engleski

CLINICAL, GENETIC AND EPIDEMIOLOGICAL STUDY OF MAJOR AUTOSOMAL RECESSIVE LIMB GIRDLE MUSCULAR DYSTROPHY (LGMD2) IN CROATIA

INTRODUCTION. In September 1998 we started a genetic and epidemiological study of muscular dystrophies (MDs) in Croatia. This report concerns results obtained for LGMD2, a group of muscle diseases presenting great clinical and genetic heterogeneity making an etiologic diagnosis very difficult and clinically in majority of patients impossible. MATERIAL AND METHODS. Specific diagnostic strategy adapted to our country of 4, 4 million people was used. RESULTS. A 7-year long study showed that calpainopathy was the prevalent LGMD2. Analysis of 30 apparently unrelated families (47 patients) with calpain 3 (CAPN3) gene mutations and LGMD has discovered six different CAPN3 mutations: 550delA, R541W, P82L, delFWSAL, R49H, Y537X, accounting for 93% of CAPN3 chromosomes in the studied population. 550 delA was the most frequent mutation found on 43/60 (72%) analyzed CAPN3 chromosomes ; other five mutations ranged from 8 to 2%. In 26 families two CAPN3 alleles were identified. In remaining 4 families with only one known CAPN3 allele, 550delA was present in 3 of 4 alleles, and P82L in one. The second, most common LGMD2 seems to be type 2I caused by mutation in fukutin related protein (FKRP). Since introduction of direct analysis of C826A, a year ago, we found five unrelated families with identical C826A mutation that results in the substitution of isoleucin for leucin. Three patients from two unrelated, informative families are affected by presumed MM/LGMD2B. Haplotype analysis using microsatellites flanking the dysferlin gene and non-invasive western blot (WB) analysis of dysferlin (DYSF) gene from peripheral blood confirmed diagnosis, but mutation(s) is/are still unidentified. DISCUSSION. Surprisingly, we have identified any sarcoglycanopathy probably because of sampling bias (small no of children) and limited methodology (lack of biopsy and WB of different proteins). Because of high frequency of healthy 550delA heterozygotes (1 in 133) and relative frequency of healthy heterozygotes for C826A mutation, which is responsible for LGMD2I (1 in 524) in our general population, we need to know both allele to confirm the diagnosis of LGMD2A and 2I. CONCLUSION. To study natural history of any LGMD2 both alleles must be known as well as genetically homogenous groups should be follow up according to as simple as possible protocol.

Limb girdle muscular dystrophies; autosomal recessive; LGMD2; 2A; 2I; 2B; Croatia; clinics; genetics; epidemiology

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