EC.O.2 - The blurred scenario of the new Calcium-related myopathies: clinical, radiological and molecular characterization of CASQ1, STIM1 and ORAI1 myopathies diagnosed in Padova neuromuscular center

Abstract

The triad is the skeletal muscle substructure responsible for excitation–contraction coupling by regulation of intracellular calcium homeostasis. A rapidly growing list of skeletal myopathies are caused by gene mutations in components of the triad (CASQ1, STIM1 and ORAI1), but the clinical and molecular features of these diseases are still largely unknown. We collected the clinical, radiological, molecular and histopathological features of patients with mutations in CASQ1, STIM1 and ORAI1 genes diagnosed at Padova neuromuscular center. Thirty patients were identified: 18 CASQ1-mutated, all but one sharing the same mutation; 10 STIM1 from a single family; 2 unrelated ORAI1. CASQ1 patients presented in the 5th decade with exercise intolerance, myalgias, rhabdomyolysis and late moderate lower limb proximal weakness. STIM1 patients presented early onset, proximal greater than distal muscle weakness and progression over time. ORAI1 patients presented exercise intolerance and myalgias. Muscle MRI of CASQ1 patients (n = 10) showed a peculiar pattern of fibro-fatty substitution (asymmetric involvement of anterior > posterior thigh and posterior leg). STIM1 patients' MRI (n = 7) showed a homogeneous pattern of substitution with a posterior-to-anterior gradient. Muscle histopathology showed in all p.Asp244Gly CASQ1 patients large optically empty vacuoles, positive to sarcoplasmic reticulum protein. STIM1 and ORAI1 patients showed typical tubular aggregates (TAs) defined histopathological. The patient presenting the novel CASQ1 mutation presented histopathological features resembling more to TA than to vascular CASQ1 pattern (NADH-positive debris). We present a large series of patients with calcium-related myopathy, caused by mutation of CASQ1, STIM1 and ORAI1. The diseases differ for clinical features (exercise intolerance vs. weakness; early vs. late onset; slow vs. rapid evolution) and histopathological pattern (TAs vs. vascular myopathy), but overlaps are frequent.