Bamaga, Ahmed K.

Weihl, Conrad C.

Neurology Genetics

English

PubMed

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Washington University School of MedicineDigital Commons@BeckerOpen Access Publications2017Establishing prevalence in rare neuromusculardiseases: A lesson from congenital myopathiesAhmed K. BamagaWashington University School of Medicine in St. LouisConrad C. WeihlWashington University School of Medicine in St. LouisFollow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubsThis Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in OpenAccess Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact engeszer@wustl.edu.Recommended CitationBamaga, Ahmed K. and Weihl, Conrad C., ,"Establishing prevalence in rare neuromuscular diseases: A lesson from congenitalmyopathies." Neurology: Genetics.3,2. . (2017).https://digitalcommons.wustl.edu/open_access_pubs/7158EDITORIALAhmed K. Bamaga, MDConrad C. Weihl, MD,PhDCorrespondence toDr. Weihl:weihlc@wustl.eduNeurol Genet2017;3:e146; doi: 10.1212/NXG.0000000000000146See articleEstablishing prevalence in rareneuromuscular diseasesA lesson from congenital myopathiesCongenital myopathies (CMs) are a heterogeneousgroup of early-onset muscle disorders with weakness,distinct histopathologic features, and normal toslightly elevated creatine kinase (CK).1 The age atonset and clinical severity can be variable, rangingfrom severely affected at birth to a milder later-onsetdisease.2 Cardiac involvement has been reported.3,4CMs are generally considered nonprogressive disor-ders. Three main categories are recognized withinthe classical CMs based on their typical histopathol-ogy: nemaline myopathy (NM), core myopathy, andcentronuclear myopathy (CNM). Inheritance inCMs may be dominant, recessive, or X-linked.Greater than 25 unique genetic causes of CM havebeen identified and different types of mutationswithin the same gene (e.g., deletions, duplications,missense, nonsense, splice-site, and frameshift mu-tations) have been identified, as well as de novodominant mutations.5In this issue of Neurology® Genetics, Witting et al.6report a comprehensive analysis of the prevalence,genotype, and phenotype of CM in patients 5 yearsand older in Denmark. The study was conducted atthe Copenhagen neuromuscular center, Rigshospitalet,Denmark, in collaboration with the Danish NationalRehabilitation Center for Neuromuscular Diseases.After identifying all registered Danish patients witha diagnosis of CM aged older than 5 years, compre-hensive clinical, histopathologic, and genetic investiga-tions were performed. This approach allowed fora unique prospective assessment of this patient groupthat has not been studied previously in CMs.The study found that the prevalence of CM inDanish patients older than 5 years (age range 5–69years with a mean of ;28 years) was 2:100,000;significantly lower than previous studies that esti-mated the prevalence at ;4:100,000.7,8 This maybe due to the exclusion of pediatric patients who havesuccumbed to their illness prior to age 5. This limi-tation, although acknowledged by the authors, under-represents an entire group of early-onset CMs withhigh mortality in the first few years of life. This mayalso account for the lower prevalence of MTM1mutations–carrying patients in this study.9,10The prevalence did not include patients who phe-notypically and pathologically fulfilled criteria forCM yet were found to have a genetic etiology consid-ered not to be associated with CM. Whether thispatient group was included in other studies is notentirely clear. However, 10 patients had mutationsin DES, COLVI, COLXII, DOK7, and RAPSN.These patients are interesting because some had path-ologic features of NM, core myopathy, and CNM.Notably, DES mutations were identified in onepatient with NM and another with core myopathy.Whether these genes explain undiagnosed causes ofCM in the global patient population remains to bedetermined. Notably, DES and genes associated withcongenital myasthenic syndrome are not routinelyincluded in CM gene panels. Therefore, neurologistsshould consider these etiologies in patients with CMand an unknown genetic cause.A genetic etiology was reached in 56% of DanishCM patients. This is somewhat lower than in othersimilar studies in which a genetic cause was foundin 67%–79% of patients.11,12 This may relate to theinclusion of patients without distinctive features onbiopsy, but a phenotype consistent with CM. Forexample, in patients with histopathologic featuresconsistent with NM, CNM, or core myopathy,a genetic diagnosis was identified in 83% of patients.By contrast, in patients with unspecific histopatho-logic features, the genetic diagnosis was achieved inonly 21% of patients.Another unique aspect of this study was the inclu-sion of patients with CM regardless of age. Indeed,the oldest patient was a 69-year-old woman witha DNM2 mutation. Although difficult to ascertainfrom the small cohort size, in general, older and youn-ger patients with CM demonstrated a consistent phe-notypic pattern of weakness depending on their genemutation. Moreover, older patients with CMFrom the Department of Neurology, Washington University School of Medicine, St. Louis, MO.Funding information and disclosures are provided at the end of the editorial. Go to Neurology.org/ng for full disclosure forms. The ArticleProcessing Charge for this editorial was waived at the discretion of the Editor.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CCBY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or usedcommercially without permission from the journal.Neurology.org/ng Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1continued being active in their education or work life.This supports the prevailing theory that CM is a non-progressive disorder.Studies such as that performed by Witting et al.,which define the prevalence and genetic heterogene-ity of a defined patient population, are the next stepin neuromuscular patient care. How the compositionof Danish CM patients relates to other countries oreven individual academic centers remains to be deter-mined. Research initiatives focused on the identifica-tion of novel genetic etiologies are important, butreporting the genetic makeup of existing patientpopulations is absolutely essential, as we entera new and exciting era of personalized neuromusculartherapeutics.STUDY FUNDINGNo targeted funding reported.DISCLOSUREDr. Bamaga reports no disclosures. Dr. Weihl has served on scientificadvisory board(s) for Novartis DSMB; has served on the editorialboard of Neuromuscular Disorders; and has received research supportfrom Ultragenyx Pharmaceuticals, NIH (AG031867; AG042095),Muscular Dystrophy Association, and Myositis Association. Go toNeurology.org/ng for full disclosure forms.REFERENCES1. Sewry CA,Wallgren-Pettersson C. Myopathology in congenitalmyopathies. Neuropathol Appl Neurobiol Epub 2016 Dec 15.2. North KN, Wang CH, Clarke N, et al. Approach to thediagnosis of congenital myopathies. Neuromuscul Disord2014;24:97–116.3. Agrawal PB, Pierson CR, Joshi M, et al. SPEG interactswith myotubularin, and its deficiency causes centronuclearmyopathy with dilated cardiomyopathy. Am J Hum Genet2014;95:218–226.4. Finsterer J, Stollberger C. Review of cardiac disease innemaline myopathy. Pediatr Neurol 2015;53:473–477.5. Nowak KJ, Ravenscroft G, Laing NG. Skeletal musclealpha-actin diseases (actinopathies): pathology and mech-anisms. Acta Neuropathol 2013;125:19–32.6. Witting N, Werlauff U, Duno M, Vissing J. Phenotypes,genotypes, and prevalence of congenital myopathies olderthan 5 years in Denmark. Neurol Genet 2017;3:e140. doi:10.1212/NXG.0000000000000140.7. Amburgey K, McNamara N, Bennett LR, McCormickME, Acsadi G, Dowling JJ. Prevalence of congenital myo-pathies in a representative pediatric United States popula-tion. Ann Neurol 2011;70:662–665.8. Sveen ML, Schwartz M, Vissing J. High prevalence andphenotype-genotype correlations of limb girdle musculardystrophy type 2I in Denmark. Ann Neurol 2006;59:808–815.9. Herman GE, Finegold M, de Gouyon B, Metzenberg A.Medical complications in long-term survivors with X-linked myotubular myop. J Pediatr 1999;134:206–214.10. Grogan PM, Tanner SM, Ørstavik KH, et al. Myopathywith skeletal asymmetry and hemidiaphragm elevation iscaused by myotubularin mutations. Neurology 2005;64:1638–1640.11. Maggi L, Scoto M, Cirak S, et al. Congenital myopathies—clinical features and frequency of individual subtypesdiagnosed over a 5-year period in the United Kingdom.Neuromuscul Disord 2013;23:195–205.12. Colombo I, Scoto M, Manzur AY, et al. Congenitalmyopathies: natural history of a large pediatric cohort.Neurology 2015;84:28–35.2 Neurology: Genetics

Establishing prevalence in rare neuromuscular diseases: A lesson from congenital myopathies

Ahmed K. Bamaga

Conrad C. Weihl

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Establishing prevalence in rare neuromuscular diseases

http://dx.doi.org/10.1212/NXG.0000000000000146

Establishing prevalence in rare neuromuscular diseases: A lesson from congenital myopathies

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