EC.O.1 - Genetic and histological characterisation of excitation-contraction coupling related structural myopathy cohort

Abstract

Tubular aggregates and cylindrical spirals appear to be related entities, both arising from the sarcoplasmic reticulum, and sometimes appearing in the same biopsy. Tubular aggregates are inclusions of regular arrays of membrane tubules, while cylindrical spirals are accumulations of spiral lamellae around a central core. Although these have been reported as secondary findings in a range of conditions, some pure genetic forms of myopathy are characterised by the presence of tubular aggregates or cylindrical spirals. Tubular aggregate myopathy typically presents in childhood, causing slowly progressive weakness and cramps. Cylindrical spiral myopathy variably causes weakness, myalgia and exertional cramps, with onset in adulthood. Both diseases are dominant. The scarcity of cases impedes genetic and functional investigation. We have a cohort of two families and 10 isolated probands with tubular aggregate myopathy or cylindrical spirals. They underwent histological investigation, electron microscopy and next-generation DNA sequencing. Tubular aggregate myopathy genetic findings include known ORAI1 mutation c.G325A, p.V109M, and a novel putative STIM1 mutation c.A356G:p.D119G, and other candidate genes. Compound heterozygous TTN variants c.28654C>T, p.Q9552* and c.A15925G, p.I5309V were found in a cylindrical spiral myopathy case. The TTN missense change is predicted to affect splicing. Functional characterisation is ongoing, including mutant cell lines, cDNA analysis and fluorescence-based calcium handling assays. Here, we describe the work to date on characterising this cohort, including the histological and genetic features.