We clarified the clinical and pathological aspects of familial amyotrophic lateral sclerosis (FALS) with SOD1 H46R heterozygous mutation in the Miyakonojo Basin, a region in southern Japan where the prevalence of ALS is 11.4 per 10(5) of the population. We studied 17 patients, including one autopsy case, in three FALS families with the mutation. The average age at disease onset in the families was 44.3+/-8.7 years, and the mean disease duration was 12+/-7.6 years, with a range of 6 to 30 years. Ten of 17 patients were unable to walk by the mean age of 56.4+/-12.2 years. The initial symptom was muscle weakness in the distal leg muscle in all patients. The autopsy findings of one FALS patient showed atrophy of lateral and anterior funiculi, decreased numbers of anterior horn cells, preserved posterior funiculus and absence of neuronal inclusion bodies. Percentages of mutant SOD1 protein measured by mass spectrometry were 14% in erythrocytes, 43% in the spinal cord, 47% in the iliopsoas muscle and 60% in the diaphragm. In this study, we confirmed that FALS with SOD1 H46R mutation showed uniform initial symptoms and slow disease progression with intra-familial variation of disease severity and that inclusion body formation is not essential in FALS with this mutation.

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The autosomal dominant cerebellar ataxias (ADCAs) are a clinically and genetically heterogeneous group of disorders. To date, at least 11 genes and 13 additional loci have been identified in ADCAs. Despite phenotypic differences, spinocerebellar ataxia 4 (SCA4) and Japanese 16q-linked ADCA type III map to the same region of 16q22.1. We report four Japanese families with pure cerebellar ataxia and a disease locus at 16q22.1. Our families yielded a peak lod score of 6.01 at marker D16S3141. To refine the candidate region, we carried out genetic linkage studies in four pedigrees with a high density set of DNA markers from chromosome 16q22.1. Our linkage data suggest that the disease locus for 16q-ADCA type III is within the 1.25-Mb interval delineated by markers 17msm and CTTT01. We screened for mutations in 36 genes within the critical region. Our critical region lies within the linkage interval reported for SCA4 and for Japanese 16q-ADCA type III. These data suggest that the ADCA that we have characterized is allelic with SCA4 and Japanese 16q-linked ADCA type III.

Dystrophin is associated with several novel sarcolemmal proteins, including a laminin-binding extracellular glycoprotein of 156 kD (a-dystroglycan) and a transmembrane glycoprotein of 50 kD (adhalin). Deficiency of adhalin characterizes a severe autosomal recessive muscular dystrophy prevalent in Arabs. Here we report for the first time two mongoloid (Japanese) patients with autosomal recessive muscular dystrophy deficient in adhalin. Interestingly, adhalin was not completely absent and was faintly detectable in a patchy distribution along the sarcolemma in our patients. Although the M and B2 subunits of laminin were preserved, the B1 subunit was greatly reduced in the basal lamina surrounding muscle fibers. Our results raise a possibility that the deficiency of adhalin may be associated with the disturbance of sarcolemma-extracellular matrix interaction leading to sarcolemmal instability. (J. Clin. Invest. 1994. 94:601-606.)

16q-ADCA (OMIM no. 117210) is an autosomal dominant spinocerebellar ataxia (AD-SCA) characterized by late-onset pure cerebellar ataxia and À16C4T substitution of the puratrophin-1 gene. Recently, a series of single-nucleotide polymorphisms (haplotype block) were found to be specific to 16q-ADCA. We screened patients with ataxia and found 62 patients, including four homozygotes who carry the C-T substitution of the puratrophin-1 gene. By further analysis of the patients with the haplotype block, we observed a single-founder effect for 16q-ADCA, even in patients who are supposed to be sporadic late cortical cerebellar atrophy (LCCA). We also observed slippage mutations of microsatellite markers, GATA01 and 17msm, in the pedigrees. We compared the clinical course of 16q-ADCA in heterozygotes and homozygotes with the haplotype block and observed no apparent gene dosage effect. 16q-ADCA accounts for 27% of AD-SCAs and is the most frequent AD-SCA in South Kyushu, Japan.

Objective:To determine the causative pathogen and investigate the effective treatment of a new type of encephalomyelitis with an unknown pathogen in Japan and report the preliminary ultrastructural and genomic characterization of the causative agent.Methods:From 2005 to 2012, we treated 4 Japanese patients with geographic clustering and comparable clinical features, serum/CSF cytology, and radiologic findings. Brain biopsy was conducted in all patients to analyze neuropathologic changes by histology, and electron microscopy was applied to reveal the features of the putative pathogen. Genomic DNA was obtained from the affected brain tissues and CSF, and an unbiased high-throughput sequencing approach was used to screen for specific genomic sequences indicative of the pathogen origin.Results:All patients exhibited progressive dementia with involuntary tongue movements. Cytologic examination of CSF revealed elevated mononuclear cells. Abnormal MRI signals were observed in temporal lobes, subcortical white matter, and spinal cord. Biopsied brain tissue exhibited aggregated periodic acid-Schiff–positive macrophages and 2–7 μm diameter round/oval bodies without nuclei or cell walls scattered around the vessels. Unbiased high-throughput sequencing identified more than 100 archaea-specific DNA fragments. All patients were responsive to trimethoprim/sulfamethoxazole (TMP-SMX) plus corticosteroid therapy.Conclusions:We report 4 cases of encephalomyelitis due to an unknown pathogen. On the basis of ultrastructural and genomic studies, we propose a new disease entity resulting from a causative pathogen having archaeal features. TMP-SMX therapy was effective against this new type of encephalomyelitis.

We, retrospectively, examined the clinical course, decline in pulmonary function, and requirements for ventilatory assistance in 54 patients with Duchenne-type muscular dystrophy (DMD) who were followed in the muscle disease ward of the National Hospital in Kagoshima, Japan, over the past 20 years. The percentage of the predicted vital capacity (%VC) declined in relation to age and stage of disease. Most patients required assisted ventilation when the %VC fell below 10%. Twenty patients were treated with a negative pressure chest respirator. Six of these died at the mean age of 23.2 years after being on the respirator for a mean period of 18 months. Fourteen patients are surviving at a mean age of 23.5 years after being on the respirator for a mean period of 39 months.