The clinical, histologic, and genotypic spectrum of SEPN1 -related myopathy

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.

Calcium and Redox Liaison: A Key Role of Selenoprotein N in Skeletal Muscle

“…Interestingly, a significant correlation between body weight and disease severity has been identified in SEPN1-RM patients. Underweight patients tend to have a moderate form of disease with preserved ambulation in adulthood, whereas the rare overweight patients reported had severe weakness of both weight-bearing and non-weight-bearing muscles, needed assisted ventilation early in childhood and lost ambulation in the second decade, confirming that alterations in BMI correlate with the phenotype of SEPN1-RM [ 6 , 13 ].…”

“…A lower percentage of the autosomal recessive forms of multi-minicore disease are due to mutations of the Selenoprotein N gene ( SEPN1/SELENON ) [ 1 , 11 ]. Different types of mutation are associated with SEPN1-related myopathy, including missense variants, small duplications/insertions, deletions, nonsense and splice mutations and also CNVs (Copy Number Variations) [ 12 , 13 , 14 ]. Recently, SEPN1 exon 1 was identified as the main mutational hotspot, and the first genotype–phenotype correlations were established, with bi-allelic null mutations significantly associated with higher disease severity [ 13 ].…”

“…In patients with SEPN1 mutations, weakness is more severe in axial (neck and trunk) muscles and is often associated with diaphragm weakness and fatigue, leading to major scoliosis and potentially lethal respiratory failure, which are phenotypical hallmarks of SEPN1-RM. Mutations in SEPN1 lead to loss of ambulation in 10% of cases and systematic functional decline from the end of the third decade [ 13 , 15 ]. SEPN1 mutations are also associated with insulin resistance and abnormal oral glucose tolerance test (OGTT) [ 16 ].…”

The Neurobiology of Selenium: Looking Back and to the Future

“…SELENON is an ER-resident membrane protein of unknown function. Mutations in SELENON that disrupt the gene or prevent selenocysteine (Sec) insertion into the protein lead to myopathy ( Villar-Quiles et al, 2020 ). Mouse and zebrafish models of SELENON-deficiency reflect aspects of the muscular phenotype, in particular the preferential affection of axial muscles ( Rederstorff et al, 2011 ).…”

Natural history, outcome measures and trial readiness in LAMA2-related muscular dystrophy and SELENON-related myopathy in children and adults: protocol of the LAST STRONG study

“…Delayed motor development is the most common presenting sign. Muscle biopsies show multi-minicores as the most common lesion, often associated with mild dystrophic features [ 2 ]. Laminin α2-related muscular dystrophy (LAMA2-MD) has a similar clinical phenotype, with an estimated prevalence of 4 in 500,000 [ 3 ].…”