학술논문
The clinical, histological, and genotypic spectrum of SEPN1-related myopathy: A case series
Document Type
Academic Journal
Author
Villar-Quiles, Rocio N; von der Hagen, Maja; Métay, Corinne; Gonzalez, Victoria; Donkervoort, Sandra; Bertini, Enrico; Castiglioni, Claudia; Chaigne, Denys; Colomer, Jaume; Cuadrado, Maria Luz; Visser, Marianne, de; Desguerre, Isabelle; Eymard, Bruno; Goemans, Nathalie; Kaindl, Angela; Lagrue, Emmanuelle; Lütschg, Jürg; Malfatti, Edoardo; Mayer, Michèle; Merlini, Luciano; Orlikowski, David; Reuner, Ulrike; Salih, Mustafa A; Schlotter-Weigel, Beate; Stoetter, Mechthild; Straub, Volker; Topaloglu, Haluk; Urtizberea, J. Andoni; van der Kooi, Anneke; Wilichowski, Ekkehard; Romero, Norma B; Fardeau, Michel; Bönnemann, Carsten G; Estournet, Brigitte; Richard, Pascale; Quijano-Roy, Susana; Schara, Ulrike; Ferreiro, Ana
Source
Neurology. Aug 12, 2020
Subject
Language
English
ISSN
0028-3878
Abstract
OBJECTIVE:: To clarify the prevalence, long-term natural history and severity determinants of SEPN1-related myopathy (SEPN1-RM), we analyzed a large international case series. METHODS:: Retrospective clinical, histological and genetic analysis of 132 pediatric and adult patients (2-58 years) followed-up for several decades. RESULTS:: The clinical phenotype was marked by severe axial muscle weakness, spinal rigidity and scoliosis (86.1%, from 8.9±4 years), with relatively-preserved limb strength and previously-unreported ophthalmoparesia in severe cases. All patients developed respiratory failure (from 10.1±6 years), 81.7% requiring ventilation while ambulant. Histopathologically, 79 muscle biopsies showed large variability, partly determined by site of biopsy and age. Multi-minicores were the most common lesion (59.5%), often associated with mild dystrophic features and occasionally with eosinophilic inclusions. Identification of 65 SEPN1 mutations, including 32 novel ones and the first pathogenic CNV, unveiled exon 1 as the main mutational hotspot and revealed the first genotype-phenotype correlations, bi-allelic null mutations being significantly associated with disease severity (p=0.017). SEPN1-RM was more severe and progressive than previously thought, leading to loss of ambulation in 10% cases, systematic functional decline from the end of the third decade and reduced lifespan even in mild cases. The main prognosis determinants were scoliosis/respiratory management, SEPN1 mutations and body mass abnormalities, which correlated with disease severity. Finally, we propose a set of severity criteria, provide quantitative data for outcome identification and establish a need for age stratification. CONCLUSION:: Our results inform clinical practice, improving diagnosis and management, and represent a major breakthrough for clinical trial readiness in this not-so-rare disease.