記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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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)日本臨床神経生理学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経免疫学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経免疫学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Membrane-less subcellular compartments play important roles in various cellular functions. Although techniques exist to identify components of cellular bodies, a comprehensive method for analyzing both static and dynamic states has not been established. Here, we apply an antibody-based in situ biotinylation proximity-labeling technique to identify components of static and dynamic nuclear bodies. Using this approach, we comprehensively identify DNA, RNA, and protein components of Cajal bodies (CBs) and then clarify their interactome. By inhibiting transcription, we capture dynamic changes in CBs. Our analysis reveals that nascent small nuclear RNAs (snRNAs) transcribed in CBs contribute to CB formation by assembling RNA-binding proteins, including frontotemporal dementia-related proteins, RNA-binding motif proteins, and heterogeneous nuclear ribonucleoproteins.

DOI： 10.1016/j.celrep.2024.114734

Scopus

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Pathogenic variants in Gap junction protein beta 1 (GJB1), which encodes Connexin 32, are known to cause X-linked Charcot-Marie-Tooth disease (CMTX), the second most common form of CMT. CMTX presents with the following five central nervous systems (CNS) phenotypes: subclinical electrophysiological abnormalities, mild fixed abnormalities on neurological examination and/or imaging, transient CNS dysfunction, cognitive impairment, and persistent CNS manifestations. CASE PRESENTATION: A 40-year-old Japanese male showed CNS symptoms, including nystagmus, prominent spastic paraplegia, and mild cerebellar ataxia, accompanied by subclinical peripheral neuropathy. Brain magnetic resonance imaging revealed hyperintensities in diffusion-weighted images of the white matter, particularly along the pyramidal tract, which had persisted since childhood. Nerve conduction assessment showed a mild decrease in motor conduction velocity, and auditory brainstem responses beyond wave II were absent. Peripheral and central conduction times in somatosensory evoked potentials elicited by stimulation of the median nerve were prolonged. Genetic analysis identified a hemizygous GJB1 variant, NM_000166.6:c.520C > T p.Pro174Ser. CONCLUSIONS: The patient in the case described here, with a GJB1 p.Pro174Ser variant, presented with a unique CNS-dominant phenotype, characterized by spastic paraplegia and persistent extensive leukoencephalopathy, rather than CMTX. Similar phenotypes have also been observed in patients with GJC2 and CLCN2 variants, likely because of the common function of these genes in regulating ion and water balance, which is essential for maintaining white matter function. CMTX should be considered within the spectrum of GJB1-related disorders, which can include patients with predominant CNS symptoms, some of which can potentially be classified as a new type of spastic paraplegia.

DOI： 10.1186/s12883-024-03823-9

PubMed

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記述言語：日本語   出版者・発行元：(株)日本プランニングセンター  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although pure GAA expansion is considered pathogenic in SCA27B, non-GAA repeat motif is mostly mixed into longer repeat sequences. This study aimed to unravel the complete sequencing of FGF14 repeat expansion to elucidate its repeat motifs and pathogenicity. METHODS: We screened FGF14 repeat expansion in a Japanese cohort of 460 molecularly undiagnosed adult-onset cerebellar ataxia patients and 1022 controls, together with 92 non-Japanese controls, and performed nanopore sequencing of FGF14 repeat expansion. RESULTS: In the Japanese population, the GCA motif was predominantly observed as the non-GAA motif, whereas the GGA motif was frequently detected in non-Japanese controls. The 5'-common flanking variant was observed in all Japanese GAA repeat alleles within normal length, demonstrating its meiotic stability against repeat expansion. In both patients and controls, pure GAA repeat was up to 400 units in length, whereas non-pathogenic GAA-GCA repeat was larger, up to 900 units, but they evolved from different haplotypes, as rs534066520, located just upstream of the repeat sequence, completely discriminated them. Both (GAA)≥250 and (GAA)≥200 were enriched in patients, whereas (GAA-GCA)≥200 was similarly observed in patients and controls, suggesting the pathogenic threshold of (GAA)≥200 for cerebellar ataxia. We identified 14 patients with SCA27B (3.0%), but their single-nucleotide polymorphism genotype indicated different founder alleles between Japanese and Caucasians. The low prevalence of SCA27B in Japanese may be due to the lower allele frequency of (GAA)≥250 in the Japanese population than in Caucasians (0.15% vs 0.32%-1.26%). CONCLUSIONS: FGF14 repeat expansion has unique features of pathogenicity and allelic origin, as revealed by a single ethnic study.

DOI： 10.1136/jnnp-2024-333541

PubMed

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記述言語：英語  

DOI： 10.1007/s00401-024-02738-6

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本高次脳機能学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nogo-Nogo receptor 1 (NgR1) signaling is significantly implicated in neurodegeneration in amyotrophic lateral sclerosis (ALS). We previously showed that lateral olfactory tract usher substance (LOTUS) is an endogenous antagonist of NgR1 that prevents all myelin-associated inhibitors (MAIs), including Nogo, from binding to NgR1. Here we investigated the role of LOTUS in ALS pathogenesis by analyzing G93A-mutated human superoxide dismutase 1 (SOD1) transgenic (Tg) mice, as an ALS model, as well as newly generated LOTUS-overexpressing SOD1 Tg mice. We examined expression profiles of LOTUS and MAIs and compared motor functions and survival periods in these mice. We also investigated motor neuron survival, glial proliferation in the lumbar spinal cord, and neuromuscular junction (NMJ) morphology. We analyzed downstream molecules of NgR1 signaling such as ROCK2, LIMK1, cofilin, and ataxin-2, and also neurotrophins. In addition, we investigated LOTUS protein levels in the ventral horn of ALS patients. We found significantly decreased LOTUS expression in both SOD1 Tg mice and ALS patients. LOTUS overexpression in SOD1 Tg mice increased lifespan and improved motor function, in association with prevention of motor neuron loss, reduced gliosis, increased NMJ innervation, maintenance of cofilin phosphorylation dynamics, decreased levels of ataxin-2, and increased levels of brain-derived neurotrophic factor (BDNF). Reduced LOTUS expression may enhance neurodegeneration in SOD1 Tg mice and ALS patients by activating NgR1 signaling, and in this study LOTUS overexpression significantly ameliorated ALS pathogenesis. LOTUS might serve as a promising therapeutic target for ALS.

DOI： 10.1038/s41420-023-01758-7

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, autosomal recessive neurodegenerative disorder caused by biallelic AAGGG/ACAGG repeat expansion (AAGGG-exp/ACAGG-exp) in RFC1. The recent identification of patients with CANVAS exhibiting compound heterozygosity for AAGGG-exp and truncating variants supports the loss-of-function of RFC1 in CANVAS patients. We investigated the pathological changes in two autopsied patients with CANVAS harboring biallelic ACAGG-exp and AAGGG-exp. RNA fluorescence in situ hybridization of the two patients revealed CCTGT- and CCCTT-containing RNA foci, respectively, in neuronal nuclei of tissues with neuronal loss. Our findings suggest that RNA toxicity may be involved in the pathogenesis of CANVAS. This article is protected by copyright. All rights reserved.

DOI： 10.1002/ana.26848

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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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)日本臨床神経生理学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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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)日本神経免疫学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：Movement Disorder Society of Japan (MDSJ)  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders characterized by progressive spasticity and weakness in the lower extremities. To date, a total of 88 types of SPG are known. To diagnose HSP, multiple technologies, including microarray, direct sequencing, multiplex ligation-dependent probe amplification, and short-read next-generation sequencing, are often chosen based on the frequency of HSP subtypes. Exome sequencing (ES) is commonly used. We used ES to analyze ten cases of HSP from eight families. We identified pathogenic variants in three cases (from three different families); however, we were unable to determine the cause of the other seven cases using ES. We therefore applied long-read sequencing to the seven undetermined HSP cases (from five families). We detected intragenic deletions within the SPAST gene in four families, and a deletion within PSEN1 in the remaining family. The size of the deletion ranged from 4.7 to 12.5 kb and involved 1-7 exons. All deletions were entirely included in one long read. We retrospectively performed an ES-based copy number variation analysis focusing on pathogenic deletions, but were not able to accurately detect these deletions. This study demonstrated the efficiency of long-read sequencing in detecting intragenic pathogenic deletions in ES-negative HSP patients.

DOI： 10.1038/s10038-023-01170-0

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The biallelic repeat expansion (AAGGG)exp in the replication factor C subunit 1 gene (RFC1) is a frequent cause of cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) as well as late-onset ataxia. The clinical spectrum of RFC1 disease has expanded since the first identification of biallelic (AAGGG)exp and includes now various nonclassical phenotypes. We have recently found biallelic (AAGGG)exp in RFC1 in patients with clinically confirmed Parkinson's disease (PD). METHODS: A nationwide cohort of 273 Finnish patients with early-onset PD was examined for the biallelic intronic expansion in RFC1. The expansion (AAGGG)exp was first screened using XL-PCRs and flanking multiplex PCR. The presence of biallelic (AAGGG)exp was then confirmed by repeat-primed PCR and, finally, the repeat length was determined by long-read sequencing. RESULTS: Three patients were found with the biallelic (AAGGG)exp in RFC1 giving a frequency of 1.10 % (0.23-3.18 %; 95 % confidence interval). The three patients fulfilled the diagnostic criteria of PD, none of them had ataxia or neuropathy, and only one patient had a mild vestibular dysfunction. The age at onset of PD symptoms was 40 - 48 years and their disease course had been unremarkable apart from the early onset. CONCLUSIONS: Our results suggest that (AAGGG)exp in RFC1 is a rare cause of early-onset PD. Other populations should be examined in order to determine, if our findings are specific to the Finnish population.

DOI： 10.1111/ene.15717

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

This study aimed to test our hypothesis that the cerebellum plays an important role in the generation of the optical-geometric illusion known as the Poggendorff illusion, the mechanism of which has been explained by accumulated experience with natural scene geometry. A total of 79 participants, comprising 28 patients with isolated cerebellar stroke, 27 patients with isolated cerebral stroke and 24 healthy controls, performed Poggendorff illusion tasks and 2 different control tasks. We also investigated core brain regions underpinning changes in the experience of the illusion effect using multivariate lesion-symptom mapping. Our results indicate that patients with isolated cerebellar stroke were significantly less likely to experience the Poggendorff illusion effect than patients with isolated cerebral stroke or healthy controls (74.6, 90.5 and 89.8%, respectively; F(2,76) = 6.675, P = 0.002). However, there were no inter-group differences in the control tasks. Lesion-symptom mapping analysis revealed that the brain lesions associated with the reduced frequency of the Poggendorff illusion effect were mainly centred on the right posteromedial cerebellar region, including the right lobules VI, VII, VIII, IX and Crus II. Our findings demonstrated, for the first time, that patients with cerebellar damage were significantly less likely to experience the Poggendorff illusion effect and that right posteromedial cerebellar lesions played an important role in this effect. These results provide new insight into alterations of a geometric illusion effect in patients with cerebellar disorders and pave the way for future clinical use of the illusion task to detect cerebellar abnormalities.

DOI： 10.1093/braincomms/fcad053

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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：Elsevier BV  

Siponimod, which is approved to treat active secondary progressive multiple sclerosis, acts as a functional antagonist of sphingosine-1-phosphate (S1P) receptor 1 (S1P1) and an agonist of S1P5. S1P1 antagonization, which inhibits lymphocyte egress from lymphoid tissues and subsequent infiltration into the central nervous system (CNS), is considered the main therapeutic mechanism of siponimod. In addition, siponimod's direct effects on CNS glial cells are another potential neuroprotective mechanism because siponimod can penetrate the blood-brain barrier and CNS glial cells express S1P receptors. However, it remains uncertain whether siponimod directly affects CNS glial cells. In this study, we investigated siponimod's effects on astrocytes using mouse primary cultures. Siponimod suppressed nuclear factor kappa B activation and pro-inflammatory cytokine production. Using antagonists for S1P1 and S1P5, we found that siponimod partially exerts its anti-inflammatory effects via S1P1, but not via S1P5. Moreover, siponimod also inhibited histone deacetylase, suggesting that siponimod exerts broad anti-inflammatory effects via S1P1 antagonization and histone deacetylase inhibition. Siponimod might suppress disease progression in multiple sclerosis in part via direct inhibition of astroglial CNS neuroinflammation.

DOI： 10.1016/j.neures.2022.08.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BackgroundEndovascular treatment (EVT) for acute large vessel occlusion has proven to be effective in randomized controlled trials. We conducted a prospective cohort study to evaluate the real-world efficacy of EVT in a metropolitan area with a large number of comprehensive stroke centers and to compare it with the results of other registries and RCTs.MethodsWe analyzed the Kanagawa Intravenous and Endovascular Treatment of Acute Ischemic Stroke registry, a prospective, multicenter observational study of patients treated by EVT and/or intravenous tissue-type plasminogen activator (tPA). Of the 2488 patients enrolled from January 2018 to June 2020, 1764 patients treated with EVT were included. The primary outcome was a good outcome, which was defined as a modified Rankin Scale (mRS) of 0 to 2 at 90 days. Secondary analysis included predicting a good outcome using multivariate logistic regression analysis.ResultsThe median age was 77 years and the median National Institute of Health Stroke Scale (NIHSS) score was 18. Pretreatment mRS score 0-2 was 87%, and direct transport was 92%. The rate of occlusion in anterior circulation was 90.3%. Successful recanalization was observed in 88.7%. The median time from onset to recanalization was 193 minutes. Good outcomes at 90 days were 43.3% in anterior circulation and 41.9% in posterior circulation. Overall mortality was 12.6%. Significant predictors for a good outcome were: age, male, direct transfer, NIHSS score, Alberta Stroke Program Early Computed Tomography Score, intravenous tPA, and successful recanalization.ConclusionsEVT in routine clinical use in a metropolitan area showed comparable good outcomes and lower mortality compared to previous studies, despite the high proportion of patients with older age, pretreatment mRS score of > 2, posterior circulation occlusion, and higher NIHSS. Those results may have been associated with more direct transport and faster onset-to-recanalization times.

DOI： 10.1177/17474930221138014

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We developed a diagnostic method for repeat expansion diseases using a long-read sequencer to improve currently available, low throughput diagnostic methods. We employed the real-time target enrichment system of the nanopore GridION sequencer using the adaptive sampling option, in which software-based target assignment is available without prior sample enrichment, and built an analysis pipeline that prioritized the disease-causing loci. Twenty-two patients with various neurological and neuromuscular diseases, including 12 with genetically diagnosed repeat expansion diseases and 10 manifesting cerebellar ataxia, but without genetic diagnosis, were analyzed. We first sequenced the 12 molecularly diagnosed patients and accurately confirmed expanded repeats in all with uniform depth of coverage across the loci. Next, we applied our method and a conventional method to 10 molecularly undiagnosed patients. Our method corrected inaccurate diagnoses of two patients by the conventional method. Our method is superior to conventional diagnostic methods in terms of speed, accuracy, and comprehensiveness.

DOI： 10.1038/s41525-022-00331-y

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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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)日本神経免疫学会  

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記述言語：日本語   出版者・発行元：(一社)日本臨床神経生理学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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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：Frontiers Media SA  

In amyotrophic lateral sclerosis (ALS), neurodegeneration is characterized by distal axonopathy that begins at the distal axons, including the neuromuscular junctions, and progresses proximally in a “dying back” manner prior to the degeneration of cell bodies. However, the molecular mechanism for distal axonopathy in ALS has not been fully addressed. Semaphorin 3A (Sema3A), a repulsive axon guidance molecule that phosphorylates collapsin response mediator proteins (CRMPs), is known to be highly expressed in Schwann cells near distal axons in a mouse model of ALS. To clarify the involvement of Sema3A–CRMP signaling in the axonal pathogenesis of ALS, we investigated the expression of phosphorylated CRMP1 (pCRMP1) in the spinal cords of 35 patients with sporadic ALS and seven disease controls. In ALS patients, we found that pCRMP1 accumulated in the proximal axons and co-localized with phosphorylated neurofilaments (pNFs), which are a major protein constituent of spheroids. Interestingly, the pCRMP1:pNF ratio of the fluorescence signal in spheroid immunostaining was inversely correlated with disease duration in 18 evaluable ALS patients, indicating that the accumulation of pCRMP1 may precede that of pNFs in spheroids or promote ALS progression. In addition, overexpression of a phospho-mimicking CRMP1 mutant inhibited axonal outgrowth in Neuro2A cells. Taken together, these results indicate that pCRMP1 may be involved in the pathogenesis of axonopathy in ALS, leading to spheroid formation through the proximal progression of axonopathy.

DOI： 10.3389/fneur.2022.994676

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We report two patients with autosomal dominant neuronal intranuclear inclusion disease (NIID) harboring the biallelic GGC repeat expansion in NOTCH2NLC to uncover the impact of repeat expansion zygosity on the clinical phenotype. The zygosity of the entire NOTCH2NLC GGC repeat expansion and DNA methylation were comprehensively evaluated using fluorescent amplicon length PCR (AL-PCR), Southern blotting and targeted long-read sequencing, and detailed genetic/epigenetic and clinical features were described. In AL-PCR, we could not recognize the wild-type allele in both patients. Targeted long-read sequencing revealed that one patient harbored a homozygous repeat expansion. The other patient harbored compound heterozygous repeat expansions. The GGC repeats and the nearest CpG island were hypomethylated in all expanded alleles in both patients. Both patients harboring the biallelic GGC repeat expansion showed a typical dementia-dominant NIID phenotype. In conclusion, the biallelic GGC repeat expansion in two typical NIID patients indicated that NOTCH2NLC-related diseases could be completely dominant.

DOI： 10.1016/j.ygeno.2022.110469

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 39-year-old man exhibited ocular flutter and cerebellar ataxia following a subacute disturbance of consciousness and partial seizure. He was diagnosed with autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy by tissue- and cell-based antibody assays. Brain single-photon emission computed tomography detected a significant increase in blood flow in the fastigial nucleus, a critical region for eye saccade control. Immunotherapies diminished the ocular flutter and reduced hyperperfusion in the fastigial nucleus. This case suggests that autoimmune GFAP astrocytopathy can cause ocular flutter and provides strong imaging evidence supporting the hypothesis that ocular flutter is caused by hyperactivity or disinhibition of the fastigial nucleus.

DOI： 10.1016/j.clineuro.2022.107307

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Ultrasonography (US) is a noninvasive and patient-friendly tool for the evaluation of peripheral nerves. In motor neuron diseases, amyotrophic lateral sclerosis (ALS) has been reported to show the atrophy of peripheral nerves on US. However, the US findings are still unclear in spinal and bulbar muscular atrophy (SBMA), an adult-onset lower motor neuron disease caused by an abnormal CAG repeat expansion in the androgen receptor gene. METHODS: We prospectively recruited and evaluated 11 patients with genetically confirmed SBMA and 9 patients with ALS diagnosed according to the revised El Escorial ALS criteria or the Awaji electrodiagnostic criteria. The C5-C7 cervical nerve roots and the median and ulnar nerves were evaluated ultrasonographically. RESULTS: The cross-sectional areas (CSAs) of the C6 and C7 nerve roots, the median nerve in the upper arm and forearm, and the ulnar nerve in the upper arm were smaller in patients with SBMA than those in patients with ALS (p < 0.05), whereas the CSAs of the C5 nerve root and the ulnar nerve in the forearm were not smaller. CONCLUSIONS: US showed that the peripheral nerves in patients with SBMA were thinner than those in patients with ALS despite similar degrees of weakness and motor neuron loss. Possible causes include additional sensory nerve involvement and longer disease duration in patients with SBMA than those in patients with ALS.

DOI： 10.1007/s10072-022-05969-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Kyphomelic dysplasia is a heterogeneous group of skeletal dysplasias characterized by severe bowing of the limbs associated with other variable findings, such as narrow thorax and abnormal facies. We searched for the genetic etiology of this disorder. Four individuals diagnosed with kyphomelic dysplasia were enrolled. We performed whole-exome sequencing and evaluated the pathogenicity of the identified variants. All individuals had de novo heterozygous variants in KIF5B encoding kinesin-1 heavy chain: two with c.272A>G:p.(Lys91Arg), one with c.584C>A:p.(Thr195Lys), and the other with c.701G>T:p.(Gly234Val). All variants involved conserved amino acids in or close to the ATPase activity-related motifs in the catalytic motor domain of the KIF5B protein. All individuals had sharp angulation of the femora and humeri, distinctive facial features, and neonatal respiratory distress. Short stature was observed in three individuals. Three developed postnatal osteoporosis with subsequent fractures, two showed brachycephaly, and two were diagnosed with optic atrophy. Our findings suggest that heterozygous KIF5B deleterious variants cause a specific form of kyphomelic dysplasia. Furthermore, alterations in kinesins cause various symptoms known as kinesinopathies, and our findings also extend the phenotypic spectrum of kinesinopathies.

DOI： 10.1111/cge.14133

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Spinocerebellar ataxia type 2 (SCA2) is caused by mutations in the ATXN2 gene in which toxic effects are triggered by expanded polyglutamine repeats within ataxin-2. SCA2 is accompanied by motor neuron degeneration as occurs in amyotrophic lateral sclerosis (ALS). We investigated the distribution patterns of ataxin-2 and transactivation-responsive DNA-binding protein 43 (TDP-43), a major disease-related protein in ALS, in the CNS of 3 SCA2 patients. Phosphorylated TDP-43 (pTDP-43)-positive lesions were widely distributed throughout the CNS and generally overlapped with 1C2 (expanded polyglutamine)-immunoreactive lesions. This distribution pattern is different from the pattern in limbic-predominant age-related TDP-43 encephalopathy. In SCA2, double immunostaining of TDP-43 and 1C2 in motor neurons revealed 3 staining patterns: cytoplasmic 1C2 and nuclear TDP-43, nucleocytoplasmic 1C2 and nuclear TDP-43, and nuclear 1C2 and cytoplasmic TDP-43, which reflect the early, active, and final stages of pathological change, respectively. The translocation of TDP-43 from the nucleus to the cytoplasm along with the translocation of 1C2 in the opposite direction indicates that nuclear accumulation of the disease-specific protein ataxin-2 affects the intracellular dynamics of TDP-43. Such a close interrelationship between mutant ataxin-2 and TDP-43 in the cell might account for the similarity of their distribution in the CNS of patients with SCA2.

DOI： 10.1093/jnen/nlac032

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Guillain-Barré syndrome (GBS) has occasionally occurred in people who have received coronavirus disease 2019 (COVID-19) vaccines. Dysgeusia is rare symptom of GBS. We herein report a rare case of sensory ataxic GBS with dysgeusia just after the second dose of the Pfizer-BioNTech COVID-19 vaccine. Although autoantibodies against glycolipids were not detected, immunotherapy with intravenous immunoglobulin and methylprednisolone pulse therapy effectively ameliorated the symptoms. Our report suggests that the COVID-19 vaccine may induce various clinical subtypes of GBS, including a rare variant with sensory ataxia and dysgeusia.

DOI： 10.2169/internalmedicine.8967-21

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記述言語：日本語   出版者・発行元：(一社)日本遺伝カウンセリング学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder that affects upper and lower motor neurons; however, its pathomechanism has not been fully elucidated. Using a comprehensive phosphoproteomic approach, we have identified elevated phosphorylation of collapsin response mediator protein 1 (Crmp1) at serine 522 in the lumbar spinal cord of ALS model mice overexpressing a human superoxide dismutase mutant (SOD1G93A). We investigated the effects of Crmp1 phosphorylation and depletion in SOD1G93A mice using Crmp1S522A (Ser522→Ala) knockin (Crmp1ki/ki ) mice in which the S522 phosphorylation site was abolished and Crmp1 knockout (Crmp1 -/-) mice, respectively. Crmp1ki/ki/SOD1G93A mice showed longer latency to fall in a rotarod test while Crmp1-/-/SOD1G93A mice showed shorter latency compared with SOD1G93A mice. Survival was prolonged in Crmp1ki/ki/SOD1G93A mice but not in Crmp1-/-/SOD1G93A mice. In agreement with these phenotypic findings, residual motor neurons and innervated neuromuscular junctions were comparatively well-preserved in Crmp1ki/ki/SOD1G93A mice without affecting microglial and astroglial pathology. Pathway analysis of proteome alterations showed that the sirtuin signaling pathway had opposite effects in Crmp1ki/ki/SOD1G93A and Crmp1-/-/SOD1G93A mice. Our study indicates that modifying CRMP1 phosphorylation is a potential therapeutic strategy for ALS.Significance StatementCollapsin response mediator protein 1 (CRMP1) is an intracellular molecule that mediates semaphorin 3A (Sema3A) signaling. Phosphoproteomic analysis showed that the Semaphorin Neuronal Repulsive Signaling Pathway, which includes Crmp1 phosphorylation at Ser522, is upregulated in SOD1G93A mice that serve as a model of amyotrophic lateral sclerosis (ALS). While deleting both copies of the Crmp1 gene (Crmp1-/- ) leads to deterioration of motor function in SOD1G93A mice, phospho-null Crmp1 (Crmp1ki/ki ) improves motor function while preventing motor neuron loss and denervation of neuromuscular junctions. Among the Sema3A-mediated axon guidance pathways, we propose that CRMP1 phosphorylation is a potential therapeutic target for ALS.

DOI： 10.1523/ENEURO.0133-22.2022

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, slow-progressing multisystem neurodegenerative disorder. Biallelic AAGGG repeat expansion in RFC1 has been identified as causative of this disease, and repeat conformation heterogeneity (ACAGG repeat) was also recently implied. To molecularly characterize this disease in Japanese patients with adult-onset ataxia, we accumulated and screened 212 candidate families by an integrated approach consisting of flanking PCR, repeat-primed PCR, Southern blotting and long-read sequencing using Sequel II, GridION or PromethION. We identified 16 patients from 11 families, of whom seven had ACAGG expansions [(ACAGG)exp/(ACAGG)exp] (ACAGG homozygotes), two had ACAGG and AAGGG expansions [(ACAGG)exp/(AAGGG)exp] (ACAGG/AAGGG compound heterozygotes) and seven had AAGGG expansions [(AAGGG)exp/(AAGGG)exp] (AAGGG homozygotes). The overall detection rate was 5.2% (11/212 families including one family having two expansion genotypes). Long-read sequencers revealed the entire sequence of both AAGGG and ACAGG repeat expansions at the nucleotide level of resolution. Clinical assessment and neuropathology results suggested that patients with ACAGG expansions have similar clinical features to previously reported patients with homozygous AAGGG expansions, although motor neuron involvement was more notable in patients with ACAGG expansions (even if one allele was involved). Furthermore, a later age of onset and slower clinical progression were implied in patients with ACAGG/AAGGG compound heterozygous expansions compared with either ACAGG or AAGGG homozygotes in our very limited cohort. Our study clearly shows the occurrence of repeat conformation heterogeneity, with possible different impacts on the affected nervous systems. The difference in disease onset and progression between compound heterozygotes and homozygotes might also be suspected but with very limited certainty due to the small sample number of cases in our study. Studies of additional patients are needed to confirm this.

DOI： 10.1093/brain/awab363

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder, characterized by the presence of eosinophilic inclusions (NIIs) within nuclei of central and peripheral nervous system cells. This study aims to identify the components of NIIs, which have been difficult to analyze directly due to their insolubility. In order to establish a method to directly identify the components of NIIs, we first analyzed the huntingtin inclusion-rich fraction obtained from the brains of Huntington disease model mice. Although the sequence with expanded polyglutamine could not be identified by liquid-chromatography mass spectrometry, amino acid analysis revealed that glutamine of the huntingtin inclusion-rich fraction increased significantly. This is compatible with the calculated amino acid content of the transgene product. Therefore, we applied this method to analyze the NIIs of diseased human brains, which may have proteins with compositionally biased regions, and identified a serine-rich protein called hornerin. Since the analyzed NII-rich fraction was also serine-rich, we suggested hornerin as a major component of the NIIs. A specific distribution of hornerin in NIID was also investigated by Matrix-assisted laser desorption/ionization imaging mass spectrometry and immunofluorescence. Finally, we confirmed a variant of hornerin by whole-exome sequencing and DNA sequencing. This study suggests that hornerin may be related to the pathological process of this NIID, and the direct analysis of NIIs, especially by amino acid analysis using the NII-rich fractions, would contribute to a deeper understanding of the disease pathogenesis.

DOI： 10.1186/s40478-022-01333-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: The basal ganglia and related dopaminergic cortical areas are important neural systems underlying motor learning and are also implicated in impulse control disorders (ICDs). Motor learning impairments and ICDs are frequently observed in Parkinson's disease (PD). Nevertheless, the relationship between motor learning ability and ICDs has not been elucidated. METHODS: We examined the relationship between motor learning ability and gambling propensity, a possible symptom for prodromal ICDs, in PD patients. Fifty-nine PD patients without clinical ICDs and 43 normal controls (NC) were administered a visuomotor rotation perturbation task and the Iowa Gambling Task (IGT) to evaluate motor learning ability and gambling propensity, respectively. Participants also performed additional cognitive assessments and underwent brain perfusion SPECT imaging. RESULTS: Better motor learning ability was significantly correlated with lower IGT scores, i.e., higher gambling propensity, in PD patients but not in NC. The higher scores on assessments reflecting prefrontal lobe function and well-preserved blood perfusion in prefrontal areas were correlated with lower IGT scores along with better motor learning ability. CONCLUSIONS: Our findings suggest that better motor learning ability and higher gambling propensity are based on better prefrontal functions, which are in accordance with the theory that the prefrontal cortex is one of the common essential regions for both motor learning and ICDs.

DOI： 10.1080/13803395.2022.2083083

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

An intronic expansion (AAGGG)exp in the RFC1 gene has recently been shown to cause recessively inherited cerebellar ataxia, neuropathy, and vestibular areflexia syndrome and, furthermore, a few patients with ataxia and parkinsonism have been reported. We investigated 569 Finnish patients with medicated parkinsonism for RFC1 and found biallelic (AAGGG)exp in three non-consanguineous patients with clinically confirmed Parkinson's disease without ataxia suggesting that RFC1-related disorders include Parkinson's disease as well.

DOI： 10.1038/s41531-021-00275-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ensci.2021.100377

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: GGC repeat expansions in NOTCH2NLC are associated with neuronal intranuclear inclusion disease. Very recently, asymptomatic carriers with NOTCH2NLC repeat expansions were reported. In these asymptomatic individuals, the CpG island in NOTCH2NLC is hypermethylated, suggesting that two factors repeat length and DNA methylation status should be considered to evaluate pathogenicity. Long-read sequencing can be used to simultaneously profile genomic and epigenomic alterations. We analyzed four sporadic cases with NOTCH2NLC repeat expansion and their phenotypically normal parents. The native genomic DNA that retains base modification was sequenced on a per-trio basis using both PacBio and Oxford Nanopore long-read sequencing technologies. A custom workflow was developed to evaluate DNA modifications. With these two technologies combined, long-range DNA methylation information was integrated with complete repeat DNA sequences to investigate the genetic origins of expanded GGC repeats in these sporadic cases. RESULTS: In all four families, asymptomatic fathers had longer expansions (median: 522, 390, 528 and 650 repeats) compared with their affected offspring (median: 93, 117, 162 and 140 repeats, respectively). These expansions are much longer than the disease-causing range previously reported (in general, 41-300 repeats). Repeat lengths were extremely variable in the father, suggesting somatic mosaicism. Instability is more frequent in alleles with uninterrupted pure GGCs. Single molecule epigenetic analysis revealed complex DNA methylation patterns and epigenetic heterogeneity. We identified an aberrant gain-of-methylation region (2.2 kb in size beyond the CpG island and GGC repeats) in asymptomatic fathers. This methylated region was unmethylated in the normal allele with bilateral transitional zones with both methylated and unmethylated CpG dinucleotides, which may be protected from methylation to ensure NOTCH2NLC expression. CONCLUSIONS: We clearly demonstrate that the four sporadic NOTCH2NLC-related cases are derived from the paternal GGC repeat contraction associated with demethylation. The entire genetic and epigenetic landscape of the NOTCH2NLC region was uncovered using the custom workflow of long-read sequence data, demonstrating the utility of this method for revealing epigenetic/mutational changes in repetitive elements, which are difficult to characterize by conventional short-read/bisulfite sequencing methods. Our approach should be useful for biomedical research, aiding the discovery of DNA methylation abnormalities through the entire genome.

DOI： 10.1186/s13148-021-01192-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Simultanagnosia is a rare neuropsychological symptom characterized by difficulty recognizing global structures while preserving perception of local detail. The condition is classified into ventral and dorsal types. Clinical presentation of ventral simultanagnosia includes a reduced ability to recognize multiple visual stimuli rapidly, that is, part-by-part recognition. Here, we report a case of ventral simultanagnosia with a unique presentation; when short-duration visual stimuli were presented, the patient could perform global recognition by improving his part-by-part approach. To investigate the relationship between local and global perception bias and the duration of the present stimulus, we conducted a visual perception test using hierarchically organized Navon figures. METHODS/RESULTS: The patient was a 62-year-old right-handed man who suffered from cerebral infarction in the right occipitotemporal lobe. He had no language dysfunction but exhibited left unilateral neglect, prosopagnosia, and ventral-type simultanagnosia. We conducted a visual perception test using the Navon figures and control figures as a visual stimulus. We randomly presented the figures for intervals of 0.2 or 20 s and let the patient report all the letters (global and/or local element) that he recognized. Global elements of the Navon letter were recognized a rate of 0% and 78.3% at intervals of 20 and 0.2 s, respectively, indicating that shorter presentation made the part-by-part approach less likely to manifest. CONCLUSIONS: We assumed that the simultanagnosia in this case was caused by failure to maintain the initially perceived global information for a long period of time during visual presentation, due to right occipitotemporal damage.

DOI： 10.1093/arclin/acab088

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The genetics of cerebellar ataxia is complex. Hundreds of causative genes have been identified, but only a few cause more than single cases. The spectrum of ataxia-causing genes differs considerably between populations. The aim of the study was to investigate the molecular epidemiology of ataxia in the Finnish population. PATIENTS AND METHODS: All patients in hospital database were reviewed for the diagnosis of unspecified ataxia. Acquired ataxias and nongenetic ataxias such as those related to infection, trauma or stroke were excluded. Sixty patients with sporadic ataxia with unknown etiology and 36 patients with familial ataxia of unknown etiology were recruited in the study. Repeat expansions in the SCA genes (ATXN1, 2, 3, 7, 8/OS, CACNA1A, TBP), FXN, and RFC1 were determined. Point mutations in POLG, SPG7 and in mitochondrial DNA (mtDNA) were investigated. In addition, DNA from 8 patients was exome sequenced. RESULTS: A genetic cause of ataxia was found in 33 patients (34.4%). Seven patients had a dominantly inherited repeat expansion in ATXN8/OS. Ten patients had mitochondrial ataxia resulting from mutations in nuclear mitochondrial genes POLG or RARS2, or from a point mutation m.8561C > G or a single deletion in mtDNA. Interestingly, five patients were biallelic for the recently identified pathogenic repeat expansion in RFC1. All the five patients presented with the phenotype of cerebellar ataxia, neuropathy, and vestibular areflexia (CANVAS). Moreover, screening of 54 patients with Charcot-Marie-Tooth neuropathy revealed four additional patients with biallelic repeat expansion in RFC1, but none of them had cerebellar symptoms. CONCLUSIONS: Expansion in ATXN8/OS results in the majority of dominant ataxias in Finland, while mutations in RFC1 and POLG are the most common cause of recessive ataxias. Our results suggest that analysis of RFC1 should be included in the routine diagnostics of idiopathic ataxia and Charcot-Marie-Tooth polyneuropathy.

DOI： 10.1186/s12883-021-02409-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Anticoagulation therapy, especially using heparin or recently developed oral direct factor Xa inhibitors (DiXals), is recommended as first-line treatment for cancer-related venous thromboembolism (VTE). However, the preventive efficacy of these anticoagulants for cancer-associated ischemic stroke is still unknown. We retrospectively investigated the efficacy of subcutaneous unfractionated heparin (UFH) and DiXals for preventing the recurrence of cancer-associated cryptogenic ischemic stroke with VTE. METHODS: We retrospectively studied consecutive patients with cancer-associated cryptogenic ischemic stroke and comorbid VTE who received subcutaneous UFH or oral DiXaIs at 9 hospitals. RESULT: Fifty-three patients (24 treated with UFH and 29 treated with DiXaIs) were enrolled. Of these, 47 demonstrated systemic metastasis (cancer stage IV). During 30-day follow-up after initiation of anticoagulation therapy, recurrent ischemic stroke was observed in only 1 patient (4%) in the UFH group and in 9 patients (31%) in the DiXal group. The incidence of major bleeding complications was similar between the 2 groups (4% and 10%, respectively). The cumulative risk of ischemic stroke recurrence within 30 days was lower with UFH than with DiXals (competing risk analysis, p = 0.008). In the DiXal group, patients who experienced recurrence showed significantly higher D-dimer levels than those without recurrence. CONCLUSION: In patients with cancer-associated cryptogenic ischemic stroke and comorbid VTE, UFH demonstrated a lower rate of recurrent ischemic stroke than DiXaIs, and there were no differences in bleeding risk between the 2 treatments. D-dimer levels at stroke onset increased the risk of recurrence in the DiXal group but not in the UFH group.

DOI： 10.1016/j.thromres.2021.08.016

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Recently, various magnetic resonance imaging (MRI) modalities have been developed to easily detect carotid and aortic plaques, but these techniques are time-consuming and vulnerable to motion artifacts. We investigated the utility of a gradient echo MRI technique known as liver acquisition with volume acceleration flexible (LAVA-Flex) to detect carotid and aortic atherosclerotic plaques. METHODS: Ten patients who underwent carotid endarterectomy (CEA) were assessed regarding the correspondence between LAVA-Flex findings and the histopathology of excised carotid plaques. In addition, 47 patients with cryptogenic ischemic stroke underwent LAVA-Flex and transesophageal echocardiography (TEE) for detection of embolic sources in the thoracic aorta. We analyzed the relationship between the thickness of the aortic plaque measured by TEE and the presence of high-intensity lesions on LAVA-Flex. RESULTS: Nine of 10 patients (90.0%) who underwent CEA showed a high-intensity carotid lesion on LAVA-Flex, which corresponded pathologically to plaques containing large lipid cores and hemorrhage. Twenty-four (51.1%) of 47 cryptogenic stroke patients showed a high-intensity lesion in the thoracic aorta on LAVA-Flex; of these, 21 (87.5%) also demonstrated a large plaque (thickness ≥4 mm) on TEE. Twenty-two (95.7%) of 23 patients without a high-intensity lesion on LAVA-Flex demonstrated no large plaque on TEE. LAVA-Flex had a sensitivity of 95.5% and a specificity of 88.0% in patients with large plaques. CONCLUSION: This study showed that LAVA-Flex successfully detected carotid and aortic plaques. This imaging technique may be useful to rapidly diagnose and evaluate carotid and aortic plaques, which are critical risk factors for aortogenic stroke.

DOI： 10.1007/s00234-021-02812-w

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記述言語：英語  

DOI： 10.1093/brain/awab183

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Mild cognitive impairment (MCI) in Parkinson's disease (PD) is considered a risk factor for PD with dementia (PDD). Verbal fluency tasks are widely used to assess executive function in PDD. However, in cases of PD with MCI (PD-MCI), the relative diagnostic accuracy of different qualitative verbal fluency measures and their related neural mechanisms remain unknown. OBJECTIVE: This study aimed to investigate the relative diagnostic accuracy of qualitative (clustering and switching) verbal fluency strategies and their correlates with functional imaging in PD-MCI. METHODS: Forty-five patients with PD (26 with MCI and 19 without MCI) and 25 healthy controls underwent comprehensive neurocognitive testing and resting-state functional magnetic resonance imaging. MCI in patients with PD was diagnosed according to established clinical criteria. The diagnostic accuracy of verbal fluency measures was determined via receiver operating characteristic analysis. Changes in brain functional connectivity between groups and across clinical measures were assessed using seed-to-voxel analyses. RESULTS: Patients with PD-MCI generated fewer words and switched less frequently in semantic and phonemic fluency tasks compared to other groups. Switching in semantic fluency showed high diagnostic accuracy for PD-MCI and was associated with reduced functional connectivity in the salience network. CONCLUSION: Our results indicate that reduced switching in semantic fluency tasks is a sensitive and specific marker for PD-MCI. Qualitative verbal fluency deficits and salience network dysfunction represent early clinical changes observed in PD-MCI.

DOI： 10.3233/JPD-202473

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A pentanucleotide TTTCA repeat insertion into a polymorphic TTTTA repeat element in SAMD12 causes benign adult familial myoclonic epilepsy. Although the precise determination of the entire SAMD12 repeat sequence is important for molecular diagnosis and research, obtaining this sequence remains challenging when using conventional genomic/genetic methods, and even short-read and long-read next-generation sequencing technologies have been insufficient. Incomplete information regarding expanded repeat sequences may hamper our understanding of the pathogenic roles played by varying numbers of repeat units, genotype-phenotype correlations, and mutational mechanisms. Here, we report a new approach for the precise determination of the entire expanded repeat sequence and present a workflow designed to improve the diagnostic rates in various repeat expansion diseases. We examined 34 clinically diagnosed benign adult familial myoclonic epilepsy patients, from 29 families using repeat-primed PCR, Southern blot, and long-read sequencing with Cas9-mediated enrichment. Two cases with questionable results from repeat-primed PCR and/or Southern blot were confirmed as pathogenic using long-read sequencing with Cas9-mediated enrichment, resulting in the identification of pathogenic SAMD12 repeat expansions in 76% of examined families (22/29). Importantly, long-read sequencing with Cas9-mediated enrichment was able to provide detailed information regarding the sizes, configurations, and compositions of the expanded repeats. The inserted TTTCA repeat size and the proportion of TTTCA sequences among the overall repeat sequences were highly variable, and a novel repeat configuration was identified. A genotype-phenotype correlation study suggested that the insertion of even short (TTTCA)14 repeats contributed to the development of benign adult familial myoclonic epilepsy. However, the sizes of the overall TTTTA and TTTCA repeat units are also likely to be involved in the pathology of benign adult familial myoclonic epilepsy. Seven unsolved SAMD12-negative cases were investigated using whole-genome long-read sequencing, and infrequent, disease-associated, repeat expansions were identified in two cases. The strategic workflow resolved two questionable SAMD12-positive cases and two previously SAMD12-negative cases, increasing the diagnostic yield from 69% (20/29 families) to 83% (24/29 families). This study indicates the significant utility of long-read sequencing technologies to explore the pathogenic contributions made by various repeat units in complex repeat expansions and to improve the overall diagnostic rate.

DOI： 10.1093/brain/awab021

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Neuroinflammation by activated microglia and astrocytes plays a critical role in progression of amyotrophic lateral sclerosis (ALS). Interleukin-19 (IL-19) is a negative-feedback regulator that limits pro-inflammatory responses of microglia in an autocrine and paracrine manner, but it remains unclear how IL-19 contributes to ALS pathogenesis. We investigated the role of IL-19 in ALS using transgenic mice carrying human superoxide dismutase 1 with the G93A mutation (SOD1G93A Tg mice). We generated IL-19-deficient SOD1G93A Tg (IL-19-/-/SOD1G93A Tg) mice by crossing SOD1G93A Tg mice with IL-19-/- mice, and then evaluated disease progression, motor function, survival rate, and pathological and biochemical alternations in the resultant mice. In addition, we assessed the effect of IL-19 on glial cells using primary microglia and astrocyte cultures from the embryonic brains of SOD1G93A Tg mice and IL-19-/-/SOD1G93A Tg mice. Expression of IL-19 in primary microglia and lumbar spinal cord was higher in SOD1G93A Tg mice than in wild-type mice. Unexpectedly, IL-19-/-/SOD1G93A Tg mice exhibited significant improvement of motor function. Ablation of IL-19 in SOD1G93A Tg mice increased expression of both neurotoxic and neuroprotective factors, including tumor necrosis factor-α (TNF-α), IL-1β, glial cell line-derived neurotrophic factor (GDNF), and transforming growth factor β1, in lumbar spinal cord. Primary microglia and astrocytes from IL-19-/-/SOD1G93A Tg mice expressed higher levels of TNF-α, resulting in release of GDNF from astrocytes. Inhibition of IL-19 signaling may alleviate ALS symptoms.

DOI： 10.1186/s13041-021-00785-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Intracellular aggregates are a common pathological hallmark of neurodegenerative diseases such as polyglutamine (polyQ) diseases, amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple system atrophy (MSA). Aggregates are mainly formed by aberrant disease-specific proteins and are accompanied by accumulation of other aggregate-interacting proteins. Although aggregate-interacting proteins have been considered to modulate the formation of aggregates and to be involved in molecular mechanisms of disease progression, the components of aggregate-interacting proteins remain unknown. In this study, we showed that small glutamine-rich tetratricopeptide repeat-containing protein alfa (SGTA) is an aggregate-interacting protein in neurodegenerative diseases. Immunohistochemistry showed that SGTA interacted with intracellular aggregates in Huntington disease (HD) cell models and neurons of HD model mice. We also revealed that SGTA colocalized with intracellular aggregates in postmortem brains of patients with polyQ diseases including spinocerebellar ataxia (SCA)1, SCA2, SCA3, and dentatorubral-pallidoluysian atrophy. In addition, SGTA colocalized with glial cytoplasmic inclusions in the brains of MSA patients, whereas no accumulation of SGTA was observed in neurons of PD and ALS patients. In vitro study showed that SGTA bound to polyQ aggregates through its C-terminal domain and SGTA overexpression reduced intracellular aggregates. These results suggest that SGTA may play a role in the formation of aggregates and may act as potential modifier of molecular pathological mechanisms of polyQ diseases and MSA.

DOI： 10.1186/s13041-021-00770-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Polymicrogyria is a common malformation of cortical development whose etiology remains elusive. We conducted whole-exome sequencing for 124 patients with polymicrogyria and identified de novo ATP1A3 variants in eight patients. Mutated ATP1A3 causes functional brain diseases, including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP), and cerebellar ataxia, areflexia, pes cavus, optic nerve atrophy, and sensorineural deafness (CAPOS). However, our patients showed no clinical features of AHC, RDP, or CAPOS and had a completely different phenotype: a severe form of polymicrogyria with epilepsy and developmental delay. Detected variants had different locations in ATP1A3 and different functional properties compared with AHC-, RDP-, or CAPOS-associated variants. In the developing cerebral cortex of mice, radial neuronal migration was impaired in neurons overexpressing the ATP1A3 variant of the most severe patients, suggesting that this variant is involved in cortical malformation pathogenesis. We propose a previously unidentified category of polymicrogyria associated with ATP1A3 abnormalities.

DOI： 10.1126/sciadv.abd2368

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Many algorithms to detect copy number variations (CNVs) using exome sequencing (ES) data have been reported and evaluated on their sensitivity and specificity, reproducibility, and precision. However, operational optimization of such algorithms for a better performance has not been fully addressed. ES of 1199 samples including 763 patients with different disease profiles was performed. ES data were analyzed to detect CNVs by both the eXome Hidden Markov Model (XHMM) and modified Nord's method. To efficiently detect rare CNVs, we aimed to decrease sequencing biases by analyzing, at the same time, the data of all unrelated samples sequenced in the same flow cell as a batch, and to eliminate sex effects of X-linked CNVs by analyzing female and male sequences separately. We also applied several filtering steps for more efficient CNV selection. The average number of CNVs detected in one sample was <5. This optimization together with targeted CNV analysis by Nord's method identified pathogenic/likely pathogenic CNVs in 34 patients (4.5%, 34/763). In particular, among 142 patients with epilepsy, the current protocol detected clinically relevant CNVs in 19 (13.4%) patients, whereas the previous protocol identified them in only 14 (9.9%) patients. Thus, this batch-based XHMM analysis efficiently selected rare pathogenic CNVs in genetic diseases.

DOI： 10.1002/humu.24129

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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）  

BACKGROUND: Foreign accent syndrome (FAS) is a rare acquired speech disorder wherein an individual's spoken accent is perceived as "foreign." Most reported cases involve left frontal brain lesions, but it is known that various other lesions can also cause FAS. To determine whether heterogeneous FAS-causing lesions are localized to a common functional speech network rather than to a single anatomical site, we employed a recently validated image analysis technique known as "lesion network mapping." METHODS: We identified 25 published cases of acquired neurogenic FAS without aphasia, and mapped each lesion volume onto a reference brain. We next identified the network of brain regions functionally connected to each FAS lesion using a connectome dataset from normative participants. Network maps were then overlapped to identify common network sites across the lesions. RESULTS: Classical lesion overlap analysis showed heterogeneity in lesion anatomical location, consistent with prior reports. However, at least 80% of lesions showed network overlap in the bilateral lower and middle portions of the precentral gyrus and in the medial frontal cortex. The left lower portion of the precentral gyrus is suggested to be the location of lesions causing apraxia of speech (AOS), and the middle portion is considered to be a larynx-specific motor area associated with the production of vowels and stop/nasal consonants and with the determination of pitch accent. CONCLUSIONS: The lesions that cause FAS are anatomically heterogeneous, but they share a common functional network located in the bilateral posterior region of the frontal lobe. This network specifically includes not only the lower portion of the central gyrus, but also its middle region, which is referred to as the larynx motor cortex and is known to be associated with phonation. Our findings suggest that disrupted networks in FAS might be anatomically different from those in AOS.

DOI： 10.1016/j.nicl.2021.102760

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記述言語：英語  

RNA polymerase III (POLR3)-related leukodystrophy is an autosomal recessive form of leukodystrophy caused by homozygous or compound heterozygous mutations of the RNA polymerase III subunit genes, including subunit A (POLR3A). With respect to the manifestation triad, hypomyelination, hypodontia, and hypogonadotropic hypogonadism, it is also known as 4H leukodystrophy. Here, we report a 41-year-old woman of POLR3-related leukodystrophy by carrying compound heterozygous pathogenic variants of c.2554A>G (p.M852V) and c.2668G>T (p.V890F) in the POLR3A gene. She was amenorrheic and became a wheelchair user from the age of 15 years and suffered from multiple episodes of pathologic fractures, starting with a subtrochanteric fracture of the right femur after a tonic seizure at age 30 years. Head magnetic resonance imaging demonstrated hypomyelination and atrophies of the cerebellum, brainstem, and corpus callosum. Laboratory examination revealed a marked decrease of gonadotropins and estrogen, low bone density, and high bone resorption markers. Administration of anti-receptor activator of nuclear factor kappa-B ligand monoclonal antibody restored bone resorption markers to a normal level and prevented further pathological bone fractures. Our case emphasizes that osteoporosis should be recognized as a potential but serious complication in POLR3-related leukodystrophy. It may be feasible to prevent pathologic fractures by intensive osteoporosis therapy after endocrinological examinations and evaluation of bone metabolism.

DOI： 10.3389/fneur.2021.622355

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記述言語：英語  

Takotsubo cardiomyopathy (TCM) is a stress-induced cardiomyopathy triggered by critical illness including severe neurological disorders. However, an association between TCM and Bickerstaff brainstem encephalitis (BBE) has rarely been described. During the current coronavirus disease 2019 (COVID-19) pandemic, growing evidence indicates that COVID-19 often leads to various neurological disorders, but there are few reports of an association between COVID-19 and BBE. Here we report a case of TCM associated with BBE triggered by COVID-19, which subsided with immunotherapy for BBE. Both transthoracic echocardiography and electrocardiography led to early and accurate diagnosis of TCM. Sustained hemodynamic instability due to TCM was immediately lessened with immunotherapy whereas additional plasmapheresis and immunotherapy were required to treat BBE. This case indicates that BBE might follow COVID-19 and TCM should be considered when hemodynamic status remains unstable in a patient with BBE.

DOI： 10.3389/fneur.2021.822247

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記述言語：英語  

Here we report three cases of anti-myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) mimicking multiple sclerosis in which seropositivity for anti-MOG antibodies occurred during disease-modifying drug dimethyl fumarate (DMF) treatment. These patients developed relapses with anti-MOG antibody seroconversion after switching from fingolimod or steroid pulse therapy to DMF, which was associated with peripheral lymphocyte recovery. MOGAD is considered a humoral immune disease, and DMF reportedly enhances Th2-skewed humoral immune activity. Therefore, we suggest that DMF, but not fingolimod, may exacerbate humoral immune imbalance and enhance autoantibody production, leading to aggravation of MOGAD.

DOI： 10.3389/fimmu.2021.625465

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Oculopharyngodistal myopathy (OPDM) is a rare hereditary muscle disease characterized by progressive distal limb weakness, ptosis, ophthalmoplegia, bulbar muscle weakness and rimmed vacuoles on muscle biopsy. Recently, CGG repeat expansions in the noncoding regions of two genes, LRP12 and GIPC1, have been reported to be causative for OPDM. Furthermore, neuronal intranuclear inclusion disease (NIID) has been recently reported to be caused by CGG repeat expansions in NOTCH2NLC. We aimed to identify and to clinicopathologically characterize patients with OPDM who have CGG repeat expansions in NOTCH2NLC (OPDM_NOTCH2NLC). Note that 211 patients from 201 families, who were clinically or clinicopathologically diagnosed with OPDM or oculopharyngeal muscular dystrophy, were screened for CGG expansions in NOTCH2NLC by repeat primed-PCR. Clinical information and muscle pathology slides of identified patients with OPDM_NOTCH2NLC were re-reviewed. Intra-myonuclear inclusions were evaluated using immunohistochemistry and electron microscopy (EM). Seven Japanese OPDM patients had CGG repeat expansions in NOTCH2NLC. All seven patients clinically demonstrated ptosis, ophthalmoplegia, dysarthria and muscle weakness; they myopathologically had intra-myonuclear inclusions stained with anti-poly-ubiquitinated proteins, anti-SUMO1 and anti-p62 antibodies, which were diagnostic of NIID (typically on skin biopsy), in addition to rimmed vacuoles. The sample for EM was available only from one patient, which demonstrated intranuclear inclusions of 12.6 ± 1.6 nm in diameter. We identified seven patients with OPDM_NOTCH2NLC. Our patients had various additional central and/or peripheral nervous system involvement, although all were clinicopathologically compatible; thus, they were diagnosed as having OPDM and expanding a phenotype of the neuromyodegenerative disease caused by CGG repeat expansions in NOTCH2NLC.

DOI： 10.1186/s40478-020-01084-4

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記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We herein report a 33-year-old woman who was an asymptomatic hepatitis B virus (HBV) carrier and presented with distal muscle weakness in the legs and asymmetrical paresthesia in the distal extremities. A nerve biopsy specimen revealed fibrinoid necrosis associated with inflammatory infiltration in the perineural space, and deposition of hepatitis B core antigen and C4d complement was detected in the vascular endothelial cells as well as around the vessels. She was diagnosed with HBV-related vasculitic neuropathy and treated with intravenous immunoglobulin (IVIG). Her symptoms completely subsided after eight weeks. Vasculitic neuropathy rarely develops in the chronic inactive stages of HBV infection. This is the first report of an HBV-inactive carrier with vasculitic neuropathy successfully treated with IVIG.

DOI： 10.2169/internalmedicine.4498-20

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Variants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear. METHODS: We examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail. RESULTS: Pathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly. CONCLUSIONS: Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.

DOI： 10.1136/jmedgenet-2020-106896

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Variants of CACNA1G, which encodes CaV3.1, have been reported to be associated with various neurological disorders. METHODS: Whole-exome sequencing of genomic DNA from 348 Japanese patients with neurodevelopmental disorders and their parents was conducted, and de novo variants of CACNA1G were extracted. The electrophysiological properties of each mutant channel were investigated by voltage-clamp and current-clamp analyses of HEK293T cells overexpressing these channels. RESULTS: Two patients diagnosed with Rett syndrome and West syndrome were found to have known pathological CACNA1G mutations reported in cerebellar ataxia cohorts: c.2881G > A, p.Ala961Thr and c.4591A > G, p.Met1531Val, respectively. One patient with Lennox-Gastaut syndrome was revealed to harbor a previously unreported heterozygous variant: c.3817A > T, p.Ile1273Phe. Clinical symptoms of the two patients with known mutations included severe developmental delay without acquisition of the ability to walk independently. The patient with a potentially novel mutation showed developmental delay, intractable seizures, and mild cerebral atrophy on MRI, but the severity of symptoms was milder than in the former two cases. Electrophysiological study using HEK293T cells demonstrated significant changes of T-type Ca2+ currents by p.Ala961Thr and p.Met1531Val SNVs, which were likely to enhance oscillation of membrane potential at low frequencies. In contrast, p.Ile1273Phe showed no significant effects in our electrophysiological evaluations, with its pathogenesis remaining undetermined. CONCLUSION: De novo variants of CACNA1G explain some neurodevelopmental disorders. Our study further provides information to understand the genotype-phenotype correlations of patients with CACNA1G mutations.

DOI： 10.1016/j.jns.2020.117047

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記述言語：英語  

DOI： 10.1002/ana.25819

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

It remains controversial whether circulating monocytes expressing CCR2 infiltrate the central nervous system (CNS) and contribute to pathogenicity of amyotrophic lateral sclerosis (ALS). A previous report used conventional immunohistochemistry to show that CCR2 is exclusively expressed by astrocytes, but not infiltrating monocytes/microglia or neurons, in the spinal cords of ALS model mice. In this study, we assessed the cellular distribution of CCR2 in the CNS of ALS mice using CCR2-reporter mice (Ccr2rfp/+-Cx3cr1gfp/+-SOD1G93A Tg mice), a more sophisticated method for directly detecting the distribution of CCR2 protein. We found that infiltration of CCR2+ monocytes in the lumbar spinal cord increased over the course of disease progression. Moreover, from the middle stage of disease, CCR2 was partially distributed in microglia and neurons, but not astrocytes, in striking contrast to the previous findings. These novel observations suggested that CCR2+ monocyte infiltration leads to CNS environmental deterioration due to toxic conversion of microglia and neurons, creating a vicious cycle of neuroinflammation and leading to acceleration of ALS pathology. Our findings also show that this reporter mouse is a useful and powerful tool for obtaining new insights into the pathomechanisms of ALS.

DOI： 10.1186/s13041-020-00607-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recently, a recessively inherited intronic repeat expansion in replication factor C1 (RFC1) was identified in cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Here, we describe a Japanese case of genetically confirmed CANVAS with autonomic failure and auditory hallucination. The case showed impaired uptake of iodine-123-metaiodobenzylguanidine and 123I-ioflupane in the cardiac sympathetic nerve and dopaminergic neurons, respectively, by single-photon emission computed tomography. Long-read sequencing identified biallelic pathogenic (AAGGG)n nucleotide repeat expansion in RFC1 and heterozygous benign (TAAAA)n and (TAGAA)n expansions in brain expressed, associated with NEDD4 (BEAN1). Enrichment of the repeat regions in RFC1 and BEAN1 using a Cas9-mediated system clearly distinguished between pathogenic and benign repeat expansions. The haplotype around RFC1 indicated that the (AAGGG)n expansion in our case was on the same ancestral allele as that of European cases. Thus, long-read sequencing facilitates precise genetic diagnosis of diseases with complex repeat structures and various expansions.

DOI： 10.1038/s10038-020-0733-y

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記述言語：英語  

Chronic tonsillitis has been attracted attention as a source of abnormal immune responses and a possible trigger of autoimmune diseases such as IgA nephritis, IgA vasculitis, palmoplantar pustulosis, psoriasis, rheumatoid arthritis, Behçet's disease, and myositis. Here we present the first report of anti-signal recognition particle antibody-associated necrotizing myopathy (anti-SRP myopathy) with IgA nephropathy and chronic tonsillitis in which the therapeutic response to intravenous immunoglobulin (IVIG) treatment was dramatically improved after tonsillectomy and accompanied by a rapid increase in ΔIgG, defined as the change in serum IgG levels 2 weeks after the start of IVIG treatment relative to pre-treatment levels. Moreover, serum anti-SRP antibody titers became undetectable after tonsillectomy even though the resected tonsils did not produce anti-SRP antibodies. Tonsillectomy should be considered when chronic tonsillitis is observed in patients with autoimmune diseases showing poor response to treatment, including anti-SRP myopathy.

DOI： 10.3389/fimmu.2020.595480

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Leukoencephalopathies comprise a broad spectrum of disorders, but the genetic background of adult leukoencephalopathies has rarely been assessed. In this study, we analyzed 101 Japanese patients with genetically unresolved adult leukoencephalopathy using whole-exome sequencing and repeat-primed polymerase chain reaction for detecting GGC expansion in NOTCH2NLC. NOTCH2NLC was recently identified as the cause of neuronal intranuclear inclusion disease. We found 12 patients with GGC expansion in NOTCH2NLC as the most frequent cause of adult leukoencephalopathy followed by NOTCH3 variants in our cohort. Furthermore, we found 1 case with de novo GGC expansion, which might explain the underlying pathogenesis of sporadic cases. ANN NEUROL 2019;86:962-968.

DOI： 10.1002/ana.25586

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: We encountered two unrelated individuals suffering from neurological disorders, including epilepsy and scoliosis. CASE PRESENTATION: Whole-exome sequencing identified the same recurrent, de novo, pathogenic variant in NUS1 [NM_138459.4:c.691 + 1C > A] in both individuals. This variant is located in the conserved cis-prenyltransferase domain of the nuclear undecaprenyl pyrophosphate synthase 1 gene (NUS1), which encodes the Nogo-B receptor, an essential catalyst for protein glycosylation. This variant was confirmed to create a new splice donor site, resulting in aberrant RNA splicing resulting in a 91-bp deletion in exon 3 in both individuals. The mutant mRNA was partially degraded by nonsense mediated mRNA decay. To date, only four de novo variants and one homozygous variant have been reported in NUS1, which cause developmental and epileptic encephalopathy, early onset Parkinson's disease, and a congenital disorder of glycosylation. Seven patients, including our two patients, have presented with epileptic seizures and intellectual disabilities. CONCLUSIONS: Our study strongly supports the finding that this recurrent, de novo, variant in NUS1 causes developmental and epileptic encephalopathy with involuntary movement, ataxia and scoliosis.

DOI： 10.1186/s12883-019-1489-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Exosomes contain many proteins associated with neurodegenerative diseases. To identify new candidate biomarkers and proteins associated with amyotrophic lateral sclerosis (ALS), we performed liquid chromatography-tandem mass spectrometry proteomic analysis of exosome-enriched fractions isolated from cerebrospinal fluid (CSF) of sporadic ALS patients using gel filtration chromatography. Proteomic data revealed that three proteins were increased and 11 proteins were decreased in ALS patients. The protein with the greatest increase in exosome-enriched fractions of CSF derived from ALS was novel INHAT repressor (NIR), which is closely associated with nucleolar function. By immunohistochemical analysis, we found that NIR was reduced in the nucleus of motor neurons in ALS patients. Our results demonstrate the potential utility of our methodology for proteomic analysis of CSF exosomes and suggest that nucleolar stress might play a role in sporadic ALS pathogenesis through the dysfunction of NIR.

DOI： 10.1016/j.neures.2019.10.010

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記述言語：英語  

DOI： 10.1212/CPJ.0000000000000599

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Spinocerebellar ataxia 42 (SCA42) is a neurodegenerative disorder recently shown to be caused by c.5144G > A (p.Arg1715His) mutation in CACNA1G, which encodes the T-type voltage-gated calcium channel CaV3.1. Here, we describe a large Japanese family with SCA42. Postmortem pathological examination revealed severe cerebellar degeneration with prominent Purkinje cell loss without ubiquitin accumulation in an SCA42 patient. To determine whether this mutation causes ataxic symptoms and neurodegeneration, we generated knock-in mice harboring c.5168G > A (p.Arg1723His) mutation in Cacna1g, corresponding to the mutation identified in the SCA42 family. Both heterozygous and homozygous mutants developed an ataxic phenotype from the age of 11-20 weeks and showed Purkinje cell loss at 50 weeks old. Degenerative change of Purkinje cells and atrophic thinning of the molecular layer were conspicuous in homozygous knock-in mice. Electrophysiological analysis of Purkinje cells using acute cerebellar slices from young mice showed that the point mutation altered the voltage dependence of CaV3.1 channel activation and reduced the rebound action potentials after hyperpolarization, although it did not significantly affect the basic properties of synaptic transmission onto Purkinje cells. Finally, we revealed that the resonance of membrane potential of neurons in the inferior olivary nucleus was decreased in knock-in mice, which indicates that p.Arg1723His CaV3.1 mutation affects climbing fiber signaling to Purkinje cells. Altogether, our study shows not only that a point mutation in CACNA1G causes an ataxic phenotype and Purkinje cell degeneration in a mouse model, but also that the electrophysiological abnormalities at an early stage of SCA42 precede Purkinje cell loss.

DOI： 10.1016/j.nbd.2019.104516

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 24-year-old Japanese man exhibited slowly progressive gait disturbance from childhood to young adulthood. Physical and physiological examinations showed the involvement of both upper and lower motor neurons, fulfilling the diagnostic criteria for amyotrophic lateral sclerosis (ALS). Mild cognitive impairment and subclinical sensory involvement were also observed. A genetic analysis revealed novel compound heterozygous mutations, c.767C>T (p.Thr256Ile) and c.800A>G (p.Asp267Gly), in the vaccinia-related kinase 1 gene (VRK1). This is the first report of a Japanese patient with a motor neuron disease phenotype caused by VRK1 mutations. This diagnosis should be considered in atypical cases of juvenile-onset and slowly progressive types of motor neuron disease.

DOI： 10.2169/internalmedicine.2126-18

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions in neuronal and somatic cells. The wide range of clinical manifestations in NIID makes ante-mortem diagnosis difficult1-8, but skin biopsy enables its ante-mortem diagnosis9-12. The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases. By linkage mapping of a large NIID family with several affected members (Family 1), we identified a 58.1 Mb linked region at 1p22.1-q21.3 with a maximum logarithm of the odds score of 4.21. By long-read sequencing, we identified a GGC repeat expansion in the 5' region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members. Furthermore, we found similar expansions in 8 unrelated families with NIID and 40 sporadic NIID cases. We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals. This work shows that repeat expansion in human-specific NOTCH2NLC, a gene that evolved by segmental duplication, causes a human disease.

DOI： 10.1038/s41588-019-0459-y

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記述言語：英語  

Fingolimod acts as a functional antagonist of the sphingosine-1-phosphate receptor and is widely used for relapsing-remitting multiple sclerosis (MS). Here we report the first case of non-traumatic acute epidural hematoma in a relapsing-remitting MS patient treated with fingolimod. Fingolimod might increase the risk of hemorrhage by enhancing vasospasm and causing vascular disruption. Switching fingolimod to other disease-modifying drugs, including dimethyl fumarate, should be considered when non-traumatic hemorrhage is observed in MS patients.

DOI： 10.3389/fneur.2019.00763

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Approximately 5% of cerebral small vessel diseases are hereditary, which include COL4A1/COL4A2-related disorders. COL4A1/COL4A2 encode type IV collagen α1/2 chains in the basement membranes of cerebral vessels. COL4A1/COL4A2 mutations impair the secretion of collagen to the extracellular matrix, thereby resulting in vessel fragility. The diagnostic yield for COL4A1/COL4A2 variants is around 20 to 30%, suggesting other mutated genes might be associated with this disease. This study aimed to identify novel genes that cause COL4A1/COL4A2-related disorders. METHODS: Whole exome sequencing was performed in 2 families with suspected COL4A1/COL4A2-related disorders. We validated the role of COLGALT1 variants by constructing a 3-dimensional structural model, evaluating collagen β (1-O) galactosyltransferase 1 (ColGalT1) protein expression and ColGalT activity by Western blotting and collagen galactosyltransferase assays, and performing in vitro RNA interference and rescue experiments. RESULTS: Exome sequencing demonstrated biallelic variants in COLGALT1 encoding ColGalT1, which was involved in the post-translational modification of type IV collagen in 2 unrelated patients: c.452 T > G (p.Leu151Arg) and c.1096delG (p.Glu366Argfs*15) in Patient 1, and c.460G > C (p.Ala154Pro) and c.1129G > C (p.Gly377Arg) in Patient 2. Three-dimensional model analysis suggested that p.Leu151Arg and p.Ala154Pro destabilized protein folding, which impaired enzymatic activity. ColGalT1 protein expression and ColGalT activity in Patient 1 were undetectable. RNA interference studies demonstrated that reduced ColGalT1 altered COL4A1 secretion, and rescue experiments showed that mutant COLGALT1 insufficiently restored COL4A1 production in cells compared with wild type. INTERPRETATION: Biallelic COLGALT1 variants cause cerebral small vessel abnormalities through a common molecular pathogenesis with COL4A1/COL4A2-related disorders. Ann Neurol 2018;84:843-853.

DOI： 10.1002/ana.25367

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Steroid pulse therapy with methylprednisolone (mPSL) succinate ester is the most common treatment for neuromyelitis optica (NMO); no cases of anaphylaxis have been reported to date. Here, we report two cases of anaphylactic shock induced by mPSL pulse therapy in patients with NMO and concurrent systemic lupus erythematosus. Both patients had received several courses of mPSL pulse therapy without any problems previously. Repeated mPSL pulse therapy and comorbid humoral autoimmune disease might increase the risk of anaphylaxis. Corticosteroids without succinate esters should be considered as an alternative therapy to prevent anaphylaxis.

DOI： 10.1177/1352458518763099

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Spinocerebellar ataxia type 21 (SCA21) is a rare subtype of autosomal dominant cerebellar ataxias, which was first identified in a French family and has been reported almost exclusively in French ancestry so far. We here report the first Japanese family with SCA21, in which all affected members examined carried a heterozygous c.509C > T:p.Pro170Leu variant in TMEM240. Their clinical features were summarized as a slowly progressive ataxia of young-adult onset (5-48 years) associated with various degree of psychomotor retardation or cognitive impairment. The MR images revealed atrophy in the cerebellum, but not in the cerebrum or brainstem. These clinical findings were consistent with those in the original French families with SCA21. Neuropathological findings in one autopsied patient showed a prominent decrease of cerebellar Purkinje cells, but no specific abnormalities outside the cerebellum.

DOI： 10.1007/s12311-018-0941-6

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/cge.13371

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cge.13371

掲載種別：研究論文（学術雑誌）  

© 2018 Japanese Society for Neuroimmunology Immune-mediated necrotizing myopathy associated with anti-signal recognition particle antibodies (anti-SRP myopathy) is representative of several subtypes of necrotizing immune-mediated myopathy, and is characterized by rapidly progressive proximal muscle weakness, dysphagia and poor responsiveness to conventional immunosuppressive therapies. We report a 71-year-old man who developed anti-SRP myopathy followed by malignant lymphoma, and whose condition dramatically improved with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone therapy. He showed progressive proximal muscle weakness with severe dysphagia, and was diagnosed with anti-SRP myopathy by antibody tests and pathological examination. He was treated with conventional immunosuppressive therapies, specifically corticosteroids, intravenous immunoglobulin and tacrolimus; however, none of these therapies were effective. Two months after starting tacrolimus, the patient developed intravascular large B-cell lymphoma, which was suspected to be an iatrogenic immunodeficiency-associated lymphoproliferative disorder. Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone therapy resulted in not only complete remission of lymphoma, but also dramatic improvement of anti-SRP myopathy. The present case suggests that rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone therapy is a potential treatment for anti-SRP myopathy.

DOI： 10.1111/cen3.12469

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掲載種別：研究論文（学術雑誌）  

Background: Dimethyl fumarate (DMF) was the second oral disease-modifying drug to be approved for multiple sclerosis (MS) in Japan, after fingolimod. Switching from fingolimod to DMF treatment is becoming increasingly common, because DMF has shown a better risk–benefit profile and an equivalent efficacy to fingolimod. Case presentation: We report a 35-year-old woman who was positive for anti-John Cunningham virus antibody and who developed severe rebound relapse of MS after switching from fingolimod to DMF. Five months after starting DMF treatment, she had a severe relapse attack with disseminated lesions in the cerebrum and cervical spinal cord. Furthermore, subsequent relapse attacks occurred with new lesions in the thoracic spinal cord, even during repeated steroid pulse therapies and plasma exchanges. The disease activity finally ceased after natalizumab administration. Conclusions: Switching from fingolimod to DMF carries the risk of MS reactivation and rebound. Natalizumab treatment for a limited period might be recommended to treat MS rebound in anti-John Cunningham virus antibody-positive patients.

DOI： 10.1111/cen3.12470

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記述言語：英語  

DOI： 10.1111/cge.13369

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記述言語：英語  

DOI： 10.1002/mdc3.12614

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Autosomal recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous neurological disorders. Through whole-exome sequencing of Japanese ARCA patients, we identified three index patients from unrelated families who had biallelic mutations in ERCC4. ERCC4 mutations have been known to cause xeroderma pigmentosum complementation group F (XP-F), Cockayne syndrome, and Fanconi anemia phenotypes. All of the patients described here showed very slowly progressive cerebellar ataxia and cognitive decline with choreiform involuntary movement, with young adolescent or midlife onset. Brain MRI demonstrated atrophy that included the cerebellum and brainstem. Of note, cutaneous symptoms were very mild: there was normal to very mild pigmentation of exposed skin areas and/or an equivocal history of pathological sunburn. However, an unscheduled DNA synthesis assay of fibroblasts from the patient revealed impairment of nucleotide excision repair. A similar phenotype was very recently recognized through genetic analysis of Caucasian cerebellar ataxia patients. Our results confirm that biallelic ERCC4 mutations cause a cerebellar ataxia-dominant phenotype with mild cutaneous symptoms, possibly accounting for a high proportion of the genetic causes of ARCA in Japan, where XP-F is prevalent.

DOI： 10.1038/s10038-017-0408-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although inflammation in the central nervous system is responsible for multiple neurological diseases, the lack of appropriate biomarkers makes it difficult to evaluate inflammatory activities in these diseases. Therefore, a new biomarker reflecting neuroinflammation is required for accurate diagnosis, appropriate therapy, and comprehension of pathogenesis of these neurological disorders. We previously reported that the cerebrospinal fluid (CSF) concentration of lateral olfactory tract usher substance (LOTUS), which promotes axonal growth as a Nogo receptor 1 antagonist, negatively correlates with disease activity in multiple sclerosis, suggesting that variation in LOTUS reflects the inflammatory activities and is a useful biomarker to evaluate the disease activity. To extend this observation, we analyzed the variation of LOTUS in the CSF of patients with bacterial and viral meningitis, which are the most common neuroinflammatory diseases. METHODS: CSF samples were retrospectively obtained from patients with meningitis (n = 40), who were followed up by CSF study at least twice, and from healthy controls (n = 27). Patients were divided into bacterial (n = 14) and viral meningitis (n = 18) after exclusion of eight patients according to the criteria of this study. LOTUS concentrations, total protein levels, and CSF cell counts in the acute and recovery phases were analyzed chronologically. We also used lipopolysaccharide-injected mice as a model of neuroinflammation to evaluate LOTUS mRNA and protein expression in the brain. RESULTS: Regardless of whether meningitis was viral or bacterial, LOTUS concentrations in the CSF of patients in acute phase were lower than those of healthy controls. As the patients recovered from meningitis, LOTUS levels in the CSF returned to the normal range. Lipopolysaccharide-injected mice also exhibited reduced LOTUS mRNA and protein expression in the brain. CONCLUSIONS: CSF levels of LOTUS correlated inversely with disease activity in both bacterial and viral meningitis, as well as in multiple sclerosis, because neuroinflammation downregulated LOTUS expression. Our data strongly suggest that variation of CSF LOTUS is associated with neuroinflammation and is useful as a biomarker for a broader range of neuroinflammatory diseases.

DOI： 10.1186/s12974-018-1084-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: In dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD), it is still debated whether white matter hyperintensities (WMH) on MRI reflect atherosclerotic cerebrovascular changes or Alzheimer's disease (AD)-related pathology such as cerebral amyloid angiopathy. To examine AD-related pathology in DLB and PDD, we compared the severity of WMH and medial temporal lobe atrophy among patients with DLB, PDD, non-demented PD (PDND), and AD. METHODS: We retrospectively studied sex- and age-matched outpatients with AD, DLB, PDD, and PDND, as well as subjects without central nervous system disorders as normal controls (n=50 each). All subjects underwent 1.5-T MRI examinations, and WMH detected by T2-weighted images or fluid-attenuated inversion recovery images were semiquantified according to the Fazekas method. Medial temporal lobe atrophy (MTA) was visually assessed by the MTA score. RESULTS: WMH were more prominent in AD, DLB, and PDD patients than in PDND patients and normal controls (NCs). DLB as well as AD showed more severe WMH than PDD. Visual assessment of medial temporal lobe atrophy showed that AD patients had the most severe atrophy, followed by DLB, PDD, and PDND patients, and NC subjects in that order. MTA scores showed significant correlations with WMH severity. CONCLUSION: Our results indicated that DLB was more similar to AD than to PDD in terms of MRI findings, suggesting that WMH in DLB may reflect mainly AD-related pathology rather than atherosclerotic cerebrovascular changes.

DOI： 10.1016/j.jns.2017.12.018

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Mutations in the MATR3 gene have been identified as a cause of familial amyotrophic lateral sclerosis, but involvement of the matrin 3 (MATR3) protein in sporadic amyotrophic lateral sclerosis (SALS) pathology has not been fully assessed. We immunohistochemically analyzed MATR3 pathology in the spinal cords of SALS and control autopsy specimens. MATR3 immunostaining of the motor neuron nuclei revealed two distinct patterns: mild and strong staining. There were no differences in the ratio of mild versus strong nuclear staining between the SALS and control cases. MATR3-containing neuronal cytoplasmic inclusions (NCIs) were observed in 60% of SALS cases. Most motor neurons with MATR3-positive NCIs exhibited a mild nuclear staining pattern. Although 16.8% of NCIs positive for transactivating response region DNA-binding protein 43 (TDP-43) were estimated as double-labeled by MATR3, no MATR3-positive or TDP-43-negative NCIs were observed. Although a previous study found that MATR3-positive NCIs are present only in cases with C9orf72 hexanucleotide repeat expansion, ubiquitin-positive granular NCIs were not observed in the cerebellum, which have been reported as specific to C9orf72-related ALS. Six ALS cases were confirmed to be negative for the GGGGCC hexanucleotide. Our results reveal that MATR3 is a component of TDP-43-positive NCIs in motor neurons, even in SALS, and indicate the broader involvement of MATR3 in ALS pathology and the heterogeneity of TDP-43-positive NCIs.

DOI： 10.1016/j.ajpath.2017.10.007

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記述言語：日本語   出版者・発行元：認知神経科学会  

DOI： 10.11253/ninchishinkeikagaku.20.89_2

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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  

The axon initial segment (AIS) is a specialized domain essential for neuronal function, the formation of which begins with localization of an ankyrin-G (AnkG) scaffold. However, the mechanism directing and maintaining AnkG localization is largely unknown. In this study, we demonstrate that in vivo knockdown of microtubule cross-linking factor 1 (MTCL1) in cerebellar Purkinje cells causes loss of axonal polarity coupled with AnkG mislocalization. MTCL1 lacking MT-stabilizing activity failed to restore these defects, and stable MT bundles spanning the AIS were disorganized in knockdown cells. Interestingly, during early postnatal development, colocalization of MTCL1 with these stable MT bundles was observed prominently in the axon hillock and proximal axon. These results indicate that MTCL1-mediated formation of stable MT bundles is crucial for maintenance of AnkG localization. We also demonstrate that Mtcl1 gene disruption results in abnormal motor coordination with Purkinje cell degeneration, and provide evidence suggesting possible involvement of MTCL1 dysfunction in the pathogenesis of spinocerebellar ataxia.

DOI： 10.15252/embj.201695630

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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：NATURE PUBLISHING GROUP  

FUS/TLS is an RNA/DNA-binding protein associated with neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Previously, we found that a prion-like domain in the N-terminus of FUS/TLS mediates co-aggregation between FUS/TLS and mutant huntingtin, the gene product of Huntington's disease (HD). Here, we show that heterozygous knockout of FUS/TLS worsened the phenotypes of model mice of (HD, but not spinal and bulbar muscular atrophy (SBMA). This difference was correlated with the degree of pathological association between disease proteins and FUS/ TLS. Co-aggregation between FUS/TLS and mutant huntingtin resulted in the depletion of free FUS/TLS protein in HD mice that was detected as a monomer in SDS-PAGE analysis. Recently, we found that FUS/ TLS paralogs, TAF15 and EWS, were up-regulated in homozygous FUS/TLS knockout mice. These two proteins were up-regulated in both HD and FUS/TLS heterozygote mice, and were further elevated in HD-TLS+/- double mutant mice, consistent with the functional impairment of FUS/TLS. These results suggest that FUS/TLS sequestration by co-aggregation is a rate-limiting factor of disease phenotypes of HD and that inclusions may have an adverse aspect, rather than being simply benign or protective. In addition, our results highlight inclusions as repositories of potential modifiers of neurodegeneration.

DOI： 10.1038/srep35236

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Recent new sequencing techniques allow the identification of novel responsible genes for autosomal recessive spinocerebellar ataxias (ARCAs). However, the same phenotypes are sometimes attributed to the different responsible genes in ARCAs. On the contrary, the same responsible genes may cause heterogeneous phenotypes with respect to the age at onset, symptoms, and the severity of the disease progression. In addition, it is an important issue to clarify whether the gene mutations identified in Caucasian patients with infantile-onset ARCAs are also observed in Japanese patients with adult-onset ARCAs. In this article we review the characteristics of several ARCAs, the existence of which has been recently identified or confirmed in Japan.

DOI： 10.5692/clinicalneurol.cn-000879

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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：SPRINGER HEIDELBERG  

The aim of this study was to analyze the pattern of magnetic resonance diffusion-weighted imaging (DWI) findings in status epilepticus in terms of clinical characteristics. Participants comprised 106 patients with status epilepticus who were admitted to our hospital and underwent DWI. Forty-five patients (42.5 %) showed abnormal findings on DWI and were divided into two groups, comprising 26 patients (24.5 %) with cortex lesions alone and 19 patients (17.9 %) with cortex and pulvinar lesions in the same hemisphere. A long duration of status epilepticus (&gt; 120 min) tended to be more prevalent among patients with cortex and pulvinar lesions (57.9 %) than among patients with cortex lesions alone (30.8 %) by univariate and multivariate analyses. Todd's palsy tended to be more frequent in patients with abnormalities on DWI (24/45, 53.3 %) than in patients with normal DWI (21/61, 34.4 %). Six of the 26 patients with cortex lesions alone (23.1 %) had taken anti-epileptic drugs before the attack compared to none of the 19 patients with both cortex and pulvinar lesions. The trend toward a longer duration of status epilepticus in patients with both cortex and pulvinar lesions favors a spreading pattern of seizure discharge from cortex to pulvinar via cortico-pulvinar pathways, and anti-epileptic drugs might, to some extent, prevent spreading of seizure discharge from cortex to pulvinar. In addition, existence of high-intensity areas on DWI at the onset of epilepsy may be a predictive factor for the occurrence of Todd's palsy.

DOI： 10.1007/s00415-015-7948-4

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記述言語：英語   出版者・発行元：NATURE PUBLISHING GROUP  

DOI： 10.1038/jhg.2015.86

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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：AMER MEDICAL ASSOC  

IMPORTANCE Although mutations in 26 causative genes have been identified in the spinocerebellar ataxias (SCAs), the causative genes in a substantial number of families with SCA remain unidentified.
OBJECTIVE To identify the causative gene of SCA in 2 Japanese families with distinct neurological symptoms and radiological presentations.
DESIGN, SETTING, AND PARTICIPANTS Clinical genetic study at a referral center of 11 members from 2 Japanese families, which started in 1997.
MAIN OUTCOMES AND MEASURES Results of neurological examinations and radiological evaluations. The causative mutation was identified using genome-wide linkage analysis and next-generation sequencing.
RESULTS Affected members (9 of 11 members [81.8%]) showed slowly progressive cerebellar ataxia (all 9 members [100%]), ocular movement disturbance (all 9 members [100%]), and pyramidal tract signs (8 of 9 members [88.9%]) with an age at onset between the second and sixth decades of life. Besides cerebellar and pontine atrophy, magnetic resonance imaging of the brain revealed the hot cross bun sign (4 of 6 members [66.7%]), pontine midline linear hyperintensity (2 of 6 members [33.3%]), or high intensity in the middle cerebellar peduncle (1 of 6 members [16.7%]), which are all reminiscent of multiple system atrophy in tested patients. Using linkage analysis combined with exome and whole-genome sequencing, we identified a novel heterozygous mutation in the ELOVL fatty acid elongase 4 (ELOVL4) gene (c.736T&gt;G, p.W246G) in both families. Haplotype analysis indicated that it was unlikely that these 2 Japanese families shared a common ancestor. Although a missense mutation in ELOVL4 (c.504G&gt;C, p.L168F) was recently reported to be associated with SCA with erythrokeratodermia variabilis (SCA34) in a French-Canadian family, signs of erythrokeratodermia variabilis were absent in our families.
CONCLUSIONS AND RELEVANCE Combined with the results of the family with SCA34 reported previously, this report confirms that mutations in ELOVL4 can cause dominantly inherited neurodegeneration severely affecting the cerebellum and brainstem. We should be aware that the presence of multiple system atrophy-like features on magnetic resonance imaging scans, together with cerebellar and brainstem atrophy, suggests SCA34, even when erythrokeratodermia variabilis is absent. The present study further broadened the spectrum of the clinical presentations of SCA34 associated with mutations in ELOVL4, which is involved in the biosynthesis of very long-chain fatty acids.

DOI： 10.1001/jamaneurol.2015.0610

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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：NATURE PUBLISHING GROUP  

Mitochondrial complex III (CIII) deficiency comprises a group of complex and heterogeneous genetic disorders. TTC19 mutations constitute a rare cause of CIII deficiency and are associated with neurological disorders in childhood and adulthood. Herein, we describe a 27-year-old Japanese man with cerebellar ataxia, spastic paraparesis, loss of deep sensation, mild frontal lobe dysfunction and transient psychiatric symptoms. Brain magnetic resonance imaging showed cerebellar atrophy and bilateral high-intensity signals in the inferior olives and regions adjacent to periaqueductal gray matter, on T2-weighted images. On whole-exome sequencing, we detected a novel homozygous frameshift mutation c.157_158dup [p.Pro54Alafs* 48] in TTC19. Mitochondrial enzyme assays confirmed mild impairment of CIII enzymatic activity in lymphoblasts, which was consistent with TTC19-related CIII deficiency. His symptoms and radiological findings demonstrated an early stage or mild form of this disease, and further clarify the characteristics of patients with rare TTC19 mutations.

DOI： 10.1038/jhg.2015.7

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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：BIOMED CENTRAL LTD  

Introduction: FUS/TLS is an RNA-binding protein whose genetic mutations or pathological inclusions are associated with neurological diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and essential tremor (ET). It is unclear whether their pathogenesis is mediated by gain or loss of function of FUS/TLS.
Results: Here, we established outbred FUS/TLS knockout mice to clarify the effects of FUS/TLS dysfunction in vivo. We obtained homozygous knockout mice that grew into adulthood. Importantly, they did not manifest ALS-or ET-like phenotypes until nearly two years. Instead, they showed distinct histological and behavioral alterations including vacuolation in hippocampus, hyperactivity, and reduction in anxiety-like behavior. Knockout mice showed transcriptome alterations including upregulation of Taf15 and Hnrnpa1, while they have normal morphology of RNA-related granules such as Gems.
Conclusions: Collectively, FUS/TLS depletion causes phenotypes possibly related to neuropsychiatric and neurodegenerative conditions, but distinct from ALS and ET, together with specific alterations in RNA metabolisms.

DOI： 10.1186/s40478-015-0202-6

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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  

Objective: The clinical significance and characteristics of neuropathy caused by folate deficiency remain to be established.
Methods: We examined the clinicopathologic features of 18 consecutive patients with neuropathy caused by folate deficiency who presented with low serum folate levels but normal blood thiamine and serum cobalamin levels in the absence of chronic alcoholism.
Results: Symptoms were relatively uniform, characterized by slowly progressive polyneuropathy with predominant involvement of the lower extremities, with a tendency to manifest as sensory rather than motor neuropathy and predominant deep rather than superficial sensory loss. The electrophysiologic features were consistent with axonal neuropathy. The histopathologic features of sural nerve biopsy specimens indicated large fiber-predominant axonal loss without segmental demyelination. Although macrocytosis was found in 7 patients, only 3 patients exhibited hemoglobin levels less than 10 g/dL. During the same study period, we found 12 patients who had low blood thiamine levels but normal serum folate and cobalamin levels without chronic alcoholism. Compared with patients who had thiamine-deficiency neuropathy, patients with a folate deficiency showed significantly slower progression (p &lt; 0.01), a tendency tomanifest sensory neuropathy (p &lt; 0.05), predominant deep sensory loss (p &lt; 0.01), and preservation of biceps tendon reflexes (p &lt; 0.05).
Conclusions: Folate-deficiency neuropathy was characterized by a slowly progressive and sensory-dominant pattern, which was different from thiamine-deficiency neuropathy (i.e., beriberi neuropathy). This study demonstrates the importance of folate deficiency in the differential diagnosis of neuropathy, particularly in countries where folic acid fortification has not yet been practiced.

DOI： 10.1212/WNL.0000000000001343

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DOI： 10.1038/hgv.2015.12

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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：NATURE PUBLISHING GROUP  

Autosomal recessive cerebellar ataxias and autosomal recessive hereditary spastic paraplegias (ARHSPs) are clinically and genetically heterogeneous neurological disorders. Herein we describe Japanese siblings with a midlife-onset, slowly progressive type of cerebellar ataxia and spastic paraplegia, without intellectual disability. Using whole exome sequencing, we identified a homozygous missense mutation in DDHD2, whose mutations were recently identified as the cause of early-onset ARHSP with intellectual disability. Brain MRI of the patient showed a thin corpus callosum. Cerebral proton magnetic resonance spectroscopy revealed an abnormal lipid peak in the basal ganglia, which has been reported as the hallmark of DDHD2-related ARHSP (SPG 54). The mutation caused a marked reduction of phospholipase A(1) activity, supporting that this mutation is the cause of SPG54. Our cases indicate that the possibility of SPG54 should also be considered when patients show a combination of adult-onset spastic ataxia and a thin corpus callosum. Magnetic resonance spectroscopy may be helpful in the differential diagnosis of patients with spastic ataxia phenotype.

DOI： 10.1038/srep07132

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記述言語：英語   出版者・発行元：NATURE PUBLISHING GROUP  

DOI： 10.1038/jhg.2014.75

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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：SPRINGER  

Cerebellar and/or vermis atrophy is recognized in various types of childhood disorders with clinical and genetic heterogeneity. Although careful evaluation of clinical features and neuroimaging can lead to correct diagnosis of disorders, their diagnosis is sometimes difficult because clinical features can overlap with each other. In this study, we performed family-based whole exome sequencing of 23 families including 25 patients with cerebellar and/or vermis atrophy in childhood, who were unable to be diagnosed solely by clinical examination. Pathological mutations of seven genes were found in ten patients from nine families (9/23, 39.1 %): compound heterozygous mutations in FOLR1, C5orf42, POLG, TPP1, PEX16, and de novo mutations in CACNA1A, and ITPR1. Patient 1A with FOLR1 mutations showed extremely low concentration of 5-methyltetrahydrofolate in the cerebrospinal fluid and serum, and Patient 6 with TPP1 mutations demonstrated markedly lowered tripeptidyl peptidase 1 activity in leukocytes. Furthermore, Patient 8 with PEX16 mutations presented a mild increase of very long chain fatty acids in the serum as supportive data for genetic diagnosis. The main clinical features of these ten patients were nonspecific and mixed, and included developmental delay, intellectual disability, ataxia, hypotonia, and epilepsy. Brain MRI revealed both cerebellar and vermis atrophy in eight patients (8/10, 80 %), vermis atrophy/hypoplasia in two patients (2/10, 20 %), and brainstem atrophy in one patient (1/10, 10 %). Our data clearly demonstrate the utility of whole exome sequencing for genetic diagnosis of childhood cerebellar and/or vermis atrophy.

DOI： 10.1007/s10048-013-0375-8

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記述言語：英語   出版者・発行元：SPRINGER  

DOI： 10.1007/s00401-013-1136-3

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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  

Microphthalmia with limb anomalies (MLA), also known as Waardenburg anophthalmia syndrome or ophthalmoacromelic syndrome, is a rare autosomal recessive disorder. Recently, we and others successfully identified SMOC1 as the causative gene for MLA. However, there are several MLA families without SMOC1 abnormality, suggesting locus heterogeneity in MLA. We aimed to identify a pathogenic mutation in one Lebanese family having an MLA-like condition without SMOC1 mutation by whole-exome sequencing (WES) combined with homozygosity mapping. A c.683C&gt;T (p.Thr228Met) in FNBP4 was found as a primary candidate, drawing the attention that FNBP4 and SMOC1 may potentially modulate BMP signaling. (c) 2013 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.a.35983

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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：CELL PRESS  

Nemaline myopathy (NEM) is a common congenital myopathy. At the very severe end of the NEM clinical spectrum are genetically unresolved cases of autosomal-recessive fetal akinesia sequence. We studied a multinational cohort of 143 severe-NEM-affected families lacking genetic diagnosis. We performed whole-exome sequencing of six families and targeted gene sequencing of additional families. We identified 19 mutations in KLHL40 (kelch-like family member 40) in 28 apparently unrelated NEM kindreds of various ethnicities. Accounting for up to 28% of the tested individuals in the Japanese cohort, KLHL40 mutations were found to be the most common cause of this severe form of NEM. Clinical features of affected individuals were severe and distinctive and included fetal akinesia or hypokinesia and contractures, fractures, respiratory failure, and swallowing difficulties at birth. Molecular modeling suggested that the missense substitutions would destabilize the protein. Protein studies showed that KLHL40 is a striated-muscle-specific protein that is absent in KLHL40-associated NEM skeletal muscle. In zebrafish, klhl40a and klhl40b expression is largely confined to the myotome and skeletal muscle, and knockdown of these isoforms results in disruption of muscle structure and loss of movement. We identified KLHL40 mutations as a frequent cause of severe autosomal-recessive NEM and showed that it plays a key role in muscle development and function. Screening of KLHL40 should be a priority in individuals who are affected by autosomal-recessive NEM and who present with prenatal symptoms and/or contractures and in all Japanese individuals with severe NEM.

DOI： 10.1016/j.ajhg.2013.05.004

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記述言語：英語   出版者・発行元：WILEY-BLACKWELL  

DOI： 10.1002/mds.25296

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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  

Mitochondrial complex III (CIII) deficiency is a relatively rare disease with high clinical and genetic heterogeneity. CIII comprises 11 subunits encoded by one mitochondrial and 10 nuclear genes. Abnormalities of the nuclear genes such as BCS1L and TTC19 encoding mitochondrial assembly factors are well known, but an explanation of the majority of CIII deficiency remains elusive. Here, we report three patients from a consanguineous Mexican family presenting with neonatal onset of hypoglycemia, lactic acidosis, ketosis, and hyperammonemia. We found a homozygous missense mutation in UQCRC2 that encodes mitochondrial ubiquinolcytochrome c reductase core protein II by whole-exome sequencing combined with linkage analysis. On the basis of structural modeling, the mutation (p.Arg183Trp) was predicted to destabilize the hydrophobic core at the subunit interface of the core protein II homodimer. In vitro studies using fibroblasts from the index patient clearly indicated CIII deficiency, as well as impaired assembly of the supercomplex formed from complexes I, III, and IV. This is the first described human disease caused by a core protein abnormality in mitochondrial CIII.

DOI： 10.1002/humu.22257

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記述言語：日本語   出版者・発行元：(株)医学書院  

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2013&ichushi_jid=J04871&link_issn=&doc_id=20130311230006&doc_link_id=1390283684968595968&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390283684968595968&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_2.gif

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

Joubert syndrome (JS) and related disorders (JSRD) are autosomal recessive and X-linked disorders characterized by hypoplasia of the cerebellar vermis with a characteristic 'molar tooth sign' on brain imaging and accompanying neurological symptoms including episodic hyperpnoea, abnormal eye movements, ataxia and intellectual disability. JSRD are clinically and genetically heterogeneous, and, to date, a total of 17 causative genes are known. We applied whole-exome sequencing (WES) to five JSRD families and found mutations in all: either CEP290, TMEM67 or INPP5E was mutated. Compared with conventional Sanger sequencing, WES appears to be advantageous with regard to speed and cost, supporting its potential utility in molecular diagnosis. Journal of Human Genetics (2013) 58, 113-115; doi:10.1038/jhg.2012.117; published online 4 October 2012

DOI： 10.1038/jhg.2012.117

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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：MOLECULAR VISION  

Purpose: Congenital cataract is one of the most frequent causes of visual impairment and childhood blindness. Approximately one quarter to one third of congenital cataract cases may have a genetic cause. However, phenotypic variability and genetic heterogeneity hamper correct genetic diagnosis. In this study, we used whole-exome sequencing (WES) to identify pathogenic mutations in two Korean families with congenital cataract.
Methods: Two affected members from each family were pooled and processed for WES. The detected variants were confirmed with direct sequencing.
Results: WES readily identified a CRYAA mutation in family A and a CRYGC mutation in family B. The c.61C&gt;T (p.R21W) mutation in CRYAA has been previously reported in a family with congenital cataract and microcornea. The novel mutation, c.124delT, in CRYGC may lead to a premature stop codon (p.C42Afs*60).
Conclusions: This study clearly shows the efficacy of WES for rapid genetic diagnosis of congenital cataract with an unknown cause. WES will be the first choice for clinical services in the near future, providing useful information for genetic counseling and family planning.

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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  

Objective: Recently, COL4A1 mutations have been reported in porencephaly and other cerebral vascular diseases, often associated with ocular, renal, and muscular features. In this study, we aimed to clarify the phenotypic spectrum and incidence of COL4A1 mutations. ' Methods: We screened for COL4A1 mutations in 61 patients with porencephaly and 10 patients with schizencephaly, which may be similarly caused by disturbed vascular supply leading to cerebral degeneration, but can be distinguished depending on time of insult.
Results: COL4A1 mutations were identified in 15 patients (21%, 10 mutations in porencephaly and 5 mutations in schizencephaly), who showed a variety of associated findings, including intracranial calcification, focal cortical dysplasia, pontocerebellar atrophy, ocular abnormalities, myopathy, elevated serum creatine kinase levels, and hemolytic anemia. Mutations include 10 missense, a nonsense, a frameshift, and 3 splice site mutations. Five mutations were confirmed as de novo events. One mutation was cosegregated with familial porencephaly, and 2 mutations were inherited from asymptomatic parents. Aberrant splicing was demonstrated by reverse transcriptase polymerase chain reaction analyses in 2 patients with splice site mutations.
Interpretation: Our study first confirmed that COL4A1 mutations are associated with schizencephaly and hemolytic anemia. Based on the finding that COL4A1 mutations were frequent in patients with porencephaly and schizencephaly, genetic testing for COL4A1 should be considered for children with these conditions. ANN NEUROL 2013;73:48-57

DOI： 10.1002/ana.23736

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記述言語：日本語   出版者・発行元：(株)医学書院  

大脳皮質基底核症候群(CBS)を呈する個々の疾患、特に主たる原因疾患である前頭側頭葉変性症(FTLD)を中心に、遺伝的背景について概説した。FTLDは蓄積タンパク質からFTLD-tau、FTLD-TDP、FTLD-UPSなどに分類される。FTLD-tauではMAPT、FTLD-TDPではGRN、C9orf72、VCP、FTLD-UPSではCHMP2Bなどの遺伝子変異が報告されている。アルツハイマー病、パーキンソン病/レビー小体型認知症、クロイツフェルト・ヤコブ病についても述べた。

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2013&ichushi_jid=J04871&link_issn=&doc_id=20130121210004&doc_link_id=1390001205035288192&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390001205035288192&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

Autosomal recessive cerebellar ataxias and autosomal recessive hereditary spastic paraplegias are clinically and genetically heterogeneous disorders with diverse neurological and non-neurological features. We herein describe a Japanese patient with a slowly progressive form of ataxia and spastic paraplegia. Using whole exome sequencing, we identified a novel homozygous frameshift mutation in SPG7, encoding paraplegin, in this patient. This is the first report of an SPG7 mutation in the Japanese population. For disorders previously undetected in a particular population, or unrecognized/atypical phenotypes, exome sequencing may facilitate molecular diagnosis.

DOI： 10.2169/internalmedicine.52.0252

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Corticobasal syndrome (CBS) is associated with different pathologies including FTLD-tau (corticobasal degeneration; CBD, progressive supranuclear palsy, and Pick disease), FTLD-TDP, Alzheimer disease, Creutzfeldt-Jakob disease, and Parkinson disease/dementia with Lewy bodies. Genetic causes of CBS are also various reflecting diverse pathology. In familial and sporadic FTLD, MAPT, GRN and C9ORF72 mutations are three major causes of the disease. A part of patients harboring these mutations could exhibit CBS. In addition, the patients with TARDBP, FUS, LRRK2 or CSF1R mutations also have potential to exhibit CBS. In sporadic cases, H1 haplotype of MAPT is known to be associated with FTLD-tau, including CBS/CBD. Despite major advances in recent years, the majority of familial and sporadic CBS cases are genetically unsolved. In particular, little is known about both familial and sporadic cases of CBS in Japanese. Further studies are needed to unveil the genetic background of CBS.

DOI： 10.5692/clinicalneurol.53.1026

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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：NATURE PUBLISHING GROUP  

Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by progressive occlusion of the terminal portion of the internal carotid arteries and their branches. A genetic background was under speculation, because of the high incidence of familial occurrence. Sibling cases usually exhibit a similar clinical course. Recently, RNF213 was identified as the first MMD susceptibility gene. The c.14576G&gt;A variant of RNF213 significantly increases the MMD risk, with an odds ratio of 190.8. Furthermore, there is a strong association between clinical phenotype and the dosage of this variant. The present study described sibling MMD cases having homozygous and heterozygous c.14576G&gt;A variant in RNF213, as well as different clinical course and disease severity. The homozygote of c.14576G&gt;A variant showed an early onset age and rapid disease progress, which resulted in significant neurological deficits with severe and wide distribution of vasculopathy. In contrast, the heterozygote of the variant showed a relatively late-onset age and mild clinical course without irreversible brain lesions with limited distribution of vasculopathy. This is the first report of sibling MMD cases with different doses of the RNF213 variant, showing its genetic impact on clinical phenotype even in members with similar genetic background. Journal of Human Genetics (2012) 57, 804-806; doi:10.1038/jhg.2012.105; published online 30 August 2012

DOI： 10.1038/jhg.2012.105

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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：SPRINGER  

Whole-exome sequencing of two affected sibs and their mother who showed a unique quadriceps-dominant form of neurogenic muscular atrophy disclosed a heterozygous DYNC1H1 mutation [p.H306R (c.917A &gt; G)]. The identical mutation was recently reported in a pedigree with the axonal form of Charcot-Marie-Tooth disease. Three other missense mutations in DYNC1H1 were also identified in families with dominant spinal muscular atrophy with lower extremity predominance. Their clinical features were consistent with those of our family. Our study has demonstrated that the same DYNC1H1 mutation could cause spinal muscular atrophy as well as distal neuropathy, indicating pleotropic effects of the mutation.

DOI： 10.1007/s10048-012-0337-6

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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  

Purpose: Ohtahara syndrome (OS) is one of the most severe and earliest forms of epilepsy. STXBP1 and ARX mutations have been reported in patients with OS. In this study, we aimed to identify new genes involved in OS by copy number analysis and whole exome sequencing.
Methods: Copy number analysis and whole exome sequencing were performed in 34 and 12 patients with OS, respectively. Fluorescence in situ hybridization, quantitative polymerase chain reaction (PCR), and breakpoint-specific and reverse-transcriptase PCR analyses were performed to characterize a deletion. Immunoblotting using lymphoblastoid cells was done to examine expression of CASK protein.
Key Findings: Genomic microarray analysis revealed a 111-kb deletion involving exon 2 of CASK at Xp11.4 in a male patient. The deletion was inherited from his mother, who was somatic mosaic for the deletion. Sequencing of the mutant transcript expressed in lymphoblastoid cell lines derived from the patient confirmed the deletion of exon 2 in the mutant transcript with a premature stop codon. Whole exome sequencing identified another male patient who was harboring a c.1A&gt;G mutation in CASK, which occurred de novo. Both patients showed severe cerebellar hypoplasia along with other congenital anomalies such as micrognathia, a high arched palate, and finger anomalies. No CASK protein was detected by immuno-blotting in lymphoblastoid cells derived from two patients.
Significance: The detected mutations are highly likely to cause the loss of function of the CASK protein in male individuals. CASK mutations have been reported in patients with intellectual disability with microcephaly and pontocerebellar hypoplasia or congenital nystagmus, and those with FG syndrome. Our data expand the clinical spectrum of CASK mutations to include OS with cerebellar hypoplasia and congenital anomalies at the most severe end.

DOI： 10.1111/j.1528-1167.2012.03548.x

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記述言語：英語   出版者・発行元：WILEY-BLACKWELL  

DOI： 10.1002/ana.23620

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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：ELSEVIER SCIENCE BV  

Recent studies have shown that aberrations of CDKL5 in female patients cause early-onset intractable seizures, severe developmental delay or regression, and Rett syndrome-like features. We report on a Japanese girl with early-onset epileptic encephalopathy, hypotonia, developmental regression, and Rett syndrome-like features. The patient showed generalized tonic seizures, and later, massive myoclonus induced by phone and light stimuli. Brain magnetic resonance imaging showed no structural brain anomalies but cerebral atrophy. Electroencephalogram showed frontal dominant diffuse poly spikes and waves. Through copy number analysis by genomic microarray, we found a microdeletion at Xp22.13. A de novo 137-kb deletion, involving exons 5-21 of CDKL5, RS1, and part of PPEF1 gene, was confirmed by quantitative PCR and breakpoint specific PCR analyses. Our report suggests that the clinical features associated with CDKL5 deletions could be implicated in Japanese patients, and that genetic testing of CDKL5, including both sequencing and deletion analyses, should be considered in girls with early-onset epileptic encephalopathy and RTT-like features. (C) 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.braindev.2011.07.004

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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：SPRINGER  

Aortic aneurysm and/or dissection (AAD) is a life-threatening condition, and several syndromes are known to be related to AAD. In this study, two new technologies, resequencing array technology (ResAT) and next-generation sequencing (NGS), were used to analyze eight genes associated with syndromic AAD in 70 patients with non-syndromic AAD. Eighteen sequence variants were detected using both ResAT and NGS. In addition one of these sequence variants was detected by ResAT only and two additional variants by NGS only. Three of the 18 variants are likely to be pathogenic (in 4.3% of AAD patients and in 8.6% of a subset of patients with thoracic AAD), highlighting the importance of genetic analysis in non-syndromic AAD. ResAT and NGS similarly detected most, but not all, of the variants. Resequencing array technology was a rapid and efficient method for detecting most nucleotide substitutions, but was unable to detect short insertions/deletions, and it is impractical to update custom arrays frequently. Next-generation sequencing was able to detect almost all types of mutation, but requires improved informatics methods.

DOI： 10.1007/s00439-011-1105-7

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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  

DOI： 10.1111/j.1399-0004.2011.01733.x

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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：NATURE PUBLISHING GROUP  

By exome sequencing, we found de novo SMARCB1 mutations in two of five individuals with typical Coffin-Siris syndrome (CSS), a rare autosomal dominant anomaly syndrome. As SMARCB1 encodes a subunit of the SWItch/Sucrose NonFermenting (SWI/SNF) complex, we screened 15 other genes encoding subunits of this complex in 23 individuals with CSS. Twenty affected individuals (87%) each had a germline mutation in one of six SWI/SNF subunit genes, including SMARCB1, SMARCA4, SMARCA2, SMARCE1, ARID1A and ARID1B.

DOI： 10.1038/ng.2219

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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 and Wilkins  

Objective: RNF213 was recently reported as a susceptibility gene for moyamoya disease (MMD). Our aim was to clarify the correlation between the RNF213 genotype and MMD phenotype. Methods: The entire coding region of the RNF213 gene was sequenced in 204 patients with MMD, and corresponding variants were checked in 62 pairs of parents, 13 mothers and 4 fathers of the patients, and 283 normal controls. Clinical information was collected. Genotypephenotype correlations were statistically analyzed. Results: The c.14576G&gt
A variant was identified in 95.1% of patients with familial MMD, 79.2% of patients with sporadic MMD, and 1.8% of controls, thus confirming its association with MMD, with an odds ratio of 259 and p &lt
0.001 for either heterozygotes or homozygotes. Homozygous c.14576G&gt
A was observed in 15 patients but not in the controls and unaffected parents. The incidence rate for homozygotes was calculated to be &gt
78%. Homozygotes had a significantly earlier age at onset compared with heterozygotes or wild types (median age at onset 3, 7, and 8 years, respectively). Of homozygotes, 60% were diagnosed with MMD before age 4, and all had infarctions as the first symptom. Infarctions at initial presentation and involvement of posterior cerebral arteries, both known as poor prognostic factors for MMD, were of significantly higher frequency in homozygotes than in heterozygotes and wild types. Variants other than c.14576G&gt
A were not associated with clinical phenotypes. Conclusions: The homozygous c.14576G&gt
A variant in RNF213 could be a good DNA biomarker for predicting the severe type of MMD, for which early medical/surgical intervention is recommended, and may provide a better monitoring and prevention strategy. Copyright © 2012 by AAN Enterprises, Inc.

DOI： 10.1212/WNL.0b013e318249f71f

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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：NATURE PUBLISHING GROUP  

Sotos syndrome is characterized by prenatal and postnatal overgrowth, characteristic craniofacial features and mental retardation. Haploinsufficiency of NSD1 causes Sotos syndrome. Recently, two microdeletions encompassing Nuclear Factor I-X (NFIX) and a nonsense mutation in NFIX have been found in three individuals with Sotos-like overgrowth features, suggesting possible involvements of NFIX abnormalities in Sotos-like features. Interestingly, seven frameshift and two splice site mutations in NFIX have also been found in nine individuals with Marshall-Smith syndrome. In this study, 48 individuals who were suspected as Sotos syndrome but showing no NSD1 abnormalities were examined for NFIX mutations by high-resolution melt analysis. We identified two heterozygous missense mutations in the DNA-binding/dimerization domain of the NFIX protein. Both mutations occurred at evolutionally conserved amino acids. The c.179T &gt; C (p.Leu60Pro) mutation occurred de novo and the c.362G &gt; C (p.Arg121Pro) mutation was inherited from possibly affected mother. Both mutations were absent in 250 healthy Japanese controls. Our study revealed that missense mutations in NFIX were able to cause Sotos-like features. Mutations in DNA-binding/dimerization domain of NFIX protein also suggest that the transcriptional regulation is abnormally fluctuated because of NFIX abnormalities. In individuals with Sotos-like features unrelated to NSD1 changes, genetic testing of NFIX should be considered. Journal of Human Genetics (2012) 57, 207-211; doi:10.1038/jhg.2012.7; published online 2 February 2012

DOI： 10.1038/jhg.2012.7

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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：NATURE PUBLISHING GROUP  

Oculofaciocardiodental syndrome (OFCD) is an X-linked dominant disorder associated with male lethality, presenting with congenital cataract, dysmorphic face, dental abnormalities and septal heart defects. Mutations in BCOR (encoding BCL-6-interacting corepressor) cause OFCD. Here, we report on a Korean family with common features of OFCD including bilateral 2nd-3rd toe syndactyly and septal heart defects in three affected females (mother and two daughters). Through the mutation screening and copy number analysis using genomic microarray, we identified a novel heterozygous mutation, c.888delG, in the BCOR gene and two interstitial microduplications at Xp22.2-22.13 and Xp21.3 in all the three affected females. The BCOR mutation may lead to a premature stop codon (p.N297IfsX80). The duplication at Xp22.2-22.13 involved the NHS gene causative for Nance-Horan syndrome, which is an X-linked disorder showing similar clinical features with OFCD in affected males, and in carrier females with milder presentation. Considering the presence of bilateral 2nd-3rd toe syndactyly and septal heart defects, which is unique to OFCD, the mutation in BCOR is likely to be the major determinant for the phenotypes in this family. Journal of Human Genetics (2012) 57, 197-201; doi:10.1038/jhg.2012.4; published online 2 February 2012

DOI： 10.1038/jhg.2012.4

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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  

We report on a female patient with early infantile epileptic encephalopathy and severe psychomotor disability possessing a de novo balanced translocation t(1;9)(q32;q13). The patient showed clonic convulsions of extremities 2 days after birth. Electroencephalogram (EEG) transiently showed atypical suppression-burst pattern. The seizures evolved to brief tonic spasms, and hypsarrhythmia on EEG was noticed at age of 5 months, indicating the transition to West syndrome. By using fluorescent in situ hybridization (FISH), southern hybridization, and inverse PCR, the translocation breakpoints were successfully determined at the nucleotide level. The 1q32.1 breakpoint was located within a segmental duplication and disrupted the gene encoding Slit-Robo Rho GTPase activating protein 2 (SRGAP2). The 9q13 breakpoint was suggested to reside in the heterochromatin region. Srgap2 has been shown to be specifically expressed in developing brain of rodents, negatively regulate neuronal migration and induce neurite outgrowth and branching. Thus, SRGAP2 is very likely to play a role in the developing human brain. This is a first report of the SRGAP2 abnormality associated with early infantile epileptic encephalopathy. (C) 2011 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.a.34363

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ajhg.2011.11.016

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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：JAPAN SOC INTERNAL MEDICINE  

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an inherited neurodegenerative disorder with symptoms of spastic ataxia, neuropathy, pyramidal sign, finger and foot deformities, and hypermyelination of retinal nerve fibers. SACS is mutated in ARSACS. The clinical diversity of ARSACS is recognized, which sometimes makes its diagnosis difficult. By using homozygosity mapping, we identified a novel homozygous c.12020C &gt; T missense mutation in a consanguineous Japanese family with atypical clinical features. In addition to the absence of spasticity and hypermyelinated retinal nerve fibers, the present case had urinary dysfunction, impotence, and severe constipation, indicating the possibility of autonomic dysfunction. Furthermore, we showed the diagnostic usefulness of MRI even for the case of atypical clinical features. It had been considered that cases without obvious spasticity were very rare, however recent reports on atypical cases as well as our case indicate that ARSACS cases without obvious spasticity might be more frequent than previously thought. We should be aware of atypical features of ARSACS for the correct diagnosis.

DOI： 10.2169/internalmedicine.51.7374

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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：CELL PRESS  

Congenital hypomyelinating disorders are a heterogeneous group of inherited leukoencephalopathies characterized by abnormal myelin formation. We have recently reported a hypomyelinating syndrome characterized by diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). We performed whole-exome sequencing of three unrelated individuals with HCAHC and identified compound heterozygous mutations in POLR3B in two individuals. The mutations include a nonsense mutation, a splice-site mutation, and two missense mutations at evolutionally conserved amino acids. Using reverse transcription-PCR and sequencing, we demonstrated that the splice-site mutation caused deletion of exon 18 from POLR3B mRNA and that the transcript harboring the nonsense mutation underwent nonsense-mediated mRNA decay. We also identified compound heterozygous missense mutations in POLR3A in the remaining individual. POLR3A and POLR3B encode the largest and second largest subunits of RNA Polymerase III (Pol III), RPC1 and RPC2, respectively. RPC1 and RPC2 together form the active center of the polymerase and contribute to the catalytic activity of the polymerase. Pol III is involved in the transcription of small noncoding RNAs, such as SS ribosomal RNA and all transfer RNAs (tRNA). We hypothesize that perturbation of Pal 111 target transcription, especially of tRNAs, could be a common pathological mechanism underlying POLR3A and POLR3B mutations.

DOI： 10.1016/j.ajhg.2011.10.003

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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  

Recent studies have shown that haploinsufficiency of MEF2C causes severe intellectual disability, epilepsy, hypotonia, and cerebral malformations. We report on a female patient with severe intellectual disability, early-onset epileptic encephalopathy, and hypoplastic corpus callosum, possessing a de novo balanced translocation, t(5; 15)(q13.3;q26.1). The patient showed upward gazing and tonic seizure of lower extremities followed by generalized clonic seizures at 4 months of age. Electroencephalogram showed hypsarrhythmia when asleep. By using fluorescent in situ hybridization (FISH), southern hybridization and inverse PCR, the translocation breakpoints were determined at the nucleotide level. The 5q14.3 breakpoint was localized 121.5-kb upstream of MEF2C. The 15q26.2 breakpoint was mapped 119-kb downstream of LOC91948 non-coding RNA. We speculate that the translocation may disrupt the proper regulation of MEF2C expression in the developing brain, resulting in severe intellectual disability and early-onset epileptic encephalopathy. (C) 2011 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.a.34289

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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  

Ohtahara syndrome (OS) is one of the most severe and earliest forms of epilepsy. We have recently identified that the de novo mutations of STXBP1 are important causes for OS. Here we report a paternal somatic mosaicism of an STXBP1 mutation. The affected daughter had onset of spasms at 1 month of age, and interictal electroencephalogram showed suppression-burst pattern, leading to the diagnosis of OS. She had a heterozygous c.902+5G&gt;A mutation of STXBP1, which affects donor splicing of exon 10, resulting in 138-bp insertion of intron 10 sequences in the transcript. The mutant transcript had a premature stop codon, and was degraded by nonsense-mediated mRNA decay in lymphoblastoid cells derived from the patient. High-resolution melting analysis of clinically unaffected parental DNAs suggested that the father was somatic mosaic for the mutation, which was also suggested by sequencing. Cloning of PCR products amplified with the paternal DNA samples extracted from blood, saliva, buccal cells, and nails suggested that 5.3%, 8.7%, 11.9%, and 16.9% of alleles harbored the mutation, respectively. This is a first report of somatic mosaicism of an STXBP1 mutation, which has implications in genetic counseling of OS.

DOI： 10.1111/j.1399-0004.2010.01575.x

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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  

DOI： 10.1111/j.1399-0004.2011.01644.x

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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：B M J PUBLISHING GROUP  

Background Conventional PCR-based direct sequencing of candidate genes for a family with X-linked leucoencephalopathy with unknown aetiology failed to identify any causative mutations.
Objective To carry out exome sequencing of entire transcripts of the whole X chromosome to investigate a family with X linked leucoencephalopathy.
Methods and results Next-generation sequencing of all the transcripts of the X chromosome, after liquid-based genome partitioning, was performed on one of the two affected male subjects (the proband) and an unaffected male subject (his brother). A nonsense mutation in MCT8 (c.1102A -&gt; T (p. R368X)) was identified in the proband. Subsequent PCR-based direct sequencing of other family members confirmed the presence of this mutation, hemizygous in the other affected brother and heterozygous in the proband&apos;s mother and maternal grandmother. MCT8 mutations usually cause abnormal thyroid function in addition to neurological abnormalities, but this proband had normal thyroid function.
Conclusion Single-lane exome next-generation sequencing is sufficient to fully analyse all the transcripts of the X chromosome. This method is particularly suitable for mutation screening of X-linked recessive disorders and can avoid biases in candidate gene choice.

DOI： 10.1136/jmg.2010.083535

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We encountered a family with two boys similarly showing brain atrophy with reduced white matter, hypoplasia of the brain stem and corpus callosum, spastic paralysis, and severe growth and mental retardation without speaking a word. The phenotype of these patients was not compatible with any known type of syndromic leukodystrophy. Presuming an X-linked disorder, we performed next-generation sequencing (NGS) of the transcripts of the entire X chromosome. A single lane of exome NGS in each patient was sufficient. Six potential mutations were found in both affected boys. Two missense mutations, including c.92T&gt
C (p.V31A) in L1CAM, were potentially pathogenic, but this remained inconclusive. The other four could be excluded. Because the patients did not show adducted thumbs or hydrocephalus, the L1CAM change in this family can be interpreted as different scenarios. Personal genome analysis using NGS is certainly powerful, but interpretation of the data can be a substantial challenge requiring a lot of tasks. © 2011 John Wiley &amp
Sons A/S.

DOI： 10.1111/j.1399-0004.2011.01721.x

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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  

Systemic juvenile idiopathic arthritis (s-JIA) is a rare inflammatory disease classified as a subtype of chronic childhood arthritis, manifested by spiking fever, erythematous skin rash, pericarditis and hepatosplenomegaly. The genetic background underlying s-JIA remains poorly defined. To detect copy number variations, we performed single nucleotide polymorphism (SNP) array analysis in 50 patients with s-JIA. We found a 13-kb intragenic deletion of CASP10 in one patient. RT-PCR of the mRNA extracted from the patient's lymphoblastoid cells revealed that CASP10 mRNA was truncated. Sequencing the mRNA revealed that this deletion resulted in a frame shift with an early stop codon. CASP10 is known as a causative gene for autoimmune lymphoproliferative syndrome (ALPS) type IIa, another childhood syndrome of lymphadenopathy and splenomegaly associated with autoimmune haemolytic anaemia and thrombocytopenia. TCR alpha beta(+) CD4/CD8 double-negative T cells in the peripheral blood as a diagnostic marker of ALPS were not high in this patient and lymphocyte apoptosis induced by anti-Fas antibody was normal, denying ALPS in the patient. The father and a sister of the patient showing no symptoms of ALPS or s-JIA, also had the same deletion. Furthermore, we found no other mutations of CASP10 in the other 49 s-JIA patients. These data suggest that the pathogenic significance of CASP10 mutations should be carefully evaluated in s-JIA or even ALPS type IIa in further studies.

DOI： 10.1111/j.1744-313X.2011.01005.x

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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：CELL PRESS  

Autosomal-recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous disorders associated with diverse neurological and nonneurological features that occur before the age of 20. Currently, mutations in more than 20 genes have been identified, but approximately half of the ARCA patients remain genetically unresolved. In this report, we describe a Japanese family in which two siblings have slow progression of a type of ARCA with psychomotor retardation. Using whole-exome sequencing combined with homozygosity mapping, we identified a homozygous missense mutation in SYT14, encoding synaptotagmin XIV (SYT14). Expression analysis of the mRNA of SYT14 by a Taq Man assay confirmed that SYT14 mRNA was highly expressed in human fetal and adult brain tissue as well as in the mouse brain (especially in the cerebellum). In an in vitro overexpression system, the mutant SYT14 showed intracellular localization different from that of the wild-type. An immunohistochemical analysis clearly showed that SYT14 is specifically localized to Purkinje cells of the cerebellum in humans and mice. Synaptotagmins are associated with exocytosis of secretory vesicles (including synaptic vesicles), indicating that the alteration of the membrane-trafficking machinery by the SYT14 mutation may represent a distinct pathomechanism associated with human neurodegenerative disorders.

DOI： 10.1016/j.ajhg.2011.07.012

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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：NATURE PUBLISHING GROUP  

Systemic-onset juvenile idiopathic arthritis (s-JIA) is a rare inflammatory disease classified as a subtype of chronic childhood arthritis, manifested by spiking fever, erythematous skin rash, pericarditis and hepatosplenomegaly. The genetic background underlying s-JIA remains poorly understood. To detect disease-related copy number variations (CNVs), we performed single-nucleotide polymorphism array analysis in 50 patients with s-JIA. We detected many CNVs, but most of them were inherited from either of normal-phenotype parents. However, in one patient, we could identify two de novo microduplications at 19q13.42 with the size of 77 and 622 kb, separated by a 109-kb segment of normal copy number. The duplications encompass NLRP family (NLRP2, NLRP9 and NLRP11) as well as IL11 and HSPBP1, all of which have an important role in inflammatory pathways. These genes may significantly contribute to the pathogenesis of s-JIA. Journal of Human Genetics (2011) 56, 343-347; doi: 10.1038/jhg.2011.16; published online 17 February 2011

DOI： 10.1038/jhg.2011.16

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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：NATURE PUBLISHING GROUP  

Premature ovarian failure (POF) is a disorder characterized by amenorrhea and elevated serum gonadotropins before 40 years of age. As X chromosomal abnormalities are often recognized in POF patients, defects of X-linked gene may contribute to POF. Four cases of POF with t(X;autosome) were genetically analyzed. All the translocation breakpoints were determined at the nucleotide level. Interestingly, COL4A6 at Xq22.3 encoding collagen type IV alpha 6 was disrupted by the translocation in one case, but in the remaining three cases, breakpoints did not involve any X-linked genes. According to the breakpoint sequences, two translocations had microhomology of a few nucleotides and the other two showed insertion of 3-8 nucleotides with unknown origin, suggesting that non-homologous end-joining is related to the formation of all the translocations. Journal of Human Genetics (2011) 56, 156-160; doi: 10.1038/jhg.2010.155; published online 9 December 2010

DOI： 10.1038/jhg.2010.155

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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-LISS  

Proximal interstitial deletions involving 20q11-q12 are very rare. Only two cases have been reported. We describe another patient with 20q11.21-q12 deletion. We precisely mapped the 6.5-Mb deletion and successfully determined the deletion landmarks at the nucleotide level. Common clinical features among the three cases include developmental delay, intractable feeding difficulties with gastroesophageal reflux, and facial dysmorphism including triangular face, hypertelorism, and hypoplastic alae nasi, indicating that the 20q11.2-q12 deletion can be a clinically recognizable syndrome. This is also supported by the fact that the three deletions overlap significantly. In addition, unique features such as arthrogryposis/fetal akinesia (hypokinesia) deformation and retinal dysplasia are recognized in the patient reported herein. (C) 2011 Wiley-Liss, Inc.

DOI： 10.1002/ajmg.a.33818

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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：CELL PRESS  

Microphthalmia with limb anomalies (MLA) is a rare autosomal-recessive disorder, presenting with anophthalmia or microphthalmia and hand and/or foot malformation. We mapped the MLA locus to 14q24 and successfully identified three homozygous (one nonsense and two splice site) mutations in the SPARC (secreted protein acidic and rich in cysteine)-related modular calcium binding 1 (SMOC1) in three families. Smoc1 is expressed in the developing optic stalk, ventral optic cup, and limbs of mouse embryos. Smoc1 null mice recapitulated MLA phenotypes, including aplasia or hypoplasia of optic nerves, hypoplastic fibula and bowed tibia, and syndactyly in limbs. A thinned and irregular ganglion cell layer and atrophy of the anteroventral part of the retina were also observed. Soft tissue syndactyly, resulting from inhibited apoptosis, was related to disturbed expression of genes involved in BMP signaling in the interdigital mesenchyme. Our findings indicate that SMOC1/Smoc1 is essential for ocular and limb development in both humans and mice.

DOI： 10.1016/j.ajhg.2010.11.012

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記述言語：英語   出版者・発行元：(公社)日本生化学会  

TLS (translocated in liposarcoma), also known as FUS (fused in sarcoma), is an RNA/DNA-binding protein that plays regulatory roles in transcription, pre-mRNA splicing and mRNA transport. Mutations in TLS are responsible for familial amyotrophic lateral sclerosis (ALS) type 6. Furthermore, TLS-containing intracellular inclusions are found in polyglutamine diseases, sporadic ALS, non-SOD1 familial ALS and a subset of frontotemporal lobar degeneration, indicating a pathological significance of TLS in a wide variety of neurodegenerative diseases. Here, we identified TLS domains that determine intracellular localization of the murine TLS. Among them, PY-NLS located in the C-terminus is a strong determinant of intracellular localization as well as splicing regulation of an E1A-derived minigene. Disruption of PY-NLS promoted the formation of cytoplasmic granules that were partially overlapped with stress granules and P-bodies. Some of the ALS-linked mutations altered both intracellular localization and splicing regulation of TLS, while most mutations alone did not affect splicing regulation. However, phospho-mimetic substitution of Ser505 (or Ser513 in human) could enhance the effects of ALS mutations, highlighting interplay between post-translational modification and ALS-linked mutations. These results demonstrate that ALS-linked mutations can variably cause loss of nuclear functions of TLS depending on the degree of impairment in nuclear localization.

DOI： 10.1093/nar/gkq1162

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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-LISS  

Ehlers-Danlos syndrome (EDS) is a heterogeneous connective tissue disorder involving skin and joint laxity and tissue fragility. A new type of EDS, similar to kyphoscoliosis type but without lysyl hydroxylase deficiency, has been investigated. We have identified a homozygous CHST14 (carbohydrate sulfotransferase 14) mutation in the two familial cases and compound heterozygous mutations in four sporadic cases. CHST14 encodes dermatan 4-O-sulfotransferase 1 (D4ST1), which transfers active sulfate from 3&apos;-phosphoadenosine 5&apos;-phosphosulfate to position 4 of the N-acetyl-D-galactosamine (GalNAc) residues of dermatan sulfate (DS). Transfection experiments of mutants and enzyme assays using fibroblast lysates of patients showed the loss of D4ST1 activity. CHST14 mutations altered the glycosaminoglycan (GAG) components in patients&apos; fibroblasts. Interestingly, DS of decorin proteoglycan, a key regulator of collagen fibril assembly, was completely lost and replaced by chondroitin sulfate (CS) in the patients&apos; fibroblasts, leading to decreased flexibility of GAG chains. The loss of the decorin DS proteoglycan due to CHST14 mutations may preclude proper collagen bundle formation or maintenance of collagen bundles while the sizes and shapes of collagen fibrils are unchanged as observed in the patients&apos; dermal tissues. These findings indicate the important role of decorin DS in the extracellular matrix and a novel pathomechanism in EDS. Hum Mutat 31: 966-974, 2010. (C) 2010 Wiley-Liss, Inc.

DOI： 10.1002/humu.21300

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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：ELSEVIER SCIENCE BV  

Pantothenate kinase-associated neurodegeneration (PKAN), formerly known as Hallervorden-Spatz syndrome (HSS), is an autosomal recessive neurodegenerative disorder characterized by iron accumulation in the brain. Mutations in the pantothenate kinase 2 (PANK2) gene are known to be responsible for PKAN. Several studies have revealed correlations between clinical phenotypes and particular PANK2 mutations. The adult-onset slowly progressive type of PKAN with PANK2 mutations is very rare. In this report, we describe siblings with the adult-onset slowly progressive type of PKAN with a novel mutation, Ile346Ser, in PANK2. The siblings had the same mutation in PANK2 and had common clinical signs such as misalignment of teeth, a high arched palate, hollow feet, a slight cognitive decline, and an apparent executive dysfunction, although they showed different patterns of movement disorders. Thus, even if PKAN patients have identical mutations, it is likely that they will present with different types of movement disorders. Brain perfusion single photon emission computed tomography in both patients showed decreased regional cerebral blood flow in the bilateral frontoparietal lobes, the globus pallidus, the striatum, and around the ventriculus quartus. Cardiac uptake of [I-123] meta-iodobenzylguanidine was normal in both patients. Analysis of genotype-phenotype correlations and the elucidation of mutational effects on pantothenate kinase 2 function, expression, and structure are important for understanding the mechanisms of PKAN. (C) 2009 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jns.2009.11.008

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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：ELSEVIER IRELAND LTD  

Neuronal intranuclear inclusions (NIIs) are the pathological hallmark of polyglutamine (polyQ) diseases. We previously found that the RNA-binding protein FUS/TLS is the major component of nuclear polyQ aggregates of a cellular model of Huntington disease. In this study, we revealed that FUS/TLS binds to NIIs in the human brains from patients with spinocerebellar ataxia type 1, 2, 3, and dentatorubral-pallidoluysian atrophy. Recent reports have revealed that mutations in FUS/TLS gene are responsible for familial amyotrophic lateral sclerosis 6 (ALS6). Our results indicated that changing FUS/TLS to an insoluble form may be a common process in polyQ diseases and ALS6. (C) 2009 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

DOI： 10.1016/j.neures.2009.10.004

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Societas Neurologica Japonica  

We report a 50-year-old woman with an unremarkable birth and developmental history, and with no family history of neurological disorders. The patient had a 6-year history of progressive cervical dystonia, oral dyskinesia, and hyperreflexia. She was initially considered to have spastic paraparesis of unknown cause. Because brain MRI showed mild atrophy of the cerebellar vermis, genetic analysis for spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, 12, and 17, and dentatorubral-pallidoluysian atrophy was performed. The results revealed an abnormal expansion of CAG repeats (38 repeats) in one allele of ATXN2, and the patient was diagnosed with spinocerebellar ataxia type 2 (SCA2). She had no major clinical features of SCA2 such as cerebellar ataxia, slow saccade, or hyporeflexia. Recent reports have shown the CAG repeat expansion in ATXN2 to be detected in patients with familial L-dopa-responsive parkinsonism. The present case suggests that CAG repeat expansion in ATXN2 may be detected in some patients with spastic paraparesis, and that wide variations of clinical manifestations exist in SCA2.

DOI： 10.5692/clinicalneurol.50.641

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：12  

We report 3 cases of spontaneous cervical epidural hematoma with sudden onset of neck pain followed by the development of unilateral limb weakness. All of the patients were initially suspected to have acute ischemic stroke. We considered using intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) to treat 2 of the 3 patients who had arrived at our hospital within 2 hours of the symptom onset. However, we did not administer rt-PA therapy to these patients because the symptoms were mild. We treated all 3 patients with other antithrombotic drugs until the diagnosis of cervical epidural hematoma was confirmed. Patients with spontaneous cervical epidural hematoma usually present with acute neck pain followed by the development of bilateral limb weakness and urine retention
unilateral limb weakness is rare. Patients with this uncommon presentation must be distinguished from stroke.

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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：NATURE PUBLISHING GROUP  

In Huntington's disease (HD), mutant Huntingtin, which contains expanded polyglutamine stretches, forms nuclear aggregates in neurons. The interactions of several transcriptional factors with mutant Huntingtin, as well as altered expression of many genes in HD models, imply the involvement of transcriptional dysregulation in the HD pathological process. The precise mechanism remains obscure, however. Here, we show that mutant Huntingtin aggregates interact with the components of the NF-Y transcriptional factor in vitro and in HD model mouse brain. An electrophoretic mobility shift assay using HD model mouse brain lysates showed reduction in NF-Y binding to the promoter region of HSP70, one of the NF-Y targets. RT-PCR analysis revealed reduced HSP70 expression in these brains. We further clarified the importance of NF-Y for HSP70 transcription in cultured neurons. These data indicate that mutant Huntingtin sequesters NF-Y, leading to the reduction of HSP70 gene expression in HD model mice brain. Because suppressive roles of HSP70 on the HD pathological process have been shown in several HD models, NF-Y could be an important target of mutant Huntingtin.

DOI： 10.1038/emboj.2008.23

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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：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Formation of intracellular aggregates is the hallmark of polyglutamine (polyQ) diseases. We analyzed the components of purified nuclear polyQ aggregates by mass spectrometry. As a result, we found that the RNA-binding protein translocated in liposarcoma (TLS) was one of the major components of nuclear polyQ aggregate-interacting proteins in a Huntington disease cell model and was also associated with neuronal intranuclear inclusions of R6/2 mice. In vitro study revealed that TLS could directly bind to truncated N-terminal huntingtin (tNhtt) aggregates but could not bind to monomer GST-tNhtt with 18, 42, or 62Q, indicating that the tNhtt protein acquired the ability to sequester TLS after forming aggregates. Thioflavin T assay and electron microscopic study further supported the idea that TLS bound to tNhtt-42Q aggregates at the early stage of tNhtt-42Q amyloid formation. Immunohistochemistry showed that TLS was associated with neuronal intranuclear inclusions of Huntington disease human brain. Because TLS has a variety of functional roles, the sequestration of TLS to polyQ aggregates may play a role in diverse pathological changes in the brains of patients with polyQ diseases.

DOI： 10.1074/jbc.M705306200

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記述言語：英語   掲載種別：論文集(書籍)内論文   出版者・発行元：ELSEVIER ACADEMIC PRESS INC  

In nine members of polyglutamine (polyQ) diseases, CAG repeat expansions of their responsible genes are observed. The disease is considered to be caused by the formation of polyQ aggregates that sequester proteins essential for cell viability. To understand the pathological process of polyQ diseases, a proteomic approach was used to identify aggregate interacting proteins (AIPs). Constructs were designed to express EGFP-fused, CAG-expanded (150Q) huntingtin exon1 under the control of an ecdysone-inducible promoter and either lacking or containing a nuclear localization signal (NLS). After induction of a stably transfected Neuro 2A cell line with ecdysone, aggregates form in either the cytoplasm or the nucleus. The aggregates in these two different compartments were isolated with different methods. Cytoplasmic aggregate particles were purified using a fluorescence-activated cell sorter (FACS) by monitoring EGFP fluorescence, whereas nuclear aggregates were purified by using the detergent insoluble nature of aggregates. The resulting highly pure aggregates were subjected to SDS-PAGE followed by Coomassie blue staining. Bands containing AIP candidates were excised, and, after in-gel digestion with trypsin, were analyzed by mass spectrometry to identify the proteins. Novel candidates were confirmed as AIPs by immunocytological analysis to observe colocalization with polyQ aggregates.
This chapter describes methods for the establishment of stable mutant cells, the purification of polyQ aggregates, and sample preparation for mass spectrometry analysis in detail.

DOI： 10.1016/S0076-6879(06)12005-4

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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：BLACKWELL PUBLISHING LTD  

Huntington disease is caused by polyglutamine (polyQ) expansion in huntingtin. Selective and progressive neuronal loss is observed in the striatum and cerebral cortex in Huntington disease. We have addressed whether expanded polyQ aggregates appear in regions of the brain apart from the striatum and cortex and whether there is a correlation between expanded polyQ aggregate formation and dysregulated transcription. We generated transgenic mouse lines expressing mutant truncated N-terminal huntingtin (expanded polyQ) fused with enhanced green fluorescent protein (EGFP) and carried out a high-density oligonucleotide array analysis using mRNA extracted from the cerebrum, followed by TaqMan RT-PCR and in situ hybridization. The transgenic mice formed expanded polyQ-EGFP fluorescent aggregates and this system allowed us to directly visualize expanded polyQ aggregates in various regions of the brain without performing immunohistochemical studies. We show here that polyQ-EGFP aggregates were intense in the hypothalamus, where the expression of six hypothalamic neuropeptide mRNAs, such as oxytocin, vasopressin and cocaine-amphetamine-regulated transcript, was down-regulated in the transgenic mouse brain without observing a significant loss of hypothalamic neurons. These results indicate that the hypothalamus is susceptible to aggregate formation in these mice and this may result in the down-regulation of specific genes in this region of the brain.

DOI： 10.1111/j.1471-4159.2005.03035.x

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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：3  

We report on a family with spinocerebellar ataxia type 1 (SCA1), in which the age at onset and the severity of the disease do not correlate with the number of CAG repeat units. Although a marked anticipation was observed in the proband, it was not a consequence of an expansion of the CAG tract. None of the expanded alleles contained CAT interruptions. The pathologic expansion in this family was stable during the paternal but not maternal transmission, where it expanded by one trinucleotide and unexpectedly did not lead to anticipation. Our observations suggest that factors other than the length of the CAG repeat play a considerable role in determination of the disease course.

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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：BLACKWELL PUBLISHING LTD  

Huntington's disease is a progressive neurodegenerative disorder that is associated with a CAG repeat expansion in the gene encoding huntingtin. We found that a 60-kDa protein was increased in Neuro2a cells expressing the N-terminal portion of huntingtin with expanded polyglutamine. We purified this protein, and, using mass spectrometry, identified it as p62, an ubiquitin-associated domain-containing protein. A specific p62 antibody stained the ubiquitylated polyQ inclusions in expanded polyglutamine-expressing cells, as well as in the brain of the huntingtin exon 1 transgenic mice. Furthermore, the level of p62 protein and mRNA was increased in expanded polyglutamine-expressing cells. We also found that p62 formed aggresome-like inclusions when p62 was increased in normal Neuro2a cells by a proteasome inhibitor. Knock-down of p62 does not affect the formation of aggresomes or polyglutamine inclusions, suggesting that p62 is recruited to the aggresome or inclusions secondary to their formation. These results suggest that p62 may play important roles as a responsive protein to a polyglutamine-induced stress rather than as a cross-linker between ubiquitylated proteins.

DOI： 10.1111/j.1471-4159.2004.02692.x

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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：ELSEVIER SCIENCE BV  

Nuclear aggregates of enhanced green fluorescent protein and nuclear localization signal-fused truncated N-terminal huntingtin containing 150 repeats of glutamine residue were purified from ecdysine-inducible mutant neuro2A cell line by sequential extraction of nuclear soluble proteins. To analyze the aggregate-interacting proteins, we subjected the nuclear aggregates to high performance liquid chromatography-mass spectrometry analysis. The resulting data revealed the presence of three new putative aggregate-interacting proteins: ubiquilin 1, ubiquilin 2 and Tollip. These proteins also associated with neuronal intranuclear inclusions in a mouse model of Huntington disease (HD). These aggregate-interacting proteins contain ubiquitin-interacting motifs, suggesting that they are recruited to the aggregates where they may lose their normal function. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.febslet.2004.06.077

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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：NATURE PUBLISHING GROUP  

Inhibition of polyglutamine-induced protein aggregation could provide treatment options for polyglutamine diseases such as Huntington disease. Here we showed through in vitro screening studies that various disaccharides can inhibit polyglutamine-mediated protein aggregation. We also found that various disaccharides reduced polyglutamine aggregates and increased survival in a cellular model of Huntington disease. Oral administration of trehalose, the most effective of these disaccharides, decreased polyglutamine aggregates in cerebrum and liver, improved motor dysfunction and extended lifespan in a transgenic mouse model of Huntington disease. We suggest that these beneficial effects are the result of trehalose binding to expanded polyglutamines and stabilizing the partially unfolded polyglutamine-containing protein. Lack of toxicity and high solubility, coupled with efficacy upon oral administration, make trehalose promising as a therapeutic drug or lead compound for the treatment of polyglutamine diseases. The saccharide-polyglutamine interaction identified here thus provides a new therapeutic strategy for polyglutamine diseases.

DOI： 10.1038/nm985

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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：ELSEVIER SCI IRELAND LTD  

We investigated how visual event-related potentials (ERPs) are modulated by visual divided attention using an S1-S2 paradigm. Stimulus S2 consisted of non-target stimuli (Stimulus 1, 2, 3) and a target stimulus (Stimulus 4). The spatial/color factor was compared between S1 and S2: same/same (Stimulus 1); same/different (Stimulus 2); different/same (Stimulus 3); and different/different (Stimulus 4). The P1/N1 (90 similar to 150 ms) showed significantly greater amplitude in Stimulus 3 than in Stimuli 1 and 2. The N2 (230 similar to 290ms) showed significantly greater amplitude in Stimulus 2 than in Stimuli 1 and 3. We assumed that the P1/N1 was related to spatial attention, enhanced by alterations to the spatial factor, and that the N2 was related to color attention, enhanced by alterations to the color factor. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：Movement Disorder Society of Japan (MDSJ)  

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記述言語：日本語   出版者・発行元：(株)へるす出版  

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J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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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)日本神経免疫学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(株)北隆館  

常染色体優性遺伝性脊髄小脳失調症42型はT型カルシウムチャネルCaV3.1をコードするCACNA1Gのミスセンス変異によって発症する疾患である。我々はCRISPR/Cas9システムを用いてCacna1g遺伝子にヒトで発見された変異を導入したモデルマウスを作成し、その結果、運動失調、プルキンエ細胞変性を再現することに成功した。また小脳・脳幹急性スライスにおいてプルキンエ細胞および下オリーブ核神経細胞の電気生理学的異常を検出した。今後本モデルマウスを用いた治療法を開発していく予定である。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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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)日本神経治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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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：日本語   出版者・発行元：(一社)日本神経免疫学会  

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記述言語：英語   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   出版者・発行元：Movement Disorder Society of Japan (MDSJ)  

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記述言語：日本語   出版者・発行元：Movement Disorder Society of Japan (MDSJ)  

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記述言語：日本語   出版者・発行元：Movement Disorder Society of Japan (MDSJ)  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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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)日本神経学会  

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J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(株)日本プランニングセンター  

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J03334&link_issn=&doc_id=20181128410005&doc_link_id=%2Fag4nbzta%2F2018%2F002409%2F006%2F0021-0025%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fag4nbzta%2F2018%2F002409%2F006%2F0021-0025%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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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)日本神経治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

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記述言語：日本語   出版者・発行元：日本神経感染症学会  

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記述言語：日本語   出版者・発行元：(株)南江堂  

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J00974&link_issn=&doc_id=20180830130055&doc_link_id=10.15106%2Fj_naika122_564&url=https%3A%2F%2Fdoi.org%2F10.15106%2Fj_naika122_564&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

記述言語：日本語   出版者・発行元：(一社)日本神経免疫学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：Movement Disorder Society of Japan (MDSJ)  

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記述言語：日本語   出版者・発行元：Movement Disorder Society of Japan (MDSJ)  

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記述言語：日本語   出版者・発行元：Movement Disorder Society of Japan (MDSJ)  

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記述言語：日本語   出版者・発行元：Movement Disorder Society of Japan (MDSJ)  

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記述言語：日本語   出版者・発行元：Movement Disorder Society of Japan (MDSJ)  

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記述言語：日本語   出版者・発行元：Movement Disorder Society of Japan (MDSJ)  

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記述言語：日本語   出版者・発行元：Movement Disorder Society of Japan (MDSJ)  

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記述言語：日本語   出版者・発行元：Movement Disorder Society of Japan (MDSJ)  

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記述言語：日本語   出版者・発行元：認知神経科学会  

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記述言語：日本語   出版者・発行元：(株)日本臨床社  

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記述言語：日本語   出版者・発行元：(株)中外医学社  

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記述言語：日本語   出版者・発行元：日本神経治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：Movement Disorder Society of Japan (MDSJ)  

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記述言語：日本語   出版者・発行元：Movement Disorder Society of Japan (MDSJ)  

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記述言語：日本語   出版者・発行元：Movement Disorder Society of Japan (MDSJ)  

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記述言語：日本語   出版者・発行元：(一社)日本神経免疫学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本高次脳機能障害学会  

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：日本語  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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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)日本神経学会  

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記述言語：日本語   出版者・発行元：日本神経感染症学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

近年のゲノムシークエンス技術の進歩により、常染色体劣性遺伝性脊髄小脳変性症の新たな責任遺伝子が次々と明らかになってきている。しかし、同じような表現型を示していても責任遺伝子が全く異なる場合や、逆に同じ責任遺伝子であっても発症年齢、症状、疾患進行が大きく異なる場合があり、診断は容易ではない。また、欧米の特に小児期発症例において同定された遺伝子変異が、本邦の成人発症例においてもみられるのかどうかは、今後も引き続き検討が必要な課題である。本稿では、主として近年本邦でも存在が確認された比較的まれと考えられる劣性遺伝性脊髄小脳変性症について概説する。(著者抄録)

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J01550&link_issn=&doc_id=20160728260001&doc_link_id=1390282680013478400&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390282680013478400&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_3.gif

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)日本神経学会  

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記述言語：日本語  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：英語   出版者・発行元：(一社)日本神経学会  

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記述言語：英語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：日本末梢神経学会  

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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)日本神経治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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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)日本神経学会  

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

神経組織への凝集蛋白質の沈着は、多くの神経変性疾患に共通して認められる現象であり、その種類、形態、分布を明らかにすることが、各疾患の病理学的診断に不可欠な要素となっている。蛋白質凝集は神経変性疾患の病態の中核をなすものであり、多方面から研究が行われている。本稿では、in vitroにおけるアミロイド線維形成の動態、代表的な凝集体形成疾患であるプリオン病における蛋白質凝集、蛋白質凝集の生理学的な意味、二次的な蛋白質凝集について解説する。(著者抄録)

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J02389&link_issn=&doc_id=20141029190011&doc_link_id=%2Fai1braid%2F2014%2F002603%2F012%2F0265-0271%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fai1braid%2F2014%2F002603%2F012%2F0265-0271%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(一社)日本脳卒中学会  

症例は79歳男性。糖尿病で内服加療を行っていたが、突然発症の右不全片麻痺を来し当院に救急搬送された。頭部MRI拡散強調画像で左内包後脚に高信号を認めた。血糖が30mg/dlと著明に低下しており50%グルコースを静注したところ症状は速やかに消失し、片麻痺の原因は低血糖によるものと考えられた。患者は過去にも低血糖による内包後脚のMRI異常信号を呈し、右不全片麻痺を発症していた。低血糖発作による脳卒中様の片麻痺は過去にも報告がみられるが、同一部位に繰り返しMRI異常信号を認めた例はこれまでにない。内包後脚が低血糖への脆弱性が高い脳組織の一つであることが示された。(著者抄録)

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J01786&link_issn=&doc_id=20141003400010&doc_link_id=%2Fdh3strok%2F2014%2F003605%2F010%2F0370-0373%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdh3strok%2F2014%2F003605%2F010%2F0370-0373%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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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)日本神経学会  

CBSの病理学的診断は多彩であり、遺伝学的背景も多彩である。病理学的には前頭側頭葉変性症(FTLD)である頻度がもっとも高く、他にAlzheimer病、Creutzfeldt-Jakob病、Parkinson病/Lewy小体型認知症などが挙げられる。FTLDの原因として頻度の高いMAPT、GRN、C9orf72変異やTARDBP、FUS、LRRK2、CSF1R変異例では臨床的にCBSを呈する可能性があることが欧米を中心に知られている。しかし日本人のCBS発症に関与する遺伝子については、単一遺伝子異常、疾患感受性遺伝子ともにまったくわかっておらず、今後多施設間で症例を集積、解析していく必要がある。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2013&ichushi_jid=J01550&link_issn=&doc_id=20140331470043&doc_link_id=130004505325&url=https%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F130004505325&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(株)医学書院  

大脳皮質基底核症候群(CBS)を呈する個々の疾患、特に主たる原因疾患である前頭側頭葉変性症(FTLD)を中心に、遺伝的背景について概説した。FTLDは蓄積タンパク質からFTLD-tau、FTLD-TDP、FTLD-UPSなどに分類される。FTLD-tauではMAPT、FTLD-TDPではGRN、C9orf72、VCP、FTLD-UPSではCHMP2Bなどの遺伝子変異が報告されている。アルツハイマー病、パーキンソン病/レビー小体型認知症、クロイツフェルト・ヤコブ病についても述べた。

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：横浜市立大学医学会  

常染色体劣性遺伝性小脳失調症(ARCA)は非進行性の小脳低形成、進行性の脊髄小脳変性症(SCA)を含む多様な疾患の総称である。現在までに20種類以上の責任遺伝子が同定されているが以前数多くの責任遺伝子未同定家系が存在する。今回、50〜60歳前後で発症した高年発症SCAの劣性遺伝性家系を経験した。この家系を対象とし、高密度のSNP(一塩基多型)アレイを用いたホモ接合性マッピングと連鎖解析により責任遺伝子局在部位を明らかにし、罹患者に関しては次世代シーケンサーを用いた遺伝子変異同定を併用することで疾患責任遺伝子単離を行った。結果SYT14のミスセンス変異c.1451G>A(p.Gly484Asp)をARCAの新たな責任遺伝子変異の候補として同定した。TaqManリアルタイムPCR法を用いてSYT14のmRNAが脳で多く発現すること、SYT14の野生型、変異型を培養細胞に強制発現させると、野生型と変異型で明らかに細胞内局在が変化することを確認した。また、SYT14に対するポリクローナル抗体を作成し、免疫染色を行い、SYT14が小脳Purkinje細胞に局在していることを確認した。以上の結果からSYT14が新たな疾患責任遺伝子である可能性が非常に高いことが確認できた。従来解析対象になりえなかった小規模家系においても上記の方法で責任遺伝子単離が可能であると思われた。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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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)日本神経治療学会  

前頭側頭葉変性症(FTLD)は、前頭側頭型認知症(FTD)、進行性非流暢性失語症(PNFA)および意味性認知症(SD)の上位概念として提唱された。FTLD(FTD、PFNA、SD)の有病率、臨床症状、診断基準、神経病理学的分類、遺伝学的側面、治療について概説した。FTLDでは運動ニューロン疾患の合併が認められる場合がある。また、FTLDの約4割に何らかの家族歴が認められるという報告がある。FTLDの進行を抑制する治療は現在のところまだない。

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2011&ichushi_jid=J02615&link_issn=&doc_id=20120111470007&doc_link_id=%2Fcq3neuro%2F2011%2F002806%2F009%2F0637-0646%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcq3neuro%2F2011%2F002806%2F009%2F0637-0646%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(有)科学評論社  

27歳、白人男性。患者は意識障害、手足の硬直感、いびきが出現し、発症から約40分で著者らの救急センターへ搬送となった。頭部CTおよびMRI、MRAにより脳底動脈閉塞に伴う脳梗塞と診断され、発症150分後より日本の承認用量であるアルテプラーゼ0.6mg/kgの投与を行った結果、出血性合併症はなく、翌日には部分的な再開通を認められた。だが、3ヵ月経過した現在も発語はなく、全介助の状態である。

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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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)日本神経学会  

症例は50歳女性である。出産歴、発達歴に異常なく、神経疾患の家族歴をみとめない。約6年間の経過で進行する頸部ジストニア、口部ジスキネジアおよび腱反射亢進を主とする症候をみとめた。原因不明の痙性対麻痺と考えたが、脳MRI上小脳虫部の軽度の萎縮をみとめたため遺伝子検査を施行したところATXN2の一方のアレルにおいてCAGリピートが38と異常伸長をみとめたため、脊髄小脳失調症2型(SCA2)と診断した。本症例ではSCA2に特徴的とされる小脳性運動失調、緩徐眼球運動、腱反射低下がみとめられず痙性対麻痺様の症候を呈したため、SCA2の臨床像の多様性を示す貴重な症例と考えられた。(著者抄録)

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2010&ichushi_jid=J01550&link_issn=&doc_id=20101005320004&doc_link_id=1390282680011154816&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390282680011154816&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_3.gif

記述言語：日本語   出版者・発行元：(一社)日本脳卒中学会  

脊髄梗塞の臨床像および予後について検討した．対象は1997年4月から2008年9月までに横浜市立大学附属2病院神経内科に入院した急性期脊髄梗塞患者14例である．発症年齢は中央値63歳，範囲は22から74歳，男7例，女7例であった．心血管疾患危険因子は高血圧6例，糖尿病5例，喫煙4例，心房細動0例，心血管疾患の既往2例で，6例ではいずれの危険因子も認めなかった．病変部位は，頸髄3例，頸胸髄3例，胸髄5例，胸腰髄が3例で，4椎体以上にわたる病変を7例で認めた．臨床像を分類すると前脊髄動脈症候群が11例，Brown-S quard症候群が1例，横断性梗塞が2例だった．初発症状は痛みが8例，脱力が4例，痺れが2例で，10例では24時間以内に症状がピークに達した．治療についてはステロイドが6例，抗血小板薬が5例，抗凝固薬が10例，7例ではこれらの治療を併用した．退院時に歩行が可能であったのは6例で，感覚障害は全例で残存した．排尿障害によって導尿あるいは膀胱バルーンカテーテルが留置されていた例は9例であった．女性，長軸方向に長い病変，横断性梗塞，脱力で発症した例では予後が悪い傾向がみられた．

DOI： 10.3995/jstroke.32.351

CiNii Books

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記述言語：日本語   出版者・発行元：一般社団法人 日本内科学会  

先行感染を伴い，両側側頭葉に出血を伴う髄膜脳炎を呈し，同時に脊髄病変を認めた急性散在性脳脊髄炎（acute disseminated encephalomyelitis，ADEM）の男性例．出血を伴う激症型ADEMでは予後不良であることが知られているが，本例は発症早期よりステロイド治療を行い良好な経過をとった稀なケースであると考えられる．<br>

DOI： 10.2169/naika.99.1656

CiNii Books

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記述言語：日本語   出版者・発行元：日本臨床社  

CiNii Books

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