P.15.12 Tubular aggregate myopathy caused by a heterozygous missense mutation in STIM1

This woman, now 33 years old, was first investigated at age 14 and previously described as a case report of tubular aggregate myopathy (Tulinius MH, Lundberg A, Oldfors A. Early-onset myopathy with tubular aggregates. Pediatric Neurol 1996;15:68–71). There was no family history of neuromuscular disease. Early motor milestones were normal. She never learned to run and at four years the parents noted she had a wide-based gait. At 12 years she lost the ability to rise from the squatting position without using her hands. The muscle weakness was slowly progressive over the years and she now presents with moderate proximal muscle weakness and wasting of both upper and lower extremities. She has slight ptosis and slight dysarthria but no ophthalmoplegia. CK has been constantly elevated 7–40 times upper normal levels. Muscle biopsy at age 14 and 30 years showed type 1 fiber predominance and numerous fibers (40–90% of all fibers), both type 1 and type 2, with tubular aggregates mainly located in the centre of the fibers and widely dispersed between myofibrils. Occasional necrotic fibers were present. Mutation analysis of STIM1 (stromal interaction molecule 1, the main Ca2 + sensor of the endoplasmic reticulum) revealed that the patient was heterozygous for a dominant missense mutation c.326A > G, p. p.His109Arg. This mutation was previously reported in two siblings in the original recent report describing mutations in STIM1 associated with tubular aggregate myopathy (Bohm J, Chevessier F, Maues De Paula A, et al. Constitutive activation of the calcium sensor STIM1 causes tubular-aggregate myopathy. Am J Hum Genet 2013;92:271–8).