engleski

The impact of molecular diagnosis on management and counselling in major inherited neuromuscular disorders

A rapid increase in our understanding of the molecular mechanisms behind many of debilitating disorders is largely due to advances in recombinant DNA technology since 1980s and early 1990s. The discovery of dystrophin gene and its defective protein in Duchenne and Becker muscular dystrophy (DMD/BMD) was crucial in two ways: 1) it showed the potency of positional cloning's strategy and gave 2) the new tool for diagnosis - protein analysis (primary or secondary reduction of proteins directly or indirectly associated with dystrophin). Combined genetic and protein analysis represent the new tools for diagnosis ; allow carrier testing and prenatal diagnosis if required. Application of these tools has discovered a big genetic heterogeneity of many muscle and nerve disorders. Considerable clinical heterogeneity can be explained by the occurrence of different mutations at a single locus. With detailed molecular information, it becomes clear that many, if not most, patients with autosomal recessive disorders are phenotypic homozygotes but are compound heterozygotes. Incidence of different neuromuscular disorders may vary, especially in inbred populations. As stated before major heterogeneity is encountered in many groups of muscle and nerve diseases, and here fairly complex investigations may be necessary to provide a precise diagnosis before any genetic counselling can be provided. Therefore the rational diagnostic approach to these disorders should be multidisciplinary with expertise in interpretation of complex diagnostic process. Here we present results of this approach and specific diagnostic strategy applied on 8-year long prospective study of genetics and epidemiology of muscular dystrophies in Croatia.

neuromuscular disorders; clinical characteristics; genetic heterogeneity; molecular diagnosis; counselling; Croatia

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