A number sign (#) is used with this entry because of evidence that vacuolar myopathy with CASQ1 aggregates (VMCQA) is caused by heterozygous mutation in the CASQ1 gene (114250) on chromosome 1q23.

Vacuolar myopathy with CASQ1 aggregates is an autosomal dominant mild muscle disorder characterized by adult onset of muscle cramping and weakness as well as increased levels of serum creatine kinase (CK). The disorder is not progressive, and some patients may be asymptomatic (summary by Rossi et al., 2014).

Tomelleri et al. (2006) reported 4 unrelated patients with mild myopathic features or asymptomatic increased serum creatine kinase. One woman reported transient painful contractures in the posterior left thigh at age 56; her sister reportedly had a diagnosis of vacuolar myopathy but did not complain of neuromuscular symptoms. A 73-year-old man had a 3-year history of lower limb myalgia and muscle weakness, and an unrelated 39-year-old man reported a 3-month history of limb myalgia and fatigability. The fourth patient was a 28-year-old man who had increased serum creatine kinase but no muscular symptoms; both his asymptomatic father and son also had increased serum creatine kinase. Skeletal muscle biopsy of all patients showed multiple vacuolar spaces of different sizes within 3 to 15% of muscle fibers, most of which were type 2B. Rare necrotic and COX-negative fibers were observed. Immunohistochemistry showed that vacuolar inclusions contained SERCA1 (ATP2A1; 108730) and CASQ1, and the levels of these proteins were increased in patient muscle, suggestive of a 'surplus protein myopathy.'

Rossi et al. (2014) reported 7 individuals from 4 unrelated Italian families with a mild myopathy. One of the families (family 3) had previously been reported by Tomelleri et al. (2006). Another unrelated patient with sporadic disease was also reported. Affected individuals had adult onset of muscle cramps, myalgia, proximal muscle weakness affecting the upper and/or lower limbs, and easy fatigability. All patients had increased serum creatine kinase, but some individuals were otherwise asymptomatic. Muscle biopsy showed vacuoles predominantly in type 2 fibers, and CASQ1-immunopositive inclusions. Other findings included decreased density of calcium release units, abnormal sarcoplasmic reticulum (SR) elements, enlarged terminal cisternae of the SR, and enlarged vesicles of SR origin.

Di Blasi et al. (2015) reported 10 patients from 3 Italian families with VMCQA. The 3 probands presented as teens or young adults with increased serum CK which was sometimes associated with muscle cramps and sometimes with very mild muscle weakness or calf muscle hypertrophy. Affected family members often had no symptoms or neurologic features except for increased serum CK. Muscle biopsy performed on 6 patients showed rare necrotic fibers, variable fiber diameter, and variable proportions of fibers, mainly type II, with vacuoles containing a granular material that showed positive immunostaining for CASQ1. Patient muscle specimens showed decreased triad formation of calcium release unit and abnormal and SR terminal cisternae.

The transmission pattern of VMCQA in the families reported by Tomelleri et al. (2006) and Rossi et al. (2014) was consistent with autosomal dominant inheritance.

In 7 members of 4 Italian families and an unrelated patient with vacuolar myopathy with CASQ1 aggregates, Rossi et al. (2014) identified a heterozygous missense mutation in the CASQ1 gene (D244G; 114250.0001). Single muscle fibers from 2 patients showed reduced responsiveness of calcium release from the SR compared to control. Transfection of the mutation into COS-7 cells showed that the mutation caused impaired polymerization of CASQ1. Expression of the mutant protein in primary rat myoblasts showed that it colocalized with RYR1 (180901) at the junctional regions of the SR, as does wildtype, but it also formed large intracellular aggregates similar to those observed in patient muscle biopsies.

Di Blasi et al. (2015) identified heterozygosity for the D244G mutation in the CASQ1 gene in 10 patients from 3 unrelated Italian families with VMCQA. The mutation, which was found by a combination of exome sequencing and direct sequencing, segregated with the disorder in the families. Haplotype analysis indicated a founder effect. Cellular transfection studies showed that both wildtype and mutant proteins tended to form aggregates within the cytoplasm, with the aggregates formed by mutated CASQ1 being larger. Electrophoretic studies showed that the mutated protein did not migrate in the same way as the normal protein, suggesting that abnormal protein aggregates likely result from abnormal polymerization of the mutated CASQ1. Di Blasi et al. (2015) concluded that the mutation adversely affects muscle fiber function by forming protein aggregates and by disrupting calcium release homeostasis in the muscle fiber, which could lead to sarcomere destabilization, altered mechanotransduction and contraction, fiber necrosis, and increased plasma CK.