Faculty Profiles - TAKASHIMA Hiroshi

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 neurology 2025.4

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

Hiyoshi M., Eltalkhawy Y.M., Abdelnaser R.A., Ono A., Monde K., Maeda Y., Mahmoud R.M., Takahashi N., Hatayama Y., Ryo A., Nozuma S., Takashima H., Kubota R., Suzu S. . M-Sec promotes the accumulation of intracellular HTLV-1 Gag puncta and the incorporation of Env into viral particles . PLoS Pathogens21 ( 1 ) e1012919 2025.1

Language：Japanese Publisher：PLoS Pathogens

We have demonstrated that the cellular protein M-Sec promotes the transmission of human T-cell leukemia virus type 1 (HTLV-1) in vitro and in vivo. Here, we show how HTLV-1 utilizes M-Sec for its efficient transmission. HTLV-1-infected CD4+ T cells expressed M-Sec at a higher level than uninfected CD4+ T cells. The ex vivo culture of the infected cells upregulated the expression of M-Sec, the level of which was sustained for a long time. The viral structural protein Gag is distributed in a punctate pattern in cells. M-Sec promoted the accumulation of large intracellular Gag puncta. This accumulation was dependent on phosphatidylinositol 4,5-bisphosphate (PIP2), since it was lost upon the removal of PIP2 binding motifs in M-Sec or the depletion of cellular PIP2. The viral envelope protein Env co-localized with the large Gag puncta induced by M-Sec. Furthermore, viral particles produced by M-Sec-expressing cells contained a higher amount of Env. Given that M-Sec alters the cellular distribution of PIP2, these results suggest that M-Sec promotes the formation of infectious viral particles through PIP2. Since the expression of M-Sec is mediated by HTLV-1 Tax protein, M-Sec appears to function in a positive feedback loop that ensures efficient HTLV-1 transmission.

DOI： 10.1371/journal.ppat.1012919

Yano C., Nakamura T., Ando M., Higuchi Y., Yuan J.H., Yoshimura A., Hobara T., Kojima F., Hiramatsu Y., Nozuma S., Sakiyama Y., Hashiguchi A., Rosales R.L., Arimura K., Takashima H. . Tibial to ulnar nerve amplitude ratio as a marker of length-dependent neuropathy . Clinical Neurophysiology Practice10 499 - 506 2025.1

Language：Japanese Publisher：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

Sakiyama Y., Yuan J.H., Yoshimura A., Takeuchi M., Maki Y., Mori T., Takei J., Ando M., Hiramatsu Y., Nozuma S., Higuchi Y., Yonezawa H., Kirishima M., Suzuki M., Kano T., Tarisawa M., Hashiguchi S., Kunii M., Sato S., Takahashi-Iwata I., Hashiguchi A., Matsuura E., Izumo S., Tanimoto A., Takashima H. . Brain biopsy and metagenomic sequencing enhance aetiological diagnosis of encephalitis . Brain Communications7 ( 3 ) fcaf165 2025

Language：Japanese Publisher：Brain Communications

Identifying the aetiology of CNS diseases, regardless of their infectious or non-infectious nature, is often intricate. Next-generation sequencing (NGS) has emerged as a powerful tool for sensitive and unbiased screening of tissue or body fluid specimens. This study aimed to investigate the underlying aetiology of patients with suspected infectious CNS diseases. Between April 2013 and October 2021, we collected brain tissue samples from 33 patients diagnosed with encephalitis or encephalitis-like CNS diseases, obtained via biopsy or autopsy, and underwent metagenomic NGS (mNGS) in conjunction with pathological evaluations. Moreover, we employed PCR-based assays and pathogen-specific immunostaining to corroborate the presence of pathogens within the tissue samples. Among the 33 patients, mNGS elucidated pathogen-specific genomic sequences in 7 cases (21.2%), including halobacteria (archaea), Balamuthia mandrillaris, Epstein-Barr virus, Toxoplasma gondii and herpes simplex virus. Additionally, brain tissue mNGS ruled out known pathogens, identifying 14 cases (42.4%) of non-infectious CNS diseases, which included neoplastic, autoimmune/inflammatory and amyloid angiopathy conditions. The adjustment of therapeutic strategies based on these findings led to improvements in clinical symptoms, imaging outcomes and patient prognosis. Brain biopsy serves as both a direct pathological research target and a valuable source of samples for unbiased high-throughput sequencing. Our study illustrates the reliability of mNGS on brain tissue, which significantly improves the diagnostic rate for suspected encephalitis or encephalitis-like diseases of unknown aetiology. These findings underscore the importance of mNGS in guiding more precise and effective therapeutic interventions for patients in clinical practice.

DOI： 10.1093/braincomms/fcaf165

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 Shinkeigaku65 ( 8 ) 601 - 606 2025

Language：Japanese Publisher：Societas Neurologica Japonica

The patient was a 41-year-old man with a history of diabetes mellitus since the age of 22 years and a family history of diabetes in his mother. He had repeated headaches, cerebellar symptoms, and bilateral cerebellar lesions on brain MRI (DWI, T2 FLAIR hyperintensities). He was previously diagnosed with cerebellitis and treated with steroids at another hospital. Upon his third relapse, he was referred to our department. Clinical findings included short stature, diabetes, elevated CSF lactate and pyruvate levels, and increased lactate levels on aerobic exercise testing. Muscle biopsy revealed mitochondrial pathological abnormalities, and genetic testing of muscle tissue identified the mitochondrial DNA m.3243 mutation. These findings led to the diagnosis of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Stroke-like lesions in MELAS can involve not only the cerebrum but also the cerebellum. When cortical-predominant lesions with associated vascular dilatation are observed, MELAS should be considered in the differential diagnosis.

DOI： 10.5692/clinicalneurol.cn-002117

Tachibana Hisatsugu, Hattori Yuka, Higuchi Yujiro, Takashima Hiroshi, Matsushita Tatsuo . A case of X-linked Charcot–Marie–Tooth disease type 1 (CMTX1) diagnosed based on recurrent brain lesions despite peripheral neuropathy responsive to immunotherapy . Rinsho Shinkeigaku65 ( 10 ) 745 - 751 2025

Language：Japanese Publisher：Societas Neurologica Japonica

The patient is a 17-year-old male. He had a history of hospitalization for influenza at the age of 11, and Brain MRI at that time showed reversible brain lesions in the splenium of the corpus callosum and cerebral white matter. Fifteen months ago, he visited the pediatrics department due to dysphagia, dysarthria, facial paralysis, and muscle weakness. Brain MRI revealed lesions similar to those observed here, and nerve conduction study revealed demyelinating neuropathy. He was treated with intravenous immunoglobulin (IVIg) and intravenous methylprednisolone, and his symptoms disappeared within a few days and Brain MRI 5 weeks after treatment revealed that the lesions had disappeared. Three months ago, while walking, the patient developed a knee strain, which was thought to be a recurrence of the immune-mediated neuropathy. His subjective symptom disappeared after administration of IVIg. The patient was diagnosed with X-linked Charcot–Marie–Tooth disease (CMTX1) based on genetic testing, which revealed a pathological variant of GJB1, c.124A>T (p.Ser42Cys). Peripheral neuropathy in CMTX1 may present with fluctuating symptoms and can be responsive to IVIg treatment. Recurrent brain lesions should also be considered in the diagnosis of CMTX1.

DOI： 10.5692/clinicalneurol.cn-002127

ANDO Masahiro, HOBARA Takahiro, HIGUCHI Yujiro, TAKASHIMA Hiroshi . Repeat expansions in inherited neuropathy: insights from LRP12, RFC1 and NOTCH2NLC . Peripheral Nerve36 ( 1 ) 14 - 20 2025

Language：Japanese Publisher：Japanese Peripheral Nerve Society

Recent advances in genetic analysis technologies have led to significant progress in identifying repeat expansion abnormalities in hereditary neuromuscular diseases. These developments have also increased the importance of repeat expansion analysis in diagnosing hereditary peripheral neuropathies ( IPN ) . In a comprehensive genetic analysis of 3,180 Japanese patients suspected of having IPN, 10.9% of the genetically diagnosed cases were found to be caused by repeat expansions in the LRP12, RFC1 and NOTCH2NLC genes. Each of these repeat expansions is associated with adult-onset symptoms. LRP12-related repeat expansions primarily manifest as motor nerve dysfunction, with most patients presenting muscle weakness and atrophy, while sensory disturbances are relatively rare. In contrast, RFC1 repeat expansions predominantly cause sensory impairments, with most patients displaying sensory neuropathy and minimal muscle weakness. Furthermore, NOTCH2NLC-related expansions are associated with intermediate electrophysiological findings, and about half of the patients also exhibit autonomic nervous system involvement, such as neurogenic bladder. These repeat expansions are critical in refining the diagnosis and understanding of the clinical spectrum of hereditary peripheral neuropathies. This review provides an in-depth overview of the clinical characteristics, electrophysiological findings, and molecular mechanisms of the LRP12, RFC1 and NOTCH2NLC repeat expansions, with a particular focus on their roles in the pathogenesis of hereditary neuropathies.

DOI： 10.69407/jpns.36.1_14

Hamada Y., Sato T., Matsuoka H., Tsuchimochi Y., Kukihara K., Kawabata Y., Iwamoto K., Takaguchi G., Higuchi Y., Takashima H. . The combination of atrial fibrillation and small vessel disease score worsen spontaneous intracerebral hemorrhage outcomes . Frontiers in Neurology16 1682520 2025

Language：Japanese Publisher：Frontiers in Neurology

Background: This study aimed to examine whether the presence of atrial fibrillation (AF), severity as judged by total small vessel disease (SVD) score, or a combination of these is associated with prognosis and hematoma volume of spontaneous intracerebral hemorrhage (sICH). Methods: This retrospective analysis investigated 608 patients who were admitted within 7 days of ICH onset between July 2012 and November 2023. The primary outcome was prognosis at 3 months after onset according to the modified Rankin Scale (mRS) score. Associations of AF, SVD and a combination of these with outcomes and hematoma volume were examined using univariate analyses, logistic regression analysis, and multiple regression analysis. Results: A total of 608 consecutive patients with sICH were screened, and 330 patients were finally included in the analysis after applying the inclusion and exclusion criteria. Among the 330 patients analyzed, 145 (43.9%) experienced poor outcomes (mRS score 4–6). The presence of AF was independently associated with poor outcome (adjusted OR 4.93, 95% CI 1.72–16.1; p = 0.002), whereas total SVD score alone was not. Multiple regression analysis with estimated hematoma volume also showed a significant association with AF (standard partial regression coefficient 0.16; p = 0.033), but not with total SVD score. However, a linear trend was observed between the combination of AF and total SVD score severity and poor outcome (total SVD score 0–1 without AF: aOR 1.00, total SVD score 2–4 without AF: 1.44, total SVD score 0–1 with AF: 4.26, total SVD score 2–4 with AF: 7.57; p for trend = 0.002). Multiple regression analysis using estimated hematoma volume also showed a synergistic effect of AF and total SVD score severity (standardized regression coefficient 0.14; p = 0.032). Conclusion: The presence of AF was associated with poor 3-month outcomes and increased estimated hematoma volume in sICH patients, whereas total SVD score alone was not. The effects of AF and SVD together appear to contribute synergistically to worsened prognosis and increased hematoma volume in sICH patients.

DOI： 10.3389/fneur.2025.1682520

Ando M., Higuchi Y., Yuan J.H., Yoshimura A., Yano C., Hobara T., Kojima F., Hiramatsu Y., Nozuma S., Nakamura T., Sakiyama Y., Mitsui J., Tsuji S., Takashima H. . Nationwide Characterization of MFN2-Related CMT in 176 Japanese Patients: Clinical and Genetic Insights . Annals of Clinical and Translational Neurology 2025

Language：Japanese Publisher：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

髙嶋博 . Letter to the Editor : Reply . 神経治療学42 ( 3 ) 450 - 450 2025

Yano C., Ando M., Higuchi Y., Yuan J.H., Yoshimura A., Hobara T., Nagatomo R., Kojima F., Hiramatsu Y., Nozuma S., Nakamura T., Sakiyama Y., Matsuoka C., Yamashita T., Kimura T., Miyazaki A., Kinjo C., Yokochi K., Yamanaka N., Matsuda N., Suichi T., Hanaoka Y., Kojima H., Todo K., Ishiura H., Mitsui J., Tsuji S., Takashima H. . INF2-Related Charcot–Marie–Tooth Disease in a Japanese Cohort: Genetic and Clinical Insights . Annals of Clinical and Translational Neurology 2025

Language：Japanese Publisher：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

Tamura M., Sugiyama A., Hirano S., Higuchi Y., Takashima H., Mori M. . Hummingbird sign in a patient with DNMT1-related disorder . Neurocase31 ( 5 ) 239 - 244 2025

Language：Japanese Publisher：Neurocase

A 63-year-old woman presented with gait disturbance, progressive hearing loss, and sensory dominant polyneuropathy. Brain MRI mainly revealed midbrain tegmental atrophy (hummingbird sign). Genetic testing identified a heterozygous DNMT1 exon 21 mutation, previously linked to autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN), although her clinical presentation resembled hereditary sensory and autonomic neuropathy type 1E (HSAN1E). A review of previously published cases with the same mutation revealed variability in sensory involvement, cerebellar signs, and sleep disorders, supporting the existence of a wide disease spectrum of DNMT1-related disorders. This case illustrates the phenotypic and radiological overlap within DNMT1-related disorders and supports the concept of a disease spectrum, rather than discrete syndromes, highlighting the diagnostic value of combining neuroimaging with genetic analysis.

DOI： 10.1080/13554794.2025.2560858

YOSHIMURA Akiko, HIGUCHI Yujiro, YUAN Jun-Hui, TAKASHIMA Hiroshi . Advances in genetic research and diagnosis of Charcot-Marie-Tooth disease . Peripheral Nerve36 ( 1 ) 7 - 13 2025

Language：Japanese Publisher：Japanese Peripheral Nerve Society

Charcot-Marie-Tooth disease ( CMT ) is a type of inherited peripheral neuropathy ( IPN ) that primarily affects motor and sensory nerves due to abnormalities in the peripheral nervous system. CMT exhibit significant genetic and clinical heterogeneity, with over 140 causative genes identified, encompassing diverse cellular localizations and functional roles. This review discusses advancements in genetic analysis techniques, including gene panel sequencing, whole-exome sequencing ( WES ) , whole-genome sequencing ( WGS ) , and long-read sequencing, which have significantly improved the diagnostic accuracy and yield. Furthermore, we also present the genetic landscape of 3,315 CMT/IPN patients in Japan ( excluding PMP22 duplication/deletion cases ) . Comprehensive analyses are essential to deepen our understanding of CMT/IPN and facilitate the development of targeted therapies and improved patient care. The discovery of repeat expansion mutations emphasizes the necessity for continuous refinements in diagnostic strategies to address novel and emerging genetic mechanisms underlying CMT/IPN.

DOI： 10.69407/jpns.36.1_7

Matsuura Eiji, Dozono Mika, Nozuma Satoshi, Takashima Hiroshi . Diagnosis of HTLV-1-associated myelopathy solely by neurological examination . NEUROINFECTION30 ( 1 ) 32 - 36 2025

矢野直志, 中村友紀, 髙嶋博 . Charcot-Marie-Tooth病の電気生理 . 臨床神経生理学52 ( 6 ) 686 - 690 2024.12

Language：Japanese Publisher：一般社団法人日本臨床神経生理学会

Charcot-Marie-Tooth病 (CMT) は遺伝性ニューロパチーの一つである。CMTでは遺伝子型と表現型の多様性が知られており, 臨床所見のみから原因遺伝子を予測することが難しく, CMTとCIDPとの鑑別に悩むケースも少なくない。加えてCMTの病態に炎症機序が重畳することで免疫治療に部分的に反応する症例もあり, 治療反応性を重視しすぎると診断の誤りを招くことがある。今回, 日本における主要なCMTサブタイプとして, PMP22重複, MPZ, GJB1, MFN2, MME変異の電気生理学的特徴について概説し, CIDPとの鑑別点を検討した。多くのCMTの原因遺伝子が明らかになり, 従来の伝導ブロックや時間的分散の有無による先天性と後天性の鑑別は困難となってきている。繰り返し言及される点だが, 最終診断は病歴, 臨床所見, 電気生理学的所見, 遺伝子解析も含め総合的に行う必要がある。

DOI： 10.11422/jscn.52.686

Takahiro Hobara, Yujiro Higuchi, Mari Yoshida, Masahito Suehara, Masahiro Ando, Jun-Hui Yuan, Akiko Yoshimura, Fumikazu Kojima, Eiji Matsuura, Yuji Okamoto, Jun Mitsui, Shoji Tsuji, Hiroshi Takashima . Genetic and pathophysiological insights from autopsied patient with primary familial brain calcification: novel MYORG variants and astrocytic implications. . Acta neuropathologica communications12 ( 1 ) 136 - 136 2024.12International journal

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

Primary familial brain calcification (PFBC) is a genetic neurological disorder characterized by symmetric brain calcifications that manifest with variable neurological symptoms. This study aimed to explore the genetic basis of PFBC and elucidate the underlying pathophysiological mechanisms. Six patients from four pedigrees with brain calcification were enrolled. Whole-exome sequencing identified two novel homozygous variants, c.488G > T (p.W163L) and c.2135G > A (p.W712*), within the myogenesis regulating glycosidase (MYORG) gene. Cerebellar ataxia (n = 5) and pyramidal signs (n = 4) were predominant symptoms, with significant clinical heterogeneity noted even within the same family. An autopsy of one patient revealed extensive brainstem calcifications, sparing the cerebral cortex, and marked by calcifications predominantly in capillaries and arterioles. The pathological study suggested morphological alterations characterized by shortened foot processes within astrocytes in regions with pronounced calcification and decreased immunoreactivity of AQP4. The morphology of astrocytes in regions without calcification remains preserved. Neuronal loss and gliosis were observed in the basal ganglia, thalamus, brainstem, cerebellum, and dentate nucleus. Notably, olivary hypertrophy, a previously undescribed feature in MYORG-PFBC, was discovered. Neuroimaging showed reduced blood flow in the cerebellum, highlighting the extent of cerebellar involvement. Among perivascular cells constituting the blood-brain barrier (BBB) and neurovascular unit, MYORG is most highly expressed in astrocytes. Astrocytes are integral components of the BBB, and their dysfunction can precipitate BBB disruption, potentially leading to brain calcification and subsequent neuronal loss. This study presents two novel homozygous variants in the MYORG gene and highlights the pivotal role of astrocytes in the development of brain calcifications, providing insights into the pathophysiological mechanisms underlying PFBC associated with MYORG variants.

DOI： 10.1186/s40478-024-01847-3