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Congenital myopathy

Hernan D Gonorazky, Carsten G Bönnemann, James J Dowling
Congenital myopathies are a clinically and genetically heterogeneous group of conditions that most commonly present at or around the time of birth with hypotonia, muscle weakness, and (often) respiratory distress. Historically, this group of disorders has been subclassified based on muscle histopathologic characteristics. There has been an explosion of gene discovery, and there are now at least 32 different genetic causes of disease. With this increased understanding of the genetic basis of disease has come the knowledge that the mutations in congenital myopathy genes can present with a wide variety of clinical phenotypes and can result in a broad spectrum of histopathologic findings on muscle biopsy...
2018: Handbook of Clinical Neurology
Virginia Huntoon, Jeffrey J Widrick, Colline Sanchez, Samantha M Rosen, Candice Kutchukian, Siqi Cao, Christopher R Pierson, Xiaoli Liu, Mark A Perrella, Alan H Beggs, Vincent Jacquemond, Pankaj B Agrawal
Centronuclear myopathies (CNM) are a subtype of congenital myopathies (CM) characterized by skeletal muscle weakness and an increase in the number of central myonuclei. We have previously identified three CNM probands, two with associated dilated cardiomyopathy, carrying striated preferentially expressed gene (SPEG) mutations. Currently, the role of SPEG in skeletal muscle function is unclear as constitutive SPEG-deficient mice developed severe dilated cardiomyopathy and died in-utero. We have generated a conditional Speg-KO mouse model and excised Speg by crosses with striated muscle-specific cre-expressing mice (MCK-Cre)...
February 20, 2018: Human Molecular Genetics
F Fattori, C Fiorillo, C Rodolico, G Tasca, M Verardo, E Bellacchio, S Pizzi, A Ciolfi, G Fagiolari, A Lupica, P Broda, M Pedemonte, M Moggio, C Bruno, M Tartaglia, E Bertini, A D'Amico
Congenital myopathies (CMs) caused by mutation in cofilin-2 gene (CFL2) show phenotypic heterogeneity ranging from early onset and rapid progressive forms to milder myopathy. Muscle histology is also heterogeneous showing rods and /or myofibrillar changes. Here, we report on three new cases, from two unrelated families, of severe CM related to novel homozygous or compound heterozygous loss-of-function mutations in CFL2. Peculiar histopathological changes showed nemaline bodies and thin filaments accumulations together to myofibrillar changes, which were evocative of the muscle findings observed in Cfl2-/- knockout mouse model...
February 19, 2018: Clinical Genetics
Atsuko Hirano, Tomohiko Takada, Mariko Senda, Hidemasa Takahashi, Takeo Suzuki
Background: Polymeraze I and transcript release factor ( PTRF ) mutations are a newly recognized disease, which cause congenital generalized lipodystrophy associated with myopathy. Case presentation: A 29-year-old man (height 126 cm; weight 22 kg) with a PTRF mutation was scheduled for mandibular dentigerous cystectomy. His primary symptoms were lipodystrophy, myopathy, long QT syndrome, refractory nephrosis, and abnormal lipid metabolism. Defibrillator pads were applied soon after the patient entered the operating room...
2018: JA Clin Rep
Nafi Dilaver, Neda Mazaheri, Reza Maroofian, Jawaher Zeighami, Tahere Seifi, Mina Zamani, Alireza Sedaghat, Gholam Reza Shariati, Hamid Galehdari
Ryanodine receptor 1 ( RYR1 ) is an intracellular calcium receptor primarily expressed in skeletal muscle with a role in excitation contraction. Both dominant and recessive mutations in the RYR1 gene cause a range of RYR1 -related myopathies and/or susceptibility to malignant hyperthermia (MH). Recently, an atypical manifestation of ptosis, variably presenting with ophthalmoplegia, facial paralysis, and scoliosis but without significant muscle weakness, has been reported in 9 cases from 4 families with bialleic variants in RYR1 ...
December 2017: Molecular Syndromology
Edward Smitaman, Dyan V Flores, Catalina Mejía Gómez, Mini N Pathria
Atraumatic disorders of skeletal muscles include congenital variants; inherited myopathies; acquired inflammatory, infectious, or ischemic disorders; neoplastic diseases; and conditions leading to muscle atrophy. These have overlapping appearances at magnetic resonance (MR) imaging and are challenging for the radiologist to differentiate. The authors organize muscle disorders into four MR imaging patterns: (a) abnormal anatomy with normal signal intensity, (b) edema/inflammation, (c) mass, and (d) atrophy, highlighting each of their key clinical and imaging findings...
February 16, 2018: Radiographics: a Review Publication of the Radiological Society of North America, Inc
Marco Savarese, Lorenzo Maggi, Anna Vihola, Per Harald Jonson, Giorgio Tasca, Lucia Ruggiero, Luca Bello, Francesca Magri, Teresa Giugliano, Annalaura Torella, Anni Evilä, Giuseppina Di Fruscio, Olivier Vanakker, Sara Gibertini, Liliana Vercelli, Alessandra Ruggieri, Carlo Antozzi, Helena Luque, Sandra Janssens, Maria Barbara Pasanisi, Chiara Fiorillo, Monika Raimondi, Manuela Ergoli, Luisa Politano, Claudio Bruno, Anna Rubegni, Marika Pane, Filippo M Santorelli, Carlo Minetti, Corrado Angelini, Jan De Bleecker, Maurizio Moggio, Tiziana Mongini, Giacomo Pietro Comi, Lucio Santoro, Eugenio Mercuri, Elena Pegoraro, Marina Mora, Peter Hackman, Bjarne Udd, Vincenzo Nigro
Importance: Mutations in the titin gene (TTN) cause a wide spectrum of genetic diseases. The interpretation of the numerous rare variants identified in TTN is a difficult challenge given its large size. Objective: To identify genetic variants in titin in a cohort of patients with muscle disorders. Design, Setting, and Participants: In this case series, 9 patients with titinopathy and 4 other patients with possibly disease-causing variants in TTN were identified...
February 12, 2018: JAMA Neurology
Vilma-Lotta Lehtokari, Maria Gardberg, Katarina Pelin, Carina Wallgren-Pettersson
We present here a Finnish nemaline myopathy family with a dominant mutation in the skeletal muscle α-actin gene, p.(Glu85Lys), segregating in three generations. The index patient, a 5-year-old boy, had the typical form of nemaline myopathy with congenital muscle weakness and motor milestones delayed but reached, while his mother never had sought medical attention for her very mild muscle weakness, and his maternal grandmother had been misdiagnosed as having myotonic dystrophy. This illustrates the clinical variability in nemaline myopathy...
December 25, 2017: Neuromuscular Disorders: NMD
Y Fan, A Liu, C Wei, H Yang, X Chang, S Wang, Y Yuan, C Bonnemann, Q Wu, X Wu, H Xiong
Collagen VI-related myopathy, caused by pathogenic variants in the genes encoding collagen VI, represents a clinical continuum from Ullrich congenital muscular dystrophy (UCMD) to Bethlem myopathy (BM). Clinical data of 60 probands and their family members were collected and muscle biopsies of 26 patients were analyzed. COL6A1, COL6A2 and COL6A3 exons were analyzed by direct sequencing or next generation sequencing (NGS). Sixty patients were characterized by delayed motor milestones, muscle weakness, skin and joint changes with forty UCMD and twenty BM...
February 8, 2018: Clinical Genetics
Nathalie Danièle, Christelle Moal, Laura Julien, Martina Marinello, Thibaud Jamet, Samia Martin, Alban Vignaud, Michael W Lawlor, Ana Buj-Bello
X-linked myotubular myopathy (XLMTM) is a severe congenital disorder in male infants that leads to generalized skeletal muscle weakness and is frequently associated with fatal respiratory failure. XLMTM is caused by loss-of-function mutations in the MTM1 gene, which encodes myotubularin, the founder member of a family of 15 homologous proteins in mammals. We recently demonstrated the therapeutic efficacy of intravenous delivery of rAAV vectors expressing MTM1 in animal models of myotubular myopathy. Here, we tested whether the closest homologues of MTM1, MTMR1, and MTMR2 (the latter being implicated in Charcot-Marie-Tooth neuropathy type 4B1) are functionally redundant and could represent a therapeutic target for XLMTM...
February 2, 2018: Journal of Neuropathology and Experimental Neurology
Soo Yeon Kim, Woo Joong Kim, Hyuna Kim, Sun Ah Choi, Jin Sook Lee, Anna Cho, Se Song Jang, Byung Chan Lim, Ki Joong Kim, Jong-Il Kim, Si Houn Hahn, Jong-Hee Chae
INTRODUCTION: We aimed to analyze the clinical and genetic characteristics of collagen VI-related myopathy. METHODS: We analyzed the clinical course and mutation spectrum in patients with collagen VI gene mutations among our congenital muscular dystrophy cohort. RESULTS: Among 24 patients with mutations in collagen VI coding genes, 13 (54.2%) were categorized as Ullrich type, and 11 (45.8%) as non-Ullrich type. Congenital orthopedic problems were similarly observed in both types, yet multiple joint contractures were found only in the Ullrich type...
February 6, 2018: Muscle & Nerve
Heinz Jungbluth, Susan Treves, Francesco Zorzato, Anna Sarkozy, Julien Ochala, Caroline Sewry, Rahul Phadke, Mathias Gautel, Francesco Muntoni
The congenital myopathies are a group of early-onset, non-dystrophic neuromuscular conditions with characteristic muscle biopsy findings, variable severity and a stable or slowly progressive course. Pronounced weakness in axial and proximal muscle groups is a common feature, and involvement of extraocular, cardiorespiratory and/or distal muscles can implicate specific genetic defects. Central core disease (CCD), multi-minicore disease (MmD), centronuclear myopathy (CNM) and nemaline myopathy were among the first congenital myopathies to be reported, and they still represent the main diagnostic categories...
February 2, 2018: Nature Reviews. Neurology
Claudia Castiglioni, Fabiana Fattori, Bjarne Udd, Maria de Los Angeles Avaria, Bernardita Suarez, Adele D'Amico, Alessandro Malandrini, Rosalba Carrozzo, Daniela Verrigni, Enrico Bertini, Giorgio Tasca
We identified three non-related patients manifesting a childhood-onset progressive neuromyopathy with congenital cataracts, delayed walking, distal weakness and wasting, glaucoma and swallowing difficulties. Electrophysiology and nerve biopsies showed a mixed axonal and demyelinating neuropathy, while muscle biopsy disclosed both neurogenic and myopathic changes with ragged red fibers, and muscle MRI showed consistent features across patients, with a peculiar concentric disto-proximal gradient of fatty replacement...
January 22, 2018: European Journal of Human Genetics: EJHG
Faeze Sadat Mohajer, Sepideh Parvizpour, Jafar Razmara, Mohd Shahir Shamsir
Congenital myopathy is a broad category of muscular diseases with symptoms appearing at the time of birth. One type of congenital myopathy is Congenital Fiber Type Disproportion (CFTD), a severely debilitating disease. The G48D and G48C mutations in the D-loop and the actin-myosin interface are the two causes of CFTD. These mutations have been shown to significantly affect the structure and function of muscle fibers. To the author's knowledge, the effects of these mutations have not yet been studied. In this work, the power stroke structure of the head domain of myosin and the wild and mutated types of actin were modeled...
January 17, 2018: Journal of Biomolecular Structure & Dynamics
Michal Berkenstadt, Ben Pode-Shakked, Ortal Barel, Hila Barash, Reuven Achiron, Yinon Gilboa, Dvora Kidron, Annick Raas-Rothschild
To describe the prenatal presentation, including ultrasonographic, histologic, and molecular findings, in 2 fetuses affected with LMOD3-related nemaline myopathy. Prenatal ultrasonographic examinations and histopathologic studies were performed on 2 fetuses with evidence of nemaline myopathy. To establish a molecular diagnosis, whole-exome sequencing was pursued for the affected fetuses. Nemaline myopathy is a common form of congenital myopathy manifesting with nonprogressive generalized muscle weakness, hypotonia, and electron-dense protein inclusions in skeletal myofibers...
January 13, 2018: Journal of Ultrasound in Medicine: Official Journal of the American Institute of Ultrasound in Medicine
B Joureau, J M de Winter, S Conijn, S J P Bogaards, I Kovacevic, A Kalganov, M Persson, J Lindqvist, G J M Stienen, T C Irving, W Ma, M Yuen, N F Clarke, D E Rassier, E Malfatti, N B Romero, A H Beggs, C A C Ottenheijm
OBJECTIVE: Nemaline myopathy (NM) is one of the most common congenital non-dystrophic myopathies and is characterized by muscle weakness, often from birth. Mutations in ACTA1 are a frequent cause of NM (i.e. NEM3). ACTA1 encodes alpha-actin 1, the main constituent of the sarcomeric thin filament. The mechanisms by which mutations in ACTA1 contribute to muscle weakness in NEM3 are incompletely understood. We hypothesized that sarcomeric dysfunction contributes to muscle weakness in NEM3 patients...
January 12, 2018: Annals of Neurology
Mi Ri Suh, Won Ah Choi, Dong Hyun Kim, Jang Woo Lee, Eun Young Kim, Seong-Woong Kang
INTRODUCTION: The purpose of this study was to investigate the 5-year outcomes of noninvasive ventilation (NIV) application in different neuromuscular disease (NMD) groups. METHODS: We categorized 180 subjects who had initiated NIV between March 2001 and August 2009 into 4 groups and followed them for > 5 y. The NIV maintenance rate and average duration, applying time, and forced vital capacity (FVC) were investigated at the time NIV was initiated and 5 y after NIV initiation in each group...
March 2018: Respiratory Care
Shireen R Lamandé, John F Bateman
Mutations in the three canonical collagen VI genes, COL6A1, COL6A2 and COL6A3, cause a spectrum of muscle disease from Bethlem myopathy at the mild end to the severe Ullrich congenital muscular dystrophy. Mutations can be either dominant or recessive and the resulting clinical severity is influenced by the way mutations impact the complex collagen VI assembly process. Most mutations are found towards the N-terminus of the triple helical collagenous domain and compromise extracellular microfibril assembly. Outside the triple helix collagen VI is highly polymorphic and discriminating mutations from rare benign changes remains a major diagnostic challenge...
December 22, 2017: Matrix Biology: Journal of the International Society for Matrix Biology
Atif A Ahmed, Priya Skaria, Nicole P Safina, Isabelle Thiffault, Alex Kats, Eugenio Taboada, Sultan Habeebu, Carol Saunders
Arthrogryposis multiplex congenita affects approximately 1 in 3,000 individuals of different ethnic backgrounds and displays an equal incidence in males and females. The underlying mechanism for congenital contracture of the joints is decreased fetal movement during intrauterine development. This disorder is associated with over 400 medical conditions and 350 known genes that display considerable variability in phenotypic expression. In this report, four fetal or perinatal autopsy cases of arthrogryposis were studied by gross morphology, microscopic histopathologic examination, and whole genome sequencing of postmortem DNA...
December 23, 2017: American Journal of Medical Genetics. Part A
Jong-Mok Lee, Jeong Geun Lim, Jin-Hong Shin, Young-Eun Park, Dae-Seong Kim
Nemaline myopathy (NM), the most common of the congenital myopathies, is caused by various genetic mutations. In this study, we attempted to identify the causative mutations of NM and to reveal any specific genotype-phenotype relationship in Korean patients with this disease. We investigated the clinical features and genotypes in 15 pathologically diagnosed NM patients, using whole exome sequencing (WES) combined with targeted sequencing and array-based comparative genomic hybridization. This strategy revealed pathogenic causative mutations in seven patients (46...
December 15, 2017: Journal of the Neurological Sciences
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