Early-Onset Myopathies: Clinical Findings, Prevalence of Subgroups and Diagnostic Approach in a Single Neuromuscular Referral Center in Germany

Article type: Research Article

Authors: Vill, K.^{a; *} | Blaschek, A.^a | Gläser, D.^b | Kuhn, M.^b | Haack, T.^{c; d; g} | Alhaddad, B.^{c; d} | Wagner, M.^{c; d; e} | Kovacs-Nagy, R.^c | Tacke, M.^a | Gerstl, L.^a | Schroeder, A.S.^a | Borggraefe, I.^a | Mueller, C.^a | Schlotter-Weigel, B.^f | Schoser, B.^f | Walter, M.C.^f | Müller-Felber, W.^a

Affiliations: [a] Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Center for Neuromuscular Disorders in Childhood. Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Germany | [b] genetikum® Center for Human Genetics, Neu-Ulm, Germany | [c] Institute of Human Genetics, Technische Universität München, Munich, Germany | [d] Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany | [e] Institute für Neurogenomik, Helmholtz Zentrum München, Neuherberg, Germany | [f] Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-Universität, München, Munich, Germany | [g] Institute of Human Genetics, University of Tübingen, Germany

Correspondence: [*] Correspondence to: Dr. med. Katharina Vill, Dr. v. Haunersches Kinderspital der LMU, Lindwurmstr. 4, 80337 München, Germany. Tel.: +49 89 4400 55110; Fax: +49 89 4400 55133; E-mail: [email protected].

Abstract: Background:Early-onset myopathies are a heterogeneous group of neuromuscular diseases with broad clinical, genetic and histopathological overlap. The diagnostic approach has considerably changed since high throughput genetic methods (next generation sequencing, NGS) became available. Objective:We present diagnostic subgroups in a single neuromuscular referral center and describe an algorithm for the diagnostic work-up. Methods:The diagnostic approach of 98 index patients was retrospectively analysed. In 56 cases targeted sequencing of a known gene was performed, in 44 patients NGS was performed using large muscle specific panels, and in 12 individuals whole exome sequencing (WES) was undertaken. One patient was diagnosed via array CGH. Clinical features of all patients are provided. Results:The final diagnosis could be found in 63 out of 98 patients (64%) with molecular genetic analysis. In 55% targeted gene sequencing could establish the genetic diagnosis. However, this rate largely depended on the presence of distinct histological or clinical features. NGS (large myopathy-related panels and WES) revealed genetic diagnosis in 58.5% (52% and 67%, respectively). The genes detected by WES in our cohort of patients were all covered by the panels. Based on our findings we propose an algorithm for a practical diagnostic approach. Prevalences:MTM1- and LAMA2-patients are the two biggest subgroups, followed by SEPN1-, RYR1- and Collagen VI-related diseases. 31% of genetically confirmed cases represents a group with overlap between “congenital myopathies (CM)” and “congenital muscular dystrophies (CMD)”. In 36% of the patients a specific genetic diagnosis could not be assigned. Conclusions:A final diagnosis can be confirmed by high throughput genetic analysis in 58.5% of the cases, which is a higher rate than reported in the literature for muscle biopsy and should in many cases be considered as a first diagnostic tool. NGS cannot replace neuromuscular expertise and a close discussion with the geneticists on NGS is mandatory. Targeted candidate gene sequencing still plays a role in selected cases with highly suspicious clinical or histological features. There is a relevant clinical and genetic overlap between the entities CM and CMD.

Keywords: Congenital myopathy, congenital muscular dystrophy, early-onset myopathy, next generation sequencing, whole exome sequencing, high throughput genetic analysis, muscle biopsy, targeted candidate gene sequencing

DOI: 10.3233/JND-170231

Journal: Journal of Neuromuscular Diseases, vol. 4, no. 4, pp. 315-325, 2017