Faculty Profiles - TAKASHIMA Hiroshi

Papers - TAKASHIMA Hiroshi

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Ito Yuko, Ochi Chikako, Yamanishi Yuki, Takashima Hiroshi, Hashiguchi Akihiro, Nagai Masahiro . A case of recurrent cerebellitis leading to the diagnosis of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) . Rinsho Shinkeigaku66 ( 3 ) 192 - 193 2026

Sato T, Tsuchimochi Y, Hamada Y, Kukihara K, Kawabata Y, Iwamoto K, Takaguchi G, Higuchi Y, Matsuoka H, Takashima H . Fibrosis-4 index and prognosis and hematoma volume: association with lobar and non-lobar intracerebral hemorrhage. . Hypertension research : official journal of the Japanese Society of Hypertension49 ( 3 ) 628 - 640 2025.12

Language：English Publisher：Hypertension Research

Liver fibrosis is a proposed risk factor for intracerebral hemorrhage (ICH) and a predictor of ICH-related mortality. However, its impact on functional outcomes and hemorrhage location remains unclear. We aimed to investigate whether liver fibrosis is associated with clinical outcomes and hematoma characteristics according to ICH location. Consecutive patients with ICH between July 2012 and November 2023 were retrospectively included. Favorable outcomes were defined as a modified Rankin Scale score of 0 to 1 at 3 months following stroke onset. We elucidated whether liver fibrosis, assessed by the Fibrosis-4 index (FIB-4 index), was associated with prognosis and hematoma volume in the entire ICH cohort, and separately in lobar and non-lobar ICH cohorts. Following screening of 608 consecutive ICH patients, 356 patients with ICH (entire cohort) who met the inclusion criteria (198 [56%] males, median age 73 years), including 69 with lobar ICH and 287 patients with non-lobar ICH, were identified. Similar to the entire ICH cohort, especially in the lobar ICH cohort, the FIB-4 index correlated negatively with favorable outcomes (prevalence ratio (PR) 0.823, 95% confidence interval (CI) 0.692–0.979, p = 0.027) and positively with hematoma volume (unstandardized coefficient 3.914, 95% CI 1.914–5.915, p < 0.001). Conversely, the FIB-4 index was associated with neither prognosis nor hematoma volume in the non-lobar ICH cohort. Liver fibrosis, as assessed by the FIB-4 index, is associated with unfavorable outcomes and hematoma volume in ICH, particularly in lobar ICH. (Figure presented.)

DOI： 10.1038/s41440-025-02487-3

Jun-Hui Yuan, Yujiro Higuchi, Masahiro Ando, Akihiro Hashiguchi, Yuji Okamoto, Yu Hiramatsu, Akiko Yoshimura, Kento Kodama, Yusuke Sakiyama, Jun Mitsui, Shoji Tsuji, Hiroshi Takashima . Respiratory complex I deficiency caused by a novel multi-exonic PUS1 deletion. . Journal of human genetics71 ( 5 ) 275 - 282 2025.12International journal

Language：English Publishing type：Research paper (scientific journal)

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

Yamashiro M., Yasutomi D., Ohya Y., Ohyama S., Takashima H., Tokashiki T. . A case of coexisting heterozygous NOTCH3 and HTRA1 mutations in cerebral small vessel disease . Human Genome Variation12 ( 1 ) 13 2025.12

Language：Japanese Publisher：Human Genome Variation

Hereditary cerebral small vessel diseases (CSVDs) include cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy caused by biallelic HTRA1, and heterozygous HTRA1-related CSVD. Here we report a case of a 53-year-old Japanese woman with coexisting NOTCH3 p.R75P and HTRA1 p.R166L mutations, each in the heterozygote. She presented with early-onset spastic paraparesis, frequent urination, cognitive impairment and baldness. We compared the clinical features of this case with known phenotypes of CADASIL caused by p.R75P, HTRA1-related CSVD. We reported cases with heterozygous HTRA1 p.R166L to discuss the potential synergistic effects of the coexisting variants.

DOI： 10.1038/s41439-025-00317-z

Jun-Hui Yuan, Yujiro Higuchi, Masahiro Ando, Yu Hiramatsu, Akiko Yoshimura, Takahiro Hobara, Fumikazu Kojima, Tomonori Nakamura, Yusuke Sakiyama, Satoshi Nozuma, Satoshi Ohyama, Jun Mitsui, Shoji Tsuji, Hiroshi Takashima . Frameshift and Copy Number Variants in SACS-Related Neuropathy. . Neurology. Genetics11 ( 6 ) e200318 2025.12International journal

Language：English Publishing type：Research paper (scientific journal)

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

Honkawa Yuta, Kuwagaki Shiori, Hayashida Hitoshi, Higuchi Yujiro, Takashima Hiroshi, Ikezoe Koji . A case of adult-onset Krabbe disease diagnosed by <i>galactocerebrosidase</i> gene mutations, presenting with an atypical phenotype . Rinsho Shinkeigaku65 ( 11 ) 808 - 812 2025.11

Language：Japanese Publisher：Societas Neurologica Japonica

<p>Adult-onset Krabbe disease is a rare neurodegenerative disorder caused by mutations in the <i>galactocerebrosidase</i> (<i>GALC</i>) gene. It typically presents with slowly progressive central nervous system involvement, primarily characterized by pyramidal tract signs. We report the case of a 74-year-old man who presented with slowly progressive, asymmetric muscle atrophy associated with peripheral neuropathy, but without any clinical evidence of pyramidal tract involvement. Neurological examination revealed muscle wasting and weakness without spasticity or pathological reflexes. Based on the clinical presentation, differential diagnoses included motor neuron disease, Charcot–Marie–Tooth disease, and chronic inflammatory demyelinating polyneuropathy. Genetic analysis revealed a known pathogenic missense variant in the <i>GALC</i> gene: c.246A>G (p.I82M), confirming the diagnosis of Krabbe disease. These mutations have been previously reported in adult-onset Krabbe disease. This case lacked typical central nervous system signs and represents an atypical phenotype that may lead to delayed diagnosis. Our findings suggest that Krabbe disease should be considered in the differential diagnosis of adult patients presenting with unexplained neuropathy and marked muscle atrophy. Genetic testing plays a critical role in identifying such atypical cases, particularly when conventional diagnostic approaches fail to provide a definitive diagnosis.</p>

DOI： 10.5692/clinicalneurol.cn-002148

矢野直志, 髙嶋博 . 特集シャルコーを讃えて-Hommage à Charcot シャルコー･マリー･トゥース病-疾患概念の確立と現況 . BRAIN and NERVE77 ( 11 ) 1176 - 1184 2025.11

Dozono M., Nozuma S., Hirakata S., Yoshida T., Kodama D., Tanaka M., Matsuura E., Kubota R., Takashima H. . Clinical Characteristics of Parkinsonism in HTLV-1-Associated Myelopathy . Annals of Clinical and Translational Neurology12 ( 10 ) 1962 - 1970 2025.10

Language：Japanese Publisher：Annals of Clinical and Translational Neurology

Objective: Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is the classic neurological manifestation of HTLV-1 infection; however, this virus has also been associated with other neurological disorders. Concurrent parkinsonism is relatively rare and presents diagnostic challenges. The present study aimed to identify the clinical characteristics of HAM/TSP with parkinsonism. Methods: This retrospective study included HAM/TSP patients hospitalized in Kagoshima University Hospital from January 2000 to March 2022. Clinical and laboratory findings of the HAM/TSP patients with parkinsonism (P-HAM) were collected from the medical records and compared with HAM/TSP patients without parkinsonism (typical HAM/TSP [T-HAM]). P-HAM cases were defined as patients presenting with any combination of rigidity, resting tremor, bradykinesia, and/or postural instability, with these symptoms not attributed to HAM/TSP. Results: Of 246 HAM/TSP patients, 11 (4.5%) presented with parkinsonism. Compared with T-HAM, the age of onset was significantly older (65.0 vs. 48.8 years, p = 0.001) in patients with P-HAM. Moreover, despite a shorter illness duration (8.5 vs. 12.5 years, p = 0.151), the Osame Motor Disability Score was significantly higher in P-HAM cases than in T-HAM cases (6.3 vs. 4.6, p = 0.0132), and all P-HAM cases had scores ≥ 4. Laboratory findings showed no differences between the groups. Interpretation: In our cohort, 4.5% of HAM/TSP patients had concomitant parkinsonism, which was associated with a later age of onset and greater disease severity. The coexistence of parkinsonism in HAM/TSP may be underrecognized, and our findings expand the clinical spectrum of neurological disease with HTLV-1 infection.

DOI： 10.1002/acn3.70121

Takeo Sato, Yuka Tsuchimochi, Yuki Hamada, Kaishi Kukihara, Yutaro Kawabata, Kana Iwamoto, Go Takaguchi, Yujiro Higuchi, Hideki Matsuoka, Hiroshi Takashima . Lower high-density lipoprotein cholesterol level is associated with hematoma expansion in acute intracerebral hemorrhage: association with hypertensive microangiopathy. . Hypertension research : official journal of the Japanese Society of Hypertension48 ( 9 ) 2326 - 2338 2025.9International journal

Language：Japanese Publishing type：Research paper (scientific journal)

The correlation between lipoprotein cholesterol levels and hematoma expansion (HE) following intracerebral hemorrhage (ICH) remains unknown. We aimed to elucidate the correlation between high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels and HE following acute ICH in entire ICH, non-lobar ICH, and lobar ICH cohorts. Consecutive patients with ICH between July 2012 and November 2023 were screened. The inclusion criteria were: (1) onset to door time within 24 h; (2) availability of serum HDL-C and LDL-C level evaluations on admission; and (3) availability of HE evaluation. We investigated the association between HDL-C and LDL-C levels and HE using Poisson regression analyses with a robust variance estimator in three models with adjustment for various factors. Screening of 608 consecutive ICH patients revealed 409 with acute ICH (204 [50%] males, median age 75 years). HE was observed in 43 patients (11%). In the entire ICH cohort, lower HDL-C was independently associated with HE in all the study models (p < 0.05). Further, a negative linear association was observed between HDL-C quartiles and HE in reference to HDL-C Quartile 4 in all the models (p < 0.05 for trend). These significant associations were also observed in the non-lobar ICH cohort, but not in the lobar ICH cohort. LDL-C was not associated with HE in any of the cohorts. In acute ICH patients, lower HDL-C was associated with HE, especially in the non-lobar ICH cohort generally caused by hypertensive microangiopathy. HDL-C might have protective potential against HE following ICH. We aimed to elucidate the correlation between high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels and hematoma expansion (HE) following acute intracerebral hemorrhage (ICH). Lower HDL-C was associated with HE, especially in the non-lobar ICH caused by hypertensive microangiopathy. HDL-C might have protective potential against HE following ICH.

DOI： 10.1038/s41440-025-02268-y

Sato Takeo, Tsuchimochi Yuka, Hamada Yuki, Kukihara Kaishi, Kawabata Yutaro, Iwamoto Kana, Takaguchi Go, Higuchi Yujiro, Matsuoka Hideki, Takashima Hiroshi . 【Current evidence and perspectives for hypertension management in Asia】Lower high-density lipoprotein cholesterol level is associated with hematoma expansion in acute intracerebral hemorrhage: association with hypertensive microangiopathy(タイトル和訳中) . Hypertension Research48 ( 9 ) 2326 - 2338 2025.9

Risa Nagatomo, Yu Hiramatsu, Yusuke Sakiyama, Hiroaki Miyahara, Takuma Nasu, Ieharu Yamazaki, Akiko Yoshimura, Masahiro Ando, Satoshi Nozuma, Yujiro Higuchi, Akio Akagi, Yasushi Iwasaki, Jun-Hui Yuan, Yuji Okamoto, Hiroshi Takashima . Systemic mitochondrial involvement in mitochondrial myopathy with episodic hyper-creatine kinase-emia: insights from an autopsy case . Journal of Neurology272 ( 9 ) 576 2025.8

Takahiro Hobara, Masahiro Ando, Yujiro Higuchi, Jun-Hui Yuan, Akiko Yoshimura, Takashi Saito, Takashi Shiihara, Shiho Okuda, Naoki Fukushima, Hiroyuki Awano, Takahito Inoue, Chikashi Yano, Fumikazu Kojima, Kento Kodama, Yu Hiramatsu, Satoshi Nozuma, Tomonori Nakamura, Yusuke Sakiyama, Akihiro Hashiguchi, Jun Mitsui, Shoji Tsuji, Hiroshi Takashima . Charcot-Marie-Tooth-like presentation in giant axonal neuropathy: clinical variability and prevalence in a large Japanese case series. . Journal of neurology272 ( 8 ) 514 - 514 2025.8International journal

Language：Japanese Publishing type：Research paper (scientific journal)

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

Yamashiro Masataka, Yasutomi Daigo, Ohya Yuichiro, Ohyama Satoshi, Takashima Hiroshi, Tokashiki Takashi . A case of coexisting heterozygous NOTCH3 and HTRA1 mutations in cerebral small vessel disease(タイトル和訳中) . Human Genome Variation12 s41439 - 025 2025.7

Kubota R., Hanada K., Saito M., Dozono M., Nozuma S., Takashima H. . High TCR Degeneracy Enhances Antiviral Efficacy of HTLV-1-Specific CTLs by Targeting Variant Viruses in HAM Patients . International Journal of Molecular Sciences26 ( 14 ) 2025.7

Language：Japanese Publisher：International Journal of Molecular Sciences

T-cell receptors (TCRs) exhibit degeneracy, enabling individual TCRs to recognize multiple altered peptide ligands (APLs) derived from a single cognate antigen. This characteristic has been involved in the pathogenesis of autoimmune diseases through cross-reactivity between microbial and self-antigens. Cytotoxic T lymphocytes (CTLs), which recognize peptide–MHC class I complexes via TCRs, play a critical role in the immune response against viral infections. However, the extent to which TCR degeneracy within a population of virus-specific CTLs contributes to effective viral control remains poorly understood. In this study, we investigated the magnitude and functional relevance of TCR degeneracy in CTLs targeting an immunodominant epitope of human T-cell leukemia virus type 1 (HTLV-1) in patients with HTLV-1-associated myelopathy (HAM). Using peripheral blood mononuclear cells (PBMCs) from these patients, we quantified TCR degeneracy at the population level by comparing CTL responses to a panel of APLs with responses to the cognate epitope. Our findings demonstrated that increased TCR degeneracy, particularly at the primary TCR contact residue at position 5 of the antigen, was inversely correlated with HTLV-1 proviral load (p = 0.038, R = −0.40), despite similar functional avidity across patient-derived CTLs. Viral sequencing further revealed that CTLs with high TCR degeneracy exerted stronger selective pressure on the virus, as indicated by a higher frequency of nonsynonymous substitutions within the epitope-encoding region in patients with highly degenerate TCR repertoires. Moreover, TCR degeneracy was positively correlated with the recognition rate of epitope variants (p = 0.018, R = 0.76), suggesting that CTLs with high TCR degeneracy exhibited enhanced recognition of naturally occurring epitope variants compared to those with low TCR degeneracy. Taken together, these results suggest that virus-specific CTLs with high TCR degeneracy possess superior antiviral capacity, characterized by broadened epitope recognition and more effective suppression of HTLV-1 infection. To our knowledge, this is the first study to systematically quantify TCR degeneracy in HTLV-1-specific CTLs and evaluate its contribution to viral control in HAM patients. These findings establish TCR degeneracy as a critical determinant of antiviral efficacy and provide a novel immunological insight into the mechanisms of viral suppression in chronic HTLV-1 infection.

DOI： 10.3390/ijms26146602

Watanabe R., Papatriantafyllou J.D., Maeda K., Aguirre G.K., Ando M., Benoit B., Grossman M., Irwin D.J., Kim B., Massimo L., McMillan C.T., Papageorgiou S.G., Phillips J.S., Shiraishi T., Sugihara Y., Suh E.R., Takashima H., Toro C., Van Deerlin V.M., Nasrallah I.M., Lee E.B. . Clinicopathological characterization of vacuolar tauopathy associated with VCP D395G . Alzheimer S and Dementia21 ( 7 ) e70427 2025.7

Language：Japanese Publisher：Alzheimer S and Dementia

INTRODUCTION: The clinical, radiological, and pathological features have not been well documented for the recently discovered autosomal-dominant vacuolar tauopathy (VT) harboring the Valosin-containing protein (VCP) p.Asp395Gly variant. METHODS: We investigated the clinical, neuropsychological, physiological, laboratory, and radiological data and neuropathological findings in five symptomatic VT cases who met the diagnostic criteria for frontotemporal dementia (FTD). Radiological data were also collected from two pre-symptomatic carriers. RESULTS: All participants had heterozygous c.1184A > G, p.Asp395Gly in VCP. All symptomatic cases exhibited cognitive, behavioral, and/or language dysfunction indicative of FTD in their 30s to 50s. Neuroimaging studies revealed marked bilateral frontal neurodegeneration and occipital lobar diffusion abnormalities. Post mortem examination of three cases and brain biopsy of one case revealed abundant three- and four-repeat tau deposition and neocortical microvacuolization. Radiological changes were not evident in two pre-symptomatic carriers in their 20s. DISCUSSION: This study reveals distinct clinical-radiological-pathological correlations in VT, expanding the spectrum of early-onset frontotemporal lobar degeneration (FTLD). Highlights: We characterized the clinical, radiological, and pathological features of vacuolar tauopathy (VT). Five VT cases exhibited a behavioral syndrome, often with aphasic features, with marked frontal lobar atrophy and hypometabolism. Magnetic resonance imaging (MRI) of VT cases revealed occipital lobar diffusion abnormalities. Diffuse neurofibrillary tangles (NFTs) and microvacuolization were observed in the neocortex, with an inverse distribution.

DOI： 10.1002/alz.70427

Chikashi Yano, Eiji Matsuura, Tomonori Nakamura, Ayako Sonoda, Ayano Shigehisa, Masahiro Ando, Satoshi Nozuma, Yujiro Higuchi, Yusuke Sakiyama, Akihiro Hashiguchi, Kumiko Michizono, Hiroshi Takashima . Visual evoked potential in myelin oligodendrocyte glycoprotein antibody-associated disease. . Multiple sclerosis and related disorders98 106408 - 106408 2025.6International journal

Language：Japanese Publishing type：Research paper (scientific journal)

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

Matsui N., Tanaka K., Kokubun N., Hatanaka Y., Ishida M., Osaki Y., Watanabe T., Watanabe O., Matsuura E., Takashima H., Sato Y., Kuwabara S., Izumi Y. . Prevalence, clinical profiles, and prognosis of Isaacs syndrome: A nationwide survey study in Japan . Journal of the Neurological Sciences472 123442 2025.5

Language：Japanese Publisher：Journal of the Neurological Sciences

Objectives: To elucidate current epidemiological, clinical, and immunological profiles, and the treatment of Isaacs syndrome in Japan. Methods: We conducted a nationwide survey using established methods. Questionnaires were sent to neurological facilities throughout Japan to identify Isaacs syndrome patients seen between April 2018 and March 2021. Results: The estimated total number of Isaacs syndrome patients was 114 (95 % confidence interval [CI]: 89.63–138.91), and the estimated prevalence was 0.091 per 100,000 population. Detailed clinical data were available for 44 patients. The median age at onset was 40 (range, 17–78 years), and 55 % were female. The median time from symptom onset to diagnosis was 24 months (range, 1–372 months). Electrodiagnostic studies showed evidence of nerve hyperexcitability in 90 % (myokymic discharges in 50 % and stimulus-induced repetitive discharges in 32 %). Of the 28 patients examined in the cell-based assay, 22 % tested positive (11 % for both leucine-rich glioma-inactivated 1 [LGI1] and contactin-associated protein-like 2 [CASPR2] antibodies and 11 % for LGI1 antibodies only). The median modified Rankin Scale (mRS) score was 2 at diagnosis and 1.5 at the last visit. A high mRS score (mRS ≥4) at baseline was an independent risk factor for poor outcomes (mRS ≥3) (Odds ratio, 20.7; 95 % CI, 2.90–209.18; p < 0.001). Conclusion: We elucidated the current epidemiological and clinical characteristics of Isaacs syndrome in Japan. Isaacs syndrome is a rare neuromuscular disorder. Electrophysiologic abnormalities were frequent, and serum antibodies were not detectable in the majority of patients. A high mRS score before treatment was a risk factor for poor outcomes.

DOI： 10.1016/j.jns.2025.123442

Peymani F, Ebihara T, Smirnov D, Kopajtich R, Ando M, Bertini E, Carrozzo R, Diodato D, Distelmaier F, Fang F, Ghezzi D, Hempel M, Iwanicka-Pronicka K, Klopstock T, Stenton SL, Lamperti C, Liu Z, Murtazina A, Okamoto Y, Okazaki Y, Piekutowska-Abramczuk D, Rötig A, Ryzhkova O, Schlein C, Shagina O, Takashima H, Tsygankova PG, Zech M, Meitinger T, Shimura M, Murayama K, Prokisch H . Pleiotropic effects of MORC2 derive from its epigenetic signature. . Brain : a journal of neurology149 ( 1 ) 163 - 177 2025.4

Language：English Publisher：Brain

Heterozygous missense mutations in MORC2 have been implicated in various clinical entities, ranging from early-onset neurodevelopmental disorders to late-onset neuropathies. The mechanism underlying the phenotypic heterogeneity and pleiotropic effects of MORC2 has remained elusive. Here, we analysed blood and fibroblast DNA methylation, transcriptomes, proteomes and phenotypes of 53 MORC2 patients. We identified a MORC2-specific DNA methylation episignature that is universal across all MORC2-associated phenotypes and conserved across different tissues. The MORC2 episignature consists mainly of DNA hypermethylation in promoter regions, leading to transcriptional repression of target genes resulting in a MORC2-specific RNA signature. Concomitant downregulation of three disease-associated genes—ERCC8, NDUFAF2 and FKTN—at different levels mirrors the variable biochemical defects and clinical manifestations observed in MORC2 patients. Silencing of NDUFAF2 accounts for the Leigh syndrome manifestation, whereas dysmorphic features are due to the repression of ERCC8. Overall, we showed that pathogenic MORC2 variants cause specific episignature, whereby methylation level variability and its repression impact on target genes explains the pleiotropy and predicts phenotypic heterogeneity in MORC2-related disorders. We predict that epigenetic variation may underlie pleiotropy in other Mendelian disorders.

DOI： 10.1093/brain/awaf159

Masahiro Ando, Yujiro Higuchi, Jun-Hui Yuan, Akiko Yoshimura, Chikashi Yano, Takahiro Hobara, Fumikazu Kojima, Yu Hiramatsu, Satoshi Nozuma, Tomonori Nakamura, Yusuke Sakiyama, Akihiro Hashiguchi, Yuji Okamoto, Takeshi Matsushige, Jun Mitsui, Shoji Tsuji, Hiroshi Takashima . SOD1-related inherited peripheral neuropathies in a Japanese cohort: genetic variants and clinical insights. . Journal of neurology272 ( 3 ) 191 - 191 2025.3International journal

Language：Japanese Publishing type：Research paper (scientific journal)

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

Nozuma S., Matsuzaki T., Tanaka M., Kodama D., Dozono M., Yoshida T., Takashima H., Kubota R. . T-Cell Receptor/CD3 Downregulation and Impaired Signaling in HTLV-1-Infected CD4+ T Cells of HAM Patients . International Journal of Molecular Sciences26 ( 4 ) 2025.2

Language：Japanese Publisher：International Journal of Molecular Sciences

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus associated with adult T-cell leukemia (ATL), a hematological malignancy, and HTLV-1-associated myelopathy (HAM), a progressive neurological disorder. HTLV-1 predominantly infects CD4+ T cells in vivo. The T-cell receptor (TCR)/CD3 complex on CD4+ helper T cells plays a pivotal role in immune responses by recognizing antigens and facilitating coordination with other immune cells. Dysfunction of the TCR/CD3 complex may impair immune function. Although CD3 downregulation has been identified as a characteristic of ATL cells, it remains uncertain whether a similar downregulation occurs in HTLV-1-infected cells from HAM patients. We hypothesized that HTLV-1 infection leads to TCR and CD3 downregulation, contributing to immune dysfunction in HAM patients. To test this hypothesis, we analyzed TCR/CD3 expression, TCR signaling, and immune responses in HTLV-1-infected cells from HAM patients. Intracellular HTLV-1 Tax detection revealed that HTLV-1 preferentially targets CD4+ over CD8+ T cells. CD3 and TCR expression levels were significantly lower in CD4+ T cells from HAM patients compared to healthy controls. Furthermore, HTLV-1-infected cells exhibited markedly reduced CD3 and TCR expression compared to uninfected cells. Impairments in TCR signaling, assessed through Lck and ZAP70 phosphorylation upon CD3 stimulation, were observed in CD4+ T cells from HAM patients compared to those from healthy controls. Notably, this reduction in TCR signaling was more pronounced in HTLV-1-infected CD4+ T cells than in uninfected CD4+ T cells in HAM patients. Additionally, cytomegalovirus (CMV)-specific CD4+ T cells detected by an addition of CMV antigens demonstrated reduced interferon-γ production in HTLV-1-infected cells compared to their uninfected counterparts. These findings suggest that TCR/CD3 downregulation and impaired TCR signaling contribute to immune dysfunction in HTLV-1-infected CD4+ T cells. As CD4+ T cells play a central role in immune responses, this mechanism may partially explain the cellular immune dysfunction to other pathogens observed in HAM patients.

DOI： 10.3390/ijms26041706

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