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Villar-Quiles, Rocio N.; Hagen, Maja von der; Metay, 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; Lutschg, Jurg; Malfatti, Edoardo; Mayer, Michele; Merlini, Luciano; Orlikowski, David; Reuner, Ulrike; Salih, Mustafa A.; Schlotter-Weigel, Beate; Stoetter, Mechthild; Straub, Volker; Topaloglu, Haluk; Urtizberea, J. Andoni; Kooi, Anneke van der; Wilichowski, Ekkehard; Romero, Norma B.; Fardeau, Michel; Bonnemann, Carsten G.; Estournet, Brigitte; Richard, Pascale; Quijano-Roy, Susana; Schara, Ulrike; Ferreiro, Ana (2020): The clinical, histologic, and genotypic spectrum ofSEPN1-related myopathy A case series. In: Neurology, Vol. 95, No. 11, E1512-E1527
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Abstract

Objective: To clarify the prevalence, long-term natural history, and severity determinants ofSEPN1-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 65SEPN1mutations, 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,SEPN1mutations, 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.