Myotonic Dystrophy
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The Genetic Background of Anticipation P Teisberg MD
JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Volume 88 April 1995 The genetic background of anticipation P Teisberg MD J R Soc Med 1995;88:185-187 Keywords: genetics; anticipation; triplet repeats; neurological disorders Anticipation was controversial impairment and increased infant mortality were observed. Anticipation may be defined as the occurrence of a genetic The sequence of events often ends in congenital MD with its disorder at progressively earlier ages in successive severe clinical manifestation of mental retardation and generations. The disease moreover occurs with increasing muscular dystrophy. Later, clinical studies confirmed these severity. The concept emerged early in this century mainly observations and described a dominant inheritance pattern through descriptive dinical studies ofmyotonic dystrophy1'2. which could not be explained by classical Mendelian Later studies have added other disease entities to a list of mechanisms8. states showing anticipation, the most notable being Another phenomenon which did not fit easily into the Huntington's disease3. In one form of inherited mental concepts of genetics was the finding that congenital MD was retardation, the fragile X syndrome, the term 'the Sherman transmitted almost exclusively via affected mothers9. paradox' describes a very similar phenomenon4. In the fragile X syndrome, anticipation is manifested in a Towards the middle of this century, basic research in different manner. This is the most common cause of familial genetics had given us a much clearer understanding of mental retardation. It segregates in families as an X-linked Mendelian inheritance. It became increasingly difficult to dominant disorder with reduced penetrance. When reconcile the originally described phenomenon of chromosomes are stained a fragile site on the X anticipation with a concept of genes as stable elements chromosome may be seen in a proportion of cells taken only changed by the rare mutation. -
Original Articles Anticipation Resulting in Elimination of the Myotonic
J7 Med Genet 1994;31:595-601 595 Original articles J Med Genet: first published as 10.1136/jmg.31.8.595 on 1 August 1994. Downloaded from Anticipation resulting in elimination of the myotonic dystrophy gene: a follow up study of one extended family C E M de Die-Smulders, C J Howeler, J F Mirandolle, H G Brunner, V Hovers, H Bruggenwirth, H J M Smeets, J P M Geraedts Abstract muscular manifestations, it is characterised by We have re-examined an extended myo- multiple systemic effects including cataract, tonic dystrophy (DM) family, previously mental retardation, cardiac involvement, and described in 1955, in order to study the testicular atrophy. Extreme variability is one of long term effects of anticipation in DM the hallmarks of the disease; clinical studies and in particular the implications for have led to the recognition of four disease types families affected by this disease. This fol- on the basis of age at onset and core symptoms: low up study provides data on 35 gene late onset (mild) type, adult onset (classical) carriers and 46 asymptomatic at risk type, childhood, and congenital type.'"3 family members in five generations. Anticipation, increasing severity and earlier Clinical anticipation, defined as the cas- age at onset in successive generations, has been cade ofmild, adult, childhood, or congen- observed in DM since the beginning of this ital disease in subsequent generations, century, but remained unexplained and contro- appeared to be a relentless process, oc- versial until recently."- With the discovery of curring in all affected branches of the an unstable CTG trinucleotide repeat in the 3' family. -
Fact Sheet 54| FRAGILE X SYNDROME This Fact Sheet
11111 Fact Sheet 54| FRAGILE X SYNDROME This fact sheet describes the condition Fragile X and includes a discussion of the symptoms, causes and available testing. In summary Fragile X is a condition caused by a change in the FMR-1 gene, on the X chromosome It is characterised by particular physical features, varying degrees of learning difficulties and behavioural and emotional problems Fragile X affects around 1 in 4,000 males and between 1 in 5,000 and 1 in 8,000 females. WHAT IS FRAGILE X SYNDROME? WHAT CAUSES FRAGILE X SYNDROME? Fragile X syndrome is the most common known Fragile X syndrome is caused by a variation in the cause of inherited intellectual disability. genetic information in the FMR-1 gene. Genes are Intellectual problems in people with fragile X made up of a string of three letter ‘words’, or syndrome can vary from mild learning difficulties triplets, using the letters A,T, C & G. The FMR-1 through to severe intellectual disability. gene codes for a protein called FMRP that is necessary for usual brain development and/or Emotional and behavioural problems may also be function. In the FMR-1 gene, the triplet word present. ‘CGG’ can be repeated many times. When the Females with fragile X syndrome show varying number of ‘CGG’ repeats in the FMR-1 gene degrees of the condition, but are usually less increases over a critical number, the gene severely affected than males. becomes so long that it becomes faulty and the production of the FMRP is disrupted. The features of the condition, and their severity, are related to the genetic information in the faulty gene causing the condition. -
This Letter Is for Families with Variant(S) in the Titin Gene, Also
This letter is for families with variant(s) in the Titin gene , also abbreviated as TTN . Changes in the Titin protein may cause muscle weakness as well as heart problems . You will need to discuss with your doctor if and how your Titin variant affects your health. What is Titin? Titin is a very large protein. It’s huge! In fact, Titin is the largest protein in the human body. The Titin protein is located in each of the individual muscle cells in our bodies. It is also found in the heart, which is a very specialized muscle. Muscles need Titin in order to work and move. You can learn more about Titin here: http://titinmyopathy.com . What is a Titin Myopathy? In medical terms, “Myo” refers to muscle and “-opathy” at the end of a word means that the word describes a medical disease or condition. So “myopathy” is a medical illness involving muscles. Myopathies result in muscle weakness and muscle fatigue. “Titin Myopathy” is a specific category of myopathy where the muscle problem is caused by a change in the Titin gene and subsequently the protein. What is a Titin-related Dystrophy? A Titin dystrophy is a muscle disorder where muscle cells break down. Dystrophies generally result in weakness that gets worse over time. A common heart problem caused by variants in the Titin gene is known as dilated cardiomyopathy. Sometimes other heart issues are also present in people with changes in their Titin gene. It is a good idea to have a checkup from a heart doctor if you have even a single variant in the Titin gene. -
The Myotonic Dystrophies: Diagnosis and Management Chris Turner,1 David Hilton-Jones2
Review J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2008.158261 on 22 February 2010. Downloaded from The myotonic dystrophies: diagnosis and management Chris Turner,1 David Hilton-Jones2 1Department of Neurology, ABSTRACT asymptomatic relatives as well as prenatal and National Hospital for Neurology There are currently two clinically and molecularly defined preimplantation diagnosis can also be performed.7 and Neurosurgery, London, UK 2Department of Clinical forms of myotonic dystrophy: (1) myotonic dystrophy Neurology, The Radcliffe type 1 (DM1), also known as ‘Steinert’s disease’; and Anticipation Infirmary, Oxford, UK (2) myotonic dystrophy type 2 (DM2), also known as DMPK alleles greater than 37 CTG repeats in length proximal myotonic myopathy. DM1 and DM2 are are unstable and may expand in length during meiosis Correspondence to progressive multisystem genetic disorders with several and mitosis. Children of a parent with DM1 may Dr C Turner, Department of Neurology, National Hospital for clinical and genetic features in common. DM1 is the most inherit repeat lengths considerably longer than those Neurology and Neurosurgery, common form of adult onset muscular dystrophy whereas present in the transmitting parent. This phenomenon Queen Square, London WC1N DM2 tends to have a milder phenotype with later onset of causes ‘anticipation’, which is the occurrence of 3BG, UK; symptoms and is rarer than DM1. This review will focus increasing disease severity and decreasing age of onset [email protected] on the clinical features, diagnosis and management of in successive generations. The presence of a larger Received 1 December 2008 DM1 and DM2 and will briefly discuss the recent repeat leads to earlier onset and more severe disease Accepted 18 December 2008 advances in the understanding of the molecular and causes the more severe phenotype of ‘congenital’ pathogenesis of these diseases with particular reference DM1 (figure 2).8 9 A child with congenital DM 1 to new treatments using gene therapy. -
X-Linked Myotubular Myopathy and Chylothorax
ARTICLE IN PRESS Neuromuscular Disorders xxx (2007) xxx–xxx www.elsevier.com/locate/nmd Case report X-linked myotubular myopathy and chylothorax Koenraad Smets * Department of Neonatology, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium Received 10 August 2007; received in revised form 4 October 2007; accepted 24 October 2007 Abstract X-linked myotubular myopathy usually presents at birth with hypotonia and respiratory distress. Phenotypic presentation, however, can be extreme variable. We report on a newborn baby, who presented with the severe form of the disease. In the second week of life, he developed a clinically relevant chylothorax, needing drainage and treatment with octreotide acetate. Pleural effusions are frequently described in patients with congenital myotonic dystrophy. To our knowledge, the association of chylothorax and X-linked myotubular myopathy has not been described to date. As chylothorax could not be attributed to any evident condition in this child, perhaps it may be added to the clinical spectrum of X-linked myotubular myopathy. Ó 2007 Elsevier B.V. All rights reserved. Keywords: X-linked myotubular myopathy; Chylothorax 1. Introduction drainage (Fig. 1). Laboratory examination was compatible with chylothorax (5230 white blood cells/ll, 98% lympho- Congenital myopathies often present with hypotonia cytes; chylomicrons were present; triglycerides 746 mg/dl). and respiratory distress from birth, although their expres- There were no central venous catheters in place who could sion may be delayed. In most cases muscle biopsy is war- have caused thrombosis, impairing lymphatic flow, neither ranted for definitive diagnosis. In some instances could any other risk factor for chylothorax be identified. -
Diverse Mechanisms of Trinucleotide Repeat Disorders: an Exploration of Fragile X Syndrome and Huntington’S Disease Cara Strobel
Undergraduate Review Volume 9 Article 30 2013 Diverse Mechanisms of Trinucleotide Repeat Disorders: An Exploration of Fragile X Syndrome and Huntington’s Disease Cara Strobel Follow this and additional works at: http://vc.bridgew.edu/undergrad_rev Part of the Cell Biology Commons Recommended Citation Strobel, Cara (2013). Diverse Mechanisms of Trinucleotide Repeat Disorders: An Exploration of Fragile X Syndrome and Huntington’s Disease. Undergraduate Review, 9, 151-156. Available at: http://vc.bridgew.edu/undergrad_rev/vol9/iss1/30 This item is available as part of Virtual Commons, the open-access institutional repository of Bridgewater State University, Bridgewater, Massachusetts. Copyright © 2013 Cara Strobel Diverse Mechanisms of Trinucleotide Repeat Disorders: An Exploration of Fragile X Syndrome and Huntington’s Disease CARA STROBEL Cara Strobel authored this essay for the Cell Biology course in the spring semester of 2012. Given free rinucleotide repeat disorders are an umbrella group of genetic diseases reign with a cell biology related topic, that have been well described clinically for a long time; however, the she wanted to explore and contrast scientific community is only beginning to understand their molecular the specifics of several prevalent basis. They are classified in two basic groups depending on the location Tof the relevant triplet repeats in a coding or a non-coding region of the genome. disorders. Cara plans to apply to Repeat expansion past a disease-specific threshold results in molecular and cellular medical school in Spring 2013. abnormalities that manifest themselves as disease symptoms. Repeat expansion is postulated to occur via slippage during DNA replication and/or transcription- mediated DNA repair. -
Skeletal Muscle Channelopathies: a Guide to Diagnosis and Management
Review Pract Neurol: first published as 10.1136/practneurol-2020-002576 on 9 February 2021. Downloaded from Skeletal muscle channelopathies: a guide to diagnosis and management Emma Matthews ,1,2 Sarah Holmes,3 Doreen Fialho2,3,4 1Atkinson- Morley ABSTRACT in the case of myotonia may be precipi- Neuromuscular Centre, St Skeletal muscle channelopathies are a group tated by sudden or initial movement, George's University Hospitals NHS Foundation Trust, London, of rare episodic genetic disorders comprising leading to falls and injury. Symptoms are UK the periodic paralyses and the non- dystrophic also exacerbated by prolonged rest, espe- 2 Department of Neuromuscular myotonias. They may cause significant morbidity, cially after preceding physical activity, and Diseases, UCL, Institute of limit vocational opportunities, be socially changes in environmental temperature.4 Neurology, London, UK 3Queen Square Centre for embarrassing, and sometimes are associated Leg muscle myotonia can cause particular Neuromuscular Diseases, with sudden cardiac death. The diagnosis is problems on public transport, with falls National Hospital for Neurology often hampered by symptoms that patients may caused by the vehicle stopping abruptly and Neurosurgery, London, UK 4Department of Clinical find difficult to describe, a normal examination or missing a destination through being Neurophysiology, King's College in the absence of symptoms, and the need unable to rise and exit quickly enough. Hospital NHS Foundation Trust, to interpret numerous tests that may be These difficulties can limit independence, London, UK normal or abnormal. However, the symptoms social activity, choice of employment Correspondence to respond very well to holistic management and (based on ability both to travel to the Dr Emma Matthews, Atkinson- pharmacological treatment, with great benefit to location and to perform certain tasks) and Morley Neuromuscular Centre, quality of life. -
Evidence-Based Guideline: Evaluation, Diagnosis, and Management Of
Evidence-based Guideline: Evaluation, Diagnosis, and Management of Facioscapulohumeral Muscular Dystrophy Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine Rabi Tawil, MD, FAAN1; John T. Kissel, MD, FAAN2; Chad Heatwole, MD, MS-CI3; Shree Pandya, PT, DPT, MS4; Gary Gronseth, MD, FAAN5; Michael Benatar, MBChB, DPhil, FAAN6 (1) MDA Neuromuscular Disease Clinic, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY (2) Department of Neurology, Wexner Medical Center, Ohio State University, Columbus, OH (3) Department of Neurology, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY (4) Department of Neurology, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY (5) Department of Neurology, University of Kansas School of Medicine, Kansas City, KS (6) Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL Correspondence to: American Academy of Neurology [email protected] 1 Approved by the Guideline Development, Dissemination, and Implementation Subcommittee on July 23, 2014; by the AAN Practice Committee on October 20, 2014; by the AANEM Board of Directors on [date]; and by the AANI Board of Directors on [date]. This guideline was endorsed by the FSH Society on December 18, 2014. 2 AUTHOR CONTRIBUTIONS Rabi Tawil: study concept and design, acquisition of data, analysis or interpretation of data, drafting/revising the manuscript, critical revision of the manuscript for important intellectual content, study supervision. John Kissel: acquisition of data, analysis or interpretation of data, critical revision of the manuscript for important intellectual content. -
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). -
Relationship Between C9orf72 Repeat Size and Clinical Phenotype
Available online at www.sciencedirect.com ScienceDirect Relationship between C9orf72 repeat size and clinical phenotype 1,2,3,4 1,2 1,2 Sara Van Mossevelde , Julie van der Zee , Marc Cruts 1,2 and Christine Van Broeckhoven Patient carriers of a C9orf72 repeat expansion exhibit Patients carrying a C9orf72 repeat expansion are remark- remarkable heterogeneous clinical and pathological able heterogeneous in clinical presentation, not only characteristics suggesting the presence of modifying factors. between families but also within families [3,4 ]. The In accordance with other repeat expansion diseases, repeat majority of the expansion carriers present clinically with length is the prime candidate as a genetic modifier. FTD and/or ALS. 73–100% of C9orf72 FTD patients Observations of earlier onset ages in younger generations of exhibit the behavioral variant (bvFTD) [5–15]. In C9orf72 large families suggested a mechanism of disease anticipation. ALS patients, the relative frequency of a bulbar symptom Yet, studies of repeat size and onset age have led to conflicting onset (29–89% [5,9,11,13,15–18]) is higher than in ALS results. Also, the correlation between repeat size and diagnosis patients without the expansion [13,16–18]. Apart from is poorly understood. We review what has been published FTD and ALS, several other clinical diagnoses have been regarding C9orf72 repeat size as modifier for phenotypic described (Figure 1) [9,19–31]. Parkinsonism is fre- characteristics. Conclusive evidence is lacking, partly due to quently reported in C9orf72 repeat expansion carriers, the difficulties in accurately defining the exact repeat size and but the expansion does not seem to be associated with the presence of repeat variability due to somatic mosaicism. -
The Natural History of Machado-Joseph Disease an Analysis of 138 Personally Examined Cases A
THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES QUEBEC COOPERATIVE STUDY OF FRIEDREICH'S ATAXIA The Natural History of Machado-Joseph Disease An analysis of 138 personally examined cases A. Barbeau, M. Roy, L. Cunha, A.N. de Vincente, R.N. Rosenberg, W.L. Nyhan, P.L. MacLeod, G. Chazot, L.B. Langston, D.M. Dawson and P. Coutinho ABSTRACT: We have examined 138 cases of a disorder previously described in people of Portuguese origin and which has received many names. By computer analysis of 46 different items of a standardized neurological examination carried out in each patient, we have been able to delineate the main components of the clinical presentation, to conclude that the marked variability in clinical expressions does not negate the homogeneity of the disorder, and to describe the natural history of this entity which should be called, for historical reasons, "Machado-Joseph Disease". This hereditary disease has an autosomal dominant pattern of inheritance, presenting as a progressive ataxia with external ophthalmoplegia, and should be classified within the group of "Ataxic multisystem degenerations". When the disease starts before the age of 20, it may present with marked spasticity, of a non progressive nature but often so severe that it can be accompanied by "Gegenhalten" countermovements and dystonic postures but little frank dystonia. There are few true extrapyramidal symptoms except akinesia. When the disease starts after the age of 50, the clinical spectrum is mostly that of an amyotrophic polyneuropathy with fasciculations accompanying the ataxia. For all the other cases the clinical picture is a c.ontinuum between these two extremes, the main determinant of the clinical phenotype being the age of onset and a secondary factor, the place of origin of the given kindred.