%0 Journal Article
%T The clinical, histologic, and genotypic spectrum of SEPN1-related myopathy: A case series.
%A Villar-Quiles RN
%A von der Hagen M
%A Métay C
%A Gonzalez V
%A Donkervoort S
%A Bertini E
%A Castiglioni C
%A Chaigne D
%A Colomer J
%A Cuadrado ML
%A de Visser M
%A Desguerre I
%A Eymard B
%A Goemans N
%A Kaindl A
%A Lagrue E
%A Lütschg J
%A Malfatti E
%A Mayer M
%A Merlini L
%A Orlikowski D
%A Reuner U
%A Salih MA
%A Schlotter-Weigel B
%A Stoetter M
%A Straub V
%A Topaloglu H
%A Urtizberea JA
%A van der Kooi A
%A Wilichowski E
%A Romero NB
%A Fardeau M
%A Bönnemann CG
%A Estournet B
%A Richard P
%A Quijano-Roy S
%A Schara U
%A Ferreiro A
%J Neurology
%V 95
%N 11
%D 09 2020 15
%M 32796131
%F 11.8
%R 10.1212/WNL.0000000000010327
%X To clarify the prevalence, long-term natural history, and severity determinants of SEPN1-related myopathy (SEPN1-RM), we analyzed a large international case series.<BR>Retrospective clinical, histologic, and genetic analysis of 132 pediatric and adult patients (2-58 years) followed up for several decades.<BR>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.<BR>Our results inform clinical practice, improving diagnosis and management, and represent a major breakthrough for clinical trial readiness in this not so rare disease.