Tubular Aggregate Myopathy Caused by an Autosomal Dominant Mutation in ORAI 1 Gene

Case Report: A juvenile patient had contractures of the calf muscles without decrease of muscle weakness, as well as an increase in creatine kinase (1,500 U/L). In addition, more symptoms were detected: a hypocalcemia, atopy, hypohidrosis, and recurrent thrombocytopenia. Some family members had similar symptoms but in varying manifestations. The muscle biopsy revealed a myopathic pattern with numerous tubular aggregates (TA). Their mechanism of formation has not been clarified. Most likely the altered calcium homeostasis leads to abnormal structures and TA formations. TA are also observed in congenital myasthenic syndromes, periodic paralysis and various syndromes caused by STIM1 and ORAI1 mutations.

Genetics: Our patient has a heterozygote ORAI1 mutation, c.292G > A, p.Gly98Ser. The store-operated Ca²⁺ release-activated Ca²⁺ channel is activated by diminished luminal Ca²⁺ levels in the endoplasmatic and sarcoplasmic reticulum and constitutes one of the major Ca²⁺ pathways in various tissues. Recessive ORAI1 mutations are already known to cause severe immunodeficiency. Autosomal dominant mutations as in our patient cause myopathy with TA.

Conclusion: The symptoms of tubular aggregate myopathy are slow progressive muscle weakness, contractures, cramps, increase of creatine kinase and hypocalcemia. The extent to which the other symptoms of our patients and the other family members can be explained by the ORAI1 mutation is being further investigated.