Abstract
Autosomal-recessive mutations of the SEPN1 (SELENON) gene cause SEPN1-related myopathy (SEPN1-RM). Patients present with early-onset severe axial weakness, scoliosis, spinal rigidity and life-threatening respiratory insufficiency, contrasting with fairly preserved limb strength and ambulation. SEPN1-RM natural history is poorly documented, hindering the implementation of clinical trials. We analyzed retrospectively the largest series of SEPN1-RM patients so far. We included patients aged 2-59 years, thus revealing disease evolution in late adulthood. First symptoms appeared within the first two years in 84.69% of cases (mean 18.2±29.8months) and were mostly neonatal hypotonia, poor head control and delayed motor milestones. Scoliosis was present in 86.1% patients from 8.9±4years; 36.8% required arthrodesis. All patients developed restrictive respiratory failure from the age of 10.1±6.2years and 81.7% required assisted ventilation from 14.7±8.9years while fully ambulant. Polysomnography detected nocturnal hypoventilation and frequent apneas in 92.9% of patients from early ages. Loss of ambulation occurred in 8 patients (8-54 years). Strikingly, we found a significant correlation between body weight and disease severity (p 0.02). While most patients were underweight (<4th percentile) and mean BMI in adults was 16.9±4, the most severe patients with early loss of ambulation and rapidly progressive respiratory failure were overweight with trunk fat accumulation. From the molecular point of view, we found 64 different SELENON mutations and we identified Exon 1 as a hot spot. We also describe the first genotype-phenotype correlations in SEPN1-RM. Homozygous mutations leading to protein absence were significantly associated with more severe forms (p 0.003). Our results improve understanding of the SEPN1-RM phenotype and natural history, contribute to improve diagnosis, management and follow-up and pave the way towards clinical trial readiness.
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