G.P.51: Clinical and genetic characterization of distal myopathies

Abstract

Mutations in over 20 genes are associated with distal myopathies. Yet, many patients remain unresolved. To genetically characterize a cohort of distal myopathies we recruited patients with distal weakness and normal motor nerve conduction studies. We used next generation sequencing methods to study a panel of 277 genes that have been associated with muscle and nerve diseases plus Sanger sequencing of not well covered target regions. Sixteen patients were included. Five were characterized as Oculopharyngo-dystal myopathies (OPD) and those were studied separately. In the general group all were sporadic cases. The average age of onset was 34years old. Three patients had facial weakness, 8 had proximal weakness, in 4 the anterior compartment of lower limbs was more severely affected and 3 the posterior compartment was more affected. Muscle biopsy showed necrotic and regenerating fibres in 5 patients, vacuoles in 3, denervative features in 2, inflammation in 1 and eosinophilic aggregates in 1. Gastrocnemius was the most commonly affected muscle in the MRI. Genetic analysis showed in four patients: a known LDB3 mutation, a novel mutation in FLNC, a possible splice site mutation in FIG4 and a known mutation in SOD1. Retrospective review of this last patient confirmed a clinical diagnosis of ALS. In the OPD group, 2 patients were related. The average age of onset was 24years old. Three patients had facial involvement, 4 had ophthalmoparesis, 4 had ptosis, 3 had proximal weakness, in 2 the posterior compartment of lower legs was predominantly involved. Two patients had muscle biopsies both having rimmed vacuoles. Expansions in PABPN1 were excluded in all. One patient was found to have a mutation in MYH2, and 1 in POLG2. The other 3 remain unresolved. Genetic causes of clinically diagnosed distal myopathies are diverse, with others yet to be identified. Even in patients with no neuropathic signs neurogenic diseases are still to be considered.