A number sign (#) is used with this entry because of evidence that tubular aggregate myopathy-2 (TAM2) is caused by heterozygous mutation in the ORAI1 gene (610277) on chromosome 12q24.

For a discussion of genetic heterogeneity of TAM, see TAM1 (160565).

Shahrizaila et al. (2004) reported a family in which a mother and her 3 children had myopathy with tubular aggregates associated with pupillary abnormalities. The mother and 2 sons had late adult-onset mild proximal muscle weakness with increased serum creatine kinase and areflexia of the lower limbs; the daughter denied muscle weakness but was found to have increased serum creatine kinase and areflexia of the lower limbs. Quadriceps muscle biopsies of the 2 affected sons showed endomysial fibrosis, fatty infiltration, abnormal fiber size variation with atrophic muscle fibers, and tubular aggregates mainly in type 1 fibers. Electron microscopy of 1 son showed that the aggregates contained granular electron-dense material consistent with dilated elements of the sarcoplasmic reticulum. Pupillary abnormalities included decreased night vision and pupillary miosis.

Endo et al. (2015) reported 6 patients from 3 unrelated Japanese families with TAM2. The patients had onset in childhood or adolescence of slowly progressive diffuse muscle weakness affecting the lower limbs and resulting in foot drop or frequent falls. All patients remained ambulant, including 2 patients in their forties, although many required orthopedic shoes. Additional features included positive Gowers sign, severe ankle contractures, rigid spine, and mild hypocalcemia. None had facial involvement. Skeletal muscle biopsy showed tubular aggregates that immunostained with ORAI1, STIM1 (605921), and markers of the sarcoplasmic reticulum. Electron microscopy showed that the aggregates were composed of numerous double-walled straight tubules aligned in parallel and arranged in a honeycomb-like pattern. Biopsies also showed dystrophic changes with regenerating fibers, increased internal nuclei, fiber size variation, and type 1 fiber predominance. A mother and son in 1 family showed brain calcifications and mild intellectual disability, respectively, which may not have been related to the muscular phenotype.

Garibaldi et al. (2017) reported an Italian father and his 2 adult children with TAM2. The patients presented in their fifties or sixties with increased serum creatine kinase. Additional symptoms were subtle and variable, ranging from muscle cramps during physical exertion in 1 patient, to muscle weakness affecting the upper and lower limbs in the other 2 patients. Muscle weakness was most significant in the proximal legs, resulting in difficulty climbing stairs in 1 patient. However, on examination, both the father and son had mild weakness of the neck flexors and abdominal muscles, as well as distal muscle weakness of the hands and ankles associated with mild tendon retractions. The patients underwent entire body MRI analysis, which revealed a pattern of abnormalities that correlated with the clinical symptoms: the lower limbs were more severely affected than the shoulder girdle muscles, and certain muscles of the thighs showed more fatty replacement than elsewhere in the legs. Muscle biopsy from 2 patients showed tubular aggregates in type 2 muscle fibers. Ultrastructural studies showed tubules were arranged in honeycomb-like structures and often composed of coaxial double-walled membrane; the inner central tubule was sometimes duplicated or multiplied within a larger single tubule. The patients also had miosis without ptosis or ophthalmoplegia. None had visual impairment or cardiac or respiratory involvement.

The transmission pattern of tubular aggregate myopathy with miosis in the family reported by Shahrizaila et al. (2004) was consistent with autosomal dominant inheritance.

In affected members of the family reported by Shahrizaila et al. (2004), Nesin et al. (2014) identified a heterozygous mutation in the ORAI1 gene (P245L; 610277.0002). The mutation was found by whole-exome sequencing. In vitro functional expression assays showed that the mutation suppressed slow calcium-dependent inactivation of ORAI1, consistent with a gain-of-function effect. Nesin et al. (2014) postulated that disordered and sustained calcium entry over long periods of time results in an environment in the sarcoplasmic reticulum that is hostile to protein folding, thus initiating the formation of tubular aggregates. The pathogenic mechanism was similar to that caused by STIM1 (605921) mutations in patients with TAM1.

In 6 patients from 3 unrelated Japanese families with TAM2, Endo et al. (2015) identified 2 different heterozygous missense mutations in the ORAI1 gene (G98S, 610277.0003 and L138F, 610277.0004). Patient-derived myotubes and HEK293 cells transfected with the mutations showed constitutive activation of store-operated calcium release-activated calcium (CRAC) channels independent of either calcium stores or STIM1 activation. The mutation in the first 2 families was found by whole-exome sequencing.

In a father and his 2 adult children, of Italian descent, with TAM2, Garibaldi et al. (2017) identified a heterozygous missense mutation in the ORAI1 gene (S97C; 610277.0008). In vitro functional expression studies in HEK293 cells showed that the variant resulted in increased rate of calcium entry, consistent with constitutive activation of the CRAC channel and a gain-of-function effect. Myotubes derived from 1 of the patients showed a similar increase in calcium entry and increased spontaneous oscillations compared to controls.