engleski

Clinical, genetic and epidemiological study of calpainopathy (LGMD2A) 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 cases impossible. LGMD2A, (MIM 253600) is an autosomal recessive disorder characterized mainly by symetrical and selective atrophy of the proximal limb muscles. It derives from defects in the human CANP3 gene, which encodes the skeletal muscle-specific member of the calpain family. CANP3 is a nonlysosomal cysteine protease whose biological functions remain unknown. Since october 1998 we started genetic and epidemiological study of muscular dystrophies in Croatia Specific diagnostic strategy was used to speed genetic study up .Emphasis was on: 1. Clinical assessment with CK, EMG, muscle CT, ECG ; 2.Genealogical study: Intensive search for secondary cases discovered through a detailed and systematic examination of parents, children and/or sibs, when necessary ; Search for consanguinity ; Geographical origine of parents. From the very beginning selection of families with at least two patients ; 3.Molecular diagnosis, and 4.Biopsy+ Western blot. Our attention was attracted by several male and female patients from small community in north-vestern part of Croatia affected by a muscular dystrophy similar to the description of juvenile limb-girdle muscular dystrophy of Reunion Island (Fardeau et al. Brain, 1996 ; 119:295). A detailed clinical and genealogical study of these 9 patients from six apparently non related families allowed to identify links between the different nuclear families. Molecular study of six analysed patients have revealed five homozygous patients for the mutation 551  in exon 4 of calpain 3 gene. (Canki-Klain N et al. Neuromuscular Disord 1999 ; 9/D.P.7:502-503). In addition to these 9 LGMD2A patients, we have found several LGMD2A families in which only one of mutated alleles is 551  and the other is still unknown. The second mutation identified in our population is Y537X. It is interessting to recall that of 97 distinct pathogenic calpain 3 mutations found so far in different countries (Richard I et al.Am J. Hum Genet 1999 ; 64:1524-40) 551  , the most frequent mutation by now in Croatia is found in 5o% LGMD2A patients in Turkish consanguineous families and some other Mediterranean countries. We agree with Richard et al.( Am J Hum Genet 1997 ; 60: 1128-38) that this mutation may be an old mutation because the marker haplotypes flanking the disease locus in studied families from France, Sicily and Turkey suggest a common mutational event rather than a recurrent coincidental mutation but we put hypothesis that 551  , may be specific or one of mutations of one Mediterranean country from which it was spread. In these speculations it should be noted that two mutations (551  and Y537X) identified by now in our population are found in Turkish population too. Aim of our study is to discover the exact genetic diagnosis of patients with various kinds of LGMDs because it is the precondition for appropriate treatment, accurate genetic counseling and better evaluation of symptomatic therapy. The anticipated results will help solve following problems in the field Knowledge of the mutation spectrum occurring in the CAPN3 gene may help in the design of efficient mutation-screening strategies for calpainopathies. It may also contribute significantly to structure/function and pathogenesis studies.

calpain; clinical characteristics; genetics; epidemiology; Croatia

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