Tubular aggregate myopathy with miosis caused by a novel mutation in ORAI1

We present clinical, histological, muscle imaging and molecular data from 3 patients (proband, his brother and father) of an Italian family affected by tubular aggregate myopathy (TAM). The proband was a 53 years-old woman with cramps and CK elevation. The muscle biopsy of his father, performed when he was 62 years old to investigate an asymptomatic hyperCKemia, revealed a tubular aggregate myopathy at histochemical and ultrastructural levels. The same findings were observed in the muscle biopsy of the brother at the age of 55. He had CK elevation and proximal lower limb weakness. All three patients had bilateral miosis. Muscle MRI revealed a very mild muscle involvement in the proband and his father, and a severe fatty replacement in the brother. All the patients carried a novel pathogenic mutation in ORAI1 gene, confirmed by a functional essay on patient myoblasts and HeLa cells harboring the missense mutation that proved a dysregulation of calcium homeostasis in the cells related to a gain-of-function effect of CRAC channel. Our findings expand the clinical and genetic spectrum of tubular aggregate myopathies.