NEW GENES AND DISEASES: EP.304 Early onset lower limp assymmetry: a new clinical phenotype of calsequestrin mutation

Abstract

Calsequestrin is a protein that handles calcium in sarcoplasmic reticulum (SR),Ca2+ transients are crucial in skeletal muscle excitation-contraction coupling. Synchronous Ca2+ release from the SR terminal cisternae into the cytoplasm and its reuptake into the SR store are granted by a structural and functional unit and their defect causes myopathy. In an 11-year-old girl, affected by lower limb asymmetry (R limb shorter of 3 cm), upper limb hypotrophy and winging scapulae were found; she had high CK:2900 U/l, her sister presented myalgias and CK:1500 U/l, the mother CK 500 U/l and grandmother had both congenital club foot. We investigated the causes of the high CK by EMG that was myopathic, muscle biopsy that showed few atrophic fibres, in ATPase rare 2C fibres, some increased NADH-TR stain at the periphery, increased central nuclei and rare basophilic fibres. We performed immunohistochemistry for dystrophin, caveolin-3, alpha-sarcoglycan, western blot for dysferlin: all normal. The girl was operated at 15 years for elongation of right femur and by epiphysiodesis left femur and the limb asymmetry was reduced to only half a centimeter: however she complained of fatiguability, especially after physical education at school, and high CK (2186 U). She presented with scoliosis, difficulty walking with calf hypertrophy. A search for the causes for hyperCKemia was done with WGS at TIGEM and resulted in detection of a pathogenetic variant of CASQ1 gene (p.ASP244Gly), coding for calsequestrin, which allowed the solution of this puzzling familial case. In 7 members of 4 Italian families with vacuolar myopathy with CASQ1 mutation calsequestrin aggregates and a similar variant was found. In CASQ1 myopathy in several cases hyperCKemia, myalgia or other vague symptoms are present: in 22 CASQ1-mutated patients from 12 families 21 sharing the same variant of our case presented symptoms in the sixth decade with exercise intolerance and myalgias and later developed mild to moderate, slowly progressive proximal weakness with quadriceps atrophy and scapular winging. In the present family, clubfoot, early onset, limb asymmetry were the predominant clinical symptoms, they could be the effect of somatic mosaicism. In this respect our patient presents an early onset and a new clinical phenotype of lower limb asymmetry that is unique. The present familial case expands the clinical phenotype of CASQ1-myopathy.