Calpainopathy in Chile, first cases reported

Limb girdle muscular dystrophy 2A (MIM#253600) is an autosomal recessive disorder caused by mutations of the CAPN3 gene, which encodes for calpain-3. We describe a series of five patients from four unrelated Chilean families harbouring CAPN3 mutations. Patients 1 to 3 were female. Current age ranged from 18 to 36 years, but symptomatic onset, mainly as lower limb weakness associated with tiptoe walking, was during the first decade in four cases. Patient 3 started at the age of 25 with a proximal-distal lower limb weakness. Patient 4 aged 21, had a history of delayed motor milestones. All presented some degree of scapular winging and Achilles tendon retraction, but hyperlordosis was patent only in females. Patients 4 and 5 showed marked generalized amyotrophy predominantly involving the thighs and the anterior arm compartment. Calf hypertrophy was present only in Patient 1 and Patient 5. Patient 5 also presented some degree of rigid spine as well as elbow and ischiotibial retractions. CK levels were increased in all cases but Patient 2 (range: 5- to 65-fold increase). Muscle biopsies showed a dystrophic pattern, with eosinophilic infiltrates in Patient 5. Neither cranial muscle involvement nor cardiac or respiratory compromise was observed in none of the patients. Whole body MRI performed on Patients 1 to 4 showed variable degrees of fatty replacement, following the pattern described for LGMD2A. Genetic screening was performed on a NGS panel of 306 genes involved in neuromuscular diseases, using HaloPlex (Agilent Technologies™) enrichment method and sequenced on the NextSeq500 (IlluminaTM) by HelixioTM (Biopôle Clermont-Limagne, France). The variant p. Arg788Serfs*14 of the CAPN3 gene (NM_000070.2) was identified for Patients 2 and 3. The novel mutation p.Gly36Valfs*21 was found in homozygous state for Patient 4 and in compound heterozygous state, associated with variants p.Arg748Gln and p.Arg788Serfs*14 for Patient 1 and 5 respectively.