school. However, these problems may be overlooked due to the unpublicized nature of NPC, given that it is a rare metabolic disorder. In this report, we present an 11-year-old male NPC patient, who suffered from clumsiness and difficulties in attention and academic and social skills. His symptoms were initially considered to be due to developmental coordination disorder (DCD) coexisting with bullying by peers. DCD is a type of neurodevelopmental disorder defined according to DSM-IV and is characterized by clumsiness that interferes with academic achievement and social integration not due to other general medical conditions. However, a detailed investigation of the patient suggested that the problems could be attributed to the onset of NPC. Clinicians should keep neurodegenerative disorders as differential diagnosis of children with multiple school problems.

DOI： 10.1155/2015/807591

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We present a case of a patient whose L1CAM gene in X-chromosome has a C924T transition. Her first son's ventriculomegaly was prenatally detected. A mature infant was born, his head circumference was large, and thumbs were bilaterally adducted. X-linked hydrocephalus (XLH) was suspected. The DNA examination revealed that both her and boy's LICAM gene had a C924T transition. She became pregnant 5 years later and amniocentesis was performed. The results of cytogenetic analysis revealed that the fetus was female. She continued her pregnancy and delivered a healthy girl. She again became pregnant 3 years later. The chromosomal analysis revealed that the fetus was male. Fetal DNA analysis determined that the fetus had the inherited mutation. She chose to terminate the pregnancy. A C924T mutation can be disease causing for XLH, and the detection of this mutation would aid in genetic counseling for the prenatal diagnosis of XLH.

DOI： 10.1111/cga.12069

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recently, de novo mutations in TBL1XR1 were found in two patients with autism spectrum disorders. Here, we report on a Japanese girl presenting with West syndrome, Rett syndrome-like and autistic features. Her initial development was normal until she developed a series of spasms at 5 months of age. Electroencephalogram at 7 months showed a pattern of hypsarrhythmia, which led to a diagnosis of West syndrome. Stereotypic hand movements appeared at 8 months of age, and autistic features such as deficits in communication, hyperactivity and excitability were observed later, at 4 years and 9 months. Whole exome sequencing of the patient and her parents revealed a de novo TBL1XR1 mutation [c.209 G>A (p.Gly70Asp)] occurring at an evolutionarily conserved amino acid in an F-box-like domain. Our report expands the clinical spectrum of TBL1XR1 mutations to West syndrome with Rett-like features, together with autistic features.

DOI： 10.1038/jhg.2014.71

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

We report a female patient who presented with intractable epileptic seizures, profound developmental delay since early infancy, and hyperkinetic movements with hand stereotypies. The patient initially developed focal seizures with multiple foci at 3 months of age. Thereafter, the seizures evolved to frequent episodes of hyperthermia-induced status epilepticus. A novel de novo SCN1A mutation was identified by whole-exome sequence analysis. This case demonstrates that SCN1A mutations may cause movement disorders as an atypical phenotype and the case history of this patient may expand our understanding of the clinical spectrum of SCN1A-associated epileptic encephalopathy. [Published with video sequences].

DOI： 10.1684/epd.2014.0649

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記述言語：英語  

DOI： 10.1111/cge.12188

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Mosaic variegated aneuploidy syndrome (Online Mendelian Inheritance in Man 257300), or premature chromatid separation syndrome, is a rare cancer-prone disorder associated with an autosomal recessive trait related to BUB1B gene mutations. The risk of malignancy is high, with rhabdomyosarcoma, Wilms tumor, and leukemia reported in several cases. Clinical features also include prenatal-onset growth retardation, microcephaly, mild dysmorphism, feeding difficulty, hypotonia, seizures, and developmental delay. PATIENT: A boy patient exhibited severe developmental delay, microcephaly, hypotonia, intractable seizures including infantile spasms with hypsarrhythmia at 6 months old, and Dandy-Walker malformation on magnetic resonance imaging. Seizures were refractory to conventional antiepileptics and treatment with adrenocorticotropic hormone. Wilms tumor and an unidentified intraorbital tumor also developed at 22 months old. RESULTS: Chromosomal analysis showed multiple aneuploid cells, and premature chromatid separation was found in all chromosomes in 59.5% of 119 cells, indicating mosaic variegated aneuploidy syndrome. CONCLUSIONS: The present case report demonstrates that mosaic variegated aneuploidy syndrome can be associated with developmental brain anomalies that lead to early-onset epileptic encephalopathy. Awareness of this disorder is important not only for proper diagnosis but also for genetic counseling of the family.

DOI： 10.1016/j.pediatrneurol.2013.05.014

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: We aimed to investigate the possible association between SCN2A mutations and early-onset epileptic encephalopathies (EOEEs). METHODS: We recruited a total of 328 patients with EOEE, including 67 patients with Ohtahara syndrome (OS) and 150 with West syndrome. SCN2A mutations were examined using high resolution melt analysis or whole exome sequencing. RESULTS: We found 14 novel SCN2A missense mutations in 15 patients: 9 of 67 OS cases (13.4%), 1 of 150 West syndrome cases (0.67%), and 5 of 111 with unclassified EOEEs (4.5%). Twelve of the 14 mutations were confirmed as de novo, and all mutations were absent in 212 control exomes. A de novo mosaic mutation (c.3976G>C) with a mutant allele frequency of 18% was detected in one patient. One mutation (c.634A>G) was found in transcript variant 3, which is a neonatal isoform. All 9 mutations in patients with OS were located in linker regions between 2 transmembrane segments. In 7 of the 9 patients with OS, EEG findings transitioned from suppression-burst pattern to hypsarrhythmia. All 15 of the patients with novel SCN2A missense mutations had intractable seizures; 3 of them were seizure-free at the last medical examination. All patients showed severe developmental delay. CONCLUSIONS: Our study confirmed that SCN2A mutations are an important genetic cause of OS. Given the wide clinical spectrum associated with SCN2A mutations, genetic testing for SCN2A should be considered for children with different epileptic conditions.

DOI： 10.1212/WNL.0b013e3182a43e57

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Heterotrimeric G proteins, composed of α, β, and γ subunits, can transduce a variety of signals from seven-transmembrane-type receptors to intracellular effectors. By whole-exome sequencing and subsequent mutation screening, we identified de novo heterozygous mutations in GNAO1, which encodes a Gαo subunit of heterotrimeric G proteins, in four individuals with epileptic encephalopathy. Two of the affected individuals also showed involuntary movements. Somatic mosaicism (approximately 35% to 50% of cells, distributed across multiple cell types, harbored the mutation) was shown in one individual. By mapping the mutation onto three-dimensional models of the Gα subunit in three different complexed states, we found that the three mutants (c.521A>G [p.Asp174Gly], c.836T>A [p.Ile279Asn], and c.572_592del [p.Thr191_Phe197del]) are predicted to destabilize the Gα subunit fold. A fourth mutant (c.607G>A), in which the Gly203 residue located within the highly conserved switch II region is substituted to Arg, is predicted to impair GTP binding and/or activation of downstream effectors, although the p.Gly203Arg substitution might not interfere with Gα binding to G-protein-coupled receptors. Transient-expression experiments suggested that localization to the plasma membrane was variably impaired in the three putatively destabilized mutants. Electrophysiological analysis showed that Gαo-mediated inhibition of calcium currents by norepinephrine tended to be lower in three of the four Gαo mutants. These data suggest that aberrant Gαo signaling can cause multiple neurodevelopmental phenotypes, including epileptic encephalopathy and involuntary movements.

DOI： 10.1016/j.ajhg.2013.07.014

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Early onset epileptic encephalopathies (EOEEs) are heterogeneous epileptic disorders caused by various abnormalities in causative genes including point mutations and copy number variations (CNVs). In this study, we performed targeted capture and sequencing of a subset of genes to detect point mutations and CNVs simultaneously. METHODS: We designed complementary RNA oligonucleotide probes against the coding exons of 35 known and potential candidate genes. We tested 68 unrelated patients, including 15 patients with previously detected mutations as positive controls. In addition to mutation detection by the Genome Analysis Toolkit, CNVs were detected by the relative depth of coverage ratio. All detected events were confirmed by Sanger sequencing or genomic microarray analysis. KEY FINDINGS: We detected all positive control mutations. In addition, in 53 patients with EOEEs, we detected 12 pathogenic mutations, including 9 point mutations (2 nonsense, 3 splice-site, and 4 missense mutations), 2 frameshift mutations, and one 3.7-Mb microdeletion. Ten of the 12 mutations occurred de novo; the other two had been previously reported as pathogenic. The entire process of targeted capture, sequencing, and analysis required 1 week for the testing of up to 24 patients. SIGNIFICANCE: Targeted capture and sequencing enables the identification of mutations of all classes causing EOEEs, highlighting its usefulness for rapid and comprehensive genetic testing.

DOI： 10.1111/epi.12203

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND OBJECTIVES: Previous reports of Fabry disease screening in dialysis patients indicate that α-galactosidase A activity alone cannot specifically and reliably identify appropriate candidates for genetic testing; a marker for secondary screening is required. Elevated plasma globotriaosylsphingosine is reported to be a hallmark of classic Fabry disease. The purpose of this study was to examine the usefulness of globotriaosylsphingosine as a secondary screening target for Fabry disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study screened 1453 patients, comprising 50% of the male dialysis patients in Niigata Prefecture between July 1, 2010 and July 31, 2011. Screening for Fabry disease was performed by measuring the plasma α-galactosidase A enzyme activity and the globotriaosylsphingosine concentration, by high-performance liquid chromatography. Genetic testing and genetic counseling were provided. RESULTS: A low level of plasma α-galactosidase A activity (≤4.0 nmol/h per milliliter) was observed in 47 patients (3.2%). Of these, 3 (0.2%) had detectable globotriaosylsphingosine levels. These patients all had α-galactosidase A gene mutations: one was p.Y173X and two were the nonpathogenic p.E66Q. The patient with p.Y173X started enzyme replacement therapy. Subsequent screening of his family identified the same mutation in his elder sister and her children. Genetic testing for 33 of the other 44 patients detected 7 patients with p.E66Q. Thus, the plasma lyso-Gb3 screen identified Fabry disease with high sensitivity (100%) and specificity (94.3%). CONCLUSIONS: Plasma globotriaosylsphingosine is a promising secondary screening target that was effective for selecting candidates for genetic counseling and testing and for uncovering unrecognized Fabry disease cases.

DOI： 10.2215/CJN.08780812

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Rett syndrome (RTT) is a neurodevelopmental disorder that is one of the most common causes of mental retardation in females. RTT diagnosis is based on distinct clinical criteria. We describe here a female patient with severe phenotype of congenital variant RTT. The patient originally presented with severe developmental delay prior to the age of 6 months and later exhibited characteristic features of RTT that included air swallowing, bruxism, and hand stereotypies. Results of an array-based comparative genomic hybridization analysis indicated there was a very small microdeletion in Xq28. Multiplex ligation-dependent probe amplification analysis further confirmed there were heterozygous deletions of intron 2, exon 3, intron 3, and part of exon 4 in MECP2. Findings in the present patient confirm the view that large MECP2 deletions are an important cause of severe congenital variant RTT. To ensure an accurate diagnosis of congenital variant RTT, a multiplex ligation-dependent probe amplification analysis of MECP2 should be performed in patients suspected of having this disorder.

DOI： 10.1016/j.braindev.2011.09.014

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: The occurrence of acute encephalopathy in children with Dravet syndrome has been reported sporadically. This study clarified the features of acute encephalopathy in children with Dravet syndrome. METHODS: Through the mailing list of the Annual Zao Conference on Pediatric Neurology, we collected 15 patients with clinically diagnosed Dravet syndrome, who had acute encephalopathy, defined as a condition with decreased consciousness with or without other neurologic symptoms, such as seizures, lasting for >24 h in association with infectious symptoms. KEY FINDINGS: There were seven boys and eight girls. A mutation of the SCN1A gene was present in nine (truncation in six and missense in three). The frequency of seizures during the 3 months before the onset of acute encephalopathy was monthly in seven children and none in three. The median age at the onset of acute encephalopathy was 44 months (range 8-184 months). All children had status epilepticus followed by coma as the initial manifestation. Two different distributions of brain lesions were observed on diffusion-weighted images during the acute phase: cerebral cortex-dominant lesions with or without deep gray matter involvement and subcortical-dominant lesions. Four children died; nine survived with severe sequelae, and two had moderate sequelae. SIGNIFICANCE: We must be aware that acute encephalopathy is an important complication in children with Dravet syndrome, and associated with fulminant clinical manifestations and a poor outcome.

DOI： 10.1111/j.1528-1167.2011.03311.x

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Early-onset absence epilepsy refers to patients with absence seizures beginning before age four and comprises a heterogeneous group of epilepsies. Onset of absence seizures in the first year of life is very rare. We report a girl with intractable absence seizures with onset at age eight months. Her seizures were characterised by loss of responsiveness, with eyes drifting upwards and some myoclonic jerks of the upper and lower limbs. These symptoms were accompanied by bilaterally symmetric high-amplitude 2-2.5 Hz generalised spike-and-wave discharges on the electroencephalogram. Her seizures were refractory to conventional antiepileptic drugs; treatment with adrenocorticotropic hormone was transiently effective. Comprehensive metabolic screening, cytogenetic, and genetic analysis did not determine an underlying cause of her condition. Patients with intractable, very early-onset absence epilepsy with a myoclonic component have an unfavourable outcome and may be classified under a new epileptic syndrome, such as "early infantile absence epilepsy".

DOI： 10.1684/epd.2011.0477

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

FOXG1 on chromosome 14 has recently been suggested as a dosage-sensitive gene. Duplication of this gene could cause severe epilepsy and developmental delay, including infantile spasms. Here, we report on a female patient diagnosed with maternal uniparental disomy of chromosome 14 and West syndrome who carried a small supernumerary marker chromosome. A chromosomal analysis revealed mosaicism of 47,XX, + mar[8]/46,XX[18]. Spectral karyotyping multicolor fluorescence in situ hybridization analysis confirmed that the marker chromosome was derived from chromosome 14. A DNA methylation test at MEG3 in 14q32.2 and microsatellite analysis using polymorphic markers on chromosome 14 confirmed that the patient had maternal uniparental disomy 14 as well as a mosaic small marker chromosome of paternal origin containing the proximal long arm of chromosome 14. Microarray-based comparative genomic hybridization analysis conclusively defined the region of the gain of genomic copy numbers at 14q11.2-q12, encompassing FOXG1. The results of the analyses of our patient provide further evidence that not only duplication but also a small increase in the dosage of FOXG1 could cause infantile spasms.

DOI： 10.1002/ajmg.a.34224

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hemiconvulsion-hemiplegia-epilepsy syndrome involves sudden and prolonged unilateral seizures, followed by transient or permanent hemiplegia and epilepsy during infancy or early childhood. Some patients with familial hemiplegic migraine and demonstrating the S218L mutation in CACNA1A experience severe attacks with unilateral cerebral edema after trivial head trauma. We report on a 5-year-old Japanese girl presenting with hemiconvulsion-hemiplegia-epilepsy syndrome after infection with parvovirus B19. Magnetic resonance imaging performed 2 days after admission revealed cerebellar atrophy and marked hyperintensity in the left hemisphere on T(2)-weighted and diffusion-weighted imaging. Magnetic resonance angiography performed 7 days after admission demonstrated obliteration of the left proximal middle cerebral artery in the acute phase. However, this finding was not evident on brain angiography performed 25 hours after magnetic resonance angiography. Genetic analysis of familial hemiplegic migraine revealed a heterozygous S218L mutation in CACNA1A. Taken together, these results suggest that vasospasms of cerebral vascular smooth muscle, with possible cortical spreading depression, may have caused the hemiconvulsions and hemiplegia in the left hemisphere. This case report is the first, to the best of our knowledge, to associate CACNA1A with hemiconvulsion-hemiplegia-epilepsy syndrome and familial hemiplegic migraine, and to suggest that similar pathogenic mechanisms may underlie these two disorders.

DOI： 10.1016/j.pediatrneurol.2011.04.010

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The authors describe herein the magnetoencephalographic findings and long-term outcome of a girl with acquired opercular epilepsy with oromotor dysfunction. She presented with brief episodes of unconsciousness, tremulous movements of the upper limbs, and negative myoclonus, in addition to convulsive seizures. She also had prolonged episodes of dysarthria and oral motor dysfunction, a gradual decrease in speech output, impairment of finger movements, and deterioration in cognitive performance over several years. Her electroencephalography (EEG) recordings showed notable continuous sharp or sharp-slow discharges during sleep. Brain magnetic resonance images revealed no structural anomalies. Magnetoencephalographic analysis showed broadly distributed epileptic foci around the sylvian fissure, including a secondary source, explaining the specific prolonged neurological dysfunction. Antiepileptic drugs could control her seizures; however, they did not improve the other neurological symptoms or epileptiform discharge on EEG. Administration of low-dose prednisolone over a long period was effective for improving the neurological impairments of this patient.

DOI： 10.1177/0883073810393307

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

We report on a female patient with Dandy-Walker malformation possibly caused by heterozygous loss of ZIC1 and ZIC4. The patient presented with mental retardation, epilepsy, and multiple congenital malformations including spina bifida, mild dysmorphic facial features including, thick eyebrows, broad nose, full lips, macroglossia, and hypoplasia of the cerebellar vermis with enlargement of the fourth ventricle on brain magnetic resonance imaging, which is consistent with Dandy-Walker malformation. A chromosome analysis showed interstitial deletion of chromosome 3q23-q25.1. Fluorescence in situ hybridization (FISH) and microarray-based genomic analysis revealed the heterozygous deletion of ZIC1 and ZIC4 loci on 3q24. Her facial features were not consistent with those observed in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) involving FOXL2 abnormality. Other deleted genes at 3q23-25.1 might contribute to the dysmorphic facial appearance. A milder phenotype as the Dandy-Walker malformation in our patient supports the idea that modifying loci/genes can influence the development of cerebellar malformation.

DOI： 10.1002/ajmg.a.33652

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pelizaeus-Merzbacher disease (PMD; MIM#312080) is a rare X-linked recessive neurodegenerative disorder. The main cause of PMD is alterations in the proteolipid protein 1 gene (PLP1) on chromosome Xq22.2. Duplications and point mutations of PLP1 have been found in 70% and 10-25% of all patients with PMD, respectively, with a wide clinical spectrum. Since the underlining genomic abnormalities are heterogeneous in patients with PMD, clarification of the genotype-phenotype correlation is the object of this study. Comprehensive genetic analyses using microarray-based comparative genomic hybridization (aCGH) analysis and genomic sequencing were applied to fifteen unrelated male patients with a clinical diagnosis of PMD. Duplicated regions were further analyzed by fiber-fluorescence in situ hybridization (FISH) analysis. Four novel and one known nucleotide alterations were identified in five patients. Five microduplications including PLP1 were identified by aCGH analysis with the sizes ranging from 374 to 951-kb. The directions of five PLP1 duplications were further investigated by fiber-FISH analysis, and all showed tandem duplications. The common manifestations of the disease in patients with PLP1 mutations or duplications in this study were nystagmus in early infancy, dysmyelination revealed by magnetic resonance imaging (MRI), and auditory brain response abnormalities. Although the grades of dysmyelination estimated by MRI findings were well correlated to the clinical phenotypes of the patients, there is no correlation between the size of the duplications and the phenotypic severity.

DOI： 10.1016/j.braindev.2009.02.011

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To delineate the significance of maternal uniparental disomy 14 (upd(14)mat) and related disorders in patients with a Prader-Willi syndrome (PWS)-like phenotype. STUDY DESIGN: We examined 78 patients with PWS-like phenotype who lacked molecular defects for PWS. The MEG3 methylation test followed by microsatellite polymorphism analysis of chromosome 14 was performed to detect upd(14)mat or other related abnormalities affecting the 14q32.2-imprinted region. RESULTS: We identified 4 patients with upd(14)mat and 1 patient with an epimutation in the 14q32.2 imprinted region. Of the 4 patients with upd(14)mat, 3 had full upd(14)mat and 1 was mosaic. CONCLUSIONS: Upd(14)mat and epimutation of 14q32.2 represent clinically discernible phenotypes and should be designated "upd(14)mat syndrome." This syndrome demonstrates a PWS-like phenotype particularly during infancy. The MEG3 methylation test can detect upd(14)mat syndrome defects and should therefore be performed for all undiagnosed infants with hypotonia.

DOI： 10.1016/j.jpeds.2009.06.045

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A novel microdeletion of 14q13.1q13.3 was identified in a patient with developmental delay and intractable epilepsy. The 2.2-Mb deletion included 15 genes, of which TULIP1 (approved gene symbol: RALGAPA1)was the only gene highly expressed in the brain. Western blotting revealed reduced amount of TULIP1 in cell lysates derived from immortalized lymphocytes of the patient, suggesting the association between TULIP1 haploinsufficiency and the patient's phenotype, then 140 patients were screened for TULIP1 mutations and four missense mutations were identified. Although all four missense mutations were common with parents, reduced TULIP1 was observed in the cell lysates with a P297T mutation identified in a conserved region among species. A full-length homolog of human TULIP1 was identified in zebrafish with 72% identity to human. Tulip1 was highly expressed in zebrafish brain, and knockdown of which resulted in brain developmental delay. Therefore, we suggest that TULIP1 is a candidate gene for developmental delay.

DOI： 10.1016/j.ygeno.2009.08.015

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: To survey the treatment situation of Dravet syndrome in Japan and to compare this result with effectiveness of stiripentol (STP) add-on therapy in an open-label multicenter study. METHODS: Medical records of patients with Dravet syndrome who visited the study institutions during 2006 were surveyed to examine the effect of antiepileptic drugs (AEDs) on clonic or tonic-clonic seizures (GTCS). Patients older than 1 year of age treated with at least one conventional AED and more than four GTCS per month were invited to participate in the STP study. Seizure status and adverse effects during the first 4 weeks of STP (50 or 1,000 mg/day) add-on therapy (early period) and during long-term treatment were compared with baseline. RESULTS: Only 15% of the treatment trials with 15 conventional AEDs in 112 patients succeeded in reducing seizures by more than 50%. With STP, GTCS were reduced more than 50% in 14 of 23 patients (61%), including 2 who became seizure-free, in the early period. Moreover, duration of seizures was shortened in 10 patients and status epilepticus decreased in 6. These effects continued in the long-term although to a lesser degree. Adverse effects (loss of appetite, sleep disturbance, ataxia, hyperactivity/irritability) disappeared after dose modification in most cases. STP was effective at a lower than initial dose in five patients. Some patients benefited from STP added on clobazam despite mutation in CYP2C19. CONCLUSION: Our data suggest that an early introduction of STP into Japan will result in substantial patient benefit.

DOI： 10.1111/j.1528-1167.2009.02179.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Prolonged febrile seizures may be followed by acute encephalopathy with neurological sequelae. To investigate the function of the blood-brain-barrier (BBB) in acute encephalopathy following prolonged febrile seizures with neurological sequelae (AEPFS), the concentrations of serum matrix metalloproteinase-9 (MMP-9) and tissue inhibitors of metalloproteinases 1 (TIMP-1) were measured by ELISA in 10 children with AEPFS, 16 with prolonged febrile seizures without encephalopathy (PFS), 20 with simple febrile seizures (SFS), 23 with convulsive status epilepticus (CSE), and 18 with West syndrome. Serum MMP-9 levels in AEPFS and PFS patients were significantly higher than those in SPS and West syndrome patients and in controls, and those in CSE patients were significantly higher than in controls. Serum TIMP-1 levels in AEPFS patients were significantly lower than those in PFS, SFS, CSE and West syndrome patients and in controls. Serum MMP-9 levels and MMP-9/TIMP-1 ratios in AEPFS patients with motor paralysis were significantly higher than for those without motor paralysis. Our results suggest that prolonged seizures are related to high serum MMP-9 levels, and that an increased MMP-9/TIMP-1 ratio in AEPFS might induce dysfunction of the BBB. Furthermore, an imbalance of serum MMP-9 and TIMP-1 levels in patients with AEPFS may be associated with severe neurological sequelae.

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Focal spike activities in Panayiotopoulos syndrome involve all brain regions in electroencephalography, and commonly reveal multiple foci, often through occipital predominance. To investigate correlations between developmental brain maturation and spike origin in Panayiotopoulos syndrome, we evaluated age-related or duration-related magnetoencephalographic spike localization in 25 patients with Panayiotopoulos syndrome. Regarding age at examination, patients with frontal spikes were significantly older than patients with spikes on rolandic, parieto-occipital, or calcarine sulci. Occipital spikes were classified into two subgroups, located at the calcarine sulcus and parieto-occipital sulcus. Both calcarine and parieto-occipital localizations were seen in patients around the same age. Follow-up magnetoencephalography was performed on three patients, and demonstrated shifting localization or disappearance of magnetoencephalographic spikes. These results suggest that the location of spike discharges is not directly related to seizure symptoms, but instead indicates maturation-related cortical hyperexcitability in patients with Panayiotopoulos syndrome.

DOI： 10.1016/j.pediatrneurol.2007.08.020

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

It is well known that an acute encephalopathy occasionally follows prolonged febrile seizures. We measured the concentrations of interferon-gamma, tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-4, IL-6, IL-10, and soluble TNF receptor 1 (sTNFR1) in serum and CSF during the acute stage in 13 children with acute encephalopathy following prolonged febrile seizures (AEPFS) and 23 with prolonged febrile seizures without encephalopathy (PFS) to investigate the pathogenesis of AEPFS. Serum IL-6, IL-10, sTNFR1, and CSF IL-6 levels were significantly higher in AEPFS and PFS compared with control subjects. CSF IL-6 levels in AEPFS were significantly higher than those in PFS, but not serum IL-6, IL-10, or sTNFR1. The CSF IL-6 levels were significantly higher than the serum levels in AEPFS, but not PFS. The serum levels of sTNFR1 and IL-10 were significantly higher than those in the CSF in AEPFS and PFS. The serum IL-10 and sTNFR1 levels in patients who did not experience a second seizure were significantly higher than those in patients who experienced a second seizure, which was characterized by clusters of complex partial seizures several days after the initial prolonged febrile seizure. Our results suggest that serum IL-6, IL-10, TNF-alpha, and CSF IL-6 are part of the regulatory system of cytokines in AEPFS.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Early infantile epileptic encephalopathy with suppression-burst pattern (EIEE) is one of the most severe and earliest forms of epilepsy, often evolving into West syndrome; however, the pathogenesis of EIEE remains unclear. ARX is a crucial gene for the development of interneurons in the fetal brain, and a polyalanine expansion mutation of ARX causes mental retardation and seizures, including those of West syndrome, in males. We screened the ARX mutation and found a hemizygous, de novo, 33-bp duplication in exon 2, 298_330dupGCGGCA(GCG)9, in two of three unrelated male patients with EIEE. This mutation is thought to expand the original 16 alanine residues to 27 alanine residues (A110_A111insAAAAAAAAAAA) in the first polyalanine tract of the ARX protein. Although EIEE is mainly associated with brain malformations, ARX is the first gene found to be responsible for idiopathic EIEE. Our observation that EIEE had a longer expansion of the polyalanine tract than is seen in West syndrome is consistent with the findings of earlier onset and more-severe phenotypes in EIEE than in West syndrome.

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

We report the clinical manifestations of a 26-month-old Japanese girl with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. She was born to healthy, nonconsanguineous parents at 37 weeks by caesarian section after prenatal ultrasonography suggested hydrocephalus. Macrocephaly and polydactyly of both lower extremities were noted at birth. At 3 months of age, epileptic seizures developed. The patient displayed impaired vision and profound global developmental delay. Magnetic resonance imaging of the brain revealed dilatation of the lateral and third ventricles with cavum septi pellucidi et vergae and generalized polymicrogyria, most prominent in both perisylvian regions and the right frontal region. Despite ventriculomegaly, radionuclide cisternography indicated normal cerebrospinal circulation, suggesting that pathogenesis of the megalencephaly was unrelated to obstructive hydrocephalus. Decreased white matter volume and abnormal signal intensity in the occipital lobes were also noted. Visual disturbance due to white matter abnormality appears to represent a significant characteristic of this syndrome. The genetic background of the syndrome remains unclear.

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担当区分：筆頭著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

We report on a six-year-old girl with frequent partial seizures secondary to multiple cavernous angiomas (CAs) since the age of 17 months. MRI showed two CAs in the left parietal and right frontal lobes. Ictal scalp video EEG demonstrated complex partial seizures of left hemispheric origin, indicating that the left parietal CA was the epileptogenic lesion. Ictal SPECT showed extensive hyper-perfusion in the left frontal and parietal lobes, indicating the left hemispheric focus. Magnetoencephalography (MEG) showed clustered equivalent current dipoles of interictal spikes in the left parietal cortex adjacent to the left parietal CA. We performed lesionectomy of the left parietal CA at 19 months old. The patient became seizure-free for four years. Postoperative MEG yielded no residual interictal spikes. Our study suggests that early surgical intervention of CA may prevent from further development of epileptic seizures. MEG can identify both the epileptogenic zone and lesion underlying the multiple CAs in the infants with catastrophic partial seizures.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Background: ARX is a paired-type homeobox gene located on the X chromosome that contains five exons with four polyalanine (PolyA) tracts, a homeodomain, and a conserved C-terminal aristaless domain. Studies in humans have demonstrated remarkable pleiotropy: malformation phenotypes are associated with protein truncation mutations and missense mutations in the homeobox; nonmalformation phenotypes, including X-linked infantile spasms (ISS), are associated with missense mutations outside of the homeobox and expansion of the PolyA tracts. Objective: To investigate the role of ARX, we performed mutation analysis in 115 boys with cryptogenic ISS. This included two pairs of brothers. Results: We found an expansion of the trinucleotide repeat that codes for the first PolyA tract from 10 to 17 GCG repeats (c.333_334ins[GCG]7) in six boys (5.2%) ages 2 to 14, from four families, including the two pairs of brothers. In addition to ISS, all six boys had severe mental retardation and generalized dystonia that appeared around the age of 6 months and worsened, eventually leading to stable severe quadriplegic dyskinesia within age 2 years. Three children experienced recurrent, life-threatening status dystonicus. In four children brain MRI showed multiple small foci of abnormal cavitation on T1 and increased signal intensity on T2 in the putamina, possibly reflecting progressive multifocal loss of tissue. Conclusion: The phenotype of infantile spasms with severe dyskinetic quadriparesis increases the number of human disorders that result from the pathologic expansion of single alanine repeats. ARX gene testing should be considered in boys with infantile spasms and dyskinetic cerebral palsy in the absence of a consistent perinatal history.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We previously reported the results of a magnetoencephalographic study in patients with Panayiotopoulos syndrome manifesting occipital epileptic discharges, in which the equivalent current dipoles of spike discharges were clustered alongside the major cortical sulci, such as parieto-occipital and calcarine. This report is the result of a magnetoencephalographic study of three patients with Panayiotopoulos syndrome exhibiting equivalent current dipoles clustering in the frontal area. Patient 1, a 13-year-old male, exhibited clustering equivalent current dipoles alongside right inferior frontal sulcus, but the orientations were irregular. Patient 2 is an 11-year-old younger brother of Patient 1, whose magnetoencephalograph revealed equivalent current dipoles clustering alongside right prefrontal sulcus and regular orientations. Patient 3 is a 10-year-old female who had equivalent current dipoles clustering alongside right superior frontal sulcus and extremely regular orientations. The locations of clustering equivalent current dipoles of frontal spike discharges were not restricted to one specific frontal sulcus but were present in various locations over the convexity of the prefrontal area. In conclusion, these findings suggest that it is inappropriate to classify Panayiotopoulos syndrome as occipital epilepsy. In addition, the result of this study, that frontal spike discharges seem to occur in relatively older patients, may suggest a correlation between brain maturation and spike occurrence.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Narcolepsy is characterized by excessive daytime sleepiness (EDS), cataplexy and other abnormal manifestations of REM sleep. Recently, it was discovered that the pathophysiology of idiopathic narcolepsy-cataplexy is linked to orexin ligand deficiency in the brain and cerebrospinal fluid. Orexin neurons localize in the posterior hypothalamic area, which was previously described as "waking center" by von Economo in 1920s. Hypersomnia due to orexin ligand deficiency can also occur during the course of other neurological conditions, such as hypothalamic tumor, encephalopathy and demyelinating disorder (i.e. symptomatic hypersomnia). We experienced 8 pediatric cases with symptomatic hypersomnia. These cases were diagnosed as brain tumor (n = 2), head trauma (n = 1), encephalopathy (n = 1), demyelinating disorder (n = 3) and infarction (n = 1). Six pediatric cases with orexin measurements from the literatures were additionally included and total 14 cases were studied. Although it is difficult to rule out the comorbidity of idiopathic narcolepsy in some cases, a review of the case histories reveals numerous unquestionable cases of symptomatic hypersomnia. In these cases, the occurrences of the hypersomnia run parallel with the rise and fall of the causative diseases. Most of symptomatic hypersomnia cases show both extended nocturnal sleep time and EDS consisting of prolonged sleep episodes of NREM sleep. The features of nocturnal sleep and EDS in symptomatic hypersomnia are more similar to idiopathic hypersomnia than to narcolepsy.

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: To clarify the usefulness of magnetoencephalography (MEG) for diagnosis of the spatial relations between spike foci and suspicious epileptogenic tubers on MRI in patients with tuberous sclerosis (TS) and to compare MEG spike foci with single-photon emission computed tomography (SPECT) findings. METHODS: We analyzed magnetic fields of epileptic spike discharges in 15 patients with TS and localization-related epilepsy (LRE) by using MEG (a whole-head 204-channel magnetometer system). We investigated the spatial relation between the equivalent current dipoles (ECDs) of interictal spike discharges and visible cortical tubers on MRI. We also compared results of MEG and MRI with SPECT findings. RESULTS: MEG detected a cluster of ECDs around one cortical tuber in six of 15 patients and clusters of ECDs around two cortical tubers in five patients. Interictal SPECT was disappointing in detection of epileptic foci in TS. However, MEG spike foci showed spatial consistency with ictal hyperperfusion areas in two patients. Three patients with single ECD clusters underwent surgical treatment: two have been seizure free, and one has obtained seizure reduction of >90%. CONCLUSIONS: ECDs were located around visible tuber nodules. MEG enabled precise localization of the epileptic foci and provided crucial information for surgical treatment in patients with TS and partial epilepsy. TS patients showing a single ECD cluster on MEG may be appropriate candidates for surgical treatment.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nonketotic hyperglycinemia (NKH) is an inborn error of metabolism characterized by accumulation of glycine in body fluids and various neurological symptoms. NKH is caused by deficiency of the glycine cleavage multi-enzyme system with three specific components encoded by GLDC, AMT, and GCSH. We undertook the first comprehensive screening for GLDC, AMT, and GCSH mutations in 69 families (56, six, and seven families with neonatal, infantile, and late-onset type NKH, respectively). GLDC or AMT mutations were identified in 75% of neonatal and 83% of infantile families, but not in late-onset type NKH. No GCSH mutation was identified in this study. GLDC mutations were identified in 36 families, and AMT mutations were detected in 11 families. In 16 of the 36 families with GLDC mutations, mutations were identified in only one allele despite sequencing of the entire coding regions. The GLDC gene consists of 25 exons. Seven of the 32 GLDC missense mutations were clustered in exon 19, which encodes the cofactor-binding site Lys754. A large deletion involving exon 1 of the GLDC gene was found in Caucasian, Oriental, and black families. Multiple origins of the exon 1 deletion were suggested by haplotype analysis with four GLDC polymorphisms. This study provides a comprehensive picture of the genetic background of NKH as it is known to date.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: To characterize the epileptogenic zone in neocortical epilepsy (NE) by using magnetoencephalography (MEG). METHODS: We defined and compared locations of single and multiple clusters of equivalent current dipoles (ECDs) for interictal spikes with MRI findings, ictal-onset zones (IOZs) from subdural electroencephalography (SDEEG), resected areas, and postsurgical outcomes of 20 patients who underwent cortical resection for medically intractable NE. RESULTS: Fourteen patients had single clusters; six had multiple clusters. Overlap of clusters and IOZs defined group A (nine patients), in which a single cluster coincided with the IOZ; group B1 (four patients), in which a single cluster was within or partially overlapped the IOZ; group B2 (five patients), in which multiple-cluster sections overlapped IOZs; group C (two patients; one single; one multiple), in which no overlap was seen. More single clusters (nine of 14) than multiple clusters (none of six) coincided with the IOZ (p = 0.014). More patients with single clusters (10 of 14) than patients with multiple clusters (one of six) had seizure-free outcomes (p = 0.049). Eight of nine patients in group A, versus three of 11 in groups B1, B2, and C, achieved seizure-free outcomes (p = 0.0098). Correlations between MRI findings and postsurgical outcomes were not statistically significant; eight of 13 patients with single lesions, one of four with no lesions, and two of three with multifocal lesions had seizure-free outcomes. CONCLUSIONS: In neocortical epilepsy, MEG ECD clusters correlated with SDEEG IOZs. Single clusters indicated discrete epileptogenic zones that required complete resection for seizure-free outcome. Multiple clusters necessitated that the multiple or extensive epileptogenic zones be completely identified and delineated by SDEEG.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

We reported a 9-year-old boy with chronic inflammatory demyelinating polyneuropathy (CIDP) showing characteristic electron microscopic study findings on a sural nerve biopsy. He came to our hospital because of muscle weakness progressing slowly for 2 years. He developed distal muscle weakness and areflexia. Cerebrospinal fluid protein was elevated without pleocytosis. Moter conduction velocities were reduced. Partial conduction block and abnormal temporal dispersion were present. The electron microscopic findings on a sural nerve biopsy comprised both active demyelinating lesions, i.e., macrophages were peeling away the myelin lamellae and phagocytosing some myelin debris, and remyelinating lesions with onion bulb formations. Some findings mimic electron microscopic changes in Guillain-Barré syndrome, although tests for the known anti-ganglioside antibodies were negative. So, he was diagnosed as having definite CIDP and prednisolone with gamma-globulin infusion was effective to ameliorate his symptoms.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Panayiotopoulos syndrome (PS) is a newly identified type of benign childhood epilepsy characterized by ictal vomiting and eye deviation. It is usually accompanied by occipital spike discharges; however, its classification as an early-onset benign childhood occipital epilepsy is controversial. To characterize this condition further, we examined the localization of equivalent current dipoles (ECDs) of spike discharges by magnetoencephalography (MEG) in patients with PS. METHODS: We studied 13 patients with a mean age at time of examination of 5 years (range, 3-14 years). MEG was measured by using a whole-head 204-channel neuromagnetometer with simultaneous EEG recordings. The estimated locations of ECDs of each peak of the spike discharges were overlaid on magnetic resonance images of the brain. RESULTS: Eleven (84.6%) patients showed clustered ECDs in the areas alongside the parietooccipital sulcus (eight of 13; 61.5%) and/or the calcarine sulcus (four of 13; 30.8%). Despite Fp-O synchronization of the spike discharges in the scalp EEG of five patients, no frontal locations of ECDs were found. All five (38.5%) boys with sylvian seizures, who also showed clustered ECDs in rolandic areas, had an earlier age at onset and higher seizure frequency than did other patients. ECD orientations were regular in all but one patient, who showed irregular and dispersed ECDs alongside bilateral calcarine sulci. CONCLUSIONS: Our results demonstrate localized cortical hyperexcitability in the areas alongside major cortical sulci in PS and indicate that PS is closely related to benign childhood epilepsy with centrotemporal spikes.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

While there is an abundance of literature describing the association of chromosome aberrations with epilepsy, only a few refer to the detailed features of epilepsy. It is important to investigate the associations between specific chromosome abnormalities and features of epilepsy to identify genes involved in epilepsy and treat them more effectively. We investigated the correlation between specific chromosome aberrations and epilepsy by sending questionnaires to the members of Kyoto Multi-institutional Study Group of Pediatric Neurology. Seventy-six patients were collected from 10 institutions. Chromosome abnormalities included: Down syndrome (n = 19); Angelman syndrome (n = 8); Prader-Willi syndrome (n = 4); 4p- syndrome (n = 3); 1q- syndrome (n = 2); 5p- syndrome (n = 2); Miller-Dieker syndrome (n = 2); 18q- syndrome; (n = 2); Klinefelter syndrome; (n = 2); and 32 other individual chromosomal aberrations. Overall, the severity of mental retardation correlated with the severity of epilepsy. We could abstract characteristic features of epilepsy in some syndromes. In Angelman and Prader-Willi syndromes, febrile seizures occurred frequently, the onset of epilepsy was in early childhood and seizure phenotype was multiple. Paroxysmal discharge of the occipital region and diffuse high voltage slow wave on electroencephalography were characteristic in Angelman syndrome. In Down syndrome, West syndrome and focal epilepsy were common and the prognosis of epilepsy in West syndrome with Down syndrome was good. In 4p- syndrome, febrile seizures were often seen, and unilateral or generalized clonic or tonic-clonic status epilepticus were characteristic. For the other chromosomal aberrations investigated here, the patient numbers were too small to abstract common features of epilepsy.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

We report a 7-year-old boy with Landau-Kleffner syndrome (LKS), with emphasis on the effect of therapy and serial MEG. The equivalent current dipoles (ECDs) of spike discharges accumulated in the bilateral Heschl gyri, predominantly on the right. Although spike discharges on the scalp EEGs disappeared by treatment with clonazepam and sodium valproate, the auditory agnosia did not improve. Therapeutic trials with conventional antiepileptic drugs were unsuccessful. A high-dose corticosteroid was effective, with disappearance of ECDs, appearance of auditory evoked fields (AEF) in the bilateral Heschl gyri on MEG, and improvement of behavioral problems and amelioration of acquired aphasia. The clinical course of this patient suggests that MEG findings are useful not only in making precise diagnosis of LKS but also in assessing and predicting the effects of treatment.

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担当区分：筆頭著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Bilateral paramedian thalamic infarcts are characterized by disturbance of consciousness, followed by persisting dementia, decreased spontaneity, apathy, amnesia and paralysis of eye movement. We report a 15-year-old boy with this syndrome, who exhibited transient coma at the onset. In addition to the typical symptoms, he complained of sensory disturbance in the lower extremities and face and the loss of taste sense. MRI showed symmetric paramedian thalamic infarction. There was no lesion in the midbrain. The etiology of infarct in this boy remained unknown despite extensive laboratory and neuroradiological examination. His sensory disturbance in the extremities and face may be due to extensive involvement of the inferolateral area of the thalamus by infarction of the paramedian thalamic artery. This patient illustrates that bilateral paramedian thalamic infarction can occur in a previously healthy child.

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掲載種別：研究論文（国際会議プロシーディングス）  

Spontaneously occurring genetic lysosomal storage diseases are as rare in other mammalian species as in man. However, the advent of gene targeting technology has revolutionized the state of animal models of genetic diseases. Nearly all lysosomal storage diseases known in man have been duplicated in the mouse. The technology now allows, not only complete inactivation of endogenous genes, but also the introduction of essentially any type of mutation. These animal models can overcome many of the limitations inherent in studies of human patients - rarity of the disease, extremely complex genetic background and logistical and ethical constraints in the design and execution of experiments with human subjects. For example, genetic manipulations of germ cells or cross-breeding experiments between two mutants are readily feasible with animal models. Two major areas of the utility of animal models are the clarification of the pathophysiology/ pathogenetic mechanism of disease and the exploration of therapeutic approaches. Examples of experiments using animal models of lysosomal storage disease are presented, primarily from studies undertaken in our own laboratory. Conclusion: Animal models have proved invaluable in extending our knowledge of the lysosomal storage diseases and exploring potential therapies.

DOI： 10.1111/j.1651-2227.2003.tb00223.x

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担当区分：筆頭著者   記述言語：日本語  

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掲載種別：研究論文（学術雑誌）  

Sphingolipid activator proteins (saposins A, B, C and D) are small homologous glycoproteins derived from a common precursor protein (prosaposin) encoded by a single gene. They are required for in vivo degradation of sphingolipids with short carbohydrate chains. Six cysteines and one glycosylation site are strictly conserved in all four saposins. Total deficiency of all saposins and specific deficiency of saposin B or C are known among human patients. A mouse model of total saposin deficiency closely mimics the human disease. However, no specific saposin A or D deficiency is known. We introduced an amino acid substitution (C106F) into the saposin A domain by the Cre/loxP system which eliminated one of the three conserved disulfide bonds. Saposin A mice developed slowly progressive hind leg paralysis with clinical onset at Ο2.5 months and survival up to 5 months. Tremors and shaking, prominent in other myelin mutants, were not obvious until the terminal stage. Pathology and analytical biochemistry were qualitatively identical to, but generally much milder than, that seen in the typical infantile globoid cell leukodystrophy (GLD) in man (Krabbe disease) and in several other mammalian species, due to genetic deficiency of lysosomal galactosylceramidase (GALC) (EC 3.2.1.46). Thus, saposin A is indispensable for in vivo degradation of galactosylceramide by GALC. It should now be recognized that, in addition to GALC deficiency, genetic saposin A deficiency could also cause chronic GLD. Genetic saposin A deficiency might be anticipated among human patients with undiagnosed late-onset chronic leukodystrophy without GALC deficiency. -/-

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）  

Cytotoxic capacity of psychosine (galactosylsphingosine) was evaluated in comparison with C6-ceramide in cultured fibroblasts and the glia-derived MOCH-1 cells that have characteristics of myelinating cells (1). Psychosine caused cytotoxic cell death and DNA fragmentation at concentrations similar to C6-ceramide and MOCH-1 cells were substantially more sensitive to their cytotoxic effects than fibroblasts. In this system, pretreatment with GM1-ganglioside failed to protect the cells from the deleterious effects of these compounds. These findings are consistent with the hypothesis that psychosine is the cytotoxic metabolite that causes apoptotic death of the oligodendrocyte in globoid cell leukodystrophy (Krabbe disease). They further suggest that the protective capacity of GM1-ganglioside is unlikely to be the explanation for the paradoxical improvement of the phenotype of globoid cell leukodystrophy in the mouse simultaneously deficient in two lysosomal β-galactosidases, galactosylceramidase and GM1-ganglioside β-galactosidase.

DOI： 10.1023/A:1010991420942

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掲載種別：研究論文（学術雑誌）  

We have generated mice doubly deficient in both synthesis and degradation of galactosylceramide by crossbreeding twitcher mice and galactosylceramide synthase (UDP-galactose:ceramide galactosyltransferase, CGT) knockout mice. The prediction that the phenotype of the doubly deficient mice should be the same as the cgt(-/-) mice, since the degrading enzyme should not be necessary if the substrate is not synthesized, proved to be only partially correct. In early stages of the disease, the doubly deficient mice (galc(-/-), cgt(-/-)) were essentially indistinguishable from the cgt(- /-) mice. However, the doubly deficient mice had a much shorter life span than cgt(-/-) mice. Both galactosylceramide and galactosylsphingosine (psychosine), were undetectable in the brain of the cgt(-/-) and the doubly deficient mice. The characteristic twitcher pathology was never seen in the galc(-/-), cgt(-/-) mice. However, after 43 days, neuronal pathology was observed in the brainstem and spinal cord. This late neuronal pathology has not been seen in the CGT knockout mice but has been described in some long surviving bone marrow-transplanted twitcher mice. Furthermore, the motor segment of the trigeminal nerve of the galc(-/-), cgt(-/-) mice showed severe degeneration not seen in either twitcher or CGT knockout mice. Thus, the galc(-/-), cgt(-/-) mice, while primarily showing the cgt(-/-) phenotype as predicted, develop late pathology that is seen only in twitcher mouse and also a unique pathology in the trigeminal nerve. These observations indicate that the functional relationship between galactosylceramidase and galactosylceramide synthase is complex.

DOI： 10.1002/(SICI)1097-4547(20000115)59:2<170::AID-JNR3>3.0.CO;2-G

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掲載種別：研究論文（学術雑誌）  

Cross-breeding of mouse mutants, each defective in either synthesis (CGT knockout) or degradation (twitcher) of galactosylceramide, generates hybrids with a genotype of galc(-/-), cgt(+/-), in addition to doubly deficient mice. They are ideally suited to test the potential usefulness of limiting synthesis of the substrate as a treatment of genetic disorders due to degradative enzyme defects. The rate of accretion of galactosylceramide in the brain of CGT knockout carrier mice (cgt(+/-)) is approximately two-thirds of the normal, suggesting a gene-level compensation for the reduced gene dosage. Phenotype of twitcher mice with a single dose of normal cgt gene was indeed milder with statistical significance, albeit only slightly. Compared among 10 paired littermates, the difference in the life span was 7 ± 3.9 days (S.D.) and the difference in the maximum attained body weight was 1.9 ± 1.2 g (S.D.). Neuropathologists were able to distinguish blindly galc(-/-), cgt(+/-) mice from galc(-/-), cgt(+/+) mice. The brain psychosine level in galc(-/-), cgt(+/-) mice was also approximately two-thirds of the galc(-/-), cgt(+/+) mice. These observations indicate that reduction of galactosylceramide synthesis to two-thirds of the normal level results in minor but clearly detectable phenotypic improvements. Because of the detrimental consequences of drastic reduction in galactosylceramide synthesis that may be required for pragmatically meaningful improvements, this approach by itself is unlikely to be useful as the sole treatment but may be helpful as a supplement to other therapies.

DOI： 10.1002/(SICI)1097-4547(20000115)59:2<179::AID-JNR4>3.0.CO;2-N

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）  

Ceramide is recognized as an intracellular mediator of cell growth, differentiation and apoptosis. Tumour necrosis factor, anti-fas antibody, radiation and anticancer drugs such as actinomycin D are known to induce apoptosis in several cell types through generation of ceramide by activation of the sphingomyelinase pathway or ceramide synthetase. In this study, we examined the occurrence of apoptosis in fibroblasts from patients with Farber disease and from sphingolipid activator protein-deficient (sap -/-) mouse. These cells accumulate ceramide as the result of genetic deficiency of acid ceramidase and the ceramidase activator (sap-D), respectively. Amounts of ceramide in fibroblasts from Farber patients and in fibroblasts from sap -/- mouse were increased 2.9-fold and 2.8-fold, respectively, over the level of controls. Despite the similar degree of ceramide accumulation, cells exhibiting apoptotic features were increased only in fibroblasts from the sap -/- mouse but not those from the Farber patients. Thymidine uptake of Farber fibroblasts was normal while that of sap -/- mouse fibroblasts was twice normal, consistent with the apparently normal growth and the different rates of apoptotic cell death in these two cell lines. These data suggest that intralysosomal accumulation of ceramide due to defective acid ceramidase or its activator may not play an important role as a mediator of apoptosis. The increased apoptosis in the cultured fibroblasts from the sap -/- mouse may be caused by mechanisms other than the ceramide accumulation. Although more frequent than normal, significant apoptotic cell death was not observed in sap -/- mouse brain in vivo.

DOI： 10.1023/A:1005590316064

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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掲載種別：研究論文（学術雑誌）  

Human amniotic epithelial (HAE) cells have been used for allotransplantation in patients with lysosomal storage disease due to lack of expression of HLA antigens. Previously, we have reported the expression of differentiation markers for both neural stem cells, and neuron and glial cells. In the present study, we investigated the presence of choline acetyltransferase (CHAT) and acetylcholine (ACh) in HAE cells using different experimental approaches. Cultured HAE cells showed strong immunoreactivity against ChAT antibody. ChAT activity in primary cells was 24.9 ±8.5 pmol/mg protein/h. Using HPLC with electrochemical detection, ACh was detected in both cell incubation media and cell pellets indicating that these cells synthesize and release ACh in a time-dependent manner. Additional confirmation of this hypothesis was gained from the data obtained from RT- PCR and Western blot analyses which revealed the expression of ChAT mRNA and ChAT protein, respectively, in HAE cells. Results of the present study suggest that HAE cells can possibly be applied for intracerebral allografting to treat neurologic diseases in which cholinergic neurons are damaged.

DOI： 10.1016/S0304-3940(97)00570-3

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）  

This paper describes characteristics of human amniotic epithelial cells (AEC) transfected with a gene of origin-defective simian virus (SV) 40 large T-antigen (pMTIOD). Normal AEC before transfection with pMTIOD exhibited only low proliferative potential under our culture conditions. On the other hand, AEC cells transfected with pMTIOD exhibited greater proliferative potentials. Flowcytometry and immunohistochemistry analyses showed that both the primary and the transfected AEC did not express appreciable levels of class II antigens. However, the expression of class I antigen of the transfected AEC cells was slightly increased. The cells obtained in this experiment have the ability to induce tumors in severely combined immunodeficiency mice. This finding suggests that established AEC line can be used as a tool to investigate possible expression of the desired gene in human AEC and the gene products, however, was not suitable as a gene carrier to the recipient. Further experiments will be required to establish AEC as a transgene carrier for somatic cell gene therapy. Copyright (C) 1997 by the Tohoku University Medical Press.

DOI： 10.1620/tjem.182.75

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE Publications  

DOI： 10.1177/155005949702800208

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その他リンク： http://journals.sagepub.com/doi/full-xml/10.1177/155005949702800208

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/s0387-7604(96)00489-5

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掲載種別：研究論文（学術雑誌）  

Prolidase deficiency is an autosomal recessive inherited disease characterized clinically by frequent infections, mental retardation, and various skin lesions. Fundamental treatments for these manifestations have not been established. We performed adenovirus-mediated gene transfer of human prolidase cDNA into fibroblasts from patients with prolidase deficiency. Infection with the adenovirus vector carrying human prolidase cDNA increased prolidase activity in fibroblasts UP to approximately 7.5 times of that of normal control fibroblasts. This indicates the feasibility of adenovirus- mediated gene therapy to treat patients with prolidase deficiency in the future.

DOI： 10.1007/BF02766940

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掲載種別：研究論文（学術雑誌）  

We report a missense mutation in an adult Japanese patient with acid alpha-glucosidase (GAA) deficiency. A TC to GT transition at nucleotides 1585-1586, was identified. This transition resulted in an amino acid substitution of Ser-529 to Val (S529V) in exon 11. We also have demonstrated that the S529V mutation abolishes the catalytic activity of the enzyme. Our data suggest that this mutation is the cause of the clinical manifestation known as adult-onset GAA deficiency. The missense mutation described here is a new mutation, and the first identified in Japanese patients with GAA deficiency.

DOI： 10.1007/BF02267074

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掲載種別：研究論文（学術雑誌）  

X-linked hydrocephalus (HSAS) is the most common form of inherited hydrocephalus characterized by hydrocephalus due to stenosis of the aqueduct of Sylvius, mental retardation, clasped thumbs, and spastic paraparesis. MASA syndrome (mental retardation, aphasia, shuffling gait and adducted thumbs) and SPG1 (X-linked complicated spastic paraplegia) are also X-linked disorders with overlapping clinical signs. Linkage analysis studies implicated the neural cell adhesion molecule L1 (L1CAM) gene as a candidate gene for these X-linked disorders. This genetic study analyzes the L1CAM gene in a Japanese family with members suffering from HSAS, and describes a deletion of five nucleotides in exon 8. Screening by BglI digestion of polymerase chain reaction (PCR) products revealed that two siblings have the same mutation and a sister was identified as a heterozygous carrier. The 5 nucleotide deletion causes a shift of the reading frame and introduces a premature stop codon 72 nucleotides downstream, which might result in a truncated protein. The mutation identified herein is a novel L1CAM mutation, which triggers hydrocephalus. We report a unique L1CAM mutation that causes HSAS: the first report of such a mutation in a Japanese family.

DOI： 10.1007/BF02185770

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/ajmg.1320560103

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掲載種別：研究論文（学術雑誌）  

Immunoreactivity of human cultured amniotic epithelial (AE) cells was investigated to evaluate the possible use of these cells as a transgene carrier in gene therapy for inborn errors of metabolism. AE cells were prepared and cultured by the methods described previously. Flow cytometry analysis revealed that these cells did not express any class II antigen at all on their surfaces. But the class I antigen was slightly expressed on their surfaces Immunoperoxidase staining was slightly positive as to the class I antigen but not to the class II antigen at all. pSV-β-galactosidase was transfected into AE cells by means of electroporation, followed by staining of the cells with X-gal. Several cells in 60 mm dish expressed β-galactosidase activity. The possible gene transfer of β-galactosidase into cultured AE cells may suggest that these cells could be used as a transgene carrier in gene therapy for inborn errors of metabolism. © 1995.

DOI： 10.1016/0963-6897(95)00008-L

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/0387-7604(94)90130-9

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/bf00210606

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その他リンク： http://link.springer.com/article/10.1007/BF00210606/fulltext.html

担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/bf00588723

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その他リンク： http://link.springer.com/article/10.1007/BF00588723/fulltext.html

掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/0387-7604(93)90033-5

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Ovid Technologies (Wolters Kluwer Health)  

DOI： 10.1212/wnl.42.7.1406

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掲載種別：研究論文（学術雑誌）  

A T‐to‐C transition mutation at nucleotide position 3,250 in the mitochondrial tRNA gene was present in a family with mitochondrial myopathy. Two of three muscle biopsies examined had complex I (NADH‐ubiquinone oxidoreductase) deficiency. Heteroplasmy of wild and mutant mitochondrial DNA was detected by Nae I digestion of the polymerase chain reaction products with a modified primer. This was found in blood or muscle samples or both from all seven members examined. Similar to the 3,243 mutation in most patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke‐like episodes), the new mutation site was located in the dihydrouridine loop and embedded in the binding region of mitochondrial transcription termination factor. Elucidation of the effects of this mutation may help clarify the role of mitochondrial tRNAs and transcription termination. Copyright © 1992 American Neurological Association Leu(UUR)

DOI： 10.1002/ana.410310617

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/0140-6736(90)93138-f

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担当区分：筆頭著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.11251/ojjscn1969.22.369

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本てんかん学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

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記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

症例は脊髄性筋萎縮症(SMA 1型)を既往にもつ3歳男児で、5ヵ月前より誤嚥性肺炎を繰り返し、今回も同様に高熱を認め前医入院となった。入院後は輸液、抗生物質の点滴が開始されたが、第3病日より呼吸状態、意識状態が悪化し、血液検査にて急性肝不全の診断で当科転院となった。入院時、腹部CTでは肝の腫大、脂肪変性を認め、入院翌日(発症後5日目)には肝性昏睡3度をきたすと共にPT 40%以下を示し、劇症肝不全へと進行した。持続血液濾過透析および血漿交換を含む集学的治療を継続したところ、全身状態および肝機能は徐々に改善し、肝移植なしに救命することができた。

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記述言語：日本語   出版者・発行元：日本先天代謝異常学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：一般社団法人 日本てんかん学会  

<i>MECP2</i> は女性に発症するRett症候群の原因遺伝子として知られてきたが、その重複により、男性の精神遅滞、てんかんなどの神経学的異常の原因となることが明らかになり<i>MECP2</i> 重複症候群と呼ばれるようになってきた。我々は、精神運動遅滞に難治てんかんと反復性感染を合併した<i>MECP2</i> を含むXq28重複例2例を経験した。症例1は16歳男性、4歳時から難治てんかんを発症し、13歳時に脳梁離断術を施行されたが改善は一時的で、以後も難治に経過している。症例2は13歳男性で、2歳時より難治てんかんを発症し、気道感染の反復もみられた。両症例ともX染色体全領域のアレイcomparative genomic hybridizationの結果、<i>MECP2</i> を含むXq28の重複がみられた。<i>MECP2</i> の重複患者は、X連鎖性精神遅滞の1％を占めるといわれている。難治てんかん、精神運動遅滞、反復性気道感染を合併する患者をみた場合には、本症を念頭に置く必要がある。<br>

DOI： 10.3805/jjes.28.24

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

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記述言語：日本語   出版者・発行元：新潟医学会  

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記述言語：英語   出版者・発行元：ELSEVIER SCIENCE BV  

Neurofilament (NF) is one of the major cytoskeleton proteins of neurons and sTNFR1 is thought to reflect the true biological activity of TNF-alpha. To evaluate the levels of the heavy subunit of neurofilament (NF-H) and soluble TNF receptor 1 (sTNFR1) in cerebrospinal fluid (CSF) as biomarkers of clinical severity of subacute sclerosing panencephalitis (SSPE), concentrations of NF-H and sTNFR1 in CSF of 34 patients with SSPE and in control subjects were measured by ELISA. The CSF NF-H levels were significantly higher in patients with SSPE than in controls (p&lt;0.0001), and those in patients in Jabbour stage III were significantly higher than in patients in stage II (p=0.015). The CSF sTNFR1 levels in SSPE patients were significantly higher than those in controls (1)=0.004), but there were no significant differences in CSF sTNFR1 levels between patients in Jabbour stages II and III. There was a significant correlation between CSF NF-H and sTNFR1 levels in patients with SSPE (p=0.011). We suggest that CSF NF-H levels can be used as a marker of development of neuronal degeneration in SSPE, and that TNF-alpha modifies the neurodestructive pathogenesis in SSPE. (C) 2008 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jneuroim.2008.09.011

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記述言語：日本語   出版者・発行元：日本てんかん学会  

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記述言語：日本語  

A case of early-onset and slowly progressive chronic inflammatory demyelinating polyneuropathy (CIDP) was reported. Her progressive gait disturbance began at six years of age and she developed pes cavus. At the age of 13 years, a diagnosis of CIDP was made, and oral corticosteroid therapy was started. This therapy was effective, but the disease relapsed soon. Muscular strength improved after supplementation of an immunosupressant with oral corticosteroid, following steroid pulse therapy. On peripheral motor conduction study, M waves showed very low amplitudes and remarkably delayed onset-latencies. New units of M wave appeared and amplitudes increased soon after initiation of the corticosteroid therapy because of an improvement of conduction block, and durations of M wave were prolonged. Then, in accordance with shortening of M wave latencies, some dispersed units were synchronized and durations reduced. At relapse, changes of M wave showed an inverse relationship to the changes of M wave with clinical improvement. The electrophysiological findings started improving 1 week after the therapy, while clinical improvement was detected several weeks later. We conclude that the change of M wave was a sensitive marker to evaluate the effect of the therapy in our CIDP case.

DOI： 10.11251/ojjscn1969.26.522

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記述言語：英語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

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記述言語：英語   出版者・発行元：脳と発達  

複合体I欠損症を強く示唆する1家系について, 症状の多様性, 筋病理, 酵素活性, エルゴメーター (以下エルゴ) 負荷, 遺伝形式を検討した.本家系は筋型家系で, 母子例が3組あり, 3人の母は姉妹で, 母性遺伝が示唆された.児は確定診断した筋力低下を示す8歳女児, 5歳男児の2例と, 酵素分析, 酸素消費の検討で正常だが, ragged-red fiberがあり, エルゴ負荷でも乳酸 (L), ピルビン酸 (P) の高値, 易疲労性を示す15歳男児であった.母の1人は易疲労性, 高L, P血症を示す発症例で, 他の2人の母は無症状だが, エルゴ負荷でL, Pの異常高値を示した.そのうち1人の母はL/P比は正常であった.ミトコンドリア異常の検索にエルゴ負荷が有用だが, 確定診断には筋病理, 酵素活性, 酸素消費の総合的検討が必要であった.

DOI： 10.11251/ojjscn1969.24.20

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