Charcot-Marie-Tooth disease and related peripheral neuropathies: the role of genetic testing

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CMT represents a clinically and genetically heterogeneous group of disorders caused by aberration of the intimate relationship between the Schwann cell sheath and the neural axon. The clinical symptoms of weakness and muscle atrophy ultimately results from axonal death and muscular denervation, the final common pathway of nerve damage. A simple clinical classification of CMT (demyelinating versus axonal) improves the yield of genetic testing and determines which genes should be tested for. In the demyelinating form, the combination of CMT1A duplication and Cx32mutation testing has a yield of approximately 80%. MPZ and PMP22 mutations are the next most common culprits. In cases of axonal CMT, Cx32 mutations are followed by MPZ mutations in the population-based studies, and there is suggestion that MFN2 mutations maybe quite common, though population based studies are not available for this gene yet. Recent discoveries of potential small molecular treatments for a specific subtype of CMT shifted the emphasis in genetic testing: instead of a molecular diagnosis for the few patients referred to tertiary care centers we need to find most patients with the potentially treatable molecular pathomechanism. While the robust amount of new information taught us about peripheral nerve function and dysfunction, it also made genetic testing for all known genes impractical in clinical practice. Today genetic testing should be utilized to address specific questions in a logical stepwise fashion based on evidence from population-based studies.

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