engleski

The impact of molecular diagnosis on managementand counselling in majorinherited neuromuscular disorders

Individual single gene unifactorial or Mendelian muscle or nerve disorders are not common but as a group they account for a significant burden of disability in a generally younger age group than affected by other neurological diseases. Our inability to treat these disorders effectively combined with their seriousness makes preventing any recurrence of them very important. For this reason it is necessary to know their exact genetic cause. This talk aims to summarise the role of clinical genetic practice in the management of the major single gene neurological diseases, and is illustrated by own experience from Croatia. A rapid increase in our understanding of the molecular mechanisms behind many of these 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 (previously known as "reverse genetics") in cloning of genes, and 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 neuromuscular disorders. Genetic heterogeneity may result from the existence of a series of different mutations at a single locus - allelic heterogeneity (e.g. DMD/BMD ; spinobulbar muscular atrophy or Kennedy's disease -androgen insensivity syndrome (AIS) or from mutation at different genetic loci - nonallelic or locus heterogeneity. For example, phenotypes such as limb girdle muscular dystrophy (LGMD), congenital myopathies and muscular dystrophies, hereditary motor and sensory neuropathies (HMSN), hereditary ataxias all have autosomal dominant, autosomal recessive, and X-linked forms. This will involve nonallelic heterogeneity in many cases, but allelic variation also can account for dominant and recessive variation at a single locus. A clinically similar Emery-Dreifuss muscular dystrophy can be caused by mutations at either of two loci, one on the X chromosome leading to a deficiency of emerin (1) and the other on chromosome 1 causing a deficiency of lamin A/C that has autosomal dominant inheritance. That both allelic and nonallelic heterogeneity may underlie a clinical phenotype is exemplified by hereditary motor and sensory neuropathies (HMSN), which exhibit both clinical and genetic heterogeneity, but was once regarded as one clinical entity or Charcot-Marie-Tooth disease (CMT). Linkage analyses have revealed more then 20 genetic loci corresponding to subtypes of HMSN (2). The most common demyelinating form, CMT1, can be inherited as an autosomal dominant, autosomal recessive or X-linked trait. In addition mutation in a single gene can result in more than one disease. The peripheral myelin protein gene - PMP22, illustrates this. People who have deletion or loss-of function mutation of the PMP22 gene suffer from hereditary neuropathy with pressure palsies or tomaculous neuropathy (MIM 162500), while people with duplication of the PMP22 gene or with activating point mutation have a clinically different neuropathy CMT1A (MIM 118220). It is increasingly obvious that most, if not all, hereditary diseases, when carefully analysed, are genetically heterogeneous. The extent of allelic heterogeneity is particularly impressive and is being rapidly defined at a molecular level. 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 (have two different mutant alleles at a given locus) at a molecular level. Now, the majority of genes involved in inherited muscle and nerve diseases have been identified, with a corresponding range of mutational mechanisms recognised. The current state of knowledge of the genes involved in inherited neuromuscular disorders can be found in each edition of the journal Neuromuscular Disorders, at the Leiden muscular dystrophy database (http&#61498 ; ; &#61487 ; ; &#61487 ; ; www.dmd.nl) and OMIM (http&#61498 ; ; &#61487 ; ; &#61487 ; ; www3.nabi.nlm.nih.gov/omim/). 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 (3). We present our results (4-7) of this approach and specific diagnostic strategy applied on 5-year long prospective, on going study of genetics and epidemiology of muscular dystrophies in Croatia. Specific diagnostic strategy based from the very beginning on selection of families with at least two patients was used to speed genetic study up. Emphasis is on 1. Detailed clinical assessment with CK, EMG, muscle CT or IRM, 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 origin of parents ; 3.Molecular diagnosis, and 4.Biopsy with Western blot, when necessary. REFERENCES 1. Canki-Klain, N et al .2000. Croat Med J 41: 389-395. 2. Neuromuscular disorders 2003 ; 13:274-5. 3. Canki-Klain N et al. 2000. Acta Myologica XIX/September: 120. 4. Canki-Klain N et al. 2000. Neurol Croat. 49/Suppl.3: 78-79. 5. Mili&aelig ; ; , A et al. 2001. Eur J Hum Genet 9/Suppl 1: 278. 6. Canki-Klain N et al. 2001. Neuromuscular Disorders.11: 634-5. 7. Mili&aelig ; ; A et al. 2002. Eur J Hum Genet 10 Suppl 1: 181.

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

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