The clinical, histologic, and genotypic spectrum of SEPN1-related myopathy: A case series.
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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, de Visser Marianne, 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
Аннотация
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.