Frequency of calpain-3 c.550delA mutation in limb girdle muscular dystrophy type 2 and isolated hyperCKemia in German patients

Calpain-3 deficiency is the most common cause of autosomal-recessive limb girdle muscular dystrophy (LGMD2). The c.550delA mutation in the CAPN3 gene was frequently identified in LGMD2A patients from Eastern Europe and is considered a Slavic founder mutation.We screened for the c.550delA mutation in unrelated German patients with LGMD2 (n = 98) and in patients with asymptomatic or minimally symptomatic (myalgia or fatigue) hyperCKemia of unknown origin (n = 102). Results of Western blot analysis were available in 75 patients with LGMD2 and 65 patients with hyperCKemia. In samples that were heterozygous for the c.550delA mutation, the whole CAPN3 gene was analyzed by sequencing in order to detect the second mutation.The c.550delA mutation was found in 8.1% of LGMD2 (n = 1 homozygous, n = 7 heterozygous) and 1.9% of hyperCKemia patients (n = 2 heterozygous). In 8 of the 9 hetrozygous patients, a second CAPN3 mutation was identified by direct sequencing. Two mutations (Val509Phe and Gln565Stop) have not been reported before. Absent or deficient calpain-3 protein in Western blot analysis was found in 22.5% of the LGMD2 patients and 11% of the patients with hyperCKemia. Western blot results were available in 9 out of the 10 patients with genetically confirmed LGMD2A and were clearly abnormal in 6 patients, suspicious in 2 and entirely normal in 1. Two LGMD2 patients with the c.550delA mutation and onset within the first 2 decades had joint contractures. Muscle biopsy revealed inflammatory changes in three patients.The CAPN3 gene mutation c.550delA is rather frequently observed in German patients with LGMD2, but also occasionally in cases with isolated hyperCKemia.