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Nishi-Tokyo-shi, Japan

Matsubara S.,Tokyo Metropolitan Neurological Hospital | Shimizu T.,Tokyo Metropolitan Neurological Hospital | Komori T.,Tokyo Metropolitan Neurological Hospital | Mori-Yoshimura M.,National Center Hospital | And 4 more authors.
Neuromuscular Disorders | Year: 2016

A middle-aged Japanese man presented with slowly progressive asymmetric weakness of legs and arm but had neither ptosis nor dysphagia. He had a family history of similar condition suggestive of autosomal dominant inheritance. A muscle biopsy showed mixture of neurogenic atrophy and myopathy with rimmed vacuoles. Furthermore we found intranuclear inclusions that had a fine structure mimicking that of inclusions reported in oculopharyngeal muscular dystrophy (OPMD). Immunohistochemical staining for polyadenylate-binding nuclear protein 1, which is identified within the nuclear inclusions of OPMD, demonstrated nuclear positivity in this case. However, OPMD was thought unlikely based on the clinical features and results of genetic analyses. Instead, a novel mutation in valosin-containing protein, c.376A>T (p.Ile126Phe), was revealed. A diagnosis of inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia was made. This is the first report of polyadenylate-binding nuclear protein 1-positive nuclear inclusions in the muscle of this condition. © 2016 Elsevier B.V. Source


Hatakeyama H.,National Institute of Neuroscience | Hatakeyama H.,Japan Science and Technology Agency | Goto Y.-I.,National Institute of Neuroscience | Goto Y.-I.,Medical Genome Center | Goto Y.-I.,Japan Science and Technology Agency
Stem Cells | Year: 2016

Mitochondria contain multiple copies of their own genome (mitochondrial DNA; mtDNA). Once mitochondria are damaged by mutant mtDNA, mitochondrial dysfunction is strongly induced, followed by symptomatic appearance of mitochondrial diseases. Major genetic causes of mitochondrial diseases are defects in mtDNA, and the others are defects of mitochondria-associating genes that are encoded in nuclear DNA (nDNA). Numerous pathogenic mutations responsible for various types of mitochondrial diseases have been identified in mtDNA; however, it remains uncertain why mitochondrial diseases present a wide variety of clinical spectrum even among patients carrying the same mtDNA mutations (e.g., variations in age of onset, in affected tissues and organs, or in disease progression and phenotypic severity). Disease-relevant induced pluripotent stem cells (iPSCs) derived from mitochondrial disease patients have therefore opened new avenues for understanding the definitive genotype-phenotype relationship of affected tissues and organs in various types of mitochondrial diseases triggered by mtDNA mutations. In this concise review, we briefly summarize several recent approaches using patient-derived iPSCs and their derivatives carrying various mtDNA mutations for applications in human mitochondrial disease modeling, drug discovery, and future regenerative therapeutics. © 2016 AlphaMed Press. Source


Watanabe Y.,Keio University | Uruha A.,National Institute of Neuroscience | Uruha A.,Medical Genome Center | Suzuki S.,Keio University | And 6 more authors.
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2016

Objective To elucidate the common and distinct clinical features of immune-mediated necrotising myopathy (IMNM), also known as necrotising autoimmune myopathy associated with autoantibodies against signal recognition particle (SRP) and 3-hydroxy- 3-methylglutaryl-coenzyme A reductase (HMGCR). Methods We examined a cohort of 460 patients with idiopathic inflammatory myopathies (IIMs) through a muscle biopsy-oriented registration study in Japan. Study entry was strictly determined by the comprehensive histological assessment to exclude other neuromuscular disorders. Anti-SRP and anti-HMGCR antibodies were detected by RNA immunoprecipitation and ELISA, respectively. Results Of 460 patients with IIM, we diagnosed 73 (16%) as having inclusion body myositis (IBM). Of 387 patients with IIMs other than IBM, the frequencies of anti-SRP and anti-HMGCR antibodies were 18% and 12%, respectively. One patient had both autoantibodies. Severe limb muscle weakness, neck weakness, dysphagia, respiratory insufficiency and muscle atrophy were more frequently observed in patients with anti-SRP antibodies than in those with anti-HMGCR antibodies. Serum creatine levels were markedly higher in the patients with autoantibodies than in those without. Histology was characterised by necrosis and regeneration of muscle fibres and was consistent with IMNM except in 1 HMGCR-positive IBM patient. Most patients were initially treated with corticosteroids; however, additional immunosuppressive drugs were required, especially in the patients with anti-SRP antibodies. Rates of unsatisfactory neurological outcome were similar in the 2 autoantibody groups. Conclusions Anti-SRP antibodies are associated with severe neurological symptoms, more so than are anti- HMGCR antibodies. Although these autoantibodies are independent serological markers associated with IMNM, patients bearing either share common characteristics. © 2016 by the BMJ Publishing Group Ltd. Source


Mori-Yoshimura M.,National Center Hospital | Nishino I.,Institute of Neuroscience | Nishino I.,Medical Genome Center
Brain and Nerve | Year: 2015

Distal myopathy with rimmed vacuoles or GNE myopathy, is an early adult-onset myopathy with slow progression that preferentially affects the tibialis anterior muscle. Severely affected patients show marked limb muscle atrophy together with respiratory dysfunction. The disease is caused by a mutation in the GNE gene that catalyzes two rate-limiting reactions in cytosolic sialic acid synthesis. Oral treatment with sialic acid metabolite prevents muscle atrophy and weakness in a mouse GNE myopathy model and a global Phase III study is currently underway. In addition, a global patient registry of neuromuscular cases is widely accepted as a useful tool to obtain epidemiological data and bolster patient recruitment for further development of this treatment strategy. Source


Yokota M.,National Institute of Neuroscience | Yokota M.,Japan Science and Technology Agency | Hatakeyama H.,National Institute of Neuroscience | Hatakeyama H.,Japan Science and Technology Agency | And 5 more authors.
Human Molecular Genetics | Year: 2015

Mitochondrial dysfunction caused by pathogenic mutations in mitochondrial tRNA genes emerges only when mutant mitochondrial DNA (mtDNA) proportions exceed intrinsic pathogenic thresholds; however, little is known about the actual proportions of mutant mtDNA that can affect particular cellular lineage-determining processes. Here, we mainly focused on the effects of mitochondrial respiratory dysfunction caused by m.3243A>G heteroplasmy in MT-TL1 gene on cellular reprogramming. We found that generation of induced pluripotent stem cells (iPSCs) was drastically depressed only by high proportions of mutant mtDNA (≥90% m.3243A>G), and these proportions were strongly associated with the degree of induced mitochondrial respiratory dysfunction. Nevertheless, all established iPSCs, even those carrying ~100% m.3243A>G, exhibited an embryonic stem cell-like pluripotent state. Therefore, our findings clearly demonstrate that loss of physiological integrity in mitochondria triggered by mutant mtDNA constitute a roadblock to cellular rejuvenation, but do not affect the maintenance of the pluripotent state. © The Author 2015. Published by Oxford University Press. All rights reserved. Source

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