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Data from: The clinical, histological, and genotypic spectrum of SEPN1-related myopathy: A case series

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Nov 05, 2020 version files 16.13 KB

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.