Current and Emerging Therapies in Becker Muscular Dystrophy (BMD)
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
Genotype–Phenotype Correlations in Duchenne and Becker Muscular Dystrophy Patients from the Canadian Neuromuscular Disease Registry
Journal of Personalized Medicine Article Genotype–Phenotype Correlations in Duchenne and Becker Muscular Dystrophy Patients from the Canadian Neuromuscular Disease Registry 1, 1, 1,2, Kenji Rowel Q. Lim y , Quynh Nguyen y and Toshifumi Yokota * 1 Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G2H7, Canada; [email protected] (K.R.Q.L.); [email protected] (Q.N.) 2 The Friends of Garrett Cumming Research & Muscular Dystrophy Canada, HM Toupin Neurological Science Research Chair, Edmonton, AB T6G2H7, Canada * Correspondence: [email protected]; Tel.: +1-780-492-1102 These authors contributed equally to this work. y Received: 29 October 2020; Accepted: 21 November 2020; Published: 23 November 2020 Abstract: Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder generally caused by out-of-frame mutations in the DMD gene. In contrast, in-frame mutations usually give rise to the milder Becker muscular dystrophy (BMD). However, this reading frame rule does not always hold true. Therefore, an understanding of the relationships between genotype and phenotype is important for informing diagnosis and disease management, as well as the development of genetic therapies. Here, we evaluated genotype–phenotype correlations in DMD and BMD patients enrolled in the Canadian Neuromuscular Disease Registry from 2012 to 2019. Data from 342 DMD and 60 BMD patients with genetic test results were analyzed. The majority of patients had deletions (71%), followed by small mutations (17%) and duplications (10%); 2% had negative results. Two deletion hotspots were identified, exons 3–20 and exons 45–55, harboring 86% of deletions. Exceptions to the reading frame rule were found in 13% of patients with deletions. -
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. -
Muscular Dystrophies and the Heart: the Emerging Role of Cardiovascular Magnetic Resonance Imaging
REVIEW Muscular dystrophies and the heart: The emerging role of cardiovascular magnetic resonance imaging Sophie Mavrogeni MD1, George Markousis-Mavrogenis MD1, Antigoni Papavasiliou MD2, Elias Gialafos MD3, Stylianos Gatzonis MD4, George Papadopoulos MD5, Genovefa Kolovou MD1 S Mavrogeni, G Markousis-Mavrogenis, A Papavasiliou, et al. hypertrophy and, potentially, evidence of myocardial necrosis, depend- Muscular dystrophies and the heart: The emerging role of ing on the type of MD. Echocardiography is a routine technique used to cardiovascular magnetic resonance imaging. Curr Res Cardiol assess left ventricular dysfunction, independent of age of onset or muta- 2015;2(2):53-62. tion. In some cases, it can also identify early, silent cardiac dysfunction. CMR is the best technique for accurate and reproducible quantification of ventricular volumes, mass and ejection fraction. CMR has docu- Muscular dystrophies (MD) constitute a group of inherited disorders, mented a pattern of epicardial fibrosis in both dystrophinopathy patients characterized by progressive skeletal muscle weakness and heart involve- and mutation carriers that can be observed even if overt muscular disease ment. Cardiac disease is common and not necessarily related to the is absent. Recently, CMR techniques, such as postcontrast myocardial T1 degree of skeletal myopathy; it may be the predominant manifestation mapping, have been used in Duchenne muscular dystrophy to detect dif- with or without any other evidence of muscular disease. Death is usually fuse myocardial fibrosis. A combined approach using clinical assessment due to ventricular dysfunction, heart block or malignant arrhythmias. and CMR evaluation may motivate early cardioprotective treatment in In addition to MD patients, female carriers may present with cardiac both patients and asymptomatic carriers, and prevent the development of involvement. -
226Th ENMC International Workshop: Towards Validated and Qualified Biomarkers for Therapy Development for Duchenne Muscular Dyst
Available online at www.sciencedirect.com ScienceDirect Neuromuscular Disorders 28 (2018) 77–86 www.elsevier.com/locate/nmd Workshop report 226th ENMC International Workshop: Towards validated and qualified biomarkers for therapy development for Duchenne muscular dystrophy 20–22 January 2017, Heemskerk, The Netherlands Annemieke Aartsma-Rus a,*, Alessandra Ferlini b,c, Elizabeth M. McNally d, Pietro Spitali a, H. Lee Sweeney e, on behalf of the workshop participants a Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands b Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Italy c Dubowitz Neuromuscular Unit, UCL, London d Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL USA e Myology Institute, Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA Received 25 July 2017 Keywords: Duchenne muscular dystrophy; Biomarker; Dystrophin; MRI; Biobank 1. Introduction therapeutic biomarkers are designed to predict or measure response to treatment [1]. Therapeutic biomarkers can indicate Twenty-three participants from 6 countries (England; whether a therapy is having an effect. This type of biomarker is Germany; Italy; Sweden, The Netherlands; USA) attended the called a pharmacodynamics biomarker and can be used to e.g. 226th ENMC workshop on Duchenne biomarkers “Towards show that a missing protein is restored after a therapy. Safety validated and qualified biomarkers for therapy development for biomarkers assess likelihood, presence, or extent of toxicity as Duchenne Muscular Dystrophy.” The meeting was a follow-up an adverse effect, e.g. through monitoring blood markers of the 204th ENMC workshop on Duchenne muscular indicative of liver or kidney damage. -
Nemaline MYOPATHY Myopathy
NEMALINENemaline MYOPATHY Myopathy due to chest muscle weakness, feeding and swallowing What is nemaline myopathy? problems, and speech difficulties. Often, children with the condition have an elongated face and a Nemaline myopathy (NM) is a group of high arched palate. rare, inherited conditions that affect muscle tone and strength. It is also What causes nemaline myopathy? The condition can be caused by a mutation in one known as rod body disease because of several different genes that are responsible for at a microscopic level, abnormal making muscle protein. Most cases of nemaline rod-shaped bodies (nemalines) can myopathy are inherited, although there are some- be seen in affected muscle tissue. times sporadic cases. People with a family history may choose to undergo genetic counseling to help At various stages in life, the muscles of understand the risks of passing the gene on to their the shoulders, upper arms, pelvis and children. thighs may be affected. Symptoms usually start anywhere from birth to What are the types of nemaline myopathy? There are two main groups of nemaline myopathy: early childhood. In rare cases, it is ‘typical’ and ‘severe.’ Typical nemaline myopathy diagnosed during adulthood. NM is the most common form, presenting usually in affects an estimated 1 in 50,000 infants with muscle weakness and floppiness. It may people -- both males and females. be slowly progressive or non progressive, and most adults are able to walk. Severe nemaline myopathy is characterized by absence of spontaneous movement What are the symptoms? or respiration at birth, and often leads to death in Symptoms vary depending on the age of onset of the first months of life. -
107Th ENMC International Workshop: the Management of Cardiac Involvement in Muscular Dystrophy and Myotonic Dystrophy
Neuromuscular Disorders 13 (2003) 166–172 www.elsevier.com/locate/nmd Workshop report 107th ENMC International Workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy. 7th–9th June 2002, Naarden, the Netherlands K. Bushby*, F. Muntoni, J.P. Bourke Department of Neuromuscular Genetics, Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK Received 1 August 2002; accepted 16 August 2002 1. Introduction symptomatic presentation [13,14]. Although evidence in these rare conditions of the effect of treatment is lacking Sixteen participants from Austria, France, Germany, [15], extrapolation from other conditions causing heart fail- Italy, the Netherlands and the UK met to discuss the cardiac ure with dilated cardiomyopathy means that there is a strong implications of the diagnosis of muscular dystrophy and case for the use of ACE inhibitors and potentially also beta myotonic dystrophy. The group included both myologists blockers, certainly in the presence of detectable abnormal- and cardiologists from nine different European centers. The ities and possibly preventatively [16–25]. aims of the workshop were to agree and report minimum The recommendations of the group are as follows. recommendations for the investigation and treatment of cardiac involvement in muscular and myotonic dystrophies, 2.1. DMD and define areas where further research is needed. During the workshop, all participants contributed to a review and † Patients should have a cardiac investigation (echo and assessment of the published evidence in each area and electrocardiogram (ECG)) at diagnosis. current practice amongst the group. Consensus statements † DMD patients should have cardiac investigations before for the management of dystrophinopathy, myotonic dystro- any surgery, every 2 years to age 10 and annually after phy, limb-girdle muscular dystrophy, Emery Dreifuss age 10. -
Clinical Exome Sequencing for Genetic Identification of Rare Mendelian Disorders
Supplementary Online Content Lee H, Deignan JL, Dorrani N, Strom SP, Kantarci S, Quintero-Rivera F, et al. Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA. doi:10.1001/jama.2014.14604. eMethods 1. Sample acquisition and pre-test sample processing eMethods 2. Exome capture and sequencing eMethods 3. Sequence data analysis eMethods 4. Variant filtration and interpretation eMethods 5. Determination of variant pathogenicity eFigure 1. UCLA Clinical Exome Sequencing (CES) workflow eFigure 2. Variant filtration workflow starting with ~21K variants across the exome and comparing the mean number of variants observed from trio-CES versus proband-CES eFigure 3. Variant classification workflow for the variants found within the primary genelist (PGL) eTable 1. Metrics used to determine the adequate quality of the sequencing test for each sample eTable 2. List of molecular diagnoses made eTable 3. List of copy number variants (CNVs) and uniparental disomy (UPD) reported and confirmatory status eTable 4. Demographic summary of 814 cases eTable 5. Molecular Diagnosis Rate of Phenotypic Subgroups by Age Group for Other Clinical Exome Sequencing References © 2014 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 This supplementary material has been provided by the authors to give readers additional information about their work. © 2014 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 eMethods 1. Sample acquisition and pre-test sample processing. Once determined by the ordering physician that the patient's presentation is clinically appropriate for CES, patients were offered the test after a counseling session ("pre-test counseling") [eFigure 1]. -
The Limb-Girdle Muscular Dystrophies and the Dystrophinopathies Review Article
Review Article 04/25/2018 on mAXWo3ZnzwrcFjDdvMDuzVysskaX4mZb8eYMgWVSPGPJOZ9l+mqFwgfuplwVY+jMyQlPQmIFeWtrhxj7jpeO+505hdQh14PDzV4LwkY42MCrzQCKIlw0d1O4YvrWMUvvHuYO4RRbviuuWR5DqyTbTk/icsrdbT0HfRYk7+ZAGvALtKGnuDXDohHaxFFu/7KNo26hIfzU/+BCy16w7w1bDw== by https://journals.lww.com/continuum from Downloaded Downloaded from Address correspondence to https://journals.lww.com/continuum Dr Stanley Jones P. Iyadurai, Ohio State University, Wexner The Limb-Girdle Medical Center, Department of Neurology, 395 W 12th Ave, Columbus, OH 43210, Muscular Dystrophies and [email protected]. Relationship Disclosure: by mAXWo3ZnzwrcFjDdvMDuzVysskaX4mZb8eYMgWVSPGPJOZ9l+mqFwgfuplwVY+jMyQlPQmIFeWtrhxj7jpeO+505hdQh14PDzV4LwkY42MCrzQCKIlw0d1O4YvrWMUvvHuYO4RRbviuuWR5DqyTbTk/icsrdbT0HfRYk7+ZAGvALtKGnuDXDohHaxFFu/7KNo26hIfzU/+BCy16w7w1bDw== Dr Iyadurai has received the Dystrophinopathies personal compensation for serving on the advisory boards of Allergan; Alnylam Stanley Jones P. Iyadurai, MSc, PhD, MD; John T. Kissel, MD, FAAN Pharmaceuticals, Inc; CSL Behring; and Pfizer, Inc. Dr Kissel has received personal ABSTRACT compensation for serving on a consulting board of AveXis, Purpose of Review: The classic approach to identifying and accurately diagnosing limb- Inc; as journal editor of Muscle girdle muscular dystrophies (LGMDs) relied heavily on phenotypic characterization and & Nerve; and as a consultant ancillary studies including muscle biopsy. Because of rapid advances in genetic sequencing for Novartis AG. Dr Kissel has received research/grant methodologies, -
Dystrophin Gene Abnormalities in Two Patients with Idiopathic Dilated Cardiomyopathy
608 Heart 1997;78:608–612 CASE STUDY Heart: first published as 10.1136/hrt.78.6.608 on 1 December 1997. Downloaded from Dystrophin gene abnormalities in two patients with idiopathic dilated cardiomyopathy Francesco Muntoni, Andrea Di Lenarda, Maurizio Porcu, Gianfranco Sinagra, Anna Mateddu, Gianni Marrosu, Alessandra Ferlini, Milena Cau, Jelena Milasin, Maria Antonietta Melis, Maria Giovanna Marrosu, Carlo Cianchetti, Antonio Sanna, Arturo Falaschi, Fulvio Camerini, Mauro Giacca, Luisa Mestroni Abstract Cardiac involvement is an integral part of Neuromuscular Unit, Two new cases of dilated cardiomyopathy DMD and BMD.4–7 In rare instances, however, Department of Paediatrics and (DC) caused by dystrophinopathy are patients can suVer from dilated cardiomyo- Neonatal Medicine, reported. One patient, a 24 year old man, pathy (DC) as the only manifestation of a dys- Hammersmith had a family history of X linked DC, while trophinopathy. This has been now recognised Hospital, London, UK the other, a 52 year old man, had sporadic in families with typical X linked DC8–11 and in F Muntoni patients with sporadic disease.12–14 Unlike A Ferlini disease. Each had abnormal dystrophin immunostaining in muscle or cardiac patients with DMD or BMD, these patients did International Centre biopsy specimens, but neither had muscle not have symptoms of muscle weakness and the for Genetic weakness. Serum creatine kinase activity only sign of neuromuscular involvement was Engineering and was raised only in the patient with familial raised serum creatine kinase (CK) activity. Biotechnology e disease. Analysis of dystrophin gene mu- Several patients had mutations clustered in the Divisione di 91112 tations showed a deletion of exons 48–49 in 5' end of the gene ; a region not aVected by Cardiologia, Ospedale mutations usually found in DMD and BMD. -
Anti-Inflammatory and General Glucocorticoid Physiology in Skeletal Muscles Affected by Duchenne Muscular Dystrophy
International Journal of Molecular Sciences Review Anti-Inflammatory and General Glucocorticoid Physiology in Skeletal Muscles Affected by Duchenne Muscular Dystrophy: Exploration of Steroid-Sparing Agents Sandrine Herbelet 1,* , Arthur Rodenbach 1 , Boel De Paepe 1,2 and Jan L. De Bleecker 1,2 1 Department of Head and Skin, Division of Neurology, Ghent University and Ghent University Hospital, C. Heymanslaan 10, 9000 Ghent, Belgium; [email protected] (A.R.); [email protected] (B.D.P.); [email protected] (J.L.D.B.) 2 Neuromuscular Reference Center, Ghent University Hospital, C. Heymanslaan 10, 9000 Ghent, Belgium * Correspondence: [email protected]; Tel.: +32-9332-89-84; Fax: +32-9332-49-71 Received: 26 May 2020; Accepted: 27 June 2020; Published: 28 June 2020 Abstract: In Duchenne muscular dystrophy (DMD), the activation of proinflammatory and metabolic cellular pathways in skeletal muscle cells is an inherent characteristic. Synthetic glucocorticoid intake counteracts the majority of these mechanisms. However, glucocorticoids induce burdensome secondary effects, including hypertension, arrhythmias, hyperglycemia, osteoporosis, weight gain, growth delay, skin thinning, cushingoid appearance, and tissue-specific glucocorticoid resistance. Hence, lowering the glucocorticoid dosage could be beneficial for DMD patients. A more profound insight into the major cellular pathways that are stabilized after synthetic glucocorticoid administration in DMD is needed when searching for the molecules able to achieve similar pathway stabilization. This review provides a concise overview of the major anti-inflammatory pathways, as well as the metabolic effects of glucocorticoids in the skeletal muscle affected in DMD. The known drugs able to stabilize these pathways, and which could potentially be combined with glucocorticoid therapy as steroid-sparing agents, are described. -
Genetic Neuromuscular Disease *
J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.73.suppl_2.ii12 on 1 December 2002. Downloaded from GENETIC NEUROMUSCULAR DISEASE Mary M Reilly, Michael G Hanna ii12* J Neurol Neurosurg Psychiatry 2002;73(Suppl II):ii12–ii21 he clinical practice of neuromuscular disease is currently undergoing enormous change as a direct result of the wealth of recent molecular genetic discoveries. Indeed, the majority of gene Tdiscoveries in the area of neurological disease relate to neuromuscular disorders. The immedi- ate impact of these discoveries is that a precise DNA based diagnosis is possible. This often gives patients accurate prognostic and genetic counselling information. It will also facilitate rational screening programmes for recognised complications such as cardiac or respiratory involvement. Unfortunately, at present many eligible patients do not benefit from or have access to such diagnostic precision, although this is changing. The discovery of new genes and proteins has opened up unexplored avenues of research into therapies for neuromuscular patients. While therapeutic trials in genetic neuromuscular diseases remain in their infancy, it seems clear that a precise DNA based diagnosis will be essential. Eligi- bility for such trials and indeed for future proven therapies will be contingent upon DNA based diagnosis. For example, it is no longer acceptable to make “limb-girdle muscular dystrophy” based on simple histochemistry, a final diagnosis. Detailed immunocytochemistry and protein chemistry in combination with DNA analysis offer the patient the best chance of a precise diagnosis from which accurate prognostication, screening, and genetic counselling will follow. In this review we describe some of the more common genetic nerve and muscle diseases encountered by adult neurologists. -
Protein Aggregate Myopathies
Review Article Protein aggregate myopathies M. C. Sharma, H. H. Goebel1 All India Institute of Medical Sciences, New Delhi, India and 1Department of Neuropathology, Johannes Gutenberg University Medical Center, Mainz, Germany Protein aggregate myopathies (PAM) are an emerging group Aggegation of proteins within muscle cells may be of lyso- of muscle diseases characterized by structural abnormali- somal or nonlysosomal nature. The former occurs, for instance, ties. Protein aggregate myopathies are marked by the ag- in the neuronal ceroid-lipofuscinoses (NCL) as components gregation of intrinsic proteins within muscle fibers and fall of lipopigments, their accretion being a morphological hall- into four major groups or conditions: (1) desmin-related mark in the NCL.[1] This lysosomal accumulation of myopathies (DRM) that include desminopathies, a-B lipopigments renders the NCL a member of the lysosomal dis- crystallinopathies, selenoproteinopathies caused by muta- orders among which type-II glycogenosis, Niemann-Pick dis- tions in the, a-B crystallin and selenoprotein N1 genes, (2) ease, mucolipidosis IV and others may affect the skeletal hereditary inclusion body myopathies, several of which have muscle. been linked to different chromosomal gene loci, but with as Nonlysosomal accumulation of proteins within muscle fibers yet unidentified protein product, (3) actinopathies marked is a hallmark of a recently emerging subgroup of myopathies, by mutations in the sarcomeric ACTA1 gene, and (4) called protein aggregate myopathies (PAM). The cause