P158 Heterozygous SPTAN1 frameshift mutations cause distal myopathy with neurogenic features
Résumé
Spectrinopathies represent an emerging theme with overlapping phenotypes ranging from peripheral or central nervous system involvement towards complex syndromic presentations. A total of 60 different reported SPTAN1 mutations is exemplary for this diversity with phenotypes spanning almost the entire neurospectrinopathy spectrum, except myopathic involvement. Through collaboration within the Solve-RD network we identified patients with unsolved progressive distal weakness and unreported SPTAN1 variants. We reached consensus on the interpretation of clinical picture, electrophysiology, muscle MRI and biopsy. Finally, SPTAN1 protein and RNA expression analysis was performed on available muscle biopsy from one of the patients. In total seven index patients, carrying heterozygous SPTAN1 frameshift variants, were included. Three showed autosomal dominant inheritance, three were sporadic and one de novo. All index patients showed early childhood (2-10 years) onset of foot dorsiflexion weakness. Some patients showed distal upper limb weakness (n=4), scoliosis (n=2) and intellectual disability (ID) (n=1). Electrophysiology showed mixed myogenic and neurogenic features. Muscle MRI (n=4) and muscle CT (n=1) showed fatty infiltration of the distal lower limb anterior compartment and/or involvement of the extensor hallucis longus muscle. Muscle biopsy showed dystrophic changes with signs of chronic denervation in three patients. We found proof of a normal protein expression but 40% reduction in SPTAN1 mRNA levels in one patient. We provide evidence for the association of SPTAN1 frameshift variants with childhood onset distal myopathic as well as neurogenic features in seven patients. This finding further extends the established spectrum of SPTAN1 haploinsufficiency associated with a variable penetrance of hereditary motor neuropathy and ID. Overlap between distal myopathic and neurogenic features could be present in other patients and may be overlooked due to phenotypic similarity.