DOCSLIB.ORG

Mitochondrial Myopathies

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Mitochondrial Myopathies Facts About Mitochondrial Myopathies Updated December 2009 Dear Friends: f you are reading this booklet, it’s probably symptoms are common in the general popula- Ibecause you’ve just received a very bewil- tion, such as heart problems, seizures and dering diagnosis: mitochondrial myopathy. diabetes. Therefore, good medical treatments What is a mitochondrial myopathy, and what already exist to help manage many symp- does the term mean? These are questions toms. my wife, Jennifer, and I struggled with when Always remember that researchers are con- our son, Michael, got his diagnosis in 1993. tinually moving toward better treatments, and Mitochondrial myopathies have many dif- ultimately, cures for mitochondrial diseases. ferent faces. As you will read in this booklet, In addition, people with disabilities have great- dozens of varieties of mitochondrial diseases er opportunities than ever before to make the have been identified, with a complex array of most of their abilities, as well as legal rights symptoms. Some symptoms can be so mild to equal employment opportunity and access that they’re hardly noticeable, while others are to public places. Children with physical and life-threatening. cognitive disabilities are guaranteed by law a public education with whatever supports they Michael’s disease causes muscle weakness, need. muscle cramping, fatigue, lack of endurance and poor balance. You or your family member MDA has been a very valuable ally as we con- may have similar symptoms, yet each case is tinue to learn to live with mitochondrial dis- unique. ease. “MDA Is Here to Help You,” on page 14, will tell you more about MDA’s many services. When we first learned that Michael had a mitochondrial myopathy, we naturally were To us, Michael is not a victim of a disease or very frightened and uncertain about the future. a syndrome, but a happy, loving, young man The Kelly family at the MDA Labor Day Telethon. As time passed, we learned that we can do of whom we’re very proud. We’ve discovered things we didn’t think would be possible — that no one can predict exactly how Michael’s we can adapt to the uncertainty, control the or Jennifer’s cases will progress. We’ve been fear, cope with changes as they occur and still blessed to see Michael lead a normal life, have a “normal,” happy family life. earning his Boy Scout Eagle Award and being inducted into the National Honor Society. In 2004 our lives were again turned upside Michael has shown that having a mitochondri- down, when my wife, Jennifer, learned she al disease doesn’t necessarily keep you from too had a mitochondrial disease. Jennifer’s accomplishing anything you set your mind to. symptoms are more severe than Michael’s; she experiences severe muscle weakness, As we struggle to adapt to the changes in our fatigue, gastrointestinal problems, respiratory lives since Jennifer’s diagnosis, it’s reassuring problems and difficulty swallowing. to know that MDA is there for us, assisting us with equipment, clinics, continuing research, This booklet has been prepared to help you and just a friendly voice that understands understand the causes of and treatments for what we are going through. mitochondrial myopathies. We have found information to be a vital tool in managing As you face the challenges ahead, we wish Michael’s and Jennifer’s diseases and achiev- you the same blessing and the comfort of ing the best possible outcome. knowing that you are not alone. From this booklet you’ll also learn a few Richard Kelly encouraging things. For example, although Mansfield, Massachusetts these are very rare disorders, many of their 2 Mitochondrial Myopathies • ©2011 MDA What Are Mitochondrial Diseases? ust as some diseases are named for the Because muscle cells and nerve cells have Jpart of the body they affect (like heart dis- especially high energy needs, muscular and ease), mitochondrial diseases are so-named neurological problems — such as muscle because they affect a specific part of the cells weakness, exercise intolerance, hearing loss, in the body. Specifically, mitochondrial dis- trouble with balance and coordination, sei- eases affect the mitochondria — tiny energy zures and learning deficits — are common factories found inside almost all our cells. features of mitochondrial disease. Other fre- quent complications include impaired vision, Mitochondria are responsible for producing heart defects, diabetes and stunted growth. most of the energy that’s needed for our Usually, a person with a mitochondrial dis- cells to function. In fact, they provide such ease has two or more of these conditions, an important source of energy that a typi- some of which occur together so regularly cal human cell contains hundreds of them. that they’re grouped into syndromes. A mitochondrial disease can shut down some or all the mitochondria, cutting off this A mitochondrial disease that causes promi- essential energy supply. nent muscular problems is called a mito- chondrial myopathy (myo means muscle, Nearly all our cells rely on mitochondria for and pathos means disease), while a mito- a steady energy supply, so a mitochondrial chondrial disease that causes both promi- disease can be a multisystem disorder affect- nent muscular and neurological problems is ing more than one type of cell, tissue or called a mitochondrial encephalomyopathy organ. The exact symptoms aren’t the same (encephalo refers to the brain). for everyone, because a person with mito- chondrial disease can have a unique mixture Despite their many potential effects, mito- of healthy and defective mitochondria, with a chondrial diseases sometimes cause little unique distribution in the body. disability. Sometimes, a person has enough healthy mitochondria to compensate for the MANY defective ones. Also, because some symp- toms of mitochondrial disease (such as diabetes or heart arrhythmia) are common in the general population, there are effective treatments for those symptoms (such as insulin or anti-arrhythmic drugs). INSIDE A SINGLE MITOCHONDRION Each mitochondrion is an energy factory that “imports” sugars and fats, breaks them down and “exports” energy (ATP). 3 Mitochondrial Myopathies • ©2011 MDA This booklet describes general causes, mitochondria. Within each mitochondrion consequences and management of mito- (singular of mitochondria), these proteins chondrial diseases, with an emphasis on make up part of an assembly line that uses myopathies and encephalomyopathies and a fuel molecules derived from food to manu- close look at the most common syndromes. facture the energy molecule ATP. This highly These include: efficient manufacturing process requires oxygen; outside the mitochondrion, there are • Kearns-Sayre syndrome (KSS) less efficient ways of producing ATP without • Leigh syndrome oxygen. • mitochondrial DNA depletion Proteins at the beginning of the mitochon- syndrome (MDS) drial assembly line act like cargo handlers, importing the fuel molecules — sugars and • mitochondrial encephalomyopathy, fats — into the mitochondrion. Next, other lactic acidosis and strokelike proteins break down the sugars and fats, episodes (MELAS) extracting energy in the form of charged par- ticles called electrons. • myoclonus epilepsy with ragged red fibers (MERRF) Proteins toward the end of the line — orga- nized into five groups called complexes I, • mitochondrial neurogastrointestinal II, III, IV and V — harness the energy from encephalomyopathy (MNGIE) those electrons to make ATP. Complexes I Mitochondrial diseases through IV shuttle the electrons down the aren’t contagious, and • neuropathy, ataxia and line and are therefore called the electron they’re not caused by retinitis pigmentosa (NARP) transport chain, and complex V actually anything a person does. • Pearson syndrome churns out ATP, so it’s also called ATP syn- thase. • progressive external ophthalmoplegia (PEO) A deficiency in one or more of these com- plexes is the typical cause of a mitochondrial What causes mitochondrial disease. (In fact, mitochondrial diseases are diseases? sometimes named for a specific deficiency, such as complex I deficiency.) First, mitochondrial diseases aren’t conta- gious, and they aren’t caused by anything a When a cell is filled with defective mitochon- person does. They’re caused by mutations, dria, it not only becomes deprived of ATP — or changes, in genes — the cells’ blueprints it can accumulate a backlog of unused fuel for making proteins. molecules and oxygen, with potentially disas- trous effects. Genes are responsible for building our bod- ies, and are passed from parents to children, In such cases, excess fuel molecules are along with any mutations or defects they used to make ATP by inefficient means, have. That means that mitochondrial diseas- which can generate potentially harmful es are inheritable, although they often affect byproducts such as lactic acid. (This also members of the same family in different occurs when a cell has an inadequate oxygen ways. (For more information about genetic supply, which can happen to muscle cells mutations and mitochondrial disease, see during strenuous exercise.) The buildup of “Does It Run in the Family?” on page 12.) lactic acid in the blood — called lactic aci- dosis — is associated with muscle fatigue, The genes involved in mitochondrial disease and might actually damage muscle and nerve normally make proteins that work inside the tissue. 4 Mitochondrial Myopathies • ©2011 MDA Meanwhile, unused oxygen in the cell can be useful. Sometimes, people with mitochon- converted into destructive compounds called drial myopathies experience loss of muscle reactive oxygen species, including so-called strength in the arms or legs, and might need free radicals. (These are the targets of so- braces or a wheelchair to get around. called antioxidant drugs and vitamins.) Exercise intolerance, also called exertional ATP derived from mitochondria provides the fatigue, refers to unusual feelings of exhaus- main source of power for muscle cell con- tion brought on by physical exertion. The traction and nerve cell firing. So, muscle cells degree of exercise intolerance varies greatly and nerve cells are especially sensitive to among individuals.
Load more

Recommended publications
  • Mitochondrial Trnaleu(Uur) May Cause an MERRF Syndrome
    J7ournal ofNeurology, Neurosurgery, and Psychiatry 1996;61:47-51 47 The A to G transition at nt 3243 of the J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.61.1.47 on 1 July 1996. Downloaded from mitochondrial tRNALeu(uuR) may cause an MERRF syndrome Gian Maria Fabrizi, Elena Cardaioli, Gaetano Salvatore Grieco, Tiziana Cavallaro, Alessandro Malandrini, Letizia Manneschi, Maria Teresa Dotti, Antonio Federico, Giancarlo Guazzi Abstract Two distinct maternally inherited encephalo- Objective-To verify the phenotype to myopathies with ragged red fibres have been genotype correlations of mitochondrial recognised on clinical grounds: MERRF, DNA (mtDNA) related disorders in an which is characterised by myoclonic epilepsy, atypical maternally inherited encephalo- skeletal myopathy, neural deafness, and optic myopathy. atrophy,' and MELAS, which is defined by Methods-Neuroradiological, morpholog- stroke-like episodes in young age, episodic ical, biochemical, and molecular genetic headache and vomiting, seizures, dementia, analyses were performed on the affected lactic acidosis, skeletal myopathy, and short members of a pedigree harbouring the stature.2 Molecular genetic studies later con- heteroplasmic A to G transition at firmed the nosological distinction between the nucleotide 3243 of the mitochondrial two disorders, showing that MERRF is strictly tRNAI-u(UR), which is usually associated associated with two mutations of the mito- with the syndrome of mitochondrial chondrial tRNALYs at nucleotides 83443 and encephalomyopathy, lactic
    [Show full text]
  • Cardiac Manifestations in Emery–Dreifuss Muscular Dystrophy
    PRACTICE | CASES CPD Cardiac manifestations in Emery–Dreifuss muscular dystrophy Whitney Faiella MD, Ricardo Bessoudo MD n Cite as: CMAJ 2018 December 3;190:E1414-7. doi: 10.1503/cmaj.180410 35-year-old man with a known history of Emery–Dreifuss muscular dystrophy called emergency medical services KEY POINTS (EMS) while at work one morning, reporting palpitations, • Emery–Dreifuss muscular dystrophy is one of many lightheadedness,A fatigue and a rapid heart rate. On arrival by neuromuscular diseases with cardiac involvement, including EMS, his pulse was documented at 195–200 beats/min, and his bradyarrhythmia, tachyarrhythmia and cardiomyopathy, and rhythm strips showed ventricular tachycardia (Figure 1A). He involves an increased risk of sudden cardiac death. underwent cardioversion and was given a bolus of amiodarone, • A recently published scientific statement highlights key cardiac 150 mg intravenously. In the emergency department and during manifestations in various forms of neuromuscular diseases and includes detailed recommendations regarding screening, admission, his symptoms persisted with rhythm strips showing follow-up and treatment for each individual disease. recurrent episodes of sustained ventricular tachycardia (Fig- • Medical optimization of cardiac function and early detection of ure 1B). He was subsequently started on an amiodarone drip and arrhythmias with subsequent insertion of a pacemaker or oral metoprolol. Echocardiography performed during admission defibrillator can be life-saving in this patient population. showed dilated cardiomyopathy with severe systolic dysfunction and an estimated ejection fraction of 23%. Cardiac catheteriza- tion was performed to rule out an ischemic cause of the cardio- With respect to the patient’s diagnosis of Emery–Dreifuss mus- myopathy and showed normal coronary arteries.
    [Show full text]
  • Multiple Presentation of Mitochondrial Disorders Arch Dis Child: First Published As 10.1136/Adc.81.3.209 on 1 September 1999
    Arch Dis Child 1999;81:209–215 209 Multiple presentation of mitochondrial disorders Arch Dis Child: first published as 10.1136/adc.81.3.209 on 1 September 1999. Downloaded from Andreea Nissenkorn, Avraham Zeharia, Dorit Lev, Aviva Fatal-Valevski, Varda Barash, Alisa Gutman, Shaul Harel, Tally Lerman-Sagie Abstract The most severely aVected organs in mito- The aim of this study was to assess the chondrial disorders are those depending on heterogeneous clinical presentations of high rate aerobic metabolism—for example, children with mitochondrial disorders the brain, skeletal and cardiac muscle, the sen- evaluated at a metabolic neurogenetic sory organs, and the kidney.125 We aimed to clinic. The charts of 36 children with describe the great variety of symptomatology in highly suspected mitochondrial disorders patients with mitochondrial disorders in Israel, were reviewed. Thirty one children were and to compare this with the common clinical diagnosed as having a mitochondrial dis- presentations in other countries. order, based on a suggestive clinical pres- entation and at least one of the accepted Patients and methods laboratory criteria; however, in five chil- Thirty six consecutive patients (20 boys and 16 dren with no laboratory criteria the diag- girls) were evaluated at the paediatric neurol- nosis remained probable. All of the ogy clinic, Dana Children’s Hospital from patients had nervous system involvement. August 1994 to August 1996 and at the meta- Twenty seven patients also had dysfunc- bolic neurogenetic clinic, Wolfson Medical tion of other systems: sensory organs in 15 Center from September 1996 to June 1998 for patients, cardiovascular system in five, suspected mitochondrial disorders.
    [Show full text]
  • Leigh Disease Associated with a Novel Mitochondrial DNA ND5 Mutation
    European Journal of Human Genetics (2002) 10, 141 ± 144 ã 2002 Nature Publishing Group All rights reserved 1018-4813/02 $25.00 www.nature.com/ejhg SHORT REPORT Leigh disease associated with a novel mitochondrial DNA ND5 mutation Robert W Taylor*,1, Andrew AM Morris2, Michael Hutchinson3 and Douglass M Turnbull1 1Department of Neurology, The Medical School, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK; 2Department of Metabolic Medicine, Great Ormond Street Hospital, London, WC1N 3JH, UK; 3Department of Neurology, St Vincent's University Hospital, Dublin, Republic of Ireland Leigh disease is a genetically heterogeneous, neurodegenerative disorder of childhood that is caused by defects of either the nuclear or mitochondrial genome. Here, we report the molecular genetic findings in a patient with neuropathological hallmarks of Leigh disease and complex I deficiency. Direct sequencing of the seven mitochondrial DNA (mtDNA)-encoded complex I (ND) genes revealed a novel missense mutation (T12706C) in the mitochondrial ND5 gene. The mutation is predicted to change an invariant amino acid in a highly conserved transmembrane helix of the mature polypeptide and was heteroplasmic in both skeletal muscle and cultured skin fibroblasts. The association of the T12706C ND5 mutation with a specific biochemical defect involving complex I is highly suggestive of a pathogenic role for this mutation. European Journal of Human Genetics (2002) 10, 141 ± 144. DOI: 10.1038/sj/ejhg/5200773 Keywords: Leigh disease; complex I; mitochondrial DNA; mutation; heteroplasmy Introduction mutations in the tRNALeu(UUR) gene,3 and a G14459A Leigh disease is a neurodegenerative condition with a variable transition in the ND6 gene that has previously been clinical course, though it usually presents during early characterised in patients with Lebers hereditary optic childhood.
    [Show full text]
  • Neuromuscular Disorders Neurology in Practice: Series Editors: Robert A
    Neuromuscular Disorders neurology in practice: series editors: robert a. gross, department of neurology, university of rochester medical center, rochester, ny, usa jonathan w. mink, department of neurology, university of rochester medical center,rochester, ny, usa Neuromuscular Disorders edited by Rabi N. Tawil, MD Professor of Neurology University of Rochester Medical Center Rochester, NY, USA Shannon Venance, MD, PhD, FRCPCP Associate Professor of Neurology The University of Western Ontario London, Ontario, Canada A John Wiley & Sons, Ltd., Publication This edition fi rst published 2011, ® 2011 by Blackwell Publishing Ltd Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing program has been merged with Wiley’s global Scientifi c, Technical and Medical business to form Wiley-Blackwell. Registered offi ce: John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial offi ces: 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA For details of our global editorial offi ces, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell The right of the author to be identifi ed as the author of this work has been asserted in accordance with the UK Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher.
    [Show full text]
  • Consensus-Based Statements for the Management of Mitochondrial Stroke-Like Episodes[Version 1; Peer Review: 2 Approved]
    Wellcome Open Research 2019, 4:201 Last updated: 02 OCT 2020 RESEARCH ARTICLE Consensus-based statements for the management of mitochondrial stroke-like episodes [version 1; peer review: 2 approved] Yi Shiau Ng 1-3, Laurence A. Bindoff4,5, Gráinne S. Gorman1-3, Rita Horvath1,6, Thomas Klopstock7-9, Michelangelo Mancuso 10, Mika H. Martikainen 11, Robert Mcfarland 1,3,12, Victoria Nesbitt13,14, Robert D. S. Pitceathly 15,16, Andrew M. Schaefer1-3, Doug M. Turnbull1-3 1Wellcome Centre for Mitochondrial Research, Newcastle University, UK, Newcastle upon Tyne, Tyne and Wear, NE2 4HH, UK 2Directorate of Neurosciences, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, Tyne and Wear, NE1 4LP, UK 3NHS Highly Specialised Service for Rare Mitohcondrial Disorders, Royal Victoria Infirmary, Newcastle upon Tyne, UK 4Department of Clinical Medicine, University of Bergen, Bergen, Norway 5Department of Neurology, Haukeland University Hospital, Bergen, Norway 6Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK 7Department of Neurology, Friedrich-Baur-Institute, University Hospital of the Ludwig-Maximilians-Universität München, Munich, Germany 8German Center for Neurodegenerative Diseases (DZNE), Munich, Germany 9Munich Cluster for Systems Neurology (SyNergy), Munich, Germany 10Department of Clinical and Experimental Medicine, Neurological Clinic, University of Pisa, Pisa, Italy 11Division of Clinical Neurosciences, University of Turku and Turku University Hospital, Turku, Finland 12Great North Children Hospital, Newcastle
    [Show full text]
  • Understanding and Coping with Mitochondrial Disease
    From the parents’ view … When we first heard that our daughter, Alexis, was diagnosed with Mitochondrial disease, we really didn't know what it was. We also learned that not too many people had heard of it before. Our daughter had many tests performed to reach the diagnosis of Mitochondrial disease. So once we received the news we were actually glad to finally have some answers. No parent wants their child to be ill, but we have learned to accept the disease and live with it on a day to day basis. We also learned that each person with Mitochondrial disease is affected differently by it. Alexis is severely affected by the disease, so each day with her is special. Meeting other children with Mitochondrial disease and their families have become a great support for us. We can relate to their daily struggles and if we need advice, they are there for us. My advice that I would give to others affected by Mitochondrial disease is to not give up. We can all fight this disease together. The hardest part sometimes is people not knowing enough about the disease. We really need to start educating people about it. Chris and Stephanie Understanding and coping with Mitochondrial disease A guide for parents The health care team at the Neuromuscular and Neurometabolic Centre wrote this book to answer some common questions about Mitochondrial disease. We hope that you will find it helpful. During your child’s care, you will meet the members of our team. We will work closely with you and your child to meet your needs.
    [Show full text]
  • How Do We Manage Stroke-Like Episodes?
    Mitochondrial diseases in adults: how do we manage stroke-like episodes? Dr Robert Pitceathly Senior Clinical Research Associate MRC Centre for Neuromuscular Diseases UCL, London Overview • Mitochondria and mitochondrial disease • What are stroke-like episodes? • Recognition of stroke-like episodes • Management of stroke-like episodes Mitochondria and mitochondrial disease The mitochondrion mtDNA and mitochondrial diseases 0 16,569 >250 pathogenic mutations Genetics of mitochondrial disease 37 genes > 1000 genes Genes of mitochondria-localised proteins linked to human disease Koopman WJ et al. N Engl J Med 2012;366:1132-1141 Genetic variability nDNA mtDNA 13 polypeptide subunits 7/44 0/4 1/11 3/14 2/16 Clinical variability Respiratory Failure Optic Atrophy / Retinitis Pigmentosa / Cataracts Cardiomyopathy / Conduction Defects CVA / Seizures / Developmental Delay Liver / Renal Failure Deafness Short stature / Marrow Failure Peripheral Diabetes Neuropathy Hypothyroidism Myopathy Clinical variability Age of onset Neonate Infant Child Adolescent Adult Elderly Congenital Lactic LS Acidosis PMPS HCM Alpers KSS MELAS CPEO MERRF NARP Exercise intolerance Myopathy How common is Mitochondrial Disease? Minimum point prevalence (mtDNA mutations): 1, in 5,000 Overt disease due to nDNA mutations: 2.9 per 100,000 Prevalence (total): 1 in 4,300 Mutation Affected ‘At Risk’ per 100,000 (CI) LHON 3.7 (2.9-4.6) 4.4 (3.7-5.3) m.3243A>G 3.5 (2.7-4.4) 4.4 (3.7-5.3) mtDNA 1.5 (1.0-2.1) 0 deletion m.8344A>G 0.2 (0.1-0.5) 0.5 (0.2-0.8) SPG7, ar 0.8 (0.5-1.3) 1.3
    [Show full text]
  • Adult-Onset Mitochondrial Myopathy J
    Postgrad Med J: first published as 10.1136/pgmj.68.797.212 on 1 March 1992. Downloaded from Postgrad Med J (1992) 68, 212 - 215 © The Fellowship of Postgraduate Medicine, 1992 Adult-onset mitochondrial myopathy J. Fernandez-Sola, J. Casademont, J.M. Grau, F. Graus', F. Cardellach, E. Pedrol and A. Urbano-Marquez Muscle Research Group, Internal Medicine Service, and 'Department ofNeurology, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain Summary: Mitochondrial diseases are polymorphic entities which may affect many organs and systems. Skeletal muscle involvement is frequent in the context of systemic mitochondrial disease, but adult-onset pure mitochondrial myopathy appears to be rare. We report 3 patients with progressive skeletal mitochondrial myopathy starting in adult age. In all cases, the proximal myopathy was the only clinical feature. Mitochondrial pathology was confirmed by evidence of ragged-red fibres in muscle histochemistry, an abnormal mitochondrial morphology in electron microscopy and by exclusion of other underlying diseases. No deletions of mitochondrial DNA were found. We emphasize the need to look for a mitochondrial disorder in some non-specific myopathies starting in adult life. Introduction Mitochondrial diseases consist ofvarious polymor- These patients usually have proximal muscleby copyright. phic pathological entities which usually involve weakness and myalgia. Muscle atrophy of the many organs and systems. They represent a wide affected areas is frequent. The whole clinical pic- clinical, pathological and biochemical spectrum.' ture is not specific and there is a wide differential Involvement ofskeletal and ocular muscles, central diagnosis including inflammatory, toxic, neoplas- and peripheral nervous system, liver, heart, blood tic, metabolic and endocrine myopathies.
    [Show full text]
  • Migraines: Genetic Studies Pietro Cortelli Mirella Mochi and Some Practical Considerations
    J Headache Pain (2003) 4:47–56 DOI 10.1007/s10194-003-0030-0 EDITORIAL Pasquale Montagna The “typical” migraines: genetic studies Pietro Cortelli Mirella Mochi and some practical considerations Abstract Epidemiological genetic, in the inflammation cascade; etc.) family and twin studies show that the did not result in uniformely accepted typical migraines carry a substantial findings. Linkage and genome wide genetic risk; they are currently con- scans gave evidence for several ceptualized as complex genetic dis- genetic susceptibility loci, still how- ౧ P. Montagna ( ) • M. Mochi eases. Several genetic association ever in need of confirmation. Careful Department of Clinical Neurosciences, University of Bologna Medical School, and linkage studies have been per- dissection of the clinical phenotypes Via Ugo Foscolo 7, I-40123 Bologna, Italy formed in the typical migraines. and trigger factors shall greatly help e-mail: [email protected] Candidate gene studies based on “a future efforts in the quest for the Tel.: +39-051-6442179 priori” pathogenic models of genetic basis of the typical Fax: +39-051-6442165 migraine (migraine as a calcium migraines. P. Cortelli channelopathy; a mitochondrial Department of Neurology, DNA disorder; a disorder in the University of Modena and Reggio Emilia, metabolism of serotonin or Key words Migraine • Aura • Modena, Italy dopamine; in vascular risk factors or Genetics • Cardiovascular risk prove heritability, since it may result from shared envi- “Typical” migraine as a complex disease: genetic ronmental factors. It is therefore interesting to note that at epidemiology, twin and segregation analysis studies least one genetic epidemiology survey found an increased disease risk for migraine in first-degree relatives com- That migraine runs in families is an ancient observation.
    [Show full text]
  • What Are Mitochondria and Mitochondrial Disease? What Does It Mean for Dysautonomia?
    The Basics: What Are Mitochondria and Mitochondrial Disease? What Does It Mean For Dysautonomia? Richard G. Boles, M.D. Medical Director, Courtagen Life Sciences, Inc. Woburn, Massachusetts Medical Geneticist in Private Practice Pasadena, California Dysautonomia International; 18-July, 2015 Herndon, Virginia Disclosure: Dr. Boles wears many hats Dr. Boles is a consultant for Courtagen, which provides diagnostic testing. • Medical Director of Courtagen Life Sciences Inc. – Test development – Test interpretation – Marketing • Researcher with prior NIH and foundation funding – Studying sequence variation that predispose towards functional disease – Treatment protocols • Clinician treating patients – Interest in functional disease (CVS, autism) (((((((((((( ! Ri chard G. Boles, M.D. – Geneticist/pediatrician 20 years at CHLA/USC! Medical Genetics ! Pasadena, California – In private practice since 2014 ! ( ! ( Richard(G.(Boles,(MD( 1( ( July(16,(2014(( Disclosure: Off-label Indications There are no approved treatments for mitochondrial disease. Everything is “off label” Payton, 15-year-old • Presented to my clinic at age 11 years. • Cyclic vomiting syndrome from ages 1-10 years, with 2-day episodes twice a month of nausea, vomiting and lethargy. • Episodes had morphed into daily migraine. • Chronic pain throughout her body. • Chronic fatigue syndrome = chief complaint. • Substantial bowel dysmotility/IBS Multiple admissions for bowel clean-outs. • Excellent student • Pedigree: probable maternal inheritance 4 TRAP1-Related Disease (T1ReD) Mitochondrion, 2015 • NextGen sequencing at age 14 years revealed the p.Ile253Val variant in the TRAP1 gene. • TRAP1 encodes a mitochondrial chaperone involved in antioxidant defense. • This patient is one of 26 unrelated cases identified by Courtagen to date who have previously unidentified disease associated with mutations in the ATPase domain.
    [Show full text]
  • Predisposition to Infection and SIRS in Primary Mitochondrial Disorders: 8 Years’ Experience in an Academic Center
    Predisposition to infection and SIRS in primary mitochondrial disorders: 8 years’ experience in an academic center Target Audience: patients and families affected by primary mitochondrial disorders, primary care providers Melissa A. Walker MD, PhD, Katherine B. Sims MD, Jolan E. Walter MD, PhD Massachusetts General Hospital, Boston, MA Infection and Immune Function in Primary Mitochondrial Disorders • Introduction • Primary mitochondrial disorders • The immune system • Review of MGH mitochondrial patient registry (8 years’ experience) • Patients & diagnoses • Experience with • Infections • System immune response syndrome (SIRS) • Immunodysfunction • Clinical implications & future directions Primary Mitochondrial Disorders • Cause: dysfunction of the mitochondrion, the “powerhouse” organelle of the cell • Mitochondrial functions • Oxidative-phosphorylation (energy production) • Fatty acid oxidation (energy metabolism) • Apoptosis (controlled cell death) • Calcium regulation • Epidemiology • Estimated ~1:4000 individuals affected Diagnosis of Primary Mitochondrial Disorders Goal: determine the probability and possible cause of primary mitochondrial disease • Problems: • No single way to diagnose • Can affect multiple organ systems • No definitive biomarker (blood test) • Not all genes known • Phenotypic variation (same gene, different symptoms) • Heteroplasmy (unequal distribution of mitochondria & their DNA in cells) & maternal inheritance • Secondary mitochondrial dysfunction can mimic primary mitochondrial disorders Diagnosis of Primary
    [Show full text]