Central Core Disease
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Periodic Paralysis: a Case Report of Normokalemic Presentation in a Young Girl
Case Report ISSN: 2574 -1241 DOI: 10.26717/BJSTR.2021.35.005673 Periodic Paralysis: A Case Report of Normokalemic Presentation in a Young Girl Lucio Ceglie, Roberta Patacchiola, Daniela Iannucci, Miriana Guarino, Lorenzo Sansone, Maria Chiara Sgarrella, Francesco Chiarelli* and Annalisa Blasetti Department of Pediatrics, University of Chieti, Italy *Corresponding author: Francesco Chiarelli, Department of Pediatrics, University of Chieti, Italy ARTICLE INFO ABSTRACT Received: April 10, 2021 The skeletal muscle channelopathies represent a rare group of neuromuscular disorders which are caused by genetic mutations regarding voltage-gated ion Published: April 21, 2021 channels, which play an important role in muscle membrane depolarization. Muscle channelopathies are broadly divided into 2 main categories: nondystrophic myotonias (NDM) and periodic paralysis (PP). Periodic paralysis (PP) are rare autosomal dominant Citation: Lucio C, Roberta P, Daniela I, neuromuscular disorders, characterized clinically by periodic attacks of muscle weakness Miriana G, Francesco C, et al., Periodic in concomitance with serum potassium level alterations. It is possible to distinguish Paralysis: A Case Report of Normokalemic normokalemic, hyperkalemic and hypokalemic paralysis. PP is caused by genetic Presentation in a Young Girl. Biomed mutations in voltage-gate ion channels like sodium, potassium, and calcium channels, J Sci & Tech Res 35(2)-2021. BJSTR. which are determinant for muscle membrane depolarization. The most common genes MS.ID.005672. involved in pathogenesis are CACN1S, SCN4A and KCNJ2, encoding calcium, sodium, and potassium channels (Table 1). Moreover, paralysis related to serum potassium values Keywords: Hypokalemia; Periodic Paral- may also occur in thyreotoxicosis [1], Liddle syndrome, Gitelman syndrome, primary ysis; Transient Paralysis; Muscular Weak- hyperaldosteronism, and acid-base balance disorders. -
The Role of Z-Disc Proteins in Myopathy and Cardiomyopathy
International Journal of Molecular Sciences Review The Role of Z-disc Proteins in Myopathy and Cardiomyopathy Kirsty Wadmore 1,†, Amar J. Azad 1,† and Katja Gehmlich 1,2,* 1 Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK; [email protected] (K.W.); [email protected] (A.J.A.) 2 Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence Oxford, University of Oxford, Oxford OX3 9DU, UK * Correspondence: [email protected]; Tel.: +44-121-414-8259 † These authors contributed equally. Abstract: The Z-disc acts as a protein-rich structure to tether thin filament in the contractile units, the sarcomeres, of striated muscle cells. Proteins found in the Z-disc are integral for maintaining the architecture of the sarcomere. They also enable it to function as a (bio-mechanical) signalling hub. Numerous proteins interact in the Z-disc to facilitate force transduction and intracellular signalling in both cardiac and skeletal muscle. This review will focus on six key Z-disc proteins: α-actinin 2, filamin C, myopalladin, myotilin, telethonin and Z-disc alternatively spliced PDZ-motif (ZASP), which have all been linked to myopathies and cardiomyopathies. We will summarise pathogenic variants identified in the six genes coding for these proteins and look at their involvement in myopathy and cardiomyopathy. Listing the Minor Allele Frequency (MAF) of these variants in the Genome Aggregation Database (GnomAD) version 3.1 will help to critically re-evaluate pathogenicity based on variant frequency in normal population cohorts. -
THE NON-DYSTROPHIC MYOPATHIES JOHN PEARCE, M.B., M.R.C.P., Department of Neurology, the General Infirmary, Leeds
Postgrad Med J: first published as 10.1136/pgmj.41.476.347 on 1 June 1965. Downloaded from POSTGRAD. MED. J. (1965), 41, 347 THE NON-DYSTROPHIC MYOPATHIES JOHN PEARCE, M.B., M.R.C.P., Department of Neurology, The General Infirmary, Leeds. THE TERM 'myopathy' is applied to any disorder Polymyositis may affect people of any age, of the muscle fibre, the muscle fibre membrane, but the age of onset is from 30 to 60 in 60% the myoneural junction, or the muscle connect- of cases. The chief symptom is weakness of ive tissue. 'Non-dystrophic myopathy' includes proximal muscles of the arms and/or legs all diseases of muscle excluding those genetically in every case. Distal muscles are affected in determined primary degenerative myopathies, one third, and the neck muscles in two thirds collectively known as Muscular Dystrophy. of patients. Fever, muscular pain and tenderness TABLE 1 are seen most often in the more acute forms, CLASSIFICATION OF NON-DYSTROPHIC MYOPATHIES and their absence should not lead to neglecting 1. Inflammatory Polymyositis as a Myopathy Connective tissue disorders polymyositis possible diagnosis. Other inflammatory mvopathies Acute polymyositis is not common, but may 2. Metabolic Familial periodic paralysis progress rapidly and involve the respiratory Myopathy Muscle glycogenoses muscles, sometimes with a fatal termination Myoglobinuric myopathies within a few weeks or months. Myopathies associated with Subacute and electrolyte imbalance chronic forms are more frequent, and present Unclassified myopathies with a progressive weakness and moderate of shoulder 3. Endocrine Thyrotoxicosis wasting and pelvic girdle muscles. Myopathy Cushing's Syndrome There is sometimes no systemic disturbance, Steroid myopathy and pain and tenderness are lacking. -
Identification of Gene Mutations in Patients with Primary Periodic
Luo et al. BMC Neurology (2019) 19:92 https://doi.org/10.1186/s12883-019-1322-6 RESEARCH ARTICLE Open Access Identification of gene mutations in patients with primary periodic paralysis using targeted next-generation sequencing Sushan Luo1†, Minjie Xu2†, Jian Sun1, Kai Qiao3, Jie Song1, Shuang Cai1, Wenhua Zhu1, Lei Zhou1, Jianying Xi1, Jiahong Lu1, Xiaohua Ni2, Tonghai Dou4 and Chongbo Zhao1,5* Abstract Background: Primary periodic paralysis is characterized by recurrent quadriplegia typically associated with abnormal serum potassium levels. The molecular diagnosis of primary PP previously based on Sanger sequencing of hot spots or exon-by-exon screening of the reported genes. Methods: We developed a gene panel that includes 10 ion channel-related genes and 245 muscular dystrophy- and myopathy-related genes and used this panel to diagnose 60 patients with primary periodic paralysis and identify the disease-causing or risk-associated gene mutations. Results: Mutations of 5 genes were discovered in 39 patients (65.0%). SCN4A, KCNJ2 and CACNA1S variants accounted for 92.5% of the patients with a genetic diagnosis. Conclusions: Targeted next-generation sequencing offers a cost-effective approach to expand the genotypes of primary periodic paralysis. A clearer genetic profile enables the prevention of paralysis attacks, avoidance of triggers and the monitoring of complications. Keywords: Primary periodic paralysis, Targeted next-generation sequencing, Gene panel, Gene mutation distribution, Calcium homeostasis. Background (SCN4A) and potassium voltage-gated channel subfamily Periodic paralysis (PP) is characterized by episodes of J member 2 (KCNJ2), that encode voltage-gated chan- muscle weakness that occur at irregular intervals due to nels in muscle membranes that generate or sustain skeletal muscle ion channelopathies. -
Distal Myopathies a Review: Highlights on Distal Myopathies with Rimmed Vacuoles
Review Article Distal myopathies a review: Highlights on distal myopathies with rimmed vacuoles May Christine V. Malicdan, Ikuya Nonaka Department of Neuromuscular Research, National Institutes of Neurosciences, National Center of Neurology and Psychiatry, Tokyo, Japan Distal myopathies are a group of heterogeneous disorders Since the discovery of the gene loci for a number classiÞ ed into one broad category due to the presentation of distal myopathies, several diseases previously of weakness involving the distal skeletal muscles. The categorized as different disorders have now proven to recent years have witnessed increasing efforts to identify be the same or allelic disorders (e.g. distal myopathy the causative genes for distal myopathies. The identiÞ cation with rimmed vacuoles and hereditary inclusion body of few causative genes made the broad classiÞ cation of myopathy, Miyoshi myopathy and limb-girdle muscular these diseases under “distal myopathies” disputable and dystrophy type 2B (LGMD 2B). added some enigma to why distal muscles are preferentially This review will focus on the most commonly affected. Nevertheless, with the clariÞ cation of the molecular known and distinct distal myopathies, using a simple basis of speciÞ c conditions, additional clues have been classification: distal myopathies with known molecular uncovered to understand the mechanism of each condition. defects [Table 1] and distal myopathies with unknown This review will give a synopsis of the common distal causative genes [Table 2]. The identification of the myopathies, presenting salient facts regarding the clinical, genes involved in distal myopathies has broadened pathological, and molecular aspects of each disease. Distal this classification into sub-categories as to the location myopathy with rimmed vacuoles, or Nonaka myopathy, will of encoded proteins: sarcomere (titin, myosin); plasma be discussed in more detail. -
Disease Mutations in the Ryanodine Receptor N-Terminal Region Couple to a Mobile Intersubunit Interface
ARTICLE Received 1 Oct 2012 | Accepted 15 Jan 2013 | Published 19 Feb 2013 DOI: 10.1038/ncomms2501 OPEN Disease mutations in the ryanodine receptor N-terminal region couple to a mobile intersubunit interface Lynn Kimlicka1, Kelvin Lau1, Ching-Chieh Tung1 & Filip Van Petegem1 Ryanodine receptors are large channels that release Ca2 þ from the endoplasmic and sar- coplasmic reticulum. Hundreds of RyR mutations can cause cardiac and skeletal muscle disorders, yet detailed mechanisms explaining their effects have been lacking. Here we compare pseudo-atomic models and propose that channel opening coincides with widen- ing of a cytoplasmic vestibule formed by the N-terminal region, thus altering an interface targeted by 20 disease mutations. We solve crystal structures of several disease mutants that affect intrasubunit domain–domain interfaces. Mutations affecting intrasubunit ionic pairs alter relative domain orientations, and thus couple to surrounding interfaces. Buried disease mutations cause structural changes that also connect to the intersubunit contact area. These results suggest that the intersubunit contact region between N-terminal domains is a prime target for disease mutations, direct or indirect, and we present a model whereby ryanodine receptors and inositol-1,4,5-trisphosphate receptors are activated by altering domain arrangements in the N-terminal region. 1 Department of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3. Correspondence and requests for materials should be addressed to F.V.P. (email: fi[email protected]). NATURE COMMUNICATIONS | 4:1506 | DOI: 10.1038/ncomms2501 | www.nature.com/naturecommunications 1 & 2013 Macmillan Publishers Limited. All rights reserved. -
Central Core Disease - a Case Report
The Korean Journal of Pathology 2004; 38: 68-71 Central Core Disease - A Case Report - Ji Hoon Kim∙Young S. Park Central core disease is a rare autosomal dominantly inherited non-progressive congenital myopa- Sung-Hye Park∙Je G. Chi thy, which is pathologically characterized by the formation of a ‘‘core’’. We report a 28-year-old female with non-progressive muscle weakness, who had a hypotonic posture at birth. The devel- Department of Pathology, Seoul National opmental milestones were delayed with her first walking at 18 months of age. She could not University College of Medicine, Seoul, run or walk a long distance and weight-bearing tasks were almost impossible. None of her Korea family members showed motor symptoms. An investigation of the electromyography and nerve conduction velocity showed non-specific results. A gastrocnemius muscle biopsy revealed Received : November 14, 2003 central cores in approximately 70% of myofibers with a type 1 myofiber predominance and Accepted : January 7, 2004 deranged sarcolemmal structures. To the best of our knowledge, this is the fifth report of cen- tral core disease in the Korean literature. Corresponding Author Sung-Hye Park, M.D. Department of Pathology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Korea Tel: 02-740-8278 Fax: 02-765-5600 E-mail: [email protected] Key Words : Myopathy, Central Core-Muscle, Skeletal-Ultrastructure Central core disease is a form of congenital non-progressive right upper extremity. The symptoms were relieved with the help myopathy, which was first described by Shy and Magee in 1956. -
Central Core Disease in Focus
Central Core Disease In Focus Fast Facts Central core disease (CCD) is a genetic muscle disease characterized by the appearance of corelike struc- tures running through the centers of muscle fibers. The cores are areas of metabolic inactivity. Symptoms vary widely in sever- ity and can begin anywhere from infancy to adulthood. They include weakness, muscle cramps, orthope- dic abnormalities (spinal curvature, foot deformities, hip dislocations) caused by the weakness, and a dan- gerous susceptibility to malignant hyperthermia, an adverse reaction to anesthesia. The disease is usually dominantly In Focus inherited, meaning only one gene mutation, inherited from one parent, CCD: A Disease with Many Faces is necessary to cause symptoms. by Margaret Wahl The underlying molecular cause of the disease is an abnormality of orty-one-year-old Sandy Doak remem- since Doak is 5 feet tall and weighs 128 calcium release from deep inside Fbers that she was never athletic, pounds, the test result said her body was the muscle fibers. Normally, a signal couldn’t do sit-ups, and always had trou- 38 percent fat. There was only one way from a nerve fiber tells a muscle fiber ble finishing physical tasks. But, she says, that could be the case, the fitness expert to contract and, after a cascade of “I never really thought I had anything and she agreed: She had very little mus- events, calcium is released in a burst wrong. I just thought I was awkward. I cle. For Doak, it was a clue that something from internal storage areas. Calcium knew I was weaker than others. -
Myopathies Infosheet
The University of Chicago Genetic Services Laboratories 5841 S. Maryland Ave., Rm. G701, MC 0077, Chicago, Illinois 60637 Toll Free: (888) UC GENES (888) 824 3637 Local: (773) 834 0555 FAX: (773) 702 9130 [email protected] dnatesting.uchicago.edu CLIA #: 14D0917593 CAP #: 18827-49 Gene tic Testing for Congenital Myopathies/Muscular Dystrophies Congenital Myopathies Congenital myopathies are typically characterized by the presence of specific structural and histochemical features on muscle biopsy and clinical presentation can include congenital hypotonia, muscle weakness, delayed motor milestones, feeding difficulties, and facial muscle involvement (1). Serum creatine kinase may be normal or elevated. Heterogeneity in presenting symptoms can occur even amongst affected members of the same family. Congenital myopathies can be divided into three main clinicopathological defined categories: nemaline myopathy, core myopathy and centronuclear myopathy (2). Nemaline Myopathy Nemaline Myopathy is characterized by weakness, hypotonia and depressed or absent deep tendon reflexes. Weakness is typically proximal, diffuse or selective, with or without facial weakness and the diagnostic hallmark is the presence of distinct rod-like inclusions in the sarcoplasm of skeletal muscle fibers (3). Core Myopathy Core Myopathy is characterized by areas lacking histochemical oxidative and glycolytic enzymatic activity on histopathological exam (2). Symptoms include proximal muscle weakness with onset either congenitally or in early childhood. Bulbar and facial weakness may also be present. Patients with core myopathy are typically subclassified as either having central core disease or multiminicore disease. Centronuclear Myopathy Centronuclear Myopathy (CNM) is a rare muscle disease associated with non-progressive or slowly progressive muscle weakness that can develop from infancy to adulthood (4, 5). -
Neurological Diseases Caused by Ion-Channel Mutations Frank Weinreich and Thomas J Jentsch*
409 Neurological diseases caused by ion-channel mutations Frank Weinreich and Thomas J Jentsch* During the past decade, mutations in several ion-channel humans. This is probably the case for important Na+-chan- genes have been shown to cause inherited neurological nel isoforms, such as those dominating excitation in diseases. This is not surprising given the large number of skeletal muscle or heart, and may also be the case for the different ion channels and their prominent role in signal two channel subunits that assemble to form M-type processing. Biophysical studies of mutant ion channels in vitro K+-channels, which are key regulators of neuronal allow detailed investigations of the basic mechanism excitability [8••,9•]. This concept is supported by the underlying these ‘channelopathies’. A full understanding of observation that many channelopathies are paroxysmal these diseases, however, requires knowing the roles these (i.e. cause transient convulsions): mutations leading to a channels play in their cellular and systemic context. Differences constant disability might be incompatible with life, or may in this context often cause different phenotypes in humans and significantly decrease the frequency of the mutation with- mice. The situation is further complicated by the developmental in the human population. In contrast to the severe effects and other secondary effects that might result from ion- symptoms associated with the loss of function of certain channel mutations. Recent studies have described the different key ion channels, the large number of ion-channel isoforms thresholds to which ion-channel function must be decreased in may lead to a functional redundancy under most circum- order to cause disease. -
Supplementary Information
Supplementary Information Structural Capacitance in Protein Evolution and Human Diseases Chen Li, Liah V T Clark, Rory Zhang, Benjamin T Porebski, Julia M. McCoey, Natalie A. Borg, Geoffrey I. Webb, Itamar Kass, Malcolm Buckle, Jiangning Song, Adrian Woolfson, and Ashley M. Buckle Supplementary tables Table S1. Disorder prediction using the human disease and polymorphisms dataseta OR DR OO OD DD DO mutations mutations 24,758 650 2,741 513 Disease 25,408 3,254 97.44% 2.56% 84.23% 15.77% 26,559 809 11,135 1,218 Non-disease 27,368 12,353 97.04% 2.96% 90.14% 9.86% ahttp://www.uniprot.org/docs/humsavar [1] (see Materials and Methdos). The numbers listed are the ones of unique mutations. ‘Unclassifiied’ mutations, according to the UniProt, were not counted. O = predicted as ordered; OR = Ordered regions D = predicted as disordered; DR = Disordered regions 1 Table S2. Mutations in long disordered regions (LDRs) of human proteins predicted to produce a DO transitiona Average # disorder # disorder # disorder # order UniProt/dbSNP Protein Mutation Disease length of predictors predictors predictorsb predictorsc LDRd in D2P2e for LDRf UHRF1-binding protein 1- A0JNW5/rs7296162 like S1147L - 4 2^ 101 6 3 A4D1E1/rs801841 Zinc finger protein 804B V1195I - 3* 2^ 37 6 1 A6NJV1/rs2272466 UPF0573 protein C2orf70 Q177L - 2* 4 34 3 1 Golgin subfamily A member A7E2F4/rs347880 8A K480N - 2* 2^ 91 N/A 2 Axonemal dynein light O14645/rs11749 intermediate polypeptide 1 A65V - 3* 3 43 N/A 2 Centrosomal protein of 290 O15078/rs374852145 kDa R2210C - 2 3 123 5 1 Fanconi -
Chapter 23 PATHOPHYSIOLOGY of MUSCLE DISORDERS LINKED TO
Chapter 23 PATHOPHYSIOLOGY OF MUSCLE DISORDERS LINKED TO MUTATIONS IN THE SKELETAL MUSCLE RYANODINE RECEPTOR Robert T. Dirksen1 and Guillermo Avila2 1 Dept. of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, USA; 2 Dept. of Biochemistry, Cinvestav-IPN, Mexico City, Mexico INTRODUCTION Skeletal muscle excitation contraction (EC) coupling involves a unique, bi-directional mechanical interaction between two different types of calcium channels: a sarcolemmal voltage-gated L-type calcium channel (dihydropyridine receptor, DHPR) and the ryanodine receptor (RyR1), a ligand-gated intracellular release channel located in the sarcoplasmic reticulum (SR) (see Dirksen852 for review). In response to sarcolemma depolarization, the DHPR undergoes a conformational change that results in activation of nearby RyR1 release channels and subsequent massive release of SR into the myoplasm (see Melzer et al.169 for review). Thus, the DHPR and RyR1 proteins are essential components of the EC coupling machinery in skeletal muscle, and thus, play a central role in muscle homeostasis. Not surprisingly, mutations and/or deletions in the genes that encode the skeletal muscle DHPR and RyR1 proteins are linked to at least five different human diseases: Malignant hyperthermia (MH), hypokalemic periodic paralysis, central core disease (CCD), multiminicore disease (MmD) and nemaline rod myopathy (NM). Mutations in RyR1 result in MH, CCD, MmD and NM, whereas DHPR mutations are linked only to MH and hypokalemic periodic paralysis. The genetic bases of these diseases, as well as the cellular mechanisms involved, have been thoroughly reviewed elsewhere.853,854 This chapter will focus on the clinical manifestations and functional defects associated with human RyR1 disease mutations and how 230 Chapter 23 these defects might contribute to the pathophysiology of the skeletal muscle ryanodinopathies.