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Objective: Multisystem proteinopathy (MSP) is an inherited disorder in which protein aggregates with TAR DNA‐binding protein of 43 kDa form in multiple organs. Mutations in VCP, HNRNPA2B1, HNRNPA1, SQSTM1, MATR3, and ANXA11 are causative for MSP. This study aimed to conduct a nationwide epidemiological survey based on the diagnostic criteria established by the Japan MSP study group. Methods: We conducted a nationwide epidemiological survey by administering primary and secondary questionnaires among 6235 specialists of the Japanese Society of Neurology. Results: In the primary survey, 47 patients with MSP were identified. In the secondary survey of 27 patients, inclusion body myopathy was the most common initial symptom (74.1%), followed by motor neuron disease (11.1%), frontotemporal dementia (FTD, 7.4%), and Paget's disease of bone (PDB, 7.4%), with no cases of parkinsonism. Inclusion body myopathy occurred most frequently during the entire course of the disease (81.5%), followed by motor neuron disease (25.9%), PDB (18.5%), FTD (14.8%), and parkinsonism (3.7%). Laboratory findings showed a high frequency of elevated serum creatine kinase levels and abnormalities on needle electromyography, muscle histology, brain magnetic resonance imaging, and perfusion single‐photon emission computed tomography. Interpretation: The low frequency of FTD and PDB may suggest that FTD and PDB may be widely underdiagnosed and undertreated in clinical practice. [ABSTRACT FROM AUTHOR]

Background: A rare muscle disease, GNE myopathy is caused by mutations in the GNE gene involved in sialic acid biosynthesis. Our recent phase II/III study has indicated that oral administration of aceneuramic acid to patients slows disease progression. Methods: We conducted a phase III, randomized, placebo-controlled, double-blind, parallel-group, multicenter study. Participants were assigned to receive an extended-release formulation of aceneuramic acid (SA-ER) or placebo. Changes in muscle strength and function over 48 weeks were compared between treatment groups using change in the upper extremity composite (UEC) score from baseline to Week 48 as the primary endpoint and the investigator-assessed efficacy rate as the key secondary endpoint. For safety, adverse events, vital signs, body weight, electrocardiogram, and clinical laboratory results were monitored. Results: A total of 14 patients were enrolled and given SA-ER (n = 10) or placebo (n = 4) tablets orally. Decrease in least square mean (LSM) change in UEC score at Week 48 with SA-ER (− 0.115 kg) was numerically smaller as compared with placebo (− 2.625 kg), with LSM difference (95% confidence interval) of 2.510 (− 1.720 to 6.740) kg. In addition, efficacy was higher with SA-ER as compared with placebo. No clinically significant adverse events or other safety concerns were observed. Conclusions: The present study reproducibly showed a trend towards slowing of loss of muscle strength and function with orally administered SA-ER, indicating supplementation with sialic acid might be a promising replacement therapy for GNE myopathy. Trial registration number: ClinicalTrials.gov (NCT04671472). [ABSTRACT FROM AUTHOR]

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a rare, slowly progressive, incurable, and hereditary neurodegenerative disease caused by the testosterone-dependent accumulation of pathogenic polyglutamine-expanded androgen receptor protein. After extensive review, two treatments for SBMA have recently been approved in Japan; this decision was based on the results of randomized controlled trials: First, anti-androgen therapy using leuprorelin acetate (leuprorelin), a disease-modifying drug that can inhibit the progression of dysphagia but has not yet been proved to improve gait function; second, cybernic treatment with a wearable cyborg hybrid assistive limb (HAL®) (Cyberdyne Inc. Tsukuba, Japan). The HAL is an innovative walking exercise system that has been shown to significantly improve gait function in eight neuromuscular diseases without reduction in muscle function, including SBMA. It is possible that the combination of these two approaches might yield better outcomes. However, the long-term effects of such a combined approach have yet to be clinically evaluated. Here, we describe the case of a 39-year-old male with SBMA who commenced anti-androgen therapy with leuprorelin 1 year previously; this was followed by cybernic treatment with HAL. The duration of walking exercise with HAL was 20–30 min a day in one session. Over 2 weeks, the patient underwent nine sessions (one course). The efficacy of HAL was evaluated by gait function tests before and after one course of cybernic treatment. Then, leuprorelin treatment was combined with cybernic sessions every 2 months for 2 years (13 courses in total). Walking ability, as evaluated by the 2-min walk test, improved by 20.3% in the first course and peaked 10 months after the commencement of combined therapy (a 59.0% improvement). Walking function was maintained throughout the period. Generally, SBMA is characterized by moderately increased serum levels of creatine kinase (CK), reflecting neuromuscular damage; interestingly, the patient's CK levels decreased dramatically with combined therapy, indicating remarkable functional improvement. Long-term combined therapy improved the patient's gait function with a steady reduction in CK levels. The combination of leuprorelin with cybernic treatment can, therefore, improve and maintain gait function without damaging the motor unit and may also suppress disease progression. [ABSTRACT FROM AUTHOR]

Background: Hereditary transthyretin‐mediated (hATTR) amyloidosis is a rapidly progressive and fatal disease. Patisiran is an RNA interference therapeutic that inhibits synthesis of disease‐causing mutant and wild‐type transthyretin (TTR) protein in hATTR amyloidosis. Aim: The efficacy and safety of patisiran were evaluated in the Phase 3 APOLLO study in patients with hATTR amyloidosis with polyneuropathy. Methods: In total, 225 patients from 19 countries, including Japan (n = 16), received patisiran 0.3 mg/kg intravenously or placebo once every 3 weeks for 18 months. Patisiran halted or improved outcomes of polyneuropathy (measured by modified Neuropathy Impairment Score +7 [mNIS+7]) and improved quality of life (QOL) (measured by Norfolk Quality of Life‐Diabetic Neuropathy questionnaire). Present analyses assess the efficacy, safety, pharmacokinetic exposure, and pharmacodynamic effect of patisiran in the Japanese sub‐population of APOLLO. Results: Consistent with the overall APOLLO population, patisiran significantly improved outcomes of polyneuropathy (mNIS+7) compared with placebo at 18 months in the APOLLO Japanese patients. Patisiran treatment also demonstrated benefit in QOL, motor strength, gait speed, nutritional status, and autonomic symptoms compared with placebo at 18 months in the Japanese sub‐population. Patisiran was generally well tolerated in Japanese patients, with most adverse events mild or moderate; safety profile was similar to the overall APOLLO population, and no deaths were observed. Patisiran pharmacokinetic exposures and TTR reduction were comparable to the overall population. Conclusions: Data in the Japanese sub‐population were consistent with those from the overall APOLLO population and indicate a notable health benefit for patisiran treatment in Japanese patients with hATTR amyloidosis with polyneuropathy. [ABSTRACT FROM AUTHOR]

Hereditary transthyretin (ATTRv) amyloidosis, also known as familial amyloid polyneuropathy, is a disease caused by the systemic deposition of variant transthyretin (TTR). Although this disease was primarily indigenous to endemic foci in Portugal, Japan, and Sweden, its prevalence has increased throughout the world. The clinical phenotypes of ATTRv amyloidosis are diverse, including neuropathy, cardiomyopathy, and oculoleptomeningeal involvement as the predominant features, depending on the mutation type and age of onset. Val30Met, one of the most common TTR mutations, exhibits varying characteristic features in the early‐onset patients from conventional endemic foci and the late‐onset patients from non‐endemic areas. Autonomic dysfunctions and dissociated sensory loss are the characteristic features of the former, whereas motor dysfunctions and loss of all sensory modalities are conspicuous in the latter. Distortion and atrophy of the Schwann cells due to the formation of amyloid fibrils seem to cause predominant small‐fiber loss in the early‐onset patients, while other mechanisms, such as microangiopathy and the toxicity of TTR oligomers, may contribute to nerve fiber loss in the late‐onset patients. In addition to liver transplantation, novel and less invasive disease‐modifying therapies, such as TTR stabilizers, short interfering RNA, and antisense oligonucleotide, have been shown to be effective in ATTRv amyloidosis patients. Given their ability to ameliorate ATTRv amyloidosis, early diagnosis and treatment are required. Physicians should be aware of the diversity in ATTRv amyloidosis because this disease can be misdiagnosed with other diseases such as chronic inflammatory demyelinating polyneuropathy and immunoglobulin light‐chain amyloidosis. [ABSTRACT FROM AUTHOR]

Background: Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, hereditary neuromuscular disease characterized by muscle atrophy, weakness, contraction fasciculation, and bulbar involvement. Although the causative gene, androgen receptor, has been identified, the development of novel therapeutics for SBMA is incomplete. In this study, the efficacy and safety of leuprorelin acetate administration for patients with SBMA, using the pooled data of two randomized-controlled trials, was studied. Methods: Two randomized double-blinded studies (JASMITT-06DB and JASMITT-11DB) were done as multicentric, investigator-initiated clinical trials in Japan. In both studies, eligible patients were randomly assigned 1:1 to receive leuprorelin acetate administration once per 12 weeks for 48 weeks. The primary endpoint was the longitudinal change of pharyngeal barium residues from the baseline data measured with videofluorographic swallowing analyses. The pooled analysis plan was decided upon after the 06B study was finished and before the 11DB study began. Results: The primary endpoint difference between the leuprorelin group and the placebo group was pharyngeal barium residue after initial swallowing, − 4.12% (95% CI, − 8.40–0.15; p = 0.058). The primary endpoint of this study does not reach significant results, although inter-group differences of pharyngeal barium residues after the initial swallowing indicated that leuprorelin acetate may be effective at each assessment point in both study groups. Conclusions: The efficacy of leuprorelin acetate for patients with SBMA was statistically similar in two randomized-controlled trials, and suggested that leuprorelin acetate may be effective and safe. Further investigations are needed to clarify the promising efficacy of the drug. [ABSTRACT FROM AUTHOR]

Summary: Background: Spinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor. At present there are no treatments for spinal and bulbar muscular atrophy, although leuprorelin suppressed the accumulation of pathogenic androgen receptors in a phase 2 trial. We aimed to assess the efficacy and safety of leuprorelin for spinal and bulbar muscular atrophy. Methods: The Japan SBMA Interventional Trial for TAP-144-SR (JASMITT) was a 48-week, randomised, double-blind, placebo-controlled trial done at 14 hospitals between August, 2006, and March, 2008. Patients with spinal and bulbar muscular atrophy were randomly assigned (1:1) by minimisation to subcutaneous 11·25 mg leuprorelin or identical placebo every 12 weeks. Patients and investigators were masked to treatment allocation. The primary endpoint was pharyngeal barium residue, which indicates incomplete bolus clearance, measured at week 48 by videofluorography. All patients who were randomly assigned and who were assessed with videofluorography at least once were included in the analyses. This study is registered with the JMACCT clinical trials registry, number JMA-IIA00009, and the UMIN clinical trials registry, number UMIN000000465. Findings: 204 patients were randomly assigned and 199 started treatment: 100 with leuprorelin and 99 with placebo. At week 48, the pharyngeal barium residue after initial swallowing had changed by −5·1% (SD 21·0) in the leuprorelin group and by 0·2% (18·2) in the placebo group (difference between groups −5·3%; 95% CI −10·8 to 0·3; p=0·063). The mean difference in pharyngeal barium residue after piecemeal deglutition at week 48 was −3·2% (−6·4 to 0·0; p=0·049), but there was no significant difference between the groups after covariate adjustment for the baseline data (−4·1 to 1·6; p=0·392). In a predefined subgroup analysis, leuprorelin treatment was associated with a greater reduction in barium residue after initial swallowing than was placebo in patients with a disease duration less than 10 years (difference between groups −9·8, −17·1 to −2·5; p=0·009). There were no significant differences in the number of drug-related adverse events between groups (57 of 100 in the leuprorelin group and 54 of 99 in the placebo group; p=0·727). Interpretation: 48 weeks of treatment with leuprorelin did not show significant effects on swallowing function in patients with spinal and bulbar muscular atrophy, although it was well tolerated. Disease duration might influence the efficacy of leuprorelin and thus further clinical trials with sensitive outcome measures should be done in subpopulations of patients. Funding: Large Scale Clinical Trial Network Project, Japan and Takeda Pharmaceuticals. [Copyright &y& Elsevier]

Two recent genetic studies reported that loss-of-function mutation of the C-terminal cargo-binding tail domain of the KIF5A gene cause amyotrophic lateral sclerosis (ALS). The aim of this study is to investigate the frequency of KIF5A variants in Japanese patients with sporadic ALS. In total, 807 sporadic ALS patients and 191 normal controls from a multicenter ALS cohort in Japan were included. Whole exome sequencing on an Illumina HiSeq 2000/2500 sequencer was used to identify and select variants within the KIF5A gene. Thirteen patients harbored a nonsynonymous variant in the KIF5A gene; These were considered variants of uncertain significance. One patient harbored a novel splice-site variant (c.2993-3C>A) in the C-terminal cargo-binding tail domain of the KIF5A gene. Functional analysis of this variant revealed that it caused skipping of exon 27. The frequency of KIF5A mutations in Japanese patients with sporadic ALS was 0.12% (1/807). This study reports a novel loss-of-function variant in KIF5A , and indicates that loss-of-function variant in KIF5A is a rare cause of sporadic ALS in Japanese patients. • Mutations in KIF5A cargo-binding domain cause amyotrophic lateral sclerosis (ALS). • We investigated frequency of KIF5A variants Japanese sporadic ALS patients. • One patient harbored a novel splice-site variant in KIF5A cargo-binding domain. • Functional analysis revealed this variant caused skipping of exon 27. • KIF5A mutations are rare in Japanese sporadic ALS patients. [ABSTRACT FROM AUTHOR]

Background: Primary lateral sclerosis (PLS) is an extremely rare condition; therefore, to date no clinical studies have been conducted. The Primary Lateral Sclerosis Functional Rating Scale (PLSFRS) was developed in the United States of America. The PLSFRS is a crucial assessment scale for international collaborative research and future clinical trials for PLS. It is useful for evaluating medical conditions through face-to-face assessments and telephone interviews such as when a face-to-face assessment is not possible due to disasters or the burden of hospital visits. This study assessed the reliability and consistency of in-person and telephone interviews using the Japanese version of the PLSFRS., Methods: We enrolled 19 Japanese patients who met the specific criteria for inclusion at the six collaborating institutions. The PLSFRS assessments were performed by two evaluators at defined time points and analyzed for intra-rater and inter-rater reliability and consistency between the in-person and telephone interviews., Results: The Japanese version of the PLSFRS was developed by a specialized company and translator, and modified to consider the Japanese lifestyle through a consensus among motor neuron specialists. The quadratic-weighted kappa coefficients for the intra-rater and the inter-rater agreement were substantial (intra-rater: 0.691-1.000, inter-rater: 0.634-1.000). Moreover, the intraclass correlation coefficient for the PLSFRS total score was 0.997 (95% confidence interval, 0.992-0.999)., Conclusions: This study provides results regarding the Japanese version of the PLSFRS intra-rater and inter-rater reliability and consistency between in-person and telephone interviews., (© 2024. The Author(s).)

Preimplantation genetic testing for monogenic disorders (PGT-M) has been implemented in Japan under a novel definition of severity to reduce the chances of giving birth to a child with an inherited genetic disorder. The redefinition of disease severity is not only about changing definitions and interpretations, but also a matter of potentially expanding the number of diseases covered by PGT-M and the range of clients, which could raise serious human rights-related issues. With the rapid development of therapies for neuromuscular diseases and the possibility of the clinical course of diseases previously considered to be serious becoming progressively becoming milder in the future, the "definition of severity" classification itself, as applied to PGT-M, may become debatable. Neurologists will thus become more involved in presymptomatic diagnosis and newborn screening for the early diagnosis and treatment to enhance the efficacy of new therapies. We also need to address the technical, social, and ethical issues surrounding genetic counselling and PGT-M, and practice holistic medicine for the patients and their families.

Background: GNE myopathy is an ultra-rare muscle disease characterized by a reduction in the synthesis of sialic acid derived from pathogenic variants in the GNE gene. No treatment has been established so far., Objective: We evaluated the safety and efficacy of oral supplementation of aceneuramic acid in patients with GNE myopathy., Methods: This multicenter, placebo-controlled, double-blind study comprised genetically confirmed GNE myopathy patients in Japan who were randomly assigned into treatment groups of sialic acid-extended release (SA-ER) tablets (6 g/day for 48 weeks) or placebo groups (4:1). The primary endpoint of effectiveness was set as the change in total upper limb muscle strength (upper extremity composite [UEC] score) from the start of administration to the final evaluation time point., Results: Among the 20 enrolled patients (SA-ER group, 16; placebo group, 4), 19 completed this 48-week study. The mean value of change in UEC score (95% confidence interval [CI]) at 48 weeks was -0.1 kg (-2.1 to 2.0) in the SA-ER group and -5.1 kg (-10.4 to 0.3) in the placebo group. The least squares mean difference (95% CI) between the groups in the covariance analysis was 4.8 kg (-0.3 to 9.9; P = 0.0635). The change in UEC score at 48 weeks was significantly higher in the SA-ER group compared with the placebo group (P = 0.0013) in the generalized estimating equation test repeated measurement analysis. In one patient in the SA-ER group, who was found to be pregnant 2 weeks after drug administration fetal death with tangled umbilical cord occurred at 13 weeks after the discontinuation of treatment. No other serious adverse effects were observed., Conclusions: The present study indicates that oral administration of SA-ER tablets is effective and safe in patients with GNE myopathy in Japan.

DNAJC7 has recently been identified as an amyotrophic lateral sclerosis (ALS) gene via large-scale exome analysis, and its involvement in ALS is still unclear in various populations. This study aimed to determine the frequencies and characteristics of the DNAJC7 variants in a Japanese ALS cohort. A total of 807 unrelated Japanese patients with sporadic ALS were screened via exome analysis. In total, we detected six rare missense variants and one splice-site variant of the DNAJC7 gene, which are not reported in the Japanese public database. Furthermore, the missense variants are located around the TPR domain, which is important for the function of DNAJC7. The total frequency of the DNAJC7 variants in Japanese ALS patients was estimated at 0.87%. Collectively, these results suggest that variants of DNAJC7 are rare cause of Japanese patients with sporadic ALS., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Mutations in the valosin-containing protein (VCP) gene are known to cause various neurodegenerative disorders. Here, we report 8 Japanese patients [6 men, 2 women; median age at onset: 49.5 (range, 35-58) years] from 5 unrelated families with VCP missense mutations. Although 7 of 8 patients were diagnosed with either inclusion body myopathy or amyotrophic lateral sclerosis, 1 patient showed demyelinating polyneuropathy, which was confirmed by longitudinal nerve conduction studies. Sural nerve biopsy of the patient revealed intranuclear ubiquitin staining in Schwann cells. Three known pathogenic VCP mutations (p.Arg191Gln, p.Arg155Cys, and p.Ile126Phe) were detected. A novel mutation, c.293 A>T (p.Asp98Val), was also identified in a patient with amyotrophic lateral sclerosis and frontotemporal dementia. This mutation was predicted to be "deleterious" or "disease causing" using in silico mutation analyses. In conclusion, demyelinating polyneuropathy may be a novel phenotype caused by VCP mutations. The p.Asp98Val mutation was found to be a novel pathogenic mutation of VCP proteinopathy. We believe our cases represent a wide clinical spectrum of VCP mutations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10 -8 ). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10 -4 ). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10 -11 ). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.

Introduction: The present study aimed to survey the prevalence of prodromal symptoms of Parkinson's disease (PD) in Japanese health checkup examinees, for identifying at-risk subjects., Methods: We conducted a questionnaire survey of annual health checkup examinees without neurological symptoms using the following self-reported questionnaires: Japanese version of the Scale for Outcomes in Parkinson's disease for Autonomic Symptoms (SCOPA-AUT); Self-administered Odor Question (SAOQ); REM Sleep Behavior Disorder Screening Scale (RBDSQ); Beck Depression Inventory-Second Edition (BDI-II); Epworth Sleepiness Scale (ESS); and Physical Activity Scale for the Elderly (PASE). The presence of prodromal symptoms was determined using the 90th percentile threshold of each questionnaire. Subjects ≥ 50 years of age with ≥ 2 core prodromal symptoms (dysautonomia, hyposmia, and RBD), were classified as at risk., Results: Between March 2017 and March 2018, 4,953 participants sufficiently answered the questionnaires. Among 2,726 subjects ≥ 50 years of age, 155 were classified as at risk. These subjects had worse values of BDI-II (12.0 ± 8.3 vs. 4.4 ± 3.8, p < 0.001) and ESS (9.6 ± 5.0 vs. 6.3 ± 3.2, p < 0.001), in addition to SCOPA-AUT, SAOQ, and RBDSQ. Male at-risk subjects showed lower values of hemoglobin (14.8 ± 1.3 vs. 15.0 ± 1.1, p = 0.032) and low density lipoprotein cholesterol (114.5 ± 30.3 vs. 123.0 ± 28.9, p = 0.004) than the examinees reporting no prodromal symptoms., Conclusion: Approximately 6% of the population aged 50 years or older was at risk for PD. Male at-risk subjects had mild hematological and metabolic changes relevant to PD.

Objective: The aim of this study is to describe and clarify the factors affecting the prognosis of Japanese patients with amyotrophic lateral sclerosis (ALS) undergoing tracheostomy invasive ventilation (TIV) therapy., Methods: We conducted a prospective longitudinal observational case-control study using a multicentre registry. ALS patients who started TIV therapy after registration (TIV group) and those who did not receive TIV (non-TIV group) were included. We compared the survival time between the TIV group and the non-TIV group using a propensity score matching analysis and evaluated the prognostic factors in the TIV group., Results: From February 2006 to January 2018, 190 patients in the TIV group and 1093 patients in the non-TIV group were included in this study. The mean age of disease onset and usage rate of gastrostomy and non-invasive ventilation therapy differed between the groups. In the propensity score matching analysis using known prognostic factors, the median overall survival time of the TIV group was significantly greater than that of the non-TIV group (11.33 years vs 4.61 years; p<0.001). Analysis using the Cox proportional hazard model suggested that older age of onset and respiratory onset was an independent factor for poor prognosis after starting TIV therapy., Conclusion: We showed that there was a significant difference of approximately 7 years in life expectancy between Japanese ALS patients who did and did not receive TIV therapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Amyotrophic lateral sclerosis (ALS) patient registries can assist in the provision of appropriate care to patients and promote therapeutic developments related to ALS. In Japan, a multicenter registration and follow-up system called the Japanese Consortium for Amyotrophic Lateral Sclerosis research (JaCALS) was built in 2006. Genomic DNA samples and B-cell lines of patients with ALS were stored and linked to clinical information. Information obtained from JaCALS shows the natural histories of Japanese patients with ALS, including their genetic backgrounds and clinical and genetic factors associated with disease progression and prognosis. Research efforts that focus on pathophysiology, identification of biomarkers related to progression and prognosis, and drug discoveries for patients with ALS are advanced using data obtained from JaCALS. In the future, we expect that JaCALS will be a source of real-world evidence, combining data from a large number of cases.

Introduction: We evaluated the morphology of amyloid fibrils in the peripheral nervous system using biopsy or autopsy specimens from hereditary transthyretin amyloidosis patients. The impact of amyloid fibril formation on neighboring tissues was also investigated., Methods: Sural nerve biopsy specimens from 34 patients were examined using electron microscopy. Twenty-eight patients had Val30Met mutations, and the remaining 6 patients had non-Val30Met mutations (i.e., Glu54Lys, Pro24Ser, Thr49Ala, Val71Ala, Val94Gly, and Ala97Gly). The patients with the Val30Met mutation included a case from Brazil (supposedly of Portuguese origin), 6 early-onset cases from endemic foci in Japan, and 21 late-onset cases from non-endemic areas in Japan., Results: Long amyloid fibers were abundant in the early-onset Val30Met cases from the Japanese endemic foci and Brazil, whereas the amyloid fibrils were generally short in the late-onset Val30Met and non-Val30Met cases. The amyloid fibrils seemed to mature from dotty structures among amorphous electron-dense extracellular materials and pull surrounding tissues during the maturation process. The distortion of Schwann cells close to amyloid fibril masses was conspicuous, particularly in cases with long amyloid fibrils. Atrophy was conspicuous in non-myelinating Schwann cells and bands of Büngner (i.e., Schwann cell subunits that previously contained myelinated axons), particularly those completely surrounded by amyloid fibrils. In contrast, the myelinated fibers tended to be only partially surrounded by amyloid fibrils and morphologically preserved due to their large size. Only a few demyelinated axons were found., Conclusion: Pre-fibrillar amyloid precursors appear to play a pivotal role during the initial phase of amyloid fibril formation. The mechanical distortion and subsequent atrophy of Schwann cells resulting from the elongation of amyloid fibrils may be related to small-fiber predominant loss, which is a classical characteristic of amyloid neuropathy. Although rather rare, the destruction of myelin (i.e., demyelination) resulting from amyloid deposition may relate to nerve conduction abnormalities mimicking chronic inflammatory demyelinating polyneuropathy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Older age is thought to be a risk factor for cognitive impairment in amyotrophic lateral sclerosis (ALS). However, very few clinical studies have investigated this relationship using sufficient numbers of healthy controls that correspond to each generation. The purpose of this study was to determine the age-related changes of Addenbrooke's Cognitive Examination-Revised (ACE-R) score in ALS patients by comparing healthy controls of various ages., Methods: 131 ALS patients (86 males, 45 females; mean age: 64.8 ± 10.2; mean education: 12.5 ± 2.7) and 151 age-, gender-, and education-matched healthy controls were enrolled. We applied ACE-R, which could evaluate not only global cognition but five cognitive subdomains that included orientation/attention, memory, verbal fluency, language, and visuospatial ability., Results: ALS patients had significantly lower total and subdomain scores of ACE-R than healthy controls. Multiple regression analysis suggested that age at examination and age at onset had significant influence on ACE-R scores. When we divided ALS patients and healthy controls into 4 groups according to age at examination for ALS, total and each subdomain scores were significantly lower with age, particularly in the older-middle and the oldest group (66.31 years or more) of ALS compared with healthy controls. Locally weighted scatterplot smoothing analysis supported that these reductions of ACE-R total and subdomain scores in ALS patients were more accelerated by approximately 60 years as compared with healthy controls., Conclusion: ALS patients showed accelerated age-related ACE-R score reduction beyond normal ageing processes.

Introduction: Spinal and bulbar muscular atrophy (SBMA) is a slowly progressive neuromuscular disease. Cold exposure often leads to worsening of motor symptoms including paresis. Although mexiletine hydrochloride administration has been shown to be effective for the treatment of several muscular diseases, its effectiveness in SBMA has not been validated to date. The trial will test it as a symptomatic drug for cold paresis. This study is the first trial to evaluate the efficacy and safety of mexiletine hydrochloride administration in patients with SBMA., Methods and Analysis: A placebo-controlled, randomised, double-blind, multicentre, crossover clinical trial will be conducted to assess the safety and efficacy of mexiletine hydrochloride in patients with SBMA. The eligible patients will be assigned randomly in a 1:1 ratio to two groups in a double-blind manner. Participants will take mexiletine hydrochloride (300 mg/day) or a placebo orally three times a day for 4 weeks (period 1). After a 1-week washout period, participants will take the other drug for 4 weeks (period 2). The primary endpoint is the difference in distal latencies between room temperature and cold exposure conditions., Ethics and Dissemination: This study will be conducted in compliance with the Helsinki Declaration and the Ethical Guidelines for Medical and Health Research Involving Human Subjects by the Japanese government and has been approved by the ethics committee of Nagoya University Graduate School of Medicine, as a central institutional review board, and by each facility. The results will be disseminated in peer-reviewed journals and at scientific conferences., Trial Registration Number: UMIN000026150; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We aimed to develop, validate, and evaluate a disease-specific outcome measure for SBMA: the Spinal and Bulbar Muscular Atrophy Functional Rating Scale (SBMAFRS). We examined the Japanese version (SBMAFRS-J) in 80 Japanese SBMA subjects to evaluate its validity and reliability. We then assessed this scale longitudinally in 41 additional SBMA subjects. The English version (SBMAFRS-E) was also tested in 15 US subjects. The total score of the SBMAFRS-J was distributed normally without an extreme ceiling or floor effect. For SBMAFRS-J, the high intra- and inter-rater agreement was confirmed (intra-class correlation coefficients [ICCs] 0.910 and 0.797, respectively), and internal consistency was satisfactory (Cronbach's alpha 0.700-0.822). In addition, SBMAFRS-J demonstrated concurrent, convergent, and discriminant validity, except for the respiratory subscale. The inter-rater reliability and internal consistency of SBMAFRS-E were also satisfactory. Longitudinally, SBMAFRS-J showed a higher sensitivity to disease progression than the existing clinical measures. In conclusion, we developed and validated a disease-specific functional rating scale for SBMA in both Japanese and English versions, although it needs to be re-assessed in interventional studies with a larger sample size including English speaking subjects., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Our objective was to elucidate the clinical factors affecting functional decline and survival in Japanese amyotrophic lateral sclerosis (ALS) patients. We constructed a multicenter prospective ALS cohort that included 451 sporadic ALS patients in the analysis. We longitudinally utilized the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) as the functional scale, and determined the timing of introduction of a tracheostomy for positive-pressure ventilation and death. A joint modelling approach was employed to identify prognostic factors for functional decline and survival. Age at onset was a common prognostic factor for both functional decline and survival (p < 0.001, p < 0.001, respectively). Female gender (p = 0.019) and initial symptoms, including upper limb weakness (p = 0.010), lower limb weakness (p = 0.008) or bulbar symptoms (p = 0.005), were related to early functional decline, whereas neck weakness as an initial symptom (p = 0.018), non-use of riluzole (p = 0.030) and proximal dominant muscle weakness in the upper extremities (p = 0.01) were related to a shorter survival time. A decline in the ALSFRS-R score was correlated with a shortened survival time (p < 0.001). In conclusion, the factors affecting functional decline and survival in ALS were common in part but different to some extent. This difference has not been previously well recognized but is informative in clinical practice and for conducting trials.

Objective: The incidence of sporadic inclusion body myositis (sIBM) in the Japanese population has increased, and some researchers have suggested that race and genetic background may influence the clinical features of the disease. The aim of this study was to clarify the demographic features of Japanese patients with sIBM., Methods: We retrospectively evaluated the demographic features of consecutive patients who were referred to our institution between 1995 and 2011 for diagnostic muscle biopsies and who subsequently were diagnosed to have sIBM., Results: Seventy-three patients comprising 54 men and 19 women received a diagnosis of sIBM during the study period. The patients were divided into two groups based on the date of diagnosis (before and including 2002, and after 2002). The annual number of patients who received a diagnosis of sIBM increased significantly from 3.6±1.6 (mean ± SD) before and including 2002 to 4.9±3.1 (mean ± SD) after 2002 (p<0.05), whereas the annual number of patients who received a diagnosis of polymyositis (PM) or dermatomyositis (DM) remained consistent from 1995 to 2011. The ratio of PM and DM to sIBM was 7.6 during the period from 1995 to 2002 and 5.5 during the period from 2003 to 2011. However, the age-adjusted annual number of patients newly diagnosed with sIBM did not increase significantly after 2002., Conclusion: The number of Japanese patients with sIBM appears to have increased in recent years; however, the characteristics of the patients have not changed. Considering the increased size of the elderly population, prolonged lifespans could explain the demographic movement of sIBM in Japan.

Objective: Spinal and bulbar muscular atrophy (SBMA) is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). Animal studies have shown that the pathogenesis of SBMA is dependent on serum testosterone level. This study is aimed at evaluating the efficacy and safety of androgen deprivation by leuprorelin acetate in patients with SBMA., Methods: Fifty SBMA patients underwent subcutaneous injections of leuprorelin acetate or placebo in a randomized, placebo-controlled trial for 48 weeks, followed by an open-label trial for an additional 96 weeks, in which 19 patients of the leuprorelin group and 15 of the placebo group received leuprorelin acetate. The patients who did not participate in the open-label trial were also followed up for the 96-week period (UMIN000000474)., Results: Leuprorelin acetate significantly extended the duration of cricopharyngeal opening in videofluorography and decreased mutant AR accumulation in scrotal skin biopsy. The patients treated with leuprorelin acetate for 144 weeks exhibited significantly greater functional scores and better swallowing parameters than those who received placebo. Autopsy of one patient who received leuprorelin acetate for 118 weeks suggested that androgen deprivation inhibits the nuclear accumulation or stabilization, or both, of mutant AR in the motor neurons of the spinal cord and brainstem., Interpretation: These observations suggest that administration of leuprorelin acetate suppresses the deterioration of neuromuscular impairment in SBMA by inhibiting the toxic accumulation of mutant AR. The results of this phase 2 trial support the start of large-scale clinical trials of androgen deprivation for SBMA.