Myotonia in DNM2-Related Centronuclear Myopathy

Total Page:16

File Type:pdf, Size:1020Kb

Myotonia in DNM2-Related Centronuclear Myopathy J Neural Transm (2014) 121:549–553 DOI 10.1007/s00702-013-1140-8 NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - ORIGINAL ARTICLE Myotonia in DNM2-related centronuclear myopathy Ron Dabby • Menachem Sadeh • Ronit Gilad • Karin Jurkat-Rott • Frank Lehmann-Horn • Esther Leshinsky-Silver Received: 26 October 2013 / Accepted: 12 December 2013 / Published online: 24 December 2013 Ó Springer-Verlag Wien 2013 Abstract Centronuclear myopathy (CNM) is a rare Keywords Dynamin 2 (DNM2) Á Myotonia Á hereditary myopathy characterized by centrally located Centronuclear myopathy Á Charcot–Marie–Tooth (CMT) muscle fiber nuclei. Mutations in the dynamin 2 (DNM2) neuropathy Á Electromyography gene are estimated to account for about 50 % of CNM cases. Electromyographic recordings in CNM may show myopathic motor unit potentials without spontaneous Introduction activity at rest. Myotonic discharges, a distinctive electrical activity caused by membrane hyperexcitability, are char- Myotonia, a condition characterized by impaired relaxation acteristic of certain neuromuscular disorders. Such activity of contracted skeletal muscles, can occur in certain neu- has been reported in only one CNM case without a known romuscular disorders. It is a disorder of muscle membrane genetic cause. We sequenced the DNM2 gene and the hyperexcitability that is caused by sarcolemmal ion chan- genes associated with myotonia (CLCN1, SCN4A, DMPK nel dysfunction (Lehmann-Horn et al. 1995; Jurkat-Rott and ZNF9) in a sporadic adult patient with CNM and and Lehmann-Horn 2005; Lossin and George 2008). myotonic discharges. Sequencing the entire coding region Hyperexcitable sarcolemma can result from specific and exon–intron boundaries revealed a heterozygous mutations in the ion channel genes, particularly the sodium c.1106g-a substitution in exon 8, resulting in a R369Q and chloride channels, or as a part of other specific muscle change in the DNM2. Sequencing the CLCN1, SCN4A, disorders, such as the myotonic dystrophies. Myotonic DMPK and ZNF9 genes ruled out mutations in these genes. discharges, without clinical myotonia, have been reported This is the first report of DNM2-related CNM presenting in patients with myofibrillary myopathy (Hanisch et al. with myotonia. The diagnosis of CNM should be consid- 2013). However, the presence of myotonia in association ered in patients with myotonic discharges of an unknown with myopathy, may serve as a valuable tool in the dif- cause. ferential diagnosis of neuromuscular diseases. The centronuclear myopathies (CNM) are inherited heterogeneous neuromuscular disorders, characterized by numerous centrally located nuclei in muscle fibers. R. Dabby (&) Á M. Sadeh Á R. Gilad X-linked myotubular myopathy is a severe disease with Departments of Neurology, Edith Wolfson Medical Center, infantile onset, characterized by marked weakness and 58100 Holon, Israel respiratory failure, and caused by mutations in the myo- e-mail: [email protected] tubularin gene (Laporte et al. 1996). Autosomal dominant K. Jurkat-Rott Á F. Lehmann-Horn and recessive forms exist with mutations in the dynamin 2 Department of Neurophysiology, Ulm University, (DNM2) (Bitoun et al. 2005), amphiphysin 2 (BIN1) (Nicot Ulm, Germany et al. 2007), and the ryanodine receptor genes (RYR1) (Jungbluth et al. 2007). E. Leshinsky-Silver Molecular Genetic Laboratory, Affiliated with Sackler Faculty of In only a few case reports myotonic discharges were Medicine, Tel Aviv University, Tel Aviv, Israel associated with centronuclear myopathy. Some of the 123 550 R. Dabby et al. reported patients had cataract at young age. In none of and had to use her arms to get up from a squatting position. them myotonic dystrophy was excluded by genetic studies, Deep tendon reflexes were normal, with flexor plantar and no genetic studies for DNM2 mutation were available response. Neither spontaneous or percussion myotonia nor then (Hawkes and Absolon 1975, Gil-Peralta et al. 1978, muscle hypertrophy were observed. Sensation was normal Vallat et al. 1985, Zanoteli et al. 1998). Here, we describe to all modalities. Physical examination was normal, there the first patient with DNM2-related CNM with myotonic was no skin rash. discharges. Serum creatine kinase (CK) was initially 11,000 IU/L (normal values \ 200), however, further values on follow- up were 800–1,200 IU/L. Motor and sensory nerve con- Case report duction studies were normal. Electromyogram (EMG) showed numerous myotonic discharges, without fibrilla- A 27-year-old woman, born in Ukraine to non-consan- tions or positive sharp waves, mainly in the proximal guineous parents of Jewish origin, immigrated to Israel at muscles of the upper and lower extremities. The myotonic age 24. Her past medical history is unremarkable, except discharges were evoked by inserting or moving the needle for orthopedic surgery in her left knee in 2003. Her father, electrode, they waxed and waned with variation of ampli- who died of a stroke at age 55, had difficulties walking and tude and frequency (Fig. 1). Motor unit potentials (MUPs) rising from a chair, which had never been investigated. were of short duration and low amplitude, particularly in Otherwise, no other family members had neurological the quadriceps muscles, with early and nearly full recruit- illnesses. ment. These findings were consistent with the diagnosis of The patient was referred to the Department of Neurol- myopathy with myotonia. Therefore, genetic testing for ogy at Wolfson Medical Center in August 2011 for eval- myotonic dystrophy types I (DM1) and II (DM2) were uation of muscle weakness in the lower extremities that had performed. The results showed normal repeat lengths in the been progressing over one year. In mid 2010, she experi- DMPK and ZNF9 genes, ruling out these diseases. A repeat enced severe pain in her left thigh shortly after strenuous EMG study several months later showed similar abundant exercise in a fitness center. After the pain subsided she myotonic discharges in the upper and lower limb muscles. noticed difficulties climbing stairs and rising from a sitting position, which slowly progressed with time. She denied muscle twitches or cramps. She noticed neither weakness Materials and methods in her upper extremities nor difficulties walking on flat surfaces. There were no sensory, visual or bulbar Muscle biopsy symptoms. Neurologic examination revealed intact cranial nerves Part of the muscle was fixed with formalin and embedded without ptosis or ophthalmoparesis, and normal strength of in paraffin. Another sample was frozen in isopentane the neck muscles. In the upper extremities, proximal and chilled in liquid nitrogen. Seven micrometer thick trans- distal muscle weakness was symmetric, 4/5 (Medical verse sections were stained with haematoxylin and eosin, Research Council Scale), of the deltoid, infraspinatus, modified Gomori trichrome, PAS, Sudan black B, NADH- pectoralis, finger extensors and interossei. In the lower tetrazolium reductase, succinate dehydrogenase and cyto- extremities, iliopsoas, glutei, ankle and toe extensors were chrome oxidase, ATPase at pH 9.4 and after preincubation all 4/5. The patient could not step on her toes and heels, at pH 4.3 and 4.6. The immunocytological reactions Fig. 1 Myotonic discharges recorded in the right vastus lateralis muscle 123 Myotonia in DNM2-related centronuclear myopathy 551 included dystrophin 1–3, sarcoglycans, merosin, caveolin almost all fibers were of type 1, with a central zone of 3, dysferlin and collagen VI. enzymatic inactivity (Fig. 2). Molecular analysis DNM2 mutation Genomic DNA was extracted from peripheral blood by the Sequencing the entire coding region and exon–intron Puregene kit (Gentra, Minneapolis, USA), according to boundaries of DNM2 revealed a heterozygous c.1106g-a the manufacturer’s instructions. Genomic DNA was used substitution in exon 8, resulting in R369Q change in the as a template for PCR amplification of each of the 21 gene product (Fig. 3). This mutation appears as pathologic exons and exon–intron boundaries of the DNM2 gene. The according to prediction software (polyphen2; score-0.8), reaction was performed in a 25 ll volume containing mutation taster (score-0.999). The substituted amino acid is 10 mM Tris–HCl, pH 8.3, 50 mM KCl, 1.5 mM MgCl2 located in the middle domain (MID) of the dynamin pro- 250 lM dNTPs, 1 lM of each primer, 100 ng of genomic tein. This mutation has been described in CNM cases DNA and 1.25U of AmpliTaq Gold DNA polymerase (Bitoun et al. 2005;Bo¨hm et al. 2012). CLCN1 and SCN4A (Perkin Elmer Applied Biosystem). An initial denaturation mutations were excluded. step of 10 min at 95 °C was carried out to activate the polymerase, followed by 35 cycles of 94 °C15s,55or 60 °C45s,72°C and 45 s and a final elongation of Discussion 10 min at 72 °C. Predicted amplicon sizes were confirmed by agarose gel electrophoresis. The amplified PCR pro- This is the first study to describe the presence of myotonia ducts were purified with the ExoSapIT kit (Amersham in a case of CNM due to a mutation in the dynamin 2 gene. Pharmacia biotech, Amersham, Buckinghanshire, UK), The R369Q mutation (p.Arg369 is changed into glutamine) according to the manufacturer’s instructions, and has been documented in four families (Bitoun et al. 2005; sequenced with fluorescently labeled dedeoxynucleotide Bo¨hm et al. 2012). The severity of the CNM phenotype terminators and an Applied Biosystem 3730A automated was moderate. The age of onset ranged from childhood to sequencer. Sequences were compared with the DNM2 adulthood, and no prominent eye movement deficits were transcript (ENST00000389253), using the DNA variant reported. In all cases, the R369Q mutation was heterozy- analysis Surveyor software, version 3.3 (http://www.soft gous, thus conferring dominant trait of inheritance. Our waregenetics.com). Polymerase chain reaction (PCR) and patient‘s father had an undiagnosed proximal weakness. direct PCR sequencing of the 23 CLCN1 and the 24 We suspect that he had the same disease, which is con- SCN4A exons were performed as described previously gruent with autosomal dominant trait inheritance.
Recommended publications
  • Spectrum of CLCN1 Mutations in Patients with Myotonia Congenita in Northern Scandinavia
    European Journal of Human Genetics (2001) 9, 903 ± 909 ã 2001 Nature Publishing Group All rights reserved 1018-4813/01 $15.00 www.nature.com/ejhg ARTICLE Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia Chen Sun*,1, Lisbeth Tranebjñrg*,1, Torberg Torbergsen2,GoÈsta Holmgren3 and Marijke Van Ghelue1,4 1Department of Medical Genetics, University Hospital of Tromsù, Tromsù, Norway; 2Department of Neurology, University Hospital of Tromsù, Tromsù, Norway; 3Department of Clinical Genetics, University Hospital of UmeaÊ, UmeaÊ,Sweden;4Department of Biochemistry, Section Molecular Biology, University of Tromsù, Tromsù, Norway Myotonia congenita is a non-dystrophic muscle disorder affecting the excitability of the skeletal muscle membrane. It can be inherited either as an autosomal dominant (Thomsen's myotonia) or an autosomal recessive (Becker's myotonia) trait. Both types are characterised by myotonia (muscle stiffness) and muscular hypertrophy, and are caused by mutations in the muscle chloride channel gene, CLCN1. At least 50 different CLCN1 mutations have been described worldwide, but in many studies only about half of the patients showed mutations in CLCN1. Limitations in the mutation detection methods and genetic heterogeneity might be explanations. In the current study, we sequenced the entire CLCN1 gene in 15 Northern Norwegian and three Northern Swedish MC families. Our data show a high prevalence of myotonia congenita in Northern Norway similar to Northern Finland, but with a much higher degree of mutation heterogeneity. In total, eight different mutations and three polymorphisms (T87T, D718D, and P727L) were detected. Three mutations (F287S, A331T, and 2284+5C4T) were novel while the others (IVS1+3A4T, 979G4A, F413C, A531V, and R894X) have been reported previously.
    [Show full text]
  • Centronuclear Myopathies Under Attack: a Plethora of Therapeutic Targets Hichem Tasfaout, Belinda Cowling, Jocelyn Laporte
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Archive Ouverte en Sciences de l'Information et de la Communication Centronuclear myopathies under attack: A plethora of therapeutic targets Hichem Tasfaout, Belinda Cowling, Jocelyn Laporte To cite this version: Hichem Tasfaout, Belinda Cowling, Jocelyn Laporte. Centronuclear myopathies under attack: A plethora of therapeutic targets. Journal of Neuromuscular Diseases, IOS Press, 2018, 5, pp.387 - 406. 10.3233/JND-180309. hal-02438924 HAL Id: hal-02438924 https://hal.archives-ouvertes.fr/hal-02438924 Submitted on 14 Jan 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Journal of Neuromuscular Diseases 5 (2018) 387–406 387 DOI 10.3233/JND-180309 IOS Press Review Centronuclear myopathies under attack: A plethora of therapeutic targets Hichem Tasfaouta,b,c,d, Belinda S. Cowlinga,b,c,d,1 and Jocelyn Laportea,b,c,d,1,∗ aDepartment of Translational Medicine and Neurogenetics, Institut de G´en´etique et de Biologie Mol´eculaire et Cellulaire (IGBMC), Illkirch, France bInstitut National de la Sant´eetdelaRechercheM´edicale (INSERM), U1258, Illkirch, France cCentre National de la Recherche Scientifique (CNRS), UMR7104, Illkirch, France dUniversit´e de Strasbourg, Illkirch, France Abstract.
    [Show full text]
  • Affected Female Carriers of MTM1 Mutations Display a Wide Spectrum
    Acta Neuropathol DOI 10.1007/s00401-017-1748-0 ORIGINAL PAPER Afected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues Valérie Biancalana1,2,3,4,5 · Sophie Scheidecker1 · Marguerite Miguet1 · Annie Laquerrière6 · Norma B. Romero7,8 · Tanya Stojkovic8 · Osorio Abath Neto9 · Sandra Mercier10,11,12 · Nicol Voermans13 · Laura Tanner14 · Curtis Rogers15 · Elisabeth Ollagnon‑Roman16 · Helen Roper17 · Célia Boutte18 · Shay Ben‑Shachar19 · Xavière Lornage2,3,4,5 · Nasim Vasli2,3,4,5 · Elise Schaefer20 · Pascal Laforet21 · Jean Pouget22 · Alexandre Moerman23 · Laurent Pasquier24 · Pascale Marcorelle25,26 · Armelle Magot12 · Benno Küsters27 · Nathalie Streichenberger28 · Christine Tranchant29 · Nicolas Dondaine1 · Raphael Schneider2,3,4,5,30 · Claire Gasnier1 · Nadège Calmels1 · Valérie Kremer31 · Karine Nguyen32 · Julie Perrier12 · Erik Jan Kamsteeg33 · Pierre Carlier34 · Robert‑Yves Carlier35 · Julie Thompson30 · Anne Boland36 · Jean‑François Deleuze36 · Michel Fardeau7,8 · Edmar Zanoteli9 · Bruno Eymard21 · Jocelyn Laporte2,3,4,5 Received: 9 May 2017 / Revised: 24 June 2017 / Accepted: 2 July 2017 © Springer-Verlag GmbH Germany 2017 Abstract X-linked myotubular myopathy (XLMTM), a females and to delineate diagnostic clues, we character- severe congenital myopathy, is caused by mutations in the ized 17 new unrelated afected females and performed a MTM1 gene located on the X chromosome. A majority of detailed comparison with previously reported cases at the afected males die in the early postnatal period, whereas clinical, muscle imaging, histological, ultrastructural and female carriers are believed to be usually asymptomatic. molecular levels. Taken together, the analysis of this large Nevertheless, several afected females have been reported. cohort of 43 cases highlights a wide spectrum of clini- To assess the phenotypic and pathological spectra of carrier cal severity ranging from severe neonatal and generalized weakness, similar to XLMTM male, to milder adult forms.
    [Show full text]
  • Periodic Paralysis
    Periodic Paralysis In Focus Dear Readers Fast Facts This “In Focus” report is the third in a series of MDA’s three-year commitment for all Hypokalemic periodic paralysis MDA comprehensive reports about the latest in periodic paralysis research as of March Hypokalemic PP can begin anywhere from neuromuscular disease research and manage- 2009 is $1,938,367. The Association’s early childhood to the 30s, with periodic ment. allocation for research on hyperkalemic attacks of severe weakness lasting hours This report focuses on the periodic and hypokalemic periodic paralysis to days. The frequency of attacks gener- paralyses, a group of disorders that result from research since 1950 is $8,125,341. ally lessens in the 40s or 50s. Permanent malfunctions in so-called ion channels, micro- MDA’s allocation for the recently weakness may persist between attacks, scopic tunnels that make possible high-speed identified Andersen-Tawil syndrome usually beginning in middle age and pro- movement of electrically charged particles is $515,430 since 2001. MDA is cur- gressing slowly over years. across barriers inside cells and between cells rently funding 11 grants in the periodic The most common underlying cause and their surroundings. paralyses. is any of several genetic mutations in When ion channels fail to open or close The periodic paralyses are gener- a gene on chromosome 1 that carries according to an exquisitely fine-tuned program, ally divided into hyperkalemic periodic instructions for a calcium channel protein episodes of paralysis of the skeletal muscles paralysis, hypokalemic periodic paralysis in skeletal muscle fibers. When this chan- and even temporary irregularities in the heart- and Andersen-Tawil syndrome.
    [Show full text]
  • Neuromyotonia in Hereditary Motor Neuropathy J Neurol Neurosurg Psychiatry: First Published As 10.1136/Jnnp.54.3.230 on 1 March 1991
    230 Journal ofNeurology, Neurosurgery, and Psychiatry 1991;54:230-235 Neuromyotonia in hereditary motor neuropathy J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.54.3.230 on 1 March 1991. Downloaded from A F Hahn, A W Parkes, C F Bolton, S A Stewart Abstract Case II2 Two siblings with a distal motor This 15 year old boy had always been clumsy. neuropathy experienced cramping and Since the age of 10, he had noticed generalised difficulty in relaxing their muscles after muscle stiffness which increased with physical voluntary contraction. Electromyogra- activity such as walking upstairs, running and phic recordings at rest revealed skating. For some time, he was aware of repetitive high voltage spontaneous elec- difficulty in releasing his grip and his fingers trical discharges that were accentuated tended to cramp on writing. He had noticed after voluntary contraction and during involuntary twitching of his fingers, forearm ischaemia. Regional neuromuscular muscles and thighs at rest and it was more blockage with curare indicated hyperex- pronounced after a forceful voluntary con- citability of peripheral nerve fibres and traction. Muscle cramping and spontaneous nerve block suggested that the ectopic muscle activity were particularly unpleasant activity originated in proximal segments when he re-entered the house in the winter, of the nerve. Symptoms were improved for example, after a game of hockey. Since the with diphenylhydantoin, carbamazepine age of twelve, he had noticed a tendency to and tocainide. trip. Subsequently he developed bilateral foot drop and weakness of his hands. He denied sensory symptoms and perspired only with The term "neuromyotonia" was coined by exertion.
    [Show full text]
  • Correlating-Phenotype-And-Genotype
    I am pleased to provide you complimentary one-time access to my article as a PDF file for your own personal use. Any further/multiple distribution, publication or commercial usage of this copyrighted material would require submission of a permission request to the publisher. Timothy M. Miller, MD, PhD Correlating phenotype and genotype in the periodic paralyses T.M. Miller, MD, PhD; M.R. Dias da Silva, MD, PhD; H.A. Miller, BS; H. Kwiecinski, MD, PhD; J.R. Mendell, MD; R. Tawil, MD; P. McManis, MD; R.C. Griggs, MD; C. Angelini, MD; S. Servidei, MD; J. Petajan, MD, PhD; M.C. Dalakas, MD; L.P.W. Ranum, PhD; Y.H. Fu, PhD; and L.J. Ptáek, MD Abstract—Background: Periodic paralyses and paramyotonia congenita are rare disorders causing disabling weakness and myotonia. Mutations in sodium, calcium, and potassium channels have been recognized as causing disease. Objective: To analyze the clinical phenotype of patients with and without discernible genotype and to identify other mutations in ion channel genes associated with disease. Methods: The authors have reviewed clinical data in patients with a diagnosis of hypokalemic periodic paralysis (56 kindreds, 71 patients), hyperkalemic periodic paralysis (47 kindreds, 99 patients), and paramyotonia congenita (24 kindreds, 56 patients). For those patients without one of the classically known mutations, the authors analyzed the entire coding region of the SCN4A, KCNE3, and KCNJ2 genes and portions of the coding region of the CACNA1S gene in order to identify new mutations. Results: Mutations were identified in approximately two thirds of kindreds with periodic paralysis or paramyotonia congenita.
    [Show full text]
  • What Is a Skeletal Muscle Channelopathy?
    Muscle Channel Patient Day 2019 Dr Emma Matthews The Team • Professor Michael Hanna • Emma Matthews • Doreen Fialho - neurophysiology • Natalie James – clinical nurse specialist • Sarah Holmes - physiotherapy • Richa Sud - genetics • Roope Mannikko – electrophysiology • Iwona Skorupinska – research nurse • Louise Germain – research nurse • Kira Baden- service manager • Jackie Kasoze-Batende– NCG manager • Jean Elliott – NCG senior secretary • Karen Suetterlin, Vino Vivekanandam • – research fellows What is a skeletal muscle channelopathy? Muscle and nerves communicate by electrical signals Electrical signals are made by the movement of positively and negatively charged ions in and out of cells The ions can only move through dedicated ion channels If the channel doesn’t work properly, you have a “channelopathy” Ion channels CHLORIDE CHANNELS • Myotonia congenita – CLCN1 • Paramyotonia congenita – SCN4A MYOTONIA SODIUM CHANNELS • Hyperkalaemic periodic paralysis – SCN4A • Hypokalaemic periodic paralysis – 80% CACNA1S CALCIUM CHANNELS – 10% SCN4A PARALYSIS • Andersen-Tawil Syndrome – KCNJ2 POTASSIUM CHANNELS Myotonia and Paralysis • Two main symptoms • Paralysis = an inexcitable muscle – Muscles are very weak or paralysed • Myotonia = an overexcited muscle – Muscle keeps contracting and become “stuck” - Nerve action potential Cl_ - + - + + + Motor nerve K+ + Na+ Na+ Muscle membrane Ach Motor end plate T-tubule Nav1.4 Ach receptors Cav1.1 and RYR1 Muscle action potential Calcium MuscleRelaxed contraction muscle Myotonia Congenita • Myotonia
    [Show full text]
  • Psykisk Utviklingshemming Og Forsinket Utvikling
    Psykisk utviklingshemming og forsinket utvikling Genpanel, versjon v03 Tabellen er sortert på gennavn (HGNC gensymbol) Navn på gen er iht. HGNC >x10 Andel av genet som har blitt lest med tilfredstillende kvalitet flere enn 10 ganger under sekvensering x10 er forventet dekning; faktisk dekning vil variere. Gen Gen (HGNC Transkript >10x Fenotype (symbol) ID) AAAS 13666 NM_015665.5 100% Achalasia-addisonianism-alacrimia syndrome OMIM AARS 20 NM_001605.2 100% Charcot-Marie-Tooth disease, axonal, type 2N OMIM Epileptic encephalopathy, early infantile, 29 OMIM AASS 17366 NM_005763.3 100% Hyperlysinemia OMIM Saccharopinuria OMIM ABCB11 42 NM_003742.2 100% Cholestasis, benign recurrent intrahepatic, 2 OMIM Cholestasis, progressive familial intrahepatic 2 OMIM ABCB7 48 NM_004299.5 100% Anemia, sideroblastic, with ataxia OMIM ABCC6 57 NM_001171.5 93% Arterial calcification, generalized, of infancy, 2 OMIM Pseudoxanthoma elasticum OMIM Pseudoxanthoma elasticum, forme fruste OMIM ABCC9 60 NM_005691.3 100% Hypertrichotic osteochondrodysplasia OMIM ABCD1 61 NM_000033.3 77% Adrenoleukodystrophy OMIM Adrenomyeloneuropathy, adult OMIM ABCD4 68 NM_005050.3 100% Methylmalonic aciduria and homocystinuria, cblJ type OMIM ABHD5 21396 NM_016006.4 100% Chanarin-Dorfman syndrome OMIM ACAD9 21497 NM_014049.4 99% Mitochondrial complex I deficiency due to ACAD9 deficiency OMIM ACADM 89 NM_000016.5 100% Acyl-CoA dehydrogenase, medium chain, deficiency of OMIM ACADS 90 NM_000017.3 100% Acyl-CoA dehydrogenase, short-chain, deficiency of OMIM ACADVL 92 NM_000018.3 100% VLCAD
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2016/0281166 A1 BHATTACHARJEE Et Al
    US 20160281 166A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0281166 A1 BHATTACHARJEE et al. (43) Pub. Date: Sep. 29, 2016 (54) METHODS AND SYSTEMIS FOR SCREENING Publication Classification DISEASES IN SUBJECTS (51) Int. Cl. (71) Applicant: PARABASE GENOMICS, INC., CI2O I/68 (2006.01) Boston, MA (US) C40B 30/02 (2006.01) (72) Inventors: Arindam BHATTACHARJEE, G06F 9/22 (2006.01) Andover, MA (US); Tanya (52) U.S. Cl. SOKOLSKY, Cambridge, MA (US); CPC ............. CI2O 1/6883 (2013.01); G06F 19/22 Edwin NAYLOR, Mt. Pleasant, SC (2013.01); C40B 30/02 (2013.01); C12O (US); Richard B. PARAD, Newton, 2600/156 (2013.01); C12O 2600/158 MA (US); Evan MAUCELI, (2013.01) Roslindale, MA (US) (21) Appl. No.: 15/078,579 (57) ABSTRACT (22) Filed: Mar. 23, 2016 Related U.S. Application Data The present disclosure provides systems, devices, and meth (60) Provisional application No. 62/136,836, filed on Mar. ods for a fast-turnaround, minimally invasive, and/or cost 23, 2015, provisional application No. 62/137,745, effective assay for Screening diseases, such as genetic dis filed on Mar. 24, 2015. orders and/or pathogens, in Subjects. Patent Application Publication Sep. 29, 2016 Sheet 1 of 23 US 2016/0281166 A1 SSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSS S{}}\\93? sau36 Patent Application Publication Sep. 29, 2016 Sheet 2 of 23 US 2016/0281166 A1 &**** ? ???zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz??º & %&&zzzzzzzzzzzzzzzzzzzzzzz &Sssssssssssssssssssssssssssssssssssssssssssssssssssssssss & s s sS ------------------------------ Patent Application Publication Sep. 29, 2016 Sheet 3 of 23 US 2016/0281166 A1 23 25 20 FG, 2. Patent Application Publication Sep. 29, 2016 Sheet 4 of 23 US 2016/0281166 A1 : S Patent Application Publication Sep.
    [Show full text]
  • Myotonia in Centronuclear Myopathy
    J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.41.12.1102 on 1 December 1978. Downloaded from Journal ofNeurology, Neurosurgery, and Psychiatry, 1978, 41, 1102-1108 Myotonia in centronuclear myopathy A. GIL-PERALTA, E. RAFEL, J. BAUTISTA, AND R ALBERCA From the Departments of Neurology and Pathology, Ciudad Sanitaria Virgen del Rocio, Seville, Spain SUMMARY Centronuclear myopathy, which is unusual because of clinical myotonia, is described in two sisters. The diagnosis was established in adult life, but the first symptoms were noticed in infancy. The outstanding points of the clinical picture were mild amyotrophy, paresis, and clinical myotonia. Myotubular myopathy (Spiro et al., 1966) is an the age of 27 years she noticed increased muscular entity defined by its morphological muscular difficulties, and needed support to climb stairs. by guest. Protected copyright. alterations. The disease displays a notable clinical Later on, paresis of the upper extremities, of variability and marked genetic heterogeneity indeterminate onset, caused difficulty in raising (Radu et al., 1977). Usually it is present early in the arms above the shoulders. These symptoms life, and is found only rarely in adults (Vital et al., were not modified by cold weather. The patient 1970). Electrical myotonia (Munsat et al., 1969; repeatedly suffered from corneal ulcers, and within Radu et al., 1977) with accompanying cataract the past year she had noticed macular skin lesions has been described in this disease (Hawkes and on the right arm. Absolon, 1975). The patient walked with a waddling gait and a We report a family in which two members dis- limp on the right side.
    [Show full text]
  • 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).
    [Show full text]
  • Prenatal Testing Requisition Form
    BAYLOR MIRACA GENETICS LABORATORIES SHIP TO: Baylor Miraca Genetics Laboratories 2450 Holcombe, Grand Blvd. -Receiving Dock PHONE: 800-411-GENE | FAX: 713-798-2787 | www.bmgl.com Houston, TX 77021-2024 Phone: 713-798-6555 PRENATAL COMPREHENSIVE REQUISITION FORM PATIENT INFORMATION NAME (LAST,FIRST, MI): DATE OF BIRTH (MM/DD/YY): HOSPITAL#: ACCESSION#: REPORTING INFORMATION ADDITIONAL PROFESSIONAL REPORT RECIPIENTS PHYSICIAN: NAME: INSTITUTION: PHONE: FAX: PHONE: FAX: NAME: EMAIL (INTERNATIONAL CLIENT REQUIREMENT): PHONE: FAX: SAMPLE INFORMATION CLINICAL INDICATION FETAL SPECIMEN TYPE Pregnancy at risk for specific genetic disorder DATE OF COLLECTION: (Complete FAMILIAL MUTATION information below) Amniotic Fluid: cc AMA PERFORMING PHYSICIAN: CVS: mg TA TC Abnormal Maternal Screen: Fetal Blood: cc GESTATIONAL AGE (GA) Calculation for AF-AFP* NTD TRI 21 TRI 18 Other: SELECT ONLY ONE: Abnormal NIPT (attach report): POC/Fetal Tissue, Type: TRI 21 TRI 13 TRI 18 Other: Cultured Amniocytes U/S DATE (MM/DD/YY): Abnormal U/S (SPECIFY): Cultured CVS GA ON U/S DATE: WKS DAYS PARENTAL BLOODS - REQUIRED FOR CMA -OR- Maternal Blood Date of Collection: Multiple Pregnancy Losses LMP DATE (MM/DD/YY): Parental Concern Paternal Blood Date of Collection: Other Indication (DETAIL AND ATTACH REPORT): *Important: U/S dating will be used if no selection is made. Name: Note: Results will differ depending on method checked. Last Name First Name U/S dating increases overall screening performance. Date of Birth: KNOWN FAMILIAL MUTATION/DISORDER SPECIFIC PRENATAL TESTING Notice: Prior to ordering testing for any of the disorders listed, you must call the lab and discuss the clinical history and sample requirements with a genetic counselor.
    [Show full text]