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Congenital myotonia

Samantha LoRusso, Benjamin Weiner, W David Arnold
Myotonic dystrophy is an autosomal dominant muscular dystrophy not only associated with muscle weakness, atrophy, and myotonia but also prominent multisystem involvement. There are 2 similar, but distinct, forms of myotonic dystrophy; type 1 is caused by a CTG repeat expansion in the DMPK gene, and type 2 is caused by a CCTG repeat expansion in the CNBP gene. Type 1 is associated with distal limb, neck flexor, and bulbar weakness and results in different phenotypic subtypes with variable onset from congenital to very late-onset as well as variable signs and symptoms...
October 2018: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
Sushan Luo, Marisol Sampedro Castañeda, Emma Matthews, Richa Sud, Michael G Hanna, Jian Sun, Jie Song, Jiahong Lu, Kai Qiao, Chongbo Zhao, Roope Männikkö
Dominantly inherited channelopathies of the skeletal muscle voltage-gated sodium channel NaV 1.4 include hypokalaemic and hyperkalaemic periodic paralysis (hypoPP and hyperPP) and myotonia. HyperPP and myotonia are caused by NaV 1.4 channel overactivity and overlap clinically. Instead, hypoPP is caused by gating pore currents through the voltage sensing domains (VSDs) of NaV 1.4 and seldom co-exists clinically with myotonia. Recessive loss-of-function NaV 1.4 mutations have been described in congenital myopathy and myasthenic syndromes...
June 26, 2018: Scientific Reports
Laurène M André, C Rosanne M Ausems, Derick G Wansink, Bé Wieringa
Myotonic dystrophy type 1 (DM1) and 2 (DM2) are autosomal dominant degenerative neuromuscular disorders characterized by progressive skeletal muscle weakness, atrophy, and myotonia with progeroid features. Although both DM1 and DM2 are characterized by skeletal muscle dysfunction and also share other clinical features, the diseases differ in the muscle groups that are affected. In DM1, distal muscles are mainly affected, whereas in DM2 problems are mostly found in proximal muscles. In addition, manifestation in DM1 is generally more severe, with possible congenital or childhood-onset of disease and prominent CNS involvement...
2018: Frontiers in Neurology
Roope Männikkö, Leonie Wong, David J Tester, Michael G Thor, Richa Sud, Dimitri M Kullmann, Mary G Sweeney, Costin Leu, Sanjay M Sisodiya, David R FitzPatrick, Margaret J Evans, Iona J M Jeffrey, Jacob Tfelt-Hansen, Marta C Cohen, Peter J Fleming, Amie Jaye, Michael A Simpson, Michael J Ackerman, Michael G Hanna, Elijah R Behr, Emma Matthews
BACKGROUND: Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant death in high-income countries. Central respiratory system dysfunction seems to contribute to these deaths. Excitation that drives contraction of skeletal respiratory muscles is controlled by the sodium channel NaV1.4, which is encoded by the gene SCN4A. Variants in NaV1.4 that directly alter skeletal muscle excitability can cause myotonia, periodic paralysis, congenital myopathy, and myasthenic syndrome...
April 14, 2018: Lancet
Estrella Fernández, Marta Latasiewicz, Laura Pelegrin, Manuel Romera, Silvana Schellini, Alicia Galindo-Ferreiro
A 37-year-old female presented with severe apraxia of lid opening (ALO) affecting the right upper lid associated with Becker congenital myotonia (MC). The patient had a history of right upper lid ptosis for 25 years that was exacerbated over the previous month with severe incapacity to open her right eye. No other associated neurological or ophthalmic symptoms were observed. The patient was treated with botulinum toxin (BoNT-A) injection into the pretarsal and lateral canthus region of the orbicularis oculi of the affected eyelid...
September 2017: Arquivos Brasileiros de Oftalmologia
Stephen C Cannon
The NaV 1.4 sodium channel is highly expressed in skeletal muscle, where it carries almost all of the inward Na+ current that generates the action potential, but is not present at significant levels in other tissues. Consequently, mutations of SCN4A encoding NaV 1.4 produce pure skeletal muscle phenotypes that now include six allelic disorders: sodium channel myotonia, paramyotonia congenita, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, congenital myasthenia, and congenital myopathy with hypotonia...
2018: Handbook of Experimental Pharmacology
S Veronica Tan, Werner J Z'Graggen, Michael G Hanna, Hugh Bostock
INTRODUCTION: The gain-of-function mutations that underlie sodium channel myotonia (SCM) and paramyotonia congenital (PMC) produce differing clinical phenotypes. We used muscle velocity recovery cycles (MVRCs) to investigate membrane properties. METHODS: MVRCs and responses to trains of stimuli were compared in patients with SCM (n = 9), PMC (n = 8), and normal controls (n = 26). RESULTS: The muscle relative refractory period was reduced in SCM, consistent with faster recovery of the mutant sodium channels from inactivation...
April 2018: Muscle & Nerve
James B Papizan, Glynnis A Garry, Svetlana Brezprozvannaya, John R McAnally, Rhonda Bassel-Duby, Ning Liu, Eric N Olson
Maintenance of muscle structure and function depends on the precise organization of contractile proteins into sarcomeres and coupling of the contractile apparatus to the sarcoplasmic reticulum (SR), which serves as the reservoir for calcium required for contraction. Several members of the Kelch superfamily of proteins, which modulate protein stability as substrate-specific adaptors for ubiquitination, have been implicated in sarcomere formation. The Kelch protein Klhl31 is expressed in a muscle-specific manner under control of the transcription factor MEF2...
October 2, 2017: Journal of Clinical Investigation
Andrew G Engel, Keeley R Redhage, David J Tester, Michael J Ackerman, Duygu Selcen
OBJECTIVE: Triadin is a component of the calcium release complex of cardiac and skeletal muscle. Our objective was to analyze the skeletal muscle phenotype of the triadin knockout syndrome. METHODS: We performed clinical evaluation, analyzed morphologic features by light and electron microscopy, and immunolocalized triadin in skeletal muscle. RESULTS: A 6-year-old boy with lifelong muscle weakness had a triadin knockout syndrome caused by compound heterozygous null mutations in triadin...
March 21, 2017: Neurology
Vanessa Schartner, Norma B Romero, Sandra Donkervoort, Susan Treves, Pinki Munot, Tyler Mark Pierson, Ivana Dabaj, Edoardo Malfatti, Irina T Zaharieva, Francesco Zorzato, Osorio Abath Neto, Guy Brochier, Xavière Lornage, Bruno Eymard, Ana Lía Taratuto, Johann Böhm, Hernan Gonorazky, Leigh Ramos-Platt, Lucy Feng, Rahul Phadke, Diana X Bharucha-Goebel, Charlotte Jane Sumner, Mai Thao Bui, Emmanuelle Lacene, Maud Beuvin, Clémence Labasse, Nicolas Dondaine, Raphael Schneider, Julie Thompson, Anne Boland, Jean-François Deleuze, Emma Matthews, Aleksandra Nadaj Pakleza, Caroline A Sewry, Valérie Biancalana, Susana Quijano-Roy, Francesco Muntoni, Michel Fardeau, Carsten G Bönnemann, Jocelyn Laporte
Muscle contraction upon nerve stimulation relies on excitation-contraction coupling (ECC) to promote the rapid and generalized release of calcium within myofibers. In skeletal muscle, ECC is performed by the direct coupling of a voltage-gated L-type Ca2+ channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca2+ release channel (ryanodine receptor; RYR1) on the sarcoplasmic reticulum (SR) component of the triad. Here, we characterize a novel class of congenital myopathy at the morphological, molecular, and functional levels...
April 2017: Acta Neuropathologica
Valeria A Sansone
PURPOSE OF REVIEW: This article describes clinical and electrical myotonia and provides an update on the classification, diagnosis, and management of myotonic disorders. RECENT FINDINGS: In the myotonic dystrophies, antisense oligonucleotides provide a general strategy to correct RNA gain of function and modulate the expression of CTG expanded repeats; they are currently being tested in a phase 1-2 randomized controlled trial in patients with adult-onset myotonic dystrophy type 1...
December 2016: Continuum: Lifelong Learning in Neurology
Cheryl A Smith, Laurie Gutmann
Myotonic dystrophy (DM1) is the most common form of adult muscular dystrophy. It is a multisystem disorder with a complex pathophysiology. Although inheritance is autosomal dominant, disease variability is attributed to anticipation, a maternal expansion bias, variable penetrance, somatic mosaicism, and a multitude of aberrant pre-mRNA splicing events. Patient presentations range from asymptomatic or mild late onset adult to severe congenital forms. Multiple organ systems may be affected. Patients may experience early cataracts, myotonia, muscle weakness/atrophy, fatigue, excessive daytime sleepiness, central/obstructive apnea, respiratory failure, cardiac arrhythmia, insulin resistance, dysphagia, GI dysmotility, cognitive impairment, Cluster C personality traits, and/or mood disorders...
December 2016: Current Treatment Options in Neurology
Mohammad Miryounesi, Soudeh Ghafouri-Fard, Majid Fardaei
Congenital recessive myotonia is a rare genetic disorder caused by mutations in CLCN1, which codes for the main skeletal muscle chloride channel ClC-1. More than 120 mutations have been found in this gene. The main feature of this disorder is muscle membrane hyperexcitability. Here, we report a 59-year male patient suffering from congenital myotonia. He had transient generalized myotonia, which started in early childhood. We analyzed CLCN1 sequence in this patient and other members of his family. We found a new missense mutation in CLCN1 gene (c...
September 2016: Iranian Journal of Medical Sciences
Yan-Xin Meng, Zhe Zhao, Hong-Rui Shen, Qi Bing, Jing Hu
OBJECTIVES: The identification of disease-specific genetic and electrophysiological patterns for myotonia congenital (MC) could help clinicians apply in the findings of genetic studies to improve diagnosis. We examined the molecular, clinical, and histopathological characteristics of eight patients with MC. METHODS: Optimization PCR was used to exclude myotonic dystrophies and the CLCN1 gene was sequenced in patients having clinical and electrophysiological features indicative of MC...
January 2016: Neurological Research
Fenfen Wu, Wentao Mi, Yu Fu, Arie Struyk, Stephen C Cannon
Over 60 mutations of SCN4A encoding the NaV1.4 sodium channel of skeletal muscle have been identified in patients with myotonia, periodic paralysis, myasthenia, or congenital myopathy. Most mutations are missense with gain-of-function defects that cause susceptibility to myotonia or periodic paralysis. Loss-of-function from enhanced inactivation or null alleles is rare and has been associated with myasthenia and congenital myopathy, while a mix of loss and gain of function changes has an uncertain relation to hypokalaemic periodic paralysis...
June 2016: Brain: a Journal of Neurology
Dennis Lal, Bernd A Neubauer, Mohammad R Toliat, Janine Altmüller, Holger Thiele, Peter Nürnberg, Clemens Kamrath, Anne Schänzer, Thomas Sander, Andreas Hahn, Michael Nothnagel
Massively parallel sequencing of whole genomes and exomes has facilitated a direct assessment of causative genetic variation, now enabling the identification of genetic factors involved in rare diseases (RD) with Mendelian inheritance patterns on an almost routine basis. Here, we describe the illustrative case of a single consanguineous family where this strategy suffered from the difficulty to distinguish between two etiologically distinct disorders, namely the co-occurrence of hereditary hypophosphatemic rickets (HRR) and congenital myopathies (CM), by their phenotypic manifestation alone...
2016: PloS One
Irina T Zaharieva, Michael G Thor, Emily C Oates, Clara van Karnebeek, Glenda Hendson, Eveline Blom, Nanna Witting, Magnhild Rasmussen, Michael T Gabbett, Gianina Ravenscroft, Maria Sframeli, Karen Suetterlin, Anna Sarkozy, Luigi D'Argenzio, Louise Hartley, Emma Matthews, Matthew Pitt, John Vissing, Martin Ballegaard, Christian Krarup, Andreas Slørdahl, Hanne Halvorsen, Xin Cynthia Ye, Lin-Hua Zhang, Nicoline Løkken, Ulla Werlauff, Mena Abdelsayed, Mark R Davis, Lucy Feng, Rahul Phadke, Caroline A Sewry, Jennifer E Morgan, Nigel G Laing, Hilary Vallance, Peter Ruben, Michael G Hanna, Suzanne Lewis, Erik-Jan Kamsteeg, Roope Männikkö, Francesco Muntoni
Congenital myopathies are a clinically and genetically heterogeneous group of muscle disorders characterized by congenital or early-onset hypotonia and muscle weakness, and specific pathological features on muscle biopsy. The phenotype ranges from foetal akinesia resulting in in utero or neonatal mortality, to milder disorders that are not life-limiting. Over the past decade, more than 20 new congenital myopathy genes have been identified. Most encode proteins involved in muscle contraction; however, mutations in ion channel-encoding genes are increasingly being recognized as a cause of this group of disorders...
March 2016: Brain: a Journal of Neurology
Vaishali M Patil, Satya P Gupta
The prime roles of mutations in the genes, encoding chloride ion channels, in various human diseases of muscle, kidney, bone and brain, such as congenital myotonia, myotonic dystrophy, cystic fibrosis, osteopetrosis, epilepsy, glioma, etc., have been well established. Chloride ion channels are also responsible for glioma progression in brain and malaria parasite in red blood cells. The present article thus emphasises on the various diseases associated with chloride channel regulation and their modulators. Studies on various chloride channels and their modulators have been discussed in detail...
2016: Current Topics in Medicinal Chemistry
Emmanuel Fournier
Many "essential" diseases that manifest themselves in the form of crises or fits (epilepsies, episodic ataxia, periodic paralyses, myotonia, heart rhythm disorders, etc.) are due to ionic channel dysfunction and are thus referred to as "channelopathies". Some of these disorders are congenital, due to mutations of genes encoding channel subunits, while others result from toxic, immune or hormonal disturbances affecting channelfunction. Channelopathies take on a wide variety of clinical forms, depending on the type of channel (sodium, potassium, calcium, chloride...
February 2014: Bulletin de L'Académie Nationale de Médecine
Nanna Witting, Ulla Werlauff, Morten Duno, John Vissing
INTRODUCTION: Congenital myopathy due to mutations in the α-actin 1 gene (ACTA1) was identified in 1999, but knowledge of prevalence and phenotype in patients who survive 5 years is lacking. METHODS: A national cohort of 91 patients aged ≥5 years and diagnosed with congenital myopathy was assessed for ACTA1 mutations and investigated clinically. RESULTS: Four patients with ACTA1 mutations were identified, yielding a prevalence of 4.4%. Patients were 10-23 years of age, and all but 1 were ambulatory...
March 2016: Muscle & Nerve
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