記述言語：日本語  

DOI： 10.11477/mf.188160960780050495

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記述言語：日本語   出版者・発行元：Neurotherapeutics  

Charcot-Marie-Tooth disease type 2 A (CMT2A) is an inherited axonal neuropathy linked to mutations in MFN2, a key regulator of mitochondrial dynamics. Currently, no effective drug therapies exist. l-arginine has shown promise in treating mitochondrial disorders, though its effect on MFN2-associated neuropathy remains uncertain. To investigate this, we used Drosophila models with the neuron-specific knockdown of Marf, the fly ortholog of MFN2, employing a temporally controlled GAL4/UAS system. Flies were administered different doses of l-arginine to examine its influence on motor ability and lifespan. To evaluate responses under mitochondrial stress, flies were also treated with rotenone, a mitochondrial complex I inhibitor. l-arginine markedly improved climbing performance under baseline conditions and extended lifespan under both baseline and stress conditions. However under rotenone-induced mitochondrial stress, high-dose l-arginine improved survival without a corresponding improvement in locomotor performance. These results support a neuroprotective role for l-arginine in MFN2-deficient Drosophila, possibly through effects on mitochondrial dynamics involving complex I. l-arginine may hold therapeutic promise for CMT2A, meriting further investigation in vertebrate models.

DOI： 10.1016/j.neurot.2026.e00900

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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：International Journal of Molecular Sciences  

DNMT1 variants are linked to complex neurodegenerative syndromes, yet their variant-specific functional and epigenomic consequences remain poorly defined. DNMT1 variants were identified in eight patients using gene-panel or whole-exome sequencing. Functional effects were assessed by site-directed mutagenesis and transient expression in HEK293T cells. Genome-wide methylation profiling of peripheral blood leukocyte DNA was performed using Nanopore sequencing, enabling direct quantification of 5-methylcytosine (5mC). CpG island-level differential methylation and gene set enrichment analysis (GSEA) were conducted. Variants in the replication foci targeting sequence (RFTS) domain (p.Y511H, p.Y540C, p.H569R) exhibited reduced DNMT1 protein expression, decreased enzymatic activity, and cytosolic aggregation. Variants in the C-terminal catalytic domain (p.A1334V and p.P1546S) showed reduced protein expression with relatively mild enzymatic impairment. Patients carrying the p.Y511H variant demonstrated a significant reduction in global 5mC levels compared with controls. Principal component analysis revealed distinct methylomic profiles separating most patients from controls, with marked intra- and inter-familial heterogeneity. CpG island-level analysis identified a single significantly hypomethylated region in p.Y511H carriers, and GSEA revealed differential enrichment of multiple Gene Ontology biological pathways. This study defines domain-dependent functional effects of DNMT1 variants and provides the first nanopore-based methylome analysis, revealing variant-specific and heterogeneous epigenomic alterations.

DOI： 10.3390/ijms27031232

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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：Neurology Neuroimmunology and Neuroinflammation  

Background and Objectives – Human T-lymphotropic virus type 1 (HTLV-1)–associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive neurologic disorder characterized by chronic inflammation in the CNS. HTLV-1–specific cytotoxic CD8+ T lymphocytes (CTLs) play a crucial role in the pathogenesis of HAM/TSP; however, the dynamics of CTLs in the CSF remain poorly understood. The aim of this study was to investigate the accumulation of HTLV-1–specific CTLs in the CSF of patients with HAM/TSP and to evaluate their association with neuroinflammation and neural damage. Methods – The frequency of HTLV-1–specific CTLs was compared between paired peripheral blood (PB) and CSF from patients with HAM/TSP and asymptomatic HTLV-1 carriers (ACs) using MHC/antigen tetramers. In addition, cytokine levels and neurofilament light chain (NfL) concentration were analyzed in the CSF of patients with HAM/TSP and ACs. Results – The frequency of HTLV-1–specific CTLs in PB was significantly higher in patients with HAM/TSP compared with ACs (median [interquartile range (IQR)] = 3.0 [0.9–8.3] % vs 0.3 [0.2–3.1] %, p < 0.01). Notably, this difference was even more pronounced in CSF, where patients with HAM/TSP exhibited a significantly elevated frequency compared with ACs (19.1 [7.9–33.4] % vs 6.1 [0.9–15.7] %, p < 0.01). Furthermore, the frequency of HTLV-1–specific CTLs in the CSF was considerably higher than in the PB of patients with HAM/TSP (p < 0.0001). The lack of accumulation of cytomegalovirus-specific CTLs indicates that HTLV-1–specific CTLs selectively accumulate in the CSF of patients with HAM/TSP. These accumulated HTLV-1–specific CTLs in the CSF significantly correlated with increased levels of cytokines in patients with HAM/TSP. In addition, CSF NfL levels were significantly higher in patients with HAM/TSP than in ACs (696 [534–1, 407] vs 429 [373–717] pg/mL, p < 0.05) and showed a positive correlation with HTLV-1 proviral load. Discussion – HTLV-1–specific CTLs selectively accumulate in the CSF of patients with HAM/TSP. Chronic inflammation, primarily driven by the interaction between proliferating HTLV-1–infected cells and accumulated HTLV-1–specific CTLs, may contribute to neural damage in patients with HAM/TSP.

DOI： 10.1212/NXI.0000000000200508

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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：Annals of Clinical and Translational Neurology  

Background: Mitofusin 2 (MFN2) is a major causative gene for axonal Charcot – Marie – Tooth disease type 2A (CMT2A), with a wide phenotypic spectrum. Comprehensive large - scale genotype – phenotype association studies are essential for understanding disease pathogenesis and improved clinical management. Methods: We conducted a nationwide retrospective study of 176 Japanese patients with genetically confirmed pathogenic or likely pathogenic MFN2 variants encompassing clinical, electrophysiological, and genetic characterization. Results: MFN2 was the second most frequent causative gene among 1211 genetically diagnosed inherited peripheral neuropathy cases in Japan. A total of 76 MFN2 variants were identified, including nine novel likely pathogenic variants. Disease onset occurred at a mean age of 11.1 years, with distal motor weakness and tibialis anterior involvement as prominent features. Sensory symptoms were present in ~60% of patients and were more common in cases with longer disease duration. Central and systemic features, including pyramidal signs, optic atrophy, and vocal cord paralysis, were also observed. Electrophysiological studies revealed a predominantly axonal sensorimotor pattern, with relatively preserved upper limb conduction and marked lower limb abnormalities. Importantly, 24 patients (16%) were non-ambulatory, with earlier onset and greater weakness. Domain-based analysis further revealed that variant location may influence age at onset. Conclusion: This large-scale study highlights the genetic and clinical diversity of MFN2-related CMT in Japan. Our findings confirm a motor-dominant, length-dependent axonal neuropathy with additional sensory and systemic features in some cases. These results emphasize the importance of early diagnosis, genotype-informed care, and long-term follow-up in managing MFN2-related CMT.

DOI： 10.1002/acn3.70218

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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：Annals of Clinical and Translational Neurology  

Background: INF2 mutations cause focal segmental glomerulosclerosis (FSGS) and Charcot–Marie–Tooth disease (CMT). Accurate genetic diagnosis is critical, as INF2-related FSGS is typically resistant to immunotherapy yet rarely recurs after transplantation, and its associated neuropathy can mimic treatable immune-mediated disorders such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Methods: We performed a multicenter study investigating 3329 Japanese patients with inherited peripheral neuropathies/CMT who underwent gene panel sequencing or whole-exome analysis between 2007 and 2024. Clinical data, including electrophysiological assessments, were obtained from the patients' medical records. Results: We identified six pathogenic INF2 variants in eight patients, all of which were located within the diaphanous inhibitory domain. Structural modeling revealed clustering of variants near the diaphanous autoregulatory domain-binding pocket, which is critical for INF2 autoinhibition. Clinically, all cases were sporadic, with a median age at neurological onset of 9 years. All patients exhibited lower limb weakness, and 6/8 (75%) had sensory disturbances. All patients also developed kidney dysfunction, with 7/8 (88%) progressing to end-stage renal disease at a median age of 15 years. Furthermore, all patients showed demyelinating neuropathy, and 2/8 (25%) received immunotherapy due to suspected immune-mediated neuropathy. Conclusion: Although INF2 variants are a rare cause of CMT in Japan, they should be considered in pediatric patients with demyelinating neuropathy and early-onset proteinuria, even in the absence of a family history. Blood and urine tests assessing renal dysfunction can provide guidance for appropriate genetic testing.

DOI： 10.1002/acn3.70205

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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：Journal of Human Genetics  

Myopathy, lactic acidosis, and sideroblastic anemia type 1 (MLASA1) is an extremely rare mitochondrial disorder caused by biallelic pathogenic variants in PUS1, which encodes a mitochondrial tRNA pseudouridine synthase essential for mitochondrial protein synthesis. We describe two affected siblings presenting with progressive myopathy, lactic acidosis, sideroblastic anemia, short stature, developmental delay, and mild cognitive impairment. Depth-based copy number variation analysis of whole-exome sequencing data revealed a novel homozygous multi-exonic deletion in PUS1. The deletion breakpoints were defined by Sanger sequencing as a 9964 bp deletion spanning part of intron 3 through exons 4–6 and extending into the 3′ untranslated region, resulting in complete loss of the C-terminal coding region. Skeletal muscle histology demonstrated ragged red fibers, whereas immunohistochemistry showed a selective and near-complete loss of NDUFB8, indicating impaired assembly of respiratory chain complex I. A systematic review of previously reported MLASA1 cases revealed marked clinical heterogeneity, including frequent developmental delay, dysmorphic features, and multi-organ involvement. These findings expand the genotypic and phenotypic landscape of MLASA1 and highlight the diagnostic value of copy number variation analysis in unresolved mitochondrial disorders. The impairment of complex I underscores the particular vulnerability of translation-dependent respiratory chain components in PUS1-related diseases.

DOI： 10.1038/s10038-025-01437-8

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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：Neurology Genetics  

Background and Objectives – Autosomal recessive spastic ataxia of Charlevoix-Saguenay, caused by biallelic SACS variants, is classically characterized by spasticity, ataxia, and peripheral neuropathy. The aim of this study was to define the clinical and genetic spectrum of SACS-related inherited peripheral neuropathies (IPNs) in Japanese patients. Methods – Targeted gene panel sequencing was performed in 3, 353 Japanese cases clinically suspected of having IPN or Charcot-Marie-Tooth (CMT) disease, with PMP22 duplication or deletions pre-excluded in demyelinating subtypes, followed by whole-exome sequencing in a subset of undiagnosed cases. Depth-based copy number variation (CNV) analysis was conducted using CovCopCan or XHMM, with validation by quantitative PCR. Results – Biallelic or putative compound heterozygous SACS variants were identified in 10 index cases, with pathogenic or likely pathogenic variants confirmed in 9 cases (0.268%; 9/3, 353). The variant spectrum included frameshift (n = 9), missense (n = 3), and nonsense (n = 2) variants, along with complete SACS gene deletions identified by CNV analysis in 2 cases. Disease onset occurred between 1 and 49 years. All patients exhibited motor and sensory neuropathy, with pyramidal signs observed in 6 patients. Cerebellar ataxia or atrophy was documented in 8 patients. Cognitive impairment was observed in 4 patients, and 1 patient presented with postural hypotension. Most patients showed a length-dependent, sensory-predominant polyneuropathy characterized by slowed nerve conduction velocities. Discussion – This study defines the contribution of SACS variants in a large case series of Japanese patients with IPN/CMT disease and delineates the heterogeneous genotypic and phenotypic spectrum of SACS-related neuropathies. The high frequency of gene-level deletions underscores the necessity of incorporating CNV analysis into the genetic diagnostic workflow for SACS-related disorders.

DOI： 10.1212/NXG.0000000000200318

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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：Journal of Neurology  

Background: Giant axonal neuropathy 1 (GAN) is a rare neurodegenerative disorder with autosomal recessive inheritance and significant phenotypic heterogeneity, ranging from milder presentations resembling Charcot–Marie–Tooth disease (CMT) to classical presentations involving central and peripheral nervous systems. We investigated the genetic and clinical spectrum of GAN in Japanese patients with inherited peripheral neuropathies (IPNs). Methods: We conducted genetic screening of 3315 Japanese patients diagnosed with IPNs between 2007 and 2023 using targeted next-generation or whole-exome sequencing. Variant pathogenicity, clinical features, and neurophysiological and neuroimaging findings were reviewed. Results: We identified seven biallelic GAN variants in five patients from four unrelated families, including one homozygous and three compound heterozygous genotypes. Two novel pathogenic variants were identified: c.922G > T (p.Glu308*) and c.456dup (p.Ala153Cysfs*27). Two families exhibited the classical phenotype, whereas the other two exhibited a CMT-like phenotype. Mean onset age was 4.4 years (range 1.5–8), and gait disturbance was the initial symptom. The most common findings included distal weakness (n = 5), sensory impairment (n = 4), scoliosis (n = 3), autonomic dysfunction (n = 2). Neurophysiologically, all patients had sensorimotor axonal polyneuropathy. One patient with mild phenotype maintained a CMT-like state without systemic involvement until the age of 43 years and was still alive at 72, representing the longest documented survival in GAN. Conclusion: This study expands the genetic and phenotypic spectrum of GAN by identifying novel variants and a long-term survivor. These findings underscore the importance of systematic genetic screening for GAN in pediatric-onset CMT, even in the absence of classical features.

DOI： 10.1007/s00415-025-13243-5

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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：Multiple Sclerosis and Related Disorders  

The visual evoked potential (VEP) patterns of optic neuritis are known to often differ between multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) but have been less reported in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). This study aimed to characterize the VEP pattern in MOGAD and evaluate its utility in distinguishing MOGAD from MS and NMOSD. We retrospectively reviewed the clinical manifestations and VEP findings in patients with MS (n = 29), NMOSD (n = 14), and MOGAD (n = 10). In eyes with acute visual impairment, VEP responses were detectable in 100 % of eyes with MOGAD, a striking difference from MS (72.7 %) and NMOSD (57.1 %). In addition, VEP abnormalities in eyes without acute visual impairment were rare in MOGAD (23.1 %) compared to MS (55.3 %) and NMOSD (42.9 %). Our results indicated that subclinical VEP abnormalities or undetectable VEP responses were less common in patients with MOGAD compared to patients with MS and NMOSD. VEP testing demonstrates potential diagnostic utility in distinguishing among these conditions.

DOI： 10.1016/j.msard.2025.106408

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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：Clinical Neurology  

This study investigated two cases. Case 1 involves a 53-year-old man who suffered from sleep apnea syndrome at age 48. Moreover, he was involved in a rear-end collision while driving and was admitted to the hospital at age. He exhibited impaired consciousness, postural tremors, and bradykinesia in the upper extremities. Subsequently, he was managed on a ventilator due to unexplained alveolar hypoventilation. Case 2 is his younger sister, a 46-year-old woman, who was being treated for depression and began to show signs of parkinsonism around age 43. The metaiodobenzylguanidine (MIBG) myocardial scintigraphy results were normal in both cases. Given that their father was also managed on a ventilator due to unexplained alveolar hypoventilation, exome analyses were performed. Both were found to have a previously reported heterozygous mutation (p.Y78C) in the DCTN1 gene and were diagnosed with Perry disease. Although MIBG myocardial scintigraphy is a useful test for diagnosing Perry disease, it is important to note that there are cases where it may yield normal results.

DOI： 10.5692/clinicalneurol.cn-001995

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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：Journal of Neurology  

Background: Inherited peripheral neuropathies (IPNs) encompass a wide range of disorders affecting the peripheral nervous system, often with complex genetic causes and frequent underdiagnosis. The variants in the superoxide dismutase 1 (SOD1) gene, primarily linked to amyotrophic lateral sclerosis (ALS), have also been associated with peripheral neuropathy. The recent approval of Tofersen, targeting SOD1-related ALS, highlights the importance of precise genetic diagnosis. This study explores the clinical and genetic profiles of SOD1-related IPNs (SOD1-IPN) in a nationwide Japanese IPN cohort. Methods: Clinical and genetic data were assessed from 1483 Japanese patients with IPN, with a focus on those harboring SOD1 pathogenic variants. The clinical evaluations included age of onset, gender, muscle weakness patterns, sensory disturbances, reflex responses, and electrophysiological findings. Results: Seventeen patients with SOD1 pathogenic variants were identified, reinforcing SOD1’s role in IPN. The average onset age was 47, with a slight male predominance. Distal muscle weakness was noted in 9 of 13 patients, and asymmetric muscle weakness and atrophy in 10 of 14 cases. Mild sensory disturbances were observed in eight patients, with some showing hyperreflexia and abnormal reflexes. Electrophysiology predominantly indicated a length-dependent, motor-dominant axonal neuropathy. Conclusion: This study reveals the clinical variability and likely underdiagnosis of SOD1-IPN, supporting the integration of SOD1 screening in IPN genetic testing, especially for patients with asymmetric, length-dependent axonal neuropathy evident in clinical and electrophysiological assessments.

DOI： 10.1007/s00415-025-12925-4

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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：Journal of Neurology Neurosurgery and Psychiatry  

Background The causative genes for over 60% of inherited peripheral neuropathy (IPN) remain unidentified. This study endeavours to enhance the genetic diagnostic rate in IPN cases by conducting screenings focused on non-coding repeat expansions. Methods We gathered data from 2424 unrelated Japanese patients diagnosed with IPN, among whom 1555 cases with unidentified genetic causes, as determined through comprehensive prescreening analyses, were selected for the study. Screening for CGG non-coding repeat expansions in LRP12, GIPC1 and RILPL1 genes was conducted using PCR and long-read sequencing technologies. Results We identified CGG repeat expansions in LRP12 from 44 cases, establishing it as the fourth most common aetiology in Japanese IPN. Most cases (29/37) exhibited distal limb weakness, without ptosis, ophthalmoplegia, facial muscle weakness or bulbar palsy. Neurogenic changes were frequently observed in both needle electromyography (97%) and skeletal muscle tissue (100%). In nerve conduction studies, 28 cases primarily showed impairment in motor nerves without concurrent involvement of sensory nerves, consistent with the phenotype of hereditary motor neuropathy. In seven cases, both motor and sensory nerves were affected, resembling the Charcot-Marie-Tooth (CMT) phenotype. Importantly, the mean CGG repeat number detected in the present patients was significantly shorter than that of patients with LRP12-oculopharyngodistal myopathy (p<0.0001). Additionally, GIPC1 and RILPL1 repeat expansions were absent in our IPN cases. Conclusion We initially elucidate LRP12 repeat expansions as a prevalent cause of CMT, highlighting the necessity for an adapted screening strategy in clinical practice, particularly when addressing patients with IPN.

DOI： 10.1136/jnnp-2024-333403

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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：Clinical Neurophysiology Practice  

Objective: To evaluate the utility of nerve conduction studies as a marker of length-dependent neuropathy. Methods: We conducted a retrospective study of 44 chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients and 365 genetically confirmed Charcot-Marie-Tooth disease (CMT) patients, including those with PMP22 duplications or mutations in GJB1, MFN2, MPZ, and MME. Nerve conduction study parameters were compared, with subgroup analyses of CIDP-mimicking CMT (genetically confirmed CMT with a prior clinical diagnosis of CIDP) and gene-based classifications. Receiver operating characteristic (ROC) analysis assessed the sensitivity and specificity of these parameters. Results: The tibial to ulnar nerve distal compound muscle action potential (T/U CMAP) amplitude ratio was significantly higher in CIDP patients compared to those with genetically confirmed CMT, CIDP-mimicking CMT, and gene-based subgroups. This ratio yielded the highest area under the curve (AUC: 0.95) among all evaluated parameters, with a cutoff value of 0.385 demonstrating high diagnostic sensitivity (95.5%) and specificity (85.5%). In CIDP-mimicking CMT group, a similar sensitivity and specificity were observed. Conclusions: The T/U CMAP amplitude ratio is a simple, robust electrophysiological index of length-dependent neuropathy. Significance: This marker offers a reliable and accessible way to distinguish between acquired and inherited neuropathies, improving diagnostic accuracy and helping prioritize genetic testing.

DOI： 10.1016/j.cnp.2025.10.006

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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：Annals of Clinical and Translational Neurology  

Background and Objectives: The GAA repeat expansion within the fibroblast growth factor 14 (FGF14) gene has been found to be associated with late-onset cerebellar ataxia. This study aimed to investigate the genetic causes of cerebellar ataxia in patients in Japan. Methods: We collected a case series of 940 index patients who presented with chronic cerebellar ataxia and remained genetically undiagnosed after our preliminary genetic screening. To investigate the FGF14 repeat locus, we employed an integrated diagnostic strategy that involved fluorescence amplicon length analysis polymerase chain reaction (PCR), repeat-primed PCR, and long-read sequencing. Results: Pathogenic FGF14 GAA repeat expansions were detected in 12 patients from 11 unrelated families. The median size of the pathogenic GAA repeat was 309 repeats (range: 270–316 repeats). In these patients, the mean age of onset was 66.9 ± 9.6 years, with episodic symptoms observed in 56% of patients and parkinsonism in 30% of patients. We also detected FGF14 repeat expansions in a patient with a phenotype of multiple system atrophy, including cerebellar ataxia, parkinsonism, autonomic ataxia, and bilateral vocal cord paralysis. Brain magnetic resonance imaging (MRI) showed normal to mild cerebellar atrophy, and a follow-up study conducted after a mean period of 6 years did not reveal any significant progression. Discussion: This study highlights the importance of FGF14 GAA repeat analysis in patients with late-onset cerebellar ataxia, particularly when they exhibit episodic symptoms, or their brain MRI shows no apparent cerebellar atrophy. Our findings contribute to a better understanding of the clinical variability of GAA-FGF14-related diseases.

DOI： 10.1002/acn3.51936

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記述言語：日本語   出版者・発行元：Clinical and Experimental Neuroimmunology  

Background: Initially associated with stiff-person syndrome, antibodies to glutamic acid decarboxylase (GAD) antibodies are now recognized as indicators of GAD antibody-spectrum disorders (GAD-SD), which encompass cerebellar ataxia, autoimmune epilepsy and limbic encephalitis. Paraneoplastic neurological syndromes associated with GAD-SD are rare, and optimal timing of surgical intervention and impact on neurological symptoms remain poorly understood. Case Presentation: We present the case of a 65-year-old woman who developed overlapping symptoms of cerebellar ataxia and stiff-person syndrome detected through high-titer GAD antibodies in both serum and cerebrospinal fluid, alongside the presence of a thymoma. Due to severe dysphagia and gait ataxia that rendered her bedridden on admission, surgical intervention was initially deferred. Instead, she received immunotherapies including intravenous methylprednisolone and intravenous immunoglobulin, which remarkably improved neurological symptoms. However, a decline in symptoms occurred on tapering oral prednisolone. Subsequently, a thoracoscopic thymectomy was carried out 27 months after symptom onset, leading to further neurological improvement and successful reduction of prednisolone. Conclusion: In paraneoplastic GAD-SD cases with severe symptoms at presentation, prioritizing immunotherapy and considering surgical intervention once the symptoms have stabilized might be advantageous.

DOI： 10.1111/cen3.12764

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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：Journal of Neurology Neurosurgery and Psychiatry  

Background NOTCH2NLC GGC repeat expansions have been associated with various neurogenerative disorders, including neuronal intranuclear inclusion disease and inherited peripheral neuropathies (IPNs). However, only a few NOTCH2NLC-related disease studies in IPN have been reported, and the clinical and genetic spectra remain unclear. Thus, this study aimed to describe the clinical and genetic manifestations of NOTCH2NLC-related IPNs. Method Among 2692 Japanese patients clinically diagnosed with IPN/Charcot-Marie-Tooth disease (CMT), we analysed NOTCH2NLC repeat expansion in 1783 unrelated patients without a genetic diagnosis. Screening and repeat size determination of NOTCH2NLC repeat expansion were performed using repeat-primed PCR and fluorescence amplicon length analysis-PCR. Results NOTCH2NLC repeat expansions were identified in 26 cases of IPN/CMT from 22 unrelated families. The mean median motor nerve conduction velocity was 41 m/s (range, 30.8-59.4), and 18 cases (69%) were classified as intermediate CMT. The mean age of onset was 32.7 (range, 7-61) years. In addition to motor sensory neuropathy symptoms, dysautonomia and involuntary movements were common (44% and 29%). Furthermore, the correlation between the age of onset or clinical symptoms and the repeat size remains unclear. Conclusions These findings of this study help us understand the clinical heterogeneity of NOTCH2NLC-related disease, such as non-length-dependent motor dominant phenotype and prominent autonomic involvement. This study also emphasise the importance of genetic screening, regardless of the age of onset and type of CMT, particularly in patients of Asian origin, presenting with intermediate conduction velocities and dysautonomia.

DOI： 10.1136/jnnp-2022-330769

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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：Jci Insight  

Human T lymphotropic virus type 1-assoicated (HTLV-1-associated) myelopathy/tropical spastic paraparesis (HAM/TSP) is a neuroinflammatory disease caused by the persistent proliferation of HTLV-1-infected T cells. Here, we performed a T cell receptor (TCR) repertoire analysis focused on HTLV-1-infected cells to identify and track the infected T cell clones that are preserved in patients with HAM/TSP and migrate to the CNS. TCRβ repertoire analysis revealed higher clonal expansion in HTLV-1-infected cells compared with noninfected cells from patients with HAM/TSP and asymptomatic carriers (ACs). TCR clonality in HTLV-1-infected cells was similar in patients with HAM/TSP and ACs. Longitudinal analysis showed that the TCR repertoire signature in HTLV-1-infected cells remained stable, and highly expanded infected clones were preserved within each patient with HAM/TSP over years. Expanded HTLV-1-infected clones revealed different distributions between cerebrospinal fluid (CSF) and peripheral blood and were enriched in the CSF of patients with HAM/TSP. Cluster analysis showed similarity in TCRβ sequences in HTLV-1-infected cells, suggesting that they proliferate after common antigen stimulation. Our results indicate that exploring TCR repertoires of HTLV-1-infected cells can elucidate individual clonal dynamics and identify potential pathogenic clones expanded in the CNS.

DOI： 10.1172/jci.insight.167422

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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：Annals of Clinical and Translational Neurology  

Objective: HTLV-1 infection causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), resulting in loss of motor function. In this Phase 2 trial, we assessed the efficacy and safety of l-arginine in patients with HAM/TSP. Methods: This open-label, single-arm, Phase 2 study enrolled patients diagnosed with HAM/TSP. Patients received l-arginine at a dose of 20 g orally for 1 week and were followed-up for 3 weeks. The primary endpoint was change in walking speed in the 10-m walk test (10MWT). The main secondary endpoints were change in Timed Up and Go Test (TUGT) time, improvement in inflammatory markers in cerebrospinal fluid (CSF), safety, and tolerability. Results: The study enrolled 20 patients (13 [65%] female) with a mean age of 67.8 years (95% CI 62.3 to 73.3). Although the primary endpoint, the changes in 10MWT time between baseline (Day 0) and Day 7, did not reach statistical significance (mean percent change in time −3.5%, 95% CI −10.8% to 3.7%; P = 0.32), a significant improvement was detected between baseline and Day 14 (−9.4%, 95% CI −16.6% to −2.2%; P = 0.01). Significant improvements were also observed in selected secondary endpoints, including in TUGT time (−9.1%, 95% CI −15.5% to −2.7%; P < 0.01), and in neopterin concentration in CSF (−2.1 pmol/mL, 95% CI −3.8 to −0.5; P = 0.01). Adverse events were infrequent, mild, and resolved rapidly. Interpretation: l-arginine therapy improved motor function and decreased CSF inflammatory markers. l-arginine thus represents a promising therapeutic option for patients with HAM/TSP. Trial Registration Number: UMIN000023854.

DOI： 10.1002/acn3.51715

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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 in Neurology  

Introduction: Genetic factors are recognized as the major reason for patients with periodic paralysis. The goal of this study was to determine the genetic causes of periodic paralysis in Japan. Methods: We obtained a Japanese nationwide case series of 119 index patients (108 men and 11 women) clinically suspected of periodic paralysis, and a gene panel analysis, targeting CACNA1S, SCN4A, and KCNJ2 genes, was conducted. Results: From 34 cases, 25 pathogenic/likely pathogenic/unknown significance variants were detected in CACNA1S (nine cases), SCN4A (19 cases), or KCNJ2 (six cases), generating a molecular diagnostic rate of 28.6%. In total, seven variants have yet been found linked to periodic paralysis previously. The diagnostic yield of patients with hypokalemic and hyperkalemic periodic paralyzes was 26.2 (17/65) and 32.7% (17/52), respectively. A considerably higher yield was procured from patients with than without positive family history (18/25 vs. 16/94), onset age ≤20 years (24/57 vs. 9/59), or recurrent paralytic attacks (31/94 vs. 3/25). Discussion: The low molecular diagnostic rate and specific genetic proportion of the present study highlight the etiological complexity of patients with periodic paralysis in Japan.

DOI： 10.3389/fneur.2023.1078195

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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 in Neurology  

Objective: Autoimmune autonomic ganglionopathy (AAG) is a rare disorder characterized by autonomic failure associated with the presence of anti-ganglionic acetylcholine receptor (gAChR) antibodies; however, several studies have reported that individuals with anti-gAChR antibodies present with central nervous system (CNS) symptoms such as impaired consciousness and seizures. In the present study, we investigated whether the presence of serum anti-gAChR antibodies correlated with autonomic symptoms in patients with functional neurological symptom disorder/conversion disorder (FNSD/CD). Methods: Clinical data were collected for 59 patients presenting with neurologically unexplained motor and sensory symptoms at the Department of Neurology and Geriatrics between January 2013 and October 2017 and who were ultimately diagnosed with FNSD/CD according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Correlations between serum anti-gAChR antibodies and clinical symptoms and laboratory data were analyzed. Data analysis was conducted in 2021. Results: Of the 59 patients with FNSD/CD, 52 (88.1%) exhibited autonomic disturbances and 16 (27.1%) were positive for serum anti-gAChR antibodies. Cardiovascular autonomic dysfunction, including orthostatic hypotension, was significantly more prevalent (75.0 vs. 34.9%, P = 0.008), whereas involuntary movements were significantly less prevalent (31.3 vs. 69.8%, P = 0.007), among anti-gAChR antibody-positive compared with -negative patients. Anti-gAChR antibody serostatus did not correlate significantly with the frequency of other autonomic, sensory, or motor symptoms analyzed. Conclusions: An autoimmune mechanism mediated by anti-gAChR antibodies may be involved in disease etiology in a subgroup of FNSD/CD patients.

DOI： 10.3389/fneur.2023.1137958

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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：Journal of Neurology  

Non-dystrophic myotonias (NDM) are rare skeletal muscle channelopathies, mainly linked to two voltage-gated ion channel genes, CLCN1 and SCN4A. The aim of this study is to identify the clinical and genetic features of patients with NDM in Japan. We collected a Japanese nationwide case series of patients with clinical diagnosis of NDM (1999–2021). Among 71 out of 88 pedigrees, using Sanger and next-generation sequencing targeting both CLCN1 and SCN4A genes, variants classified as pathogenic/likely pathogenic/unknown significance were detected from CLCN1 (31 probands), SCN4A (36 probands), or both genes (4 probands), and 11 of them were novel. Pedigrees carrying mono-allelic CLCN1 variants were more commonly seen than that with bi-allelic/double variants (24:7). Compared to patients with CLCN1 variants, patients harboring SCN4A variants showed younger onset age (5.64 ± 4.70 years vs. 9.23 ± 5.21 years), fewer warm-up phenomenon, but more paramyotonia, hyperCKemia, transient muscle weakness, and cold-induced myotonia. Haplotype analysis verified founder effects of the hot spot variants in both CLCN1 (p.T539A) and SCN4A (p.T1313M). This study reveals variants in CLCN1 and SCN4A from 80.7% of our case series, extending genetic spectrum of NDM, and would further our understanding of clinical similarity/diversity between CLCN1- and SCN4A-related NDM, as well as the genetic racial differences.

DOI： 10.1007/s00415-022-11305-6

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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：Cerebellum  

The presence of fragile X mental retardation 1 (FMR1) premutation has been linked to patients with a certain type of cerebellar ataxia, the fragile X-associated tremor/ataxia syndrome (FXTAS). However, its prevalence in Japan has yet to be clarified. The aim of the present study is to determine the prevalence of FXTAS in Japanese patients with cerebellar ataxia and to describe their clinical characteristics. DNA samples were collected from 1328 Japanese patients with cerebellar ataxia, referred for genetic diagnosis. Among them, 995 patients with negative results for the most common spinocerebellar ataxia subtypes were screened for FMR1 premutation. Comprehensive clinical and radiological analyses were performed for the patients harbouring FMR1 premutation. We herein identified FMR1 premutation from one female and two male patients, who satisfied both clinical and radiological criteria of FXTAS (0.3%; 3/995) as well. Both male patients presented with high signal intensity of corticomedullary junction on diffusion-weighted magnetic resonance imaging, a finding comparable to that of neuronal intranuclear inclusion disease. The female patient mimicked multiple system atrophy in the early stages of her disease and developed aseptic meningitis with a suspected immune-mediated mechanism after the onset of FXTAS, which made her unique. Despite the lower prevalence rate in Japan than the previous reports in other countries, the present study emphasises the necessity to consider FXTAS with undiagnosed ataxia, regardless of men or women, particularly for those cases presenting with similar clinical and radiological findings with multiple system atrophy or neuronal intranuclear inclusion disease.

DOI： 10.1007/s12311-021-01323-x

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記述言語：英語   出版者・発行元：Nature Publishing Group  

複数の日本人家系から、NEFH遺伝子に関連した臨床/遺伝学的スペクトラムが認められたため報告した。Charcot-Marie-Tooth(CMT)病および脊髄性筋萎縮症(SMA)を含む、日本全国の神経筋疾患患者から得た全エクソームシークエンシングデータを用いて、NEFH遺伝子の全てのバリアントを解析した。その結果、臨床的にCMTと診断された3家系(男性6例、女性1例、検査時年齢55歳～81歳)と、SMAと診断された1家系(男性1例、検査時年齢38歳)から、NEFH遺伝子にバリアントc.3017dup (p.Pro1007Alafs*56)が同定された。また、典型的な末梢神経障害を呈した患者に加え、CMT患者1例には錐体路兆候が、SMA患者には上腕三頭筋と大腿四頭筋に特徴的な、重度の筋力低下も認められた。さらに、これら4家系が全て鹿児島県在住の家系で、その後のハプロタイプ解析では、創始者効果が強く示唆された。本報はNEFH遺伝子の創始者変異に関する初報告例となり、得られた知見により、NEFH遺伝子関連疾患の表現型スペクトラムが拡大された。

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Annals of Clinical and Translational Neurology  

Background: Recessive mutations in SLC12A6 have been linked to hereditary motor sensory neuropathy with agenesis of the corpus callosum. Patients with early-onset peripheral neuropathy associated with SLC12A6 heterozygous variants were reported in 2016. Only five families and three variants have been reported to date, and the spectrum is unclear. Here, we aim to describe the clinical and mutation spectra of SLC12A6-related Charcot–Marie–Tooth (CMT) disease in Japanese patients. Methods: We extracted SLC12A6 variants from our DNA microarray and targeted resequencing data obtained from 2598 patients with clinically suspected CMT who were referred to our genetic laboratory by neurological or neuropediatric departments across Japan. And we summarized the clinical and genetic features of these patients. Results: In seven unrelated families, we identified one previously reported and three novel likely pathogenic SLC12A6 heterozygous variants, as well as two variants of uncertain significance. The mean age of onset for these patients was 17.5 ± 16.1 years. Regarding electrophysiology, the median motor nerve conduction velocity was 39.6 ± 9.5 m/sec. For the first time, we observed intellectual disability in three patients. One patient developed epilepsy, and her brain MRI revealed frontal and temporal lobe atrophy without changes in white matter and corpus callosum. Conclusions: Screening for the SLC12A6 gene should be considered in patients with CMT, particularly those with central nervous system lesions, such as cognitive impairment and epilepsy, regardless of the CMT subtype.

DOI： 10.1002/acn3.51603

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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：Journal of Human Genetics  

Background and aims: Mutations in neurofilament genes have been linked to several neuromuscular disorders. The neurofilament heavy (NEFH) gene was identified as the causative gene of Charcot–Marie–Tooth disease type 2CC (CMT2CC) in 2016, with a toxic gain of function mechanism caused by the translation and aggregation of cryptic amyloidogenic element (CAE) in the 3′ untranslated region (UTR). But the NEFH-related clinical and genetic spectrums are still unclear in Japan. Methods: We analyzed all variants in the NEFH gene from our in-house whole-exome sequencing data, established from Japanese nationwide patients with neuromuscular disorders, including Charcot–Marie–Tooth (CMT) disease and spinal muscular atrophy (SMA). Results: We identified a c.3017dup (p.Pro1007Alafs*56) variant in NEFH from three families clinically diagnosed with CMT, and one family with SMA. In addition to the patients presented with typical peripheral neuropathies, pyramidal signs were observed from one CMT patient. Whereas the SMA patients showed severe characteristic weakness of triceps brachii and quadriceps femoris. All of these four families reside in Kagoshima Prefecture of Japan, and a following haplotype analysis strongly suggests a founder effect. Interpretation: This is the original report referring to a founder mutation in NEFH. The clinical diversity in our study, comprising CMT, with or without pyramidal signs, and SMA, suggest an extensive involvement of peripheral nerve, anterior horn cells, or both. Our findings broaden the phenotypic spectrum of NEFH-related disorders.

DOI： 10.1038/s10038-022-01019-y

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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：Biomedicines  

Various genomic variants were linked to inherited peripheral neuropathies (IPNs), including large duplication/deletion and repeat expansion, making genetic diagnosis challenging. This large case series aimed to identify the genetic characteristics of Japanese patients with IPNs. We collected data on 2695 IPN cases throughout Japan, in which PMP22 copy number variation (CNV) was pre-excluded. Genetic analyses were performed using DNA microarrays, next-generation sequencing-based gene panel sequencing, whole-exome sequencing, CNV analysis, and RFC1 repeat expansion analysis. The overall diagnostic rate and the genetic spectrum of patients were summa-rized. We identified 909 cases with suspected IPNs, pathogenic or likely pathogenic variants. The most common causative genes were MFN2, GJB1, MPZ, and MME. MFN2 was the most common cause for early-onset patients, whereas GJB1 and MPZ were the leading causes of middle-onset and late-onset patients, respectively. Meanwhile, GJB1 and MFN2 were leading causes for demyelinating and axonal subtypes, respectively. Additionally, we identified CNVs in MPZ and GJB1 genes and RFC1 repeat expansions. Comprehensive genetic analyses explicitly demonstrated the genetic basis of our IPN case series. A further understanding of the clinical characteristics of IPN and genetic spectrum would assist in developing efficient genetic testing strategies and facilitate early diagnosis.

DOI： 10.3390/biomedicines10071546

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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：Annals of Clinical and Translational Neurology  

Background: Biallelic POLR3B mutations cause a rare hypomyelinating leukodystrophy. De novo POLR3B heterozygous mutations were recently associated with afferent ataxia, spasticity, variable intellectual disability, and epilepsy, and predominantly demyelinating sensorimotor peripheral neuropathy. Methods: We performed whole-exome sequencing (WES) of DNA samples from 804 Charcot–Marie–Tooth (CMT) cases that could not be genetically diagnosed by DNA-targeted resequencing microarray using next-generation sequencers. Using WES data, we analyzed the POLR3B mutations and confirmed their clinical features. Results: We identified de novo POLR3B heterozygous missense mutations in two patients. These patients presented with early-onset demyelinating sensorimotor neuropathy without ataxia, spasticity, or cognitive impairment. Patient 1 showed mild cerebellar atrophy and spinal cord atrophy on magnetic resonance imaging and eventually died of respiratory failure in her 50s. We classified these mutations as pathogenic based on segregation studies, comparison with control database, and in silico analysis. Conclusion: Our study is the third report on patients with demyelinating CMT harboring heterozygous POLR3B mutations and verifies the pathogenicity of POLR3B mutations in CMT. Although extremely rare in our large Japanese case series, POLR3B mutations should be added to the CMT-related gene panel for comprehensive genetic screening, particularly for patients with early-onset demyelinating CMT.

DOI： 10.1002/acn3.51555

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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 in Neurology  

Non-coding repeat expansions within RFC1 and NOTCH2NLC genes have lately been linked to multisystem neurodegenerative diseases, which also shed light on yet undiagnosed patients with inherited peripheral neuropathies. The aim of this study was to identify the genetic basis of patients with hereditary sensory and autonomic neuropathy (HSAN). We collected 79 unrelated DNA samples clinically suspected with HSAN from multiple regions of Japan. Mutation screening was first performed using gene panel sequencing and whole-exome sequencing. Pathogenic/likely pathogenic variants were identified from genes of WNK1/HSN2 (6 cases), SCN9A (3 cases), NTRK1 (3 cases), and DNMT1 (2 cases). Subsequently, long-range flanking PCR and repeat-primed PCR were applied to analyze repeat expansions in RFC1 and NOTCH2NLC. Bi-allelic RFC1 repeat expansions were detected from 20 adult-onset HSAN patients, consisting of [(AAGGG)exp/(AAGGG)exp] (8 cases), [(ACAGG)exp/(ACAGG)exp] (8 cases), and [(AAGGG)exp/(ACAGG)exp] (4 cases). GGC repeat expansion in NOTCH2NLC was found in 1 case. Single-nucleotide variant-based haplotype analysis of patients harboring disease-associated repeat expansions in RFC1 revealed distinguishable haplotypes among subgroups with different repeat genotypes. These findings substantially redefine the genetic spectrum of HSAN, where multi-type RFC1 repeat expansions account for 25.3% of all patients, highlighting the necessity of genetic screening, particularly for adult-onset patients.

DOI： 10.3389/fneur.2022.986504

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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 in Neurology  

The recessive intronic pentanucleotide repeat AAGGG expansion of replication factor complex subunit 1 (RFC1) is associated with cerebellar ataxia, sensory neuropathy, and vestibular areflexia syndrome. And the clinical spectrum has been continuously expanding. We conducted this study to demonstrate the clinical and genetic features of a large-scale case series of Japanese patients with cerebellar ataxia with RFC1 repeat expansions. We examined 1,289 Japanese patients with cerebellar ataxia and analyzed RFC1 repeat expansions in 840 patients, excluding those with genetic diagnoses or an autosomal dominant inheritance pattern. For individuals where no product was obtained by flanking polymerase chain reaction (PCR), repeat-primed PCR was performed using primers specific for the following four repeat motifs: AAAAG, AAAGG, AAGGG, and ACAGG. RFC1 analysis revealed multitype biallelic pathogenic repeat expansions in 15 patients, including (AAGGG)exp/(AAGGG)exp in seven patients, (ACAGG)exp/(ACAGG)exp in three patients, (AAGGG)exp/(ACAGG)exp in four patients, and (AAGGG)exp/(AAAGG)<inf>15</inf>(AAGGG)exp in one patient. Clinical analysis showed various combinations of cerebellar ataxia, vestibular dysfunction, neuropathy, cognitive decline, autonomic dysfunction, chronic cough, pyramidal tract disorder, parkinsonism, involuntary movement, and muscle fasciculation. Pathological RFC1 repeat expansions account for 1.8% (15/840) of undiagnosed patients with cerebellar ataxia and sporadic/recessive/unclassified inheritance. Screening of RFC1 repeat expansions should be considered in patients with cerebellar ataxia, irrespective of their subtype and onset age.

DOI： 10.3389/fneur.2022.952493

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

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

DOI： 10.1016/j.neurobiolaging.2020.06.017

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

出版者・発行元：一般社団法人 日本内科学会  

<p>We herein report a 50-year-old man with alcoholic cirrhosis who developed loss of consciousness and tremor of the upper limbs. Magnetic resonance imaging findings were suggestive of limbic encephalitis with bilateral hippocampal damage, and a cerebrospinal fluid (CSF) examination confirmed anti-N-methyl-D-aspartate (NMDA) and anti-glutamate receptor antibodies. Despite initial corticosteroid therapy, meningeal irritation symptoms appeared, owing to the development of cryptococcal meningitis (CM), diagnosed by the detection of cryptococcal capsular polysaccharide antigen in the follow-up CSF analysis. Cerebral infarction with reversible stenosis of major cerebral arteries during the clinical course was also observed. Following administration of antifungals and corticosteroids, the number of cells in the CSF gradually declined, and NMDA receptor antibodies disappeared. Our study demonstrates the unique coexistence of CM with anti-NMDA receptor encephalitis in adults. </p>

DOI： 10.2169/internalmedicine.4629-20

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出版者・発行元：日本神経学会  

<p>症例は43歳男性である．緩徐に進行する構音障害と歩行失調，幼児退行などの精神症状，脳幹・小脳の萎縮性所見より脊髄小脳変性症が疑われ入院した．口内炎，陰部潰瘍，毛囊炎様皮疹，HLA-B51をみとめ，髄液IL-6高値より慢性進行型神経ベーチェット病と診断した．ステロイド，メトトレキサートの治療効果に乏しく，インフリキシマブで髄液IL-6の減少が得られたが症状は改善しなかった．本症例は広範に不可逆性の脳組織障害が生じた難治例と考えられた．脳幹の萎縮が進行する前に免疫治療を介入すべき疾患であり，精神症状と運動失調症がみられる症例では診断に有用である髄液IL-6を測定することが望ましい．</p>

DOI： 10.5692/clinicalneurol.cn-001086

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出版者・発行元：日本神経治療学会  

<p>We reviewed the recent advances in therapeutics of spinocerebellar degeneration (SCD) that were published in 2017. This article introduces the outline of therapies with antisense oligonucleotide, docosahexaenoic acid, mesenchymal stem cells, acetyl–DL–leucine, and rehabilitation using wearable devices and virtual reality. We expect that these treatments will contribute to patients with SCD.</p>

DOI： 10.15082/jsnt.35.5_605

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出版者・発行元：一般社団法人 日本内科学会  

<p>42歳，男性．全身の発汗低下を主訴に受診した．起立性低血圧や頻尿を伴い，広汎な自律神経障害が示唆された．皮膚生検で汗腺及び血管周囲にリンパ球浸潤を認め，抗ganglionicアセチルコリン受容体抗体陽性が判明した．通常，同抗体は自己免疫性自律神経節障害（autoimmune autonomic ganglionopathy：AAG）の原因となるが，汗腺への直接作用は明らかでない．本症例には汗腺と自律神経節障害の両者の特徴が混在し，ステロイド治療が有効であった．</p>

DOI： 10.2169/naika.107.95

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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：Journal of Dermatology  

DOI： 10.1111/1346-8138.13870

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記述言語：英語   出版者・発行元：The Japanese Society of Internal Medicine  

Mitochondrial myopathy with episodic hyper-creatine kinase (CK)-emia (MIMECK) is a new disease entity characterized by episodic or persistent muscle weakness and elevated CK levels. We herein report two cases of MIMECK with the findings of histopathological studies. Histopathological examinations revealed strongly succinate dehydrogenase-reactive vessels. Electron microscopy showed abnormal mitochondria in the vessels and proliferating and vacuolated mitochondria under the sarcolemma. Both patients exhibited recurrent severe myalgia, weakness and increased CK levels. L-arginine treatment significantly ameliorated their muscle symptoms. These findings indicate that mitochondrial angiopathy plays an important role in the pathophysiology of MIMECK. L-arginine may be a potential therapeutic agent for this disorder.<br>

DOI： 10.2169/internalmedicine.54.5444

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記述言語：英語   出版者・発行元：The Japanese Society of Internal Medicine  

Emery-Dreifuss muscular dystrophy (EDMD) is caused by mutations in the <i>EMD</i> gene on the X chromosome, which codes for emerin, an inner nuclear membrane protein. Monoclonal antibodies against the N-terminus of emerin protein are used to screen for emerin deficiency in clinical practice. However, these tests may not accurately reflect the disease in some cases. We herein describe the identification of a splice site mutation in the <i>EMD</i> gene in a Japanese patient who suffered from complete atrioventricular conduction block, mild muscle weakness and joint contracture, and a persistently elevated serum creatine kinase level. We used multiple antibodies to confirm the presence of a novel truncating mutation in emerin without the transmembrane region and C-terminus in the skeletal muscle.<br>

DOI： 10.2169/internalmedicine.53.8922

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記述言語：日本語   出版者・発行元：日本神経学会  

症例は70歳男性である．右上肢の脱力および感覚障害にて発症した．病初期はCIDPと診断され，一時的に免疫グロブリン大量静注療法，ステロイドなどの免疫療法の効果がみられたが，しだいに治療抵抗性の経過を辿り進行した．後に，<i>PMP22</i>遺伝子重複が判明し，CMT1Aと診断された．腓腹神経生検では onion bulb形成に加え炎症細胞の浸潤をともなう脱髄がみとめられた．その後も，筋力低下は四肢・体幹に急速に拡大し，球麻痺，呼吸筋麻痺も出現し，発症から約4年の経過で死亡した．病理解剖にてALSと組織診断した．本症例はCMT1AにALSを合併したはじめての症例報告である．<br>

DOI： 10.5692/clinicalneurol.52.750

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

担当区分：筆頭著者   記述言語：日本語   掲載種別：速報，短報，研究ノート等（学術雑誌）