The clinical, histologic, and genotypic spectrum of SEPN1-related myopathy: A case series

Rocio N. Villar-Quiles, Maja von der Hagen, Corinne Métay, Victoria Gonzalez, Sandra Donkervoort, Enrico Bertini, Claudia Castiglioni, Denys Chaigne, Jaume Colomer, Maria Luz Cuadrado, Marianne de Visser, Isabelle Desguerre, Bruno Eymard, Nathalie Goemans, Angela Kaindl, Emmanuelle Lagrue, Jürg Lütschg, Edoardo Malfatti, Michèle Mayer, Luciano MerliniDavid Orlikowski, Ulrike Reuner, Mustafa A. Salih, Beate Schlotter-Weigel, Mechthild Stoetter, Volker Straub, Haluk Topaloglu, J. Andoni Urtizberea, Anneke van der Kooi, Ekkehard Wilichowski, Norma B. Romero, Michel Fardeau, Carsten G. Bönnemann, Brigitte Estournet, Pascale Richard, Susana Quijano-Roy, Ulrike Schara, Ana Ferreiro

Research output: Contribution to journalArticlepeer-review


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, histologic, 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 ophthalmoparesis 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 copy number variation, 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% of 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. 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.

Original languageEnglish
Pages (from-to)e1512-e1527
Issue number11
Publication statusPublished - Sep 15 2020

ASJC Scopus subject areas

  • Clinical Neurology


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