DOCSLIB.ORG

The Limb-Girdle Muscular Dystrophies and the Dystrophinopathies Review Article

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
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, several additional LGMDs have been molecularly characterized, and the funding as principal investigator diagnostic approach to these disorders has been simplified. This article summarizes the of a study from the National epidemiology, clinical features, and genetic defects underlying the LGMDs. Institutes of Health and has received funding for clinical Recent Findings: In recent years, the advent of next-generation sequencing has heralded trials from AveXis, Inc; an era of molecular diagnosis in conjunction with physical characterization. Inadvertently, AxelaCare Health Solutions, this process has also led to the ‘‘next-generation aftermath,’’ whereby variants of unknown LLC; BioMarin; CSL Behring; Cytokinetics, Inc; Ionis significance are identified in most patients. Similar to the published diagnostic and treat- Pharmaceuticals; and Quintiles, ment guidelines for Duchenne muscular dystrophy, diagnostic and treatment guidelines Inc; and receives publishing have recently been published for LGMDs. In addition, the first medication (based on the royalties from Oxford University Press. exon-skipping strategy) for treatment of patients with a subset of Duchenne muscular Unlabeled Use of dystrophy has been recently approved by the US Food and Drug Administration (FDA). Products/Investigational Summary: The LGMDs are a heterogeneous group of hereditary, progressive, and Use Disclosure: Drs Iyadurai and Kissel degenerative neuromuscular disorders that present with primary symptoms of shoulder discuss the unlabeled/ girdle and pelvic girdle weakness. Although a combination of clinical and molecular genetic investigational use of evaluations may be sufficient for accurate diagnosis of LGMDs in many cases, the corticosteroids to treat Duchenne muscular dystrophy. contribution of imaging and histopathologic correlations still remains a critical, if not a * 2016 American Academy necessary, component of evaluation in some cases. of Neurology. Continuum (Minneap Minn) 2016;22(6):1954–1977. INTRODUCTION tities (eg, Emery-Dreifuss muscular dys- The limb-girdle muscular dystrophies trophy) and with entities not necessarily (LGMDs) are a heterogeneous group of presenting in a limb-girdle pattern of genetic disorders generally characterized weakness (eg, dysferlinopathies). by weakness of the shoulder and the pelvic The dawn of molecular genetics in the girdle muscles. Based on the inheritance 1990s and, more recently, the increasing patterns, autosomal dominant (LGMD application of next-generation massive type 1), autosomal recessive (LGMD parallel-sequencing technologies have type 2), and X-linked forms of LGMD resulted in a fundamental change in how Supplemental digital content: have been described. Successive letters of these disorders are defined, identified, Videos accompanying this article are cited in the text as thealphabethavebeenusedtonamethe diagnosed, and managed. For example, Supplemental Digital Content. LGMDs according to the chronology of in the traditional approach, muscle bi- on 04/25/2018 Videos may be accessed by clicking on links provided in the identification of the genetic locus. While opsies were performed routinely on es- HTML, PDF, and app versions straightforward and convenient, this sys- sentially all patients with LGMD as part of this article; the URLs are pro- vided in the print version. Video tem has sometimes generated confusion of the characterization and diagnostic legends begin on page 1976. in regard to more traditionally named en- process. However, the lack of specificity 1954 www.ContinuumJournal.com December 2016 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS and significant overlap in biopsy find- shoulder girdle muscles, although specific h Limb-girdle muscular ings among the various LGMDs (eg, the disorders may initially manifest more dystrophies have an presence of inflammatory cells) have prominently in one region (eg, hips) com- estimated incidence of rendered this invasive technique less pared to the shoulders. With progression, 1 to 6 out of 100,000. useful and necessary in this day of readily weakness may spread outside of the h Limb-girdle muscular available genetic testing. However, some pelvic and the shoulder girdle to more dystrophies are of muscle biopsy findings are fairly charac- distal groups, the neck and axial muscles, dominant, recessive, or teristic of certain LGMDs (eg, the pres- or both. Depending on the type of LGMD, X-linked forms. ence of eosinophils in calpainopathy) and the pulmonary musculature and heart h The typical pattern of are useful diagnostic tools in some cases may also be involved. Creatine kinase weakness in limb-girdle when next-generation sequencing analysis (CK) levels may be normal, mildly elevated muscular dystrophies of a patient with LGMD fails to establish (usually in LGMD1s), or highly elevated involves the shoulder a genetic diagnosis. Similarly, ultrasound (usually in LGMD2s or X-linked LGMD) girdle and the pelvic girdle muscles, with or MRI of the muscle may be helpful in depending on the disorder. Extraocular variable involvement of providing data about the pattern of in- muscles are usually spared, as are cranial the cardiac and volved muscles and serve as a useful guide muscles, except in certain disorders where pulmonary musculature. for the appropriate muscle for biopsy or the facial muscles may be involved. h The combination of to help guide focused genetic testing. The current diagnostic approach still phenotypic evaluation, relies on careful phenotypic delineation electrodiagnostic and EPIDEMIOLOGY of the pattern of weakness, a search for muscle biopsy features, The LGMDs have a general estimated in- other associated features (eg, contractures, and gene panel testing cidence of 1 to 6 out of 100,000. How- heart involvement), distinctive EMG find- are helpful in diagnosis ever, this is likely an underestimate ings (including abnormal spontaneous of the limb-girdle muscular dystrophies. given that significant genetic, phenotypic, activity, complex repetitive discharges, h and regional variability confound these myotonic discharges), and focused genetic Contractures and figures, as do variable and incomplete testing for suspected causative gene de- scoliosis are common in limb-girdle muscular penetrance, and care access. While fects. Currently, multigene next-generation dystrophies. population-based whole-genome sequenc- panels are commercially available and ing strategies may be helpful in estimating permit testing of a large number of genes the prevalence more accurately, this in one step. For example, specific LGMD approach is currently not practical be- panels may evaluate 25 to 35 genes, or cause of the cost and labor intensiveness a general myopathy panel may evaluate of the current whole-genome sequenc- 180 genes in a single pass. Although pow- ing technologies. In the United States, erful, the process of screening multiple calpainopathy, dysferlinopathy, and genes at the same time (multigene panel dystrophinopathies are the most com- testing) for LGMDs typically results in mon forms of LGMD. identification of multiple so-called vari- ants of unknown significance. These may CLINICAL FEATURES AND include novel variants not reported in DIAGNOSIS disease or population databases, which Although the LGMDs are, by definition, in many cases are not causative. When var- congenital disorders, clinical manifesta- iants of unknown significance (either tions can begin at almost any time from single or multiple) are identified, family early childhood to late adulthood. Most of testing to establish segregation as well as the disorders, in fact, manifest in adult- additional muscle biopsy studies (such as hood with a range of presentation as immunostaining) may help establish the late as the seventies and eighties. LGMDs diagnosis, at least in some cases. While often manifest with the simultaneous intuitively and intellectually appealing, onset of
Load more

Recommended publications
  • Emery-Dreifuss Muscular Dystrophy: the Most Recognizable Laminopathy
    Review paper Emery-Dreifuss muscular dystrophy: the most recognizable laminopathy Agnieszka Madej-Pilarczyk, Andrzej Kochański Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland The authors dedicate this review to Prof. Irena Hausmanowa-Petrusewicz. Folia Neuropathol 2016; 54 (1): 1-8 DOI: 10.5114/fn.2016.58910 Abstract Emery-Dreifuss muscular dystrophy (EDMD), a rare inherited disease, is characterized clinically by humero-peroneal muscle atrophy and weakness, multijoint contractures, spine rigidity and cardiac insufficiency with conduction defects. There are at least six types of EDMD known so far, of which five have been associated with mutations in genes encoding nuclear proteins. The majority of the EDMD cases described so far are of the emerinopathy (EDMD1) kind, with a recessive X-linked mode of inheritance, or else laminopathy (EDMD2), with an autosomal dominant mode of inheritance. In the work described here, the authors have sought to describe the history by which EDMD came to be distinguished as a separate entity, as well as the clinical and genetic characteristics of the disease, the pathophysiolo- gy of lamin-related muscular diseases and, finally, therapeutic issues, prevention and ethical aspects. Key words: Emery-Dreifuss muscular dystrophy, emerin, lamin A/C, laminopathy, LMNA gene. embryo nic development [14,35]. Lamin A/C plays the Introduction role of a structural integrator in a cell nucleus, ensur- Laminopathies fall within a group of rare diseas- ing the maintenance of the latter’s shape, as well as es connected with structural/functional defects of its mechanical endurance (mechanotransduction). the proteins making up the nuclear envelope (which It takes part in regulation of the cell-division cycle, is composed of inner and outer nuclear membranes).
    [Show full text]
  • Educational Paper Ciliopathies
    Eur J Pediatr (2012) 171:1285–1300 DOI 10.1007/s00431-011-1553-z REVIEW Educational paper Ciliopathies Carsten Bergmann Received: 11 June 2011 /Accepted: 3 August 2011 /Published online: 7 September 2011 # The Author(s) 2011. This article is published with open access at Springerlink.com Abstract Cilia are antenna-like organelles found on the (NPHP) . Ivemark syndrome . Meckel syndrome (MKS) . surface of most cells. They transduce molecular signals Joubert syndrome (JBTS) . Bardet–Biedl syndrome (BBS) . and facilitate interactions between cells and their Alstrom syndrome . Short-rib polydactyly syndromes . environment. Ciliary dysfunction has been shown to Jeune syndrome (ATD) . Ellis-van Crefeld syndrome (EVC) . underlie a broad range of overlapping, clinically and Sensenbrenner syndrome . Primary ciliary dyskinesia genetically heterogeneous phenotypes, collectively (Kartagener syndrome) . von Hippel-Lindau (VHL) . termed ciliopathies. Literally, all organs can be affected. Tuberous sclerosis (TSC) . Oligogenic inheritance . Modifier. Frequent cilia-related manifestations are (poly)cystic Mutational load kidney disease, retinal degeneration, situs inversus, cardiac defects, polydactyly, other skeletal abnormalities, and defects of the central and peripheral nervous Introduction system, occurring either isolated or as part of syn- dromes. Characterization of ciliopathies and the decisive Defective cellular organelles such as mitochondria, perox- role of primary cilia in signal transduction and cell isomes, and lysosomes are well-known
    [Show full text]
  • Three New Cases of Dilated Cardiomyopathy Caused by Mutations in LMNA Gene
    Acta Myologica • 2017; XXXVI: p. 207-212 Three new cases of dilated cardiomyopathy caused by mutations in LMNA gene Larysa N. Sivitskaya1, Nina G. Danilenko1, Tatiyana G. Vaikhanskaya2, Tatsiyana V. Kurushka2 and Oleg G. Davydenko1 1 Institute of Genetics and Cytology, National Academy of Sciences of Belarus, Minsk, Belarus; 2 Republican Scientific and Practical Center of Cardiology, Minsk, Belarus Three cases of delated cardiomyopathy (DCM) with conduc- Mutations in LMNA affect lamins’ dimerization and as- tion defects (OMIM 115200), limb girdle muscular dystrophy sembly (1, 2). It apparently leads to nuclear stability loss 1B (OMIM 159001) and autosomal dominant Emery-Dreifuss and inability to perform functions in its entirety. The muscular dystrophy 2 (OMIM 181350), all associated with dif- ferent LMNA mutations are presented. Three heterozygous mutations in LMNA lead to at least 10 clinically distinct missense mutations were identified in unrelated patients – p. phenotypes, termed laminopathies, affecting different W520R (c.1558T > C), p.T528R (с.1583С > G) and p.R190P tissues including cardiac and skeletal muscle, cutane- (c.569G > C). We consider these variants as pathogenic, lead- ous, nervous and adipose tissue. There is no explicit ing to isolated DCM with conduction defects or syndromic relation between syndrome development and mutation DCM forms with limb-girdle muscular dystrophy and Emery- domain localization. A number of hot spots were de- Dreifuss muscular dystrophy. The mutations were not detected in the ethnically matched control group and publicly available scribed in LMNA, but the mutations common for lami- population databases. Their de novo occurrence led to the de- nopathies were not found.
    [Show full text]
  • Ciliopathiesneuromuscularciliopathies Disorders Disorders Ciliopathiesciliopathies
    NeuromuscularCiliopathiesNeuromuscularCiliopathies Disorders Disorders CiliopathiesCiliopathies AboutAbout EGL EGL Genet Geneticsics EGLEGL Genetics Genetics specializes specializes in ingenetic genetic diagnostic diagnostic testing, testing, with with ne nearlyarly 50 50 years years of of clinical clinical experience experience and and board-certified board-certified labor laboratoryatory directorsdirectors and and genetic genetic counselors counselors reporting reporting out out cases. cases. EGL EGL Genet Geneticsics offers offers a combineda combined 1000 1000 molecular molecular genetics, genetics, biochemical biochemical genetics,genetics, and and cytogenetics cytogenetics tests tests under under one one roof roof and and custom custom test testinging for for all all medically medically relevant relevant genes, genes, for for domestic domestic andand international international clients. clients. EquallyEqually important important to to improving improving patient patient care care through through quality quality genetic genetic testing testing is is the the contribution contribution EGL EGL Genetics Genetics makes makes back back to to thethe scientific scientific and and medical medical communities. communities. EGL EGL Genetics Genetics is is one one of of only only a afew few clinical clinical diagnostic diagnostic laboratories laboratories to to openly openly share share data data withwith the the NCBI NCBI freely freely available available public public database database ClinVar ClinVar (>35,000 (>35,000 variants variants on on >1700 >1700 genes) genes) and and is isalso also the the only only laboratory laboratory with with a a frefree oen olinnlein dea dtabtaabsaes (eE m(EVmCVlaCslas)s,s f)e, afetuatruinrgin ag vaa vraiarniatn ctl acslasisfiscifiactiaotino sne saercahrc ahn adn rde rpeoprot rrte rqeuqeuset sint tinetrefarcfaec, ew, hwichhic fha cfailcitialiteatse rsa praidp id interactiveinteractive curation curation and and reporting reporting of of variants.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • Genetic Mutations and Mechanisms in Dilated Cardiomyopathy
    Genetic mutations and mechanisms in dilated cardiomyopathy Elizabeth M. McNally, … , Jessica R. Golbus, Megan J. Puckelwartz J Clin Invest. 2013;123(1):19-26. https://doi.org/10.1172/JCI62862. Review Series Genetic mutations account for a significant percentage of cardiomyopathies, which are a leading cause of congestive heart failure. In hypertrophic cardiomyopathy (HCM), cardiac output is limited by the thickened myocardium through impaired filling and outflow. Mutations in the genes encoding the thick filament components myosin heavy chain and myosin binding protein C (MYH7 and MYBPC3) together explain 75% of inherited HCMs, leading to the observation that HCM is a disease of the sarcomere. Many mutations are “private” or rare variants, often unique to families. In contrast, dilated cardiomyopathy (DCM) is far more genetically heterogeneous, with mutations in genes encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium-handling proteins. DCM is characterized by enlarged ventricular dimensions and impaired systolic and diastolic function. Private mutations account for most DCMs, with few hotspots or recurring mutations. More than 50 single genes are linked to inherited DCM, including many genes that also link to HCM. Relatively few clinical clues guide the diagnosis of inherited DCM, but emerging evidence supports the use of genetic testing to identify those patients at risk for faster disease progression, congestive heart failure, and arrhythmia. Find the latest version: https://jci.me/62862/pdf Review series Genetic mutations and mechanisms in dilated cardiomyopathy Elizabeth M. McNally, Jessica R. Golbus, and Megan J. Puckelwartz Department of Human Genetics, University of Chicago, Chicago, Illinois, USA. Genetic mutations account for a significant percentage of cardiomyopathies, which are a leading cause of conges- tive heart failure.
    [Show full text]
  • Ciliopathies Gene Panel
    Ciliopathies Gene Panel Contact details Introduction Molecular Genetics Service The ciliopathies are a heterogeneous group of conditions with considerable phenotypic overlap. Level 6, Barclay House These inherited diseases are caused by defects in cilia; hair-like projections present on most 37 Queen Square cells, with roles in key human developmental processes via their motility and signalling functions. Ciliopathies are often lethal and multiple organ systems are affected. Ciliopathies are London, WC1N 3BH united in being genetically heterogeneous conditions and the different subtypes can share T +44 (0) 20 7762 6888 many clinical features, predominantly cystic kidney disease, but also retinal, respiratory, F +44 (0) 20 7813 8578 skeletal, hepatic and neurological defects in addition to metabolic defects, laterality defects and polydactyly. Their clinical variability can make ciliopathies hard to recognise, reflecting the ubiquity of cilia. Gene panels currently offer the best solution to tackling mutational analysis of Samples required genetically heterogeneous conditions such as the ciliopathies. Ciliopathies affect approximately 5ml venous blood in plastic EDTA 1:2,000 births. bottles (>1ml from neonates) Ciliopathies are generally inherited in an autosomal recessive manner, with some autosomal Prenatal testing must be arranged dominant and X-linked exceptions. in advance, through a Clinical Genetics department if possible. Referrals Amniotic fluid or CV samples Patients presenting with a ciliopathy; due to the phenotypic variability this could be a diverse set should be sent to Cytogenetics for of features. For guidance contact the laboratory or Dr Hannah Mitchison dissecting and culturing, with ([email protected]) / Prof Phil Beales ([email protected]) instructions to forward the sample to the Regional Molecular Genetics Referrals will be accepted from clinical geneticists and consultants in nephrology, metabolic, laboratory for analysis respiratory and retinal diseases.
    [Show full text]
  • 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.
    [Show full text]
  • Current and Emerging Therapies in Becker Muscular Dystrophy (BMD)
    Acta Myologica • 2019; XXXVIII: p. 172-179 OPEN ACCESS © Gaetano Conte Academy - Mediterranean Society of Myology Current and emerging therapies in Becker muscular dystrophy (BMD) Corrado Angelini, Roberta Marozzo and Valentina Pegoraro Neuromuscular Center, IRCCS San Camillo Hospital, Venice, Italy Becker muscular dystrophy (BMD) has onset usually in child- tients with a deletion in the dystrophin gene that have nor- hood, frequently by 11 years. BMD can present in several ways mal muscle strength and endurance, but present high CK, such as waddling gait, exercise related cramps with or with- and so far their follow-up and treatment recommenda- out myoglobinuria. Rarely cardiomyopathy might be the pre- senting feature. The evolution is variable. BMD is caused by tions are still a matter of debate. Patients with early cardi- dystrophin deficiency due to inframe deletions, mutations or omyopathy are also a possible variant of BMD (4, 5) and duplications in dystrophin gene (Xp21.2) We review here the may be susceptible either to specific drug therapy and/or evolution and current therapy presenting a personal series of to cardiac transplantation (6-8). Here we cover emerging cases followed for over two decades, with multifactorial treat- therapies considering follow-up, and exemplifying some ment regimen. Early treatment includes steroid treatment that phenotypes and treatments by a few study cases. has been analized and personalized for each case. Early treat- ment of cardiomyopathy with ACE inhibitors is recommended and referral for cardiac transplantation is appropriate in severe cases. Management includes multidisciplinary care with physi- Pathophysiology and rationale of otherapy to reduce joint contractures and prolong walking.
    [Show full text]
  • S41467-020-18249-3.Pdf
    ARTICLE https://doi.org/10.1038/s41467-020-18249-3 OPEN Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain Lei Zhao1,2,17, Zhongqi Li 1,2,17, Joaquim S. L. Vong2,3,17, Xinyi Chen1,2, Hei-Ming Lai1,2,4,5,6, Leo Y. C. Yan1,2, Junzhe Huang1,2, Samuel K. H. Sy1,2,7, Xiaoyu Tian 8, Yu Huang 8, Ho Yin Edwin Chan5,9, Hon-Cheong So6,8, ✉ ✉ Wai-Lung Ng 10, Yamei Tang11, Wei-Jye Lin12,13, Vincent C. T. Mok1,5,6,14,15 &HoKo 1,2,4,5,6,8,14,16 1234567890():,; The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovas- cular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation- dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which pro- minently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood–brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed tran- scriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible.
    [Show full text]
  • Profilin-1 Is Required for Survival of Adult Hematopoietic Stem Cells
    Extended methods Immunohistochemistry HepG-2, SMMC-7721, and 293T cells were obtained from Cell Resource Center of Shanghai Institute for Biological Science, Chinese Academy Science, Shanghai, China. HUVEC cells were kindly provided by Prof. Ping-Jin Gao at Institute of Health Sciences (Shanghai, China). All these cell lines were cultured in DMEM with 10% FBS. MDA- MB-231 cell line was kindly provided by Prof. Ming-Yao Liu (East China Normal University, Shanghai, China) and was cultured in Leibovitz L-15 medium with 10% FBS. All these cell lines were originally purchased from ATCC. MDA-MB-231, SMMC-7721 or HepG2 cells were grown on coverslips in 24-well plates and fixed in either 4% paraformaldehyde or pre-chilled methanol (-20°C) for 10 min. In some cases, WT or VPS33B-null Lin-Sca-1+c-Kit+Flk2-CD34- LT-HSCs were collected by flow cytometry and fixed for immunofluorescence staining. Cells were then blocked with 3% BSA in PBS for 60 min followed by incubation with primary antibodies overnight. The antibodies used were anti-HA (Sigma), anti-Flag (Sigma), anti-VPS33B (Sigma), anti- VPS16B (Abcam), anti-GDI2 (Proteintech), anti-LAMP1 (Proteintech), anti-FLOT1 (Abways), anti-CD63 (Proteintech), anti-ANGPTL2 (R&D system), anti-ANGPTL3 (R&D system), anti-TPO (Abways), anti-GLUT1 (Proteintech), anti-LDHA (Proteintech), anti-PKM2 (CST), anti-RAB11A (Abways), anti-RAB27A (Abways) and anti-V5 (Biodragon). Fluorescent-conjugated secondary antibodies (Alexa Fluor® 488 or Alexa Fluor® 555) against mouse, rabbit, or goat were obtained from the Thermo Scientific Inc. The details for all the antibodies are listed in Table S3.
    [Show full text]