Publications by authors named "Ichizo Nishino"

516 Publications

Imaging-based evaluation of pathogenicity by novel DNM2 variants associated with centronuclear myopathy.

Hum Mutat 2021 Nov 27. Epub 2021 Nov 27.

National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, Japan.

Centronuclear myopathy is a group of inherited congenital diseases showing clinically progressive muscle weakness associated with the presence of centralized myonuclei, diagnosed by genetic testing and muscle biopsy. The gene encoding dynamin 2, DNM2, has been identified as a causative gene for an autosomal dominant form of centronuclear myopathy. However, the information of a DNM2 variant alone is not always sufficient to gain a definitive diagnosis as the pathogenicity of many gene variants is currently unknown. In this study, we identified 5 novel DNM2 variants in our cohort. To establish the pathogenicity of these variants without using clinicopathological information, we used a simple in cellulo imaging-based assay for T-tubule-like structures to provide quantitative data that enable objective determination of pathogenicity by novel DNM2 variants. With this assay, we demonstrated that the phenotypes induced by mutant dynamin 2 in cellulo are well correlated with biochemical gain-of-function features of mutant dynamin 2 as well as the clinicopathological phenotypes of each patient. Our approach of combining an in cellulo assay with clinical information of the patients also explains the course of a disease progression by the pathogenesis of each variant in DNM2-associated centronuclear myopathy. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/humu.24307DOI Listing
November 2021

A case of delayed diagnosis of Becker muscular dystrophy due to underlying developmental disorders.

Brain Dev 2021 Nov 12. Epub 2021 Nov 12.

Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Japan.

Background: Developmental disorders associated with Becker muscular dystrophy (BMD), possibly resulting from a lack of dystrophin in the brain, have been reported, but their importance is not fully understood. We report a case of a BMD patient who had been socially withdrawn due to mental retardation and autism spectrum disorder and could not receive appropriate medical services, resulting in delayed detection of severe cardiomyopathy and embolic strokes which developed as complications of BMD.

Case Report: The case is a 41-year-old male. In elementary school, he was the slowest runner in his class and had poor grades. He started missing school due to bullying in junior high school and had been socially withdrawn for 24 years. He developed difficulty walking due to progressive muscle weakness in the extremities and lost ambulation at age 36. At age 41, he was referred to our hospital by public health support services to address his social withdrawal. Muscle biopsy led to the diagnosis of BMD. Psychological examination revealed mild mental retardation and autism spectrum disorder, which may have resulted in social isolation. He had severe cardiomyopathy and asymptomatic cerebral infarction due to heart failure.

Conclusion: In BMD patients, developmental disorders can potentially hinder access to appropriate medical treatment. BMD is an important differential diagnosis for physically disabled children with developmental disorders. Early intellectual and psychological interventions and evaluation of complications are important for improving patient prognosis and quality of life.
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http://dx.doi.org/10.1016/j.braindev.2021.10.010DOI Listing
November 2021

Nemaline Myopathy Initially Diagnosed as Right Heart Failure with Type 2 Respiratory Failure.

Intern Med 2021 Nov 13. Epub 2021 Nov 13.

Department of Neurology, Fujita Health University, School of Medicine, Japan.

Nemaline myopathy (NM) is a rare muscle disease with various clinical types. In some cases, NM can lead to type 2 respiratory failure and right heart failure. We herein report a patient with congenital NM with nebulin gene mutation who presented with acute right heart failure and type 2 respiratory failure due to respiratory muscle paralysis after upper respiratory tract infection, needing a permanent ventilator for assistance. However, the limb and trunk muscle strengths were within normal limits. This case showed that NM should be considered as a cause of right heart failure and type 2 respiratory failure.
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http://dx.doi.org/10.2169/internalmedicine.8314-21DOI Listing
November 2021

Assessment of thrombocytopenia, sleep apnea, and cardiac involvement in GNE myopathy patients.

Muscle Nerve 2021 Oct 30. Epub 2021 Oct 30.

Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.

Introduction: We previously identified UDP-N-acetylglucosamine 2-epimerase (GNE) myopathy patients with sleep apnea and a past history of thrombocytopenia, but without disease-specific cardiac involvement. This study aimed to clarify the occurrence, severity, and serial changes of these complications.

Methods: Thirty-three genetically confirmed GNE myopathy patients who participated in a 5-y longitudinal observational history study underwent platelet count and platelet-associated immunoglobulin G (PA-IgG) measurements, a sleep study, and electrocardiography (ECG), Holter ECG, and echocardiogram examinations.

Results: Among the 33 patients, three had low platelet counts and 17 out of 26 were PA-IgG positive. No patient exhibited bleeding tendencies, and 3 out of 28 had low platelet counts. Muscle weakness was more pronounced, and summed MMT and grip power significantly lower, in PA-IgG-positive patients than in PA-IgG-negative patients. Of 19 patients, 7, 4, and 3 who underwent a sleep study had mild, moderate, and severe sleep apnea, respectively, and three started continuous positive airway pressure (CPAP). The respiratory disturbance index was not significantly correlated with physical evaluation items or forced vital capacity. All patients underwent ECG, 32 underwent cardiac ultrasound, and 25 underwent Holter ECG. No disease-specific cardiac involvement was noted, no serial changes during the follow-up period were observed for ECG and echocardiography, and none of the patients required therapy for cardiac abnormalities.

Discussion: PA-IgG is a potential disease biomarker in GNE myopathy patients, although its significance needs to be clarified. While none of the patients in this study experienced cardiomyopathy or arrythmia due to myopathy, sleep apnea was identified as a frequent complication.
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http://dx.doi.org/10.1002/mus.27451DOI Listing
October 2021

Mild form of Danon disease: two case reports.

Neuromuscul Disord 2021 Jul 31. Epub 2021 Jul 31.

Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Danon disease is typically lethal by the mid-twenties in male patients due to cardiomyopathy. This report aims to describe two unrelated male patients showing mild manifestations of the disease. A 39-year-old man presented with a 10-year history of elevated serum creatine kinase levels with slowly progressive muscle weakness. Muscle pathology showed autophagic vacuoles with sarcolemmal features. Genetic testing revealed a hemizygous mutation in exon 9b, an alternatively spliced exon, of lysosome-associated membrane protein-2 (LAMP-2) (c.1097_1098delAA). Cardiac testing showed asymptomatic mild left ventricular hypertrophy. He had borderline intelligence. Early stage of retinopathy was detected. Another male patient, currently 53-year-old, had asymptomatic supraventricular extrasystole and muscle weakness but no intellectual disability, harboring the same mutation. He also had retinopathy. The present patients commonly carry a mutation in exon 9b of LAMP-2, suggesting that mutations in the exon are associated with a mild form of Danon disease.
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http://dx.doi.org/10.1016/j.nmd.2021.07.017DOI Listing
July 2021

DA-Raf and the MEK inhibitor trametinib reverse skeletal myocyte differentiation inhibition or muscle atrophy caused by myostatin and GDF11 through the non-Smad Ras-ERK pathway.

J Biochem 2021 Oct 22. Epub 2021 Oct 22.

Department of Biology, Graduate School of Science, Chiba University, 1-33 Yayoicho, Inageku, Chiba, Chiba 263-8522, Japan.

Myostatin (Mstn) and GDF11 are critical factors that are involved in muscle atrophy in the young and sarcopenia in the elderly, respectively. These TGF-β superfamily proteins activate not only Smad signaling but also non-Smad signaling including the Ras-mediated ERK pathway (Raf-MEK-ERK phosphorylation cascade). Although Mstn and GDF11 have been shown to induce muscle atrophy or sarcopenia by Smad2/3-mediated Akt inhibition, participation of the non-Smad Ras-ERK pathway in atrophy and sarcopenia has not been well determined. We show here that both Mstn and GDF11 prevented skeletal myocyte differentiation but that the MEK inhibitor U0126 or trametinib restored differentiation in Mstn- or GDF11-treated myocytes. These MEK inhibitors induced the expression of DA-Raf1 (DA-Raf), which is a dominant-negative antagonist of the Ras-ERK pathway. Exogenous expression of DA-Raf in Mstn- or GDF11-treated myocytes restored differentiation. Furthermore, administration of trametinib to aged mice resulted in an increase in myofiber size, or recovery from muscle atrophy. The trametinib administration downregulated ERK activity in these muscles. These results imply that the Mstn/GDF11-induced Ras-ERK pathway plays critical roles in the inhibition of myocyte differentiation and muscle regeneration, which leads to muscle atrophy. Trametinib and similar approved drugs might be applicable to the treatment of muscle atrophy in sarcopenia or cachexia.
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http://dx.doi.org/10.1093/jb/mvab116DOI Listing
October 2021

A Japanese Patient with Hereditary Myopathy with Early Respiratory Failure Due to the p.P31732L Mutation of Titin.

Intern Med 2021 Oct 19. Epub 2021 Oct 19.

Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Japan.

Hereditary myopathy with early respiratory failure (HMERF) is caused by titin A-band mutations in exon 344 and is considered quite rare. Respiratory insufficiency can be the sole symptom in the disease course. We herein report the first Japanese HMERF patient with a p.P31732 L mutation in titin. The patient manifested respiratory failure and mild weakness of the neck flexor muscle at 69 years old and showed fatty replacement of the bilateral semitendinosus muscles on muscle imaging. Our case indicates that HMERF with a heterozygous p.P31732 L mutation should be included in the differential diagnosis of muscular diseases presenting with early respiratory failure.
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http://dx.doi.org/10.2169/internalmedicine.7733-21DOI Listing
October 2021

TRAPPC11-related muscular dystrophy with hypoglycosylation of alpha-dystroglycan in skeletal muscle and brain.

Neuropathol Appl Neurobiol 2021 Oct 14. Epub 2021 Oct 14.

Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Aims: TRAPPC11, a subunit of the transport protein particle (TRAPP) complex, is important for complex integrity and anterograde membrane transport from the endoplasmic reticulum (ER) to the ER-Golgi intermediate compartment. Several individuals with TRAPPC11 mutations have been reported with muscle weakness and other features including brain, liver, skeletal and eye involvement. A detailed analysis of brain and muscle pathology will further our understanding of the presentation and aetiology of TRAPPC11 disease.

Methods: We describe five cases of early-onset TRAPPC11-related muscular dystrophy with a systematic review of muscle pathology in all five individuals, post-mortem brain pathology findings in one and membrane trafficking assays in another.

Results: All affected individuals presented in infancy with muscle weakness, motor delay and elevated serum creatine kinase (CK). Additional features included cataracts, liver disease, intellectual disability, cardiomyopathy, movement disorder and structural brain abnormalities. Muscle pathology in all five revealed dystrophic changes, universal hypoglycosylation of alpha-dystroglycan and variably reduced dystrophin-associated complex proteins. Membrane trafficking assays showed defective Golgi trafficking in one individual. Neuropathological examination of one individual revealed cerebellar atrophy, granule cell hypoplasia, Purkinje cell (PC) loss, degeneration and dendrite dystrophy, reduced alpha-dystroglycan (IIH6) expression in PC and dentate neurones and absence of neuronal migration defects.

Conclusions: This report suggests that recessive mutations in TRAPPC11 are linked to muscular dystrophies with hypoglycosylation of alpha-dystroglycan. The structural cerebellar involvement that we document for the first time resembles the neuropathology reported in N-linked congenital disorders of glycosylation (CDG) such as PMM2-CDG, suggesting defects in multiple glycosylation pathways in this condition.
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http://dx.doi.org/10.1111/nan.12771DOI Listing
October 2021

An autopsied case of ADSSL1 myopathy.

Neuromuscul Disord 2021 Jul 20. Epub 2021 Jul 20.

Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8553, Japan.

ADSSL1 myopathy is an inherited myopathy with limb weakness, respiratory muscle paralysis, dysphagia, and myocardial symptoms. We present an autopsy case of a 66-year-old male carrying compound heterozygous variants c.781G>A (p.D261N) and c.919delA (p.I307fs) in ADSSL1. He had not run fast since school with no family history. He showed a gradual progression of limb weakness and developed dyspnoea, dysphagia, and Brugada syndrome at the age of 56. The magnetic resonance imaging (MRI) revealed bright tongue sign. Muscle biopsy showed only chronic myopathic changes. He died of respiratory muscle weakness at the age of 66. Autopsy revealed that there were many fibres with vacuoles and nemaline rods in the biceps brachii, tongue, diaphragm, and iliopsoas. Many lipopigments and nuclear clumps were also detected. The myocardium and central nervous system had only nonspecific age-related changes. This is the first autopsied case to clarify the terminal state of ADSSL1 myopathy.
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http://dx.doi.org/10.1016/j.nmd.2021.07.011DOI Listing
July 2021

A review of core myopathy: central core disease, multiminicore disease, dusty core disease, and core-rod myopathy.

Neuromuscul Disord 2021 10 17;31(10):968-977. Epub 2021 Sep 17.

Department of Neuromuscular Research, National Center of Neurology and Psychiatry (NCNP), National Institute of Neuroscience, 4-1-1 Ogawahigashi, Tokyo 187-8502, Japan; Medical Genome Center, NCNP, Tokyo, Kodaira, Japan. Electronic address:

Core myopathies are clinically, pathologically, and genetically heterogeneous muscle diseases. Their onset and clinical severity are variable. Core myopathies are diagnosed by muscle biopsy showing focally reduced oxidative enzyme activity and can be pathologically divided into central core disease, multiminicore disease, dusty core disease, and core-rod myopathy. Although RYR1-related myopathy is the most common core myopathy, an increasing number of other causative genes have been reported, including SELENON, MYH2, MYH7, TTN, CCDC78, UNC45B, ACTN2, MEGF10, CFL2, KBTBD13, and TRIP4. Furthermore, the genes originally reported to cause nemaline myopathy, namely ACTA1, NEB, and TNNT1, have been recently associated with core-rod myopathy. Genetic analysis allows us to diagnose each core myopathy more accurately. In this review, we aim to provide up-to-date information about core myopathies.
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http://dx.doi.org/10.1016/j.nmd.2021.08.015DOI Listing
October 2021

Maximal Multistage Shuttle Run Test-induced Myalgia in a Patient with Muscle Phosphorylase B Kinase Deficiency.

Intern Med 2021 Oct 5. Epub 2021 Oct 5.

Department of Neurology, Kawasaki Medical School, Japan.

Muscle phosphorylase b kinase (PHK) deficiency is a rare mild metabolic disorder caused by mutations of the PHKA1 gene encoding the αM subunit of PHK. A 16-year-old boy experienced myalgia during the maximal multistage 20-m shuttle run test targeting the maximal oxygen consumption. Although an ischemic forearm exercise test was normal, a muscle biopsy revealed subsarcolemmal glycogen accumulation. He harbored a novel insertion mutation in the PHKA1 gene that resulted in premature termination of the αM subunit close to the C-terminus. Compared with previously reported cases, his reduction in PHK activity was relatively mild.
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http://dx.doi.org/10.2169/internalmedicine.8137-21DOI Listing
October 2021

Deep convolutional neural network-based algorithm for muscle biopsy diagnosis.

Lab Invest 2021 Oct 2. Epub 2021 Oct 2.

Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Histopathologic evaluation of muscle biopsy samples is essential for classifying and diagnosing muscle diseases. However, the numbers of experienced specialists and pathologists are limited. Although new technologies such as artificial intelligence are expected to improve medical reach, their use with rare diseases, such as muscle diseases, is challenging because of the limited availability of training datasets. To address this gap, we developed an algorithm based on deep convolutional neural networks (CNNs) and collected 4041 microscopic images of 1400 hematoxylin-and-eosin-stained pathology slides stored in the National Center of Neurology and Psychiatry for training CNNs. Our trained algorithm differentiated idiopathic inflammatory myopathies (mostly treatable) from hereditary muscle diseases (mostly non-treatable) with an area under the curve (AUC) of 0.996 and achieved better sensitivity and specificity than the diagnoses done by nine physicians under limited diseases and conditions. Furthermore, it successfully and accurately classified four subtypes of the idiopathic inflammatory myopathies with an average AUC of 0.958 and classified seven subtypes of hereditary muscle disease with an average AUC of 0.936. We also established a method to validate the similarity between the predictions made by the algorithm and the seven physicians using visualization technology and clarified the validity of the predictions. These results support the reliability of the algorithm and suggest that our algorithm has the potential to be used straightforwardly in a clinical setting.
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http://dx.doi.org/10.1038/s41374-021-00647-wDOI Listing
October 2021

MLIP causes recessive myopathy with rhabdomyolysis, myalgia and baseline elevated  serum creatine kinase.

Brain 2021 Oct;144(9):2722-2731

Department of Chemistry and Earth Science, College of Arts and Sciences, Qatar University, Qatar.

Striated muscle needs to maintain cellular homeostasis in adaptation to increases in physiological and metabolic demands. Failure to do so can result in rhabdomyolysis. The identification of novel genetic conditions associated with rhabdomyolysis helps to shed light on hitherto unrecognized homeostatic mechanisms. Here we report seven individuals in six families from different ethnic backgrounds with biallelic variants in MLIP, which encodes the muscular lamin A/C-interacting protein, MLIP. Patients presented with a consistent phenotype characterized by mild muscle weakness, exercise-induced muscle pain, variable susceptibility to episodes of rhabdomyolysis, and persistent basal elevated serum creatine kinase levels. The biallelic truncating variants were predicted to result in disruption of the nuclear localizing signal of MLIP. Additionally, reduced overall RNA expression levels of the predominant MLIP isoform were observed in patients' skeletal muscle. Collectively, our data increase the understanding of the genetic landscape of rhabdomyolysis to now include MLIP as a novel disease gene in humans and solidifies MLIP's role in normal and diseased skeletal muscle homeostasis.
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http://dx.doi.org/10.1093/brain/awab275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8536936PMC
October 2021

Successful treatment of congenital myasthenic syndrome caused by a novel compound heterozygous variant in RAPSN.

Brain Dev 2021 Sep 23. Epub 2021 Sep 23.

Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, Japan; Medical Genome Center, NCNP, Kodaira, Tokyo, Japan.

Background: Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous neuromuscular disorder characterized by muscle weakness and caused by mutations in more than 35 different genes. This condition should not be overlooked as a subset of patients with CMS are treatable. However, the diagnosis of CMS is often difficult due to the broad variability in disease severity and course.

Case Report: A five-year-old boy without remarkable family history was born with marked general muscle hypotonia and weakness, respiratory insufficiency, anomalies, and multiple joint contractures. Congenital myopathy was suspected based upon type 1 fiber predominance on muscle biopsy. However, he was diagnosed with CMS at age 4 years when his ptosis and ophthalmoplegia were found to be improved by edrophonium chloride and repetitive nerve stimulation showed attenuation of compound muscle action potentials. An exome sequencing identified a compound heterozygous missense variant of c.737C > T (p.A246V) and a novel intronic insertion c.1166 + 4_1166 + 5insAAGCCCACCAC in RAPSN. RT-PCR analysis which showed the skipping of exon 7 in a skeletal muscle sample confirmed that the intronic insertion was pathogenic. His myasthenic symptoms were remarkably improved by pyridostigmine.

Conclusion: The patient's diagnosis of CMS was confirmed by exome sequencing, and RT-PCR revealed that the skipping of exon 7 in RAPSN was caused by a novel intronic insertion. The genetic information uncovered in this case should therefore be added to the collection of tools for diagnosing and treating CMS.
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http://dx.doi.org/10.1016/j.braindev.2021.09.001DOI Listing
September 2021

Visualizing Muscle Sialic Acid Expression in the GNED207VTgGne-/- Cmah-/- Model of GNE Myopathy: A Comparison of Dietary and Gene Therapy Approaches.

J Neuromuscul Dis 2021 Sep 10. Epub 2021 Sep 10.

Center for Gene Therapy, Abigail Wexner Research Institute Children's Drive Columbus, OH, USA.

Background: GNE myopathy (GNEM) is a rare, adult-onset, inclusion body myopathy that results from partial loss of function mutations in the GNE gene. GNE encodes UDP-GlcNAc epimerase/Mannose-6 kinase, a protein with two enzymatic activities that comprise the committed step in biosynthesis of sialic acid (SA), an essential glycan that appears on the terminal positions of many extracellular oligosaccharide chains. These GNE mutations can cause a reduction of SA in many tissues, although pathology is restricted to skeletal muscles through a poorly understood mechanism.

Objective: Despite recent advances in the field, it remains unclear which therapeutic avenue is most promising for the restoration of SA level in skeletal muscle affected by GNEM. Our objective was to assess dietary and gene therapy strategies for GNEM in Cmah-deficient GNED207VTgGne-/- mice, a model that allows for the visualization of orally delivered N-glycolylneuraminic acid (Neu5Gc), one of the two predominant SA forms in muscle.

Methods: Methods included in situ physiology studies of the tibialis anterior muscle, studies of ambulation and limb grip strength, and muscle staining using MAA, SNA, and anti-Neu5Gc antibody, along with qPCR, qRT-PCR, western blot, and HPLC studies to assess virally introduced DNA, GNE gene expression, GNE protein expression, and SA expression.

Results: We found that a diet enriched in Neu5Gc-containing glycoproteins had no impact on Neu5Gc immunostaining in muscles of GNEM model mice. Delivery of a single high dose oral Neu5Gc therapy, however, did increase Neu5Gc immunostaining, though to levels below those found in wild type mice. Delivery of a single dose of GNE gene therapy using a recombinant Adeno Associated Virus (rAAV) vector with a liver-specific or a muscle-specific promoter both caused increased muscle Neu5Gc immunostaining that exceeded that seen with single dose monosaccharide therapy.

Conclusions: Our findings indicate that dietary loading of Neu5Gc-containing glycoproteins is not effective in increasing muscle Neu5Gc expression, while single dose oral Neu5Gc monosaccharide or GNE gene therapy are. Neu5Gc immunostaining, however, showed greater changes than did lectin staining or HPLC analysis. Taken together, these results suggest that Neu5Gc immunostaining may be more sensitive technique to follow SA expression than other more commonly used methods and that liver expression of GNE may contribute overall muscle SA content.
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http://dx.doi.org/10.3233/JND-200575DOI Listing
September 2021

FKRP mutations cause congenital muscular dystrophy 1C and limb-girdle muscular dystrophy 2I in Asian patients.

J Clin Neurosci 2021 Oct 28;92:215-221. Epub 2021 Aug 28.

Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawa-Higashi-cho, Kodaira, Tokyo 187-8502, Japan.

Mutation in the fukutin-related protein (FKRP) gene causes alpha-dystroglycanopathies, a group of autosomal recessive disorders associated with defective glycosylated alpha-dystroglycan (α-DG). The disease phenotype shows a broad spectrum, from the most severe congenital form involving brain and eye anomalies to milder limb-girdle form. FKRP-related alpha-dystroglycanopathies are common in European countries. However, a limited number of patients have been reported in Asian countries. Here, we presented the clinical, pathological, and genetic findings of nine patients with FKRP mutations identified at a single muscle repository center in Japan. Three and six patients were diagnosed with congenital muscular dystrophy type 1C and limb-girdle muscular dystrophy 2I, respectively. None of our Asian patients showed the most severe form of alpha-dystroglycanopathy. While all patients showed a reduction in glycosylated α-DG levels, to variable degrees, these levels did not correlate to clinical severity. Fifteen distinct pathogenic mutations were identified in our cohort, including five novel mutations. Unlike in the populations belonging to European countries, no common mutation was found in our cohort.
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http://dx.doi.org/10.1016/j.jocn.2021.08.014DOI Listing
October 2021

A recurrent homozygous ACTN2 variant associated with core myopathy.

Acta Neuropathol 2021 10 1;142(4):785-788. Epub 2021 Sep 1.

Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, 187-8551, Japan.

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http://dx.doi.org/10.1007/s00401-021-02363-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423689PMC
October 2021

Neuropathy/intranuclear inclusion bodies in oculopharyngodistal myopathy: A case report.

eNeurologicalSci 2021 Sep 4;24:100348. Epub 2021 Jun 4.

Department of Neuropathology (Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital & Institute of Gerontology (TMGHIG), Tokyo, Japan.

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http://dx.doi.org/10.1016/j.ensci.2021.100348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385282PMC
September 2021

Myoclonic Epilepsy with Ragged-red Fibers with Intranuclear Inclusions.

Intern Med 2021 Aug 24. Epub 2021 Aug 24.

Department of Neurology, Tokyo Metropolitan Neurological Hospital (TMNH), Japan.

We herein report a case of myoclonic epilepsy with ragged-red fibers (MERRF) harboring a novel variant in mitochondrial cysteine transfer RNA (MT-TC). A 68-year-old woman presented with progressive myoclonic epilepsy with optic atrophy and peripheral neuropathy. A skin biopsy revealed p62-positive intranuclear inclusions. No mutations were found in the causative genes for diseases known to be related to intranuclear inclusions; however, a novel variant in MT-TC was found. The association between intranuclear inclusions and this newly identified MERRF-associated variant is unclear; however, the rare complication of intranuclear inclusions in a patient with typical MERRF symptoms should be noted for future studies.
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http://dx.doi.org/10.2169/internalmedicine.7767-21DOI Listing
August 2021

A novel RyR1-selective inhibitor prevents and rescues sudden death in mouse models of malignant hyperthermia and heat stroke.

Nat Commun 2021 07 13;12(1):4293. Epub 2021 Jul 13.

Department of Pharmacology, Juntendo University School of Medicine, Tokyo, Japan.

Mutations in the type 1 ryanodine receptor (RyR1), a Ca release channel in skeletal muscle, hyperactivate the channel to cause malignant hyperthermia (MH) and are implicated in severe heat stroke. Dantrolene, the only approved drug for MH, has the disadvantages of having very poor water solubility and long plasma half-life. We show here that an oxolinic acid-derivative RyR1-selective inhibitor, 6,7-(methylenedioxy)-1-octyl-4-quinolone-3-carboxylic acid (Compound 1, Cpd1), effectively prevents and treats MH and heat stroke in several mouse models relevant to MH. Cpd1 reduces resting intracellular Ca, inhibits halothane- and isoflurane-induced Ca release, suppresses caffeine-induced contracture in skeletal muscle, reduces sarcolemmal cation influx, and prevents or reverses the fulminant MH crisis induced by isoflurane anesthesia and rescues animals from heat stroke caused by environmental heat stress. Notably, Cpd1 has great advantages of better water solubility and rapid clearance in vivo over dantrolene. Cpd1 has the potential to be a promising candidate for effective treatment of patients carrying RyR1 mutations.
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http://dx.doi.org/10.1038/s41467-021-24644-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277899PMC
July 2021

A Japanese case of oculopharyngeal muscular dystrophy (OPMD) with PABPN1 c.35G > C; p.Gly12Ala point mutation.

BMC Neurol 2021 Jul 5;21(1):265. Epub 2021 Jul 5.

Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-0841, Japan.

Background: Oculopharyngeal muscular dystrophy (OPMD) is a late-onset muscular dystrophy characterised by slowly progressive ptosis, dysphagia, and proximal limb muscle weakness. A common cause of OPMD is the short expansion of a GCG or GCA trinucleotide repeat in PABPN1 gene.

Case Presentation: A 78-year-old woman presented with ptosis and gradually progressive dysphagia. Her son had the same symptoms. A physical examination and muscle imaging (MRI and ultrasound) showed impairment of the tongue, proximal muscles of the upper limbs, and flexor muscles of the lower limbs. Needle-electromyography (EMG) of bulbar and facial muscles revealed a myopathic pattern. Based on the characteristic muscle involvement pattern and needle-EMG findings, we suspected that the patient had OPMD. Gene analysis revealed PABPN1 c.35G > C point mutation, which mimicked the effect of a common causative repeat expansion mutation of OPMD.

Conclusion: We herein describe the first reported Japanese case of OPMD with PABPN1 point mutation, suggesting that this mutation is causative in Asians as well as in Europeans, in whom it was originally reported.
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http://dx.doi.org/10.1186/s12883-021-02300-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256512PMC
July 2021

A symptomatic male carrier of Duchenne muscular dystrophy with Klinefelter's syndrome mimicking Becker muscular dystrophy.

Neuromuscul Disord 2021 07 27;31(7):666-672. Epub 2021 Apr 27.

Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.

Duchenne and Becker muscular dystrophy (DMD/BMD) are commonly inherited muscle disorders. We report a 31-year-old male who had muscle symptoms with left-right differences and intellectual disability. He was diagnosed with BMD at age 15 primarily based on muscle biopsy findings. A few years later, DMD gene analysis revealed that he was a heterozygous carrier of a normal copy of the gene and a mutated copy with an exon 45-54 deletion, which is expected to result in an out-of-frame mutation. A karyotype analysis was compatible with XXY Klinefelter's syndrome. The analysis of X-chromosome inactivation (XCI) using his skeletal muscle sample revealed a skewed XCI pattern. This is the first reported case of a symptomatic male carrier of DMD caused by skewed XCI in Klinefelter's syndrome with a genetically proven heterozygous mutation of the DMD gene. The skewed XCI pattern could also explain the left-right differences in skeletal muscle symptoms observed in this patient.
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http://dx.doi.org/10.1016/j.nmd.2021.04.006DOI Listing
July 2021

Causative variant profile of collagen VI-related dystrophy in Japan.

Orphanet J Rare Dis 2021 06 24;16(1):284. Epub 2021 Jun 24.

Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawa-Higashi, Kodaira, Tokyo, 187-8502, Japan.

Background: Collagen VI-related dystrophy spans a clinical continuum from severe Ullrich congenital muscular dystrophy to milder Bethlem myopathy. This disease is caused by causative variants in COL6A1, COL6A2, or COL6A3. Most reported causative variants are de novo; therefore, to identify possible associated causative variants, comprehensive large cohort studies are required for different ethnicities.

Methods: We retrospectively reviewed clinical information, muscle histology, and genetic analyses from 147 Japanese patients representing 130 families, whose samples were sent for diagnosis to the National Center of Neurology and Psychiatry between July 1979 and January 2020. Genetic analyses were conducted by gene-based resequencing, targeted panel resequencing, and whole exome sequencing, in combination with cDNA analysis.

Results: Of a total of 130 families with 1-5 members with collagen VI-related dystrophy, 120 had mono-allelic and 10 had bi-allelic variants in COL6A1, COL6A2, or COL6A3. Among them, 60 variants were in COL6A1, 57 in COL6A2, and 23 in COL6A3, including 37 novel variants. Mono-allelic variants were classified into four groups: missense (69, 58%), splicing (40, 33%), small in-frame deletion (7, 6%), and large genomic deletion (4, 3%). Variants in the triple helical domains accounted for 88% (105/120) of all mono-allelic variants.

Conclusions: We report the causative variant profile of a large set of Japanese cases of collagen VI-related dystrophy. This dataset can be used as a reference to support genetic diagnosis and variant-specific treatment.
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http://dx.doi.org/10.1186/s13023-021-01921-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223365PMC
June 2021

Anti-nuclear matrix protein 2 antibody-positive inflammatory myopathies represent extensive myositis without dermatomyositis-specific rash.

Rheumatology (Oxford) 2021 Jun 21. Epub 2021 Jun 21.

Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.

Objectives: Myositis-specific autoantibodies (MSAs) define distinct clinical subsets of idiopathic inflammatory myopathies (IIMs). The anti-nuclear matrix protein 2 (NXP2) antibody, a MSA detected in juvenile/adult IIMs, has been reported to be associated with a high risk of subcutaneous calcinosis, subcutaneous oedema, and internal malignancies. The study aimed to clarify the clinical features of anti-NXP2 antibody-positive IIMs in detail.

Methods: This multi-centre retrospective observational study on 76 anti-NXP2 antibody-positive patients. The antibody was detected via a serological assay using immunoprecipitation and western blotting. The patients were selected from 162 consecutive Japanese patients with IIMs.

Results: The cohort of anti-NXP2 antibody-positive IIMs included 29 juvenile patients and 47 adult patients. Twenty-seven (35.5%) patients presented with polymyositis phenotype without dermatomyositis-specific skin manifestations (heliotrope rash or Gottron sign/papules); this was more common in the adults than children (48.9% vs. 15.8%, P < 0.01). Nine (11.8%) patients had subcutaneous calcinosis, and 20 (26.3%) patients had subcutaneous oedema. In addition, the proportion of patients with muscle weakness extending to the distal limbs was high (36 patients [47.4%]) in this cohort. Adult patients had a higher prevalence of malignancy than the general population (age-standardised incidence ratio of malignancies: 22.4).

Conclusion: Anti-NXP2 antibody-positive IIMs, which include dermatomyositis sine dermatitis, are characterised by atypical skin manifestations and extensive muscular involvement.
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http://dx.doi.org/10.1093/rheumatology/keab518DOI Listing
June 2021

Clinicopathologic Features of Oculopharyngodistal Myopathy With LRP12 CGG Repeat Expansions Compared With Other Oculopharyngodistal Myopathy Subtypes.

JAMA Neurol 2021 Jul;78(7):853-863

Department of Neurology, Nara Medical University, Nara, Japan.

Importance: Repeat expansion of CGG in LRP12 has been identified as the causative variation of oculopharyngodistal myopathy (OPDM). However, to our knowledge, the clinicopathologic features of OPDM with CGG repeat expansion in LRP12 (hereafter referred to as OPDM_LRP12) remain unknown.

Objective: To identify and characterize the clinicopathologic features of patients with OPDM_LRP12.

Design, Setting, And Participants: This case series included 208 patients with a clinical or clinicopathologic diagnosis of oculopharyngeal muscular dystrophy (OPDM) from January 1, 1978, to December 31, 2020. Patients with GCN repeat expansions in PABPN1 were excluded from the study. Repeat expansions of CGG in LRP12 were screened by repeat primed polymerase chain reaction and/or Southern blot.

Main Outcomes And Measures: Clinical information, muscle imaging data obtained by either computed tomography or magnetic resonance imaging, and muscle pathologic characteristics.

Results: Sixty-five Japanese patients with OPDM (40 men [62%]; mean [SD] age at onset, 41.0 [10.1] years) from 59 families with CGG repeat expansions in LRP12 were identified. This represents the most common OPDM subtype among all patients in Japan with genetically diagnosed OPDM. The expansions ranged from 85 to 289 repeats. A negative correlation was observed between the repeat size and the age at onset (r2 = 0.188, P = .001). The most common initial symptoms were ptosis and muscle weakness, present in 24 patients (37%). Limb muscle weakness was predominantly distal in 53 of 64 patients (83%), but 2 of 64 patients (3%) had predominantly proximal muscle weakness. Ptosis was observed in 62 of 64 patients (97%), and dysphagia or dysarthria was observed in 63 of 64 patients (98%). A total of 21 of 64 patients (33%) had asymmetric muscle weakness. Aspiration pneumonia was seen in 11 of 64 patients (17%), and 5 of 64 patients (8%) required mechanical ventilation. Seven of 64 patients (11%) developed cardiac abnormalities, and 5 of 64 patients (8%) developed neurologic abnormalities. Asymmetric muscle involvement was detected on computed tomography scans in 6 of 27 patients (22%) and on magnetic resonance imaging scans in 4 of 15 patients (27%), with the soleus and the medial head of the gastrocnemius being the worst affected. All 42 muscle biopsy samples showed rimmed vacuoles. Intranuclear tubulofilamentous inclusions were observed in only 1 of 5 patients.

Conclusions And Relevance: This study suggests that OPDM_LRP12 is the most frequent OPDM subtype in Japan and is characterized by oculopharyngeal weakness, distal myopathy that especially affects the soleus and gastrocnemius muscles, and rimmed vacuoles in muscle biopsy.
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http://dx.doi.org/10.1001/jamaneurol.2021.1509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164150PMC
July 2021

Inflammatory features in sporadic late-onset nemaline myopathy are independent from monoclonal gammopathy.

Brain Pathol 2021 05;31(3):e12962

Department of Neuropathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

Sporadic late-onset nemaline myopathy (SLONM) is a rare adult-onset non-hereditary disease with subacute proximal muscle and often axial muscle weakness, characterized by the presence of nemaline bodies in skeletal muscle biopsies. Considering its association with concurrent monoclonal gammopathy of undetermined significance (MGUS), the disease is classified into two major subtypes (1) SLONM without MGUS (SLONM-noMGUS) and (2) with MGUS (SLONM-MGUS) association. SLONM associated with HIV infection (SLONM-HIV) is also reported. SLONM-MGUS has been shown to be associated with poorer prognosis and required aggressive treatment including high-dose melphalan and autologous stem cell transplantation. The approach is currently debatable as recent reports suggested effectiveness of intravenous immunoglobulin as initial treatment with indifference of overall survival despite the presence of MGUS. Our study aimed to find an underlying basis by review of pathological features in 49 muscle biopsy proven-SLONM from two large tertiary centers in Japan and Germany (n = 49: SLONM-noMGUS = 34, SLONM-MGUS = 13, SLONM-HIV = 2). We compared pathological findings in SLONM-noMGUS and SLONM-MGUS and focused on the presence of any detectable inflammatory features by immunohistochemistry. The clinical and histological features in SLONM-noMGUS and SLONM-MGUS were not distinctively different except for more common regenerating fibers (>5% of myofibers) present in SLONM-MGUS (p < 0.01). HLA-ABC expression and fine granular p62 were observed in 66.7% and 78.3% of SLONM, respectively. The predominant inflammatory cells were CD68 cells. The inflammatory cells showed positive correlations with the percentage of nemaline-containing fibers (p < 0.001). In conclusion, inflammatory features are present although rather mild in SLONM. This finding contributes to the hypothesis of an acquired inflammatory disease pathogenesis and opens the possibility to offer immunotherapy in SLONM with inflammatory features regardless of the monoclonal gammopathy status.
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http://dx.doi.org/10.1111/bpa.12962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412091PMC
May 2021

[A Japanese family with POMT2-related limb girdle muscular dystrophy].

Rinsho Shinkeigaku 2021 Jun 20;61(6):378-384. Epub 2021 May 20.

Department of Neurology, National Hospital Organization Nagasaki Kawatana Medical Center.

Mutations in the gene encoding the protein O-mannosyl-transferase 2 (POMT2) are known to cause autosomal recessive limb girdle muscular dystrophy type 14 (LGMDR14). No Japanese patient with LGMDR14 has been reported previously. Here, we report three patients with LGMDR14 in one family. The first and second patients harbored a novel homozygous mutation of c.1568A>G, while the third harbored a compound heterozygous mutation of c.1568A>G and c.869C>T. The novel c.1568A>G mutation is classified as likely pathogenic by the guideline of the American College of Medical Genetics and Genomics. Similar to previous cases, all three patients presented difficulty walking and cognitive impairment, and the hamstring muscles were severely affected. Although eye abnormality has only been reported in one previous case, two our patients showed eye abnormalities. As POMT2 enzymatic activity has been demonstrated in the mammalian retina, an eye abnormality may represent a phenotype associated with POMT2 mutation.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001547DOI Listing
June 2021

Underlying diseases in sporadic presentation of high creatine kinase levels in girls.

Clin Chim Acta 2021 Aug 7;519:198-203. Epub 2021 May 7.

Department of Pediatrics, Hyogo College of Medicine, Nishinomiya, Japan.

Background: Persistent creatine kinase (CK) elevation can occur due to various conditions. Identifying the causes of hyperCKemia is crucial for enabling appropriate follow-up and care. Girls with elevated CK levels may be carriers of Duchenne/Becker muscular dystrophy (DMD/BMD), making diagnosis more difficult than that in boys. This study aimed to elucidate the underlying causes of high CK levels in girls.

Methods: Fourteen girls (seven symptomatic, seven asymptomatic) with persistently elevated CK levels but without a family history of muscle diseases were referred to our hospital between April 2014 and August 2018. Muscle biopsy and/or genetic analysis were conducted for diagnoses.

Results: Among the symptomatic girls, six (85.7%) had muscular dystrophy (five DMD/BMD carriers, and one sarcoglycanopathy [limb-girdle muscular dystrophy: LGMDR4]), and one had dermatomyositis. Among the asymptomatic girls, four (57.1%) had muscular dystrophy (three DMD/BMD carriers, and one calpainopathy [LGMDR1]), and three were undiagnosed.

Conclusion: Our results indicate that muscular dystrophy, including DMD/BMD carriers, must be considered in girls with highperCKemia regardless of symptoms presentation, and in symptomatic girls with dermatomyositis. Investigations in girls with hyperCKemia should be performed under proper ethical considerations. Further research is necessary to develop a diagnostic strategy for girls with hyperCKemia.
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http://dx.doi.org/10.1016/j.cca.2021.05.003DOI Listing
August 2021
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