engleski

Clinical, genetic and epidemiological study of prevalent autosomal recessive limb girdle muscular dystrophies (LGMD2) in Croatia

Autosomal recessive limb-girdle muscular dystrophies (LGMD2) form a group of muscle diseases presenting great clinical and genetic heterogeneity making an etiologic diagnosis very difficult and clinically in majority of patients impossible. Here we report results concerning LGMD2 obtained during 10-years long prospective study on clinical, genetic and epidemiological aspects of muscular dystrophies (MDs) in Croatia. Specific diagnostic strategy was used to speed genetic study up. Emphasis was on: 1.Clinical assessment with CK, EMG ; muscle CT or IRM and ECG ; 2. Genealogical study with intensive search for secondary cases discovered through a detailed and systematic examination of parents, children and/ or sibs, when necessary ; Search for consanguinity ; Geografical origine of parents. From the very beginning selection of families with at least two patients ; 3. Indirect or direct molecular analysis. The study showed that calpainopathy (LGMD2A) was the prevalent LGMD2. Analysis of 36 apparently unrelated families with 52 patients discovered eight different CAPN3 mutations: 550delA, R541W, P82L, delFWSAL, R49H, Y537X, 2242C>T and 1696G>A including 95% of CAPN3 chromosomes in the studied population. 550delA was the most frequent mutation found on 53/72 (73, 3%) chromosomes. Other seven mutations ranged from 8, 3% to 1, and 3%. In 33 of 36 families, two CAPN3 alleles were identified. In remaining 3 families with only one known CAPN3 allele, 550delA was present in 2 of 6, and P82L in one of alleles. The second, most common LGMD2 seems to be type 2I caused by mutation in FKRP. Direct analysis of only one mutation (C826A) allowed us to identify six unrelated families. One of six homozygous C826A probands was in addition heterozygote for 550delA. Dysferlinopathy was found in three patients from two unrelated, informative families. Diagnosis was based on clinical features (LGMD2B / MM), haplotype analysis and non¬invasive monocyte Western blotting. Molecular analysis finally confirmed diagnosis discovering two novel DYSF mutations. Surprisingly, we haven't identified any sarcoglycanopathy, probably because of sampling bias (small number of children) and limited methodology (lack of muscle biopsy and WB of different proteins). Because of high frequency of healthy 550delA heterozygotes (1 in 133) and C826A heterozygotes (1 in 404) in our general population, we need to know both allele to confirm the diagnosis of LGMD type 2A and 2I. In conclusion knowledge of the mutation spectrum occurring in the CAPN3 should help in the design of efficient mutation-screening strategies for calpainopathies in our country. Concerning study of natural history of any LGMD2, both alleles should be known. Moreover, the follow up of genetically homogenous patients' groups using well defined, but as simple as possible protocols would be advisable. Keywords: LGMD2, clinical characteristics, genetics, epidemiology, Croatia Supported in part by Ministry of Science and Technology Republic of Croatia research grand 108-0000000-3435

LGMD2; clinical characteristics; genetics; epidemiology;

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