Molekulare Variabilität der monogenen peripheren Neuropathien

Zusammenfassung

Die Charcot-Marie-Tooth-(CMT-)Erkrankungen, synonym zu den hereditären motorischen und sensiblen Neuropathien (HMSN), umfassen eine klinisch und genetisch heterogene Gruppe von Erkrankungen des peripheren Nervensystems. Traditionell wird zwischen demyelinisierender (CMT1, Dejerine-Sottas-Syndrom [DSS] und CMT4) sowie axonaler Form (CMT2) unterschieden. Bei etwa 70% der Patienten mit demyelinisierender Form liegt eine 1,4 Mb große Tandem-Duplikation im Chromosom 17p11.2-12 (CMT Typ 1A) vor. Die reziproke Deletion ist die häufigste Ursache der familiären rekurrierenden Neuropathie (HNPP, auch tomakulöse Neuropathie genannt). Die beiden Erkrankungen werden auf einen jeweils entgegengesetzten Gendosiseffekt des peripheren Myelinprotein-22-Gens (PMP22) zurückgeführt. Die intensive Forschung der vergangenen 11 Jahre hat zur Kenntnis von etwa 10 ursächlichen Genen und über 30 assoziierten Genorten geführt. Die Kenntnisse über die vielfältigen ursächlichen Gene haben auch zu einem differenzierteren Verständnis der häufig gemischt axonaldemyelinisierenden Phänotypen geführt. Die Analyse dieser Gene und Proteine wird zu weiteren Einsichten in die molekulare und zelluläre Basis des neuronalen Metabolismus und damit der peripheren Neuropathien führen.

Summary

Charcot-Marie-Tooth (CMT) diseases, also called hereditary motor and sensory neuropathy (HMSN), comprise a clinically as well as genetically heterogeneous group of diseases of the peripheral nervous system. The different subgroups are traditionally differentiated in demyelinating (CMT1, Dejerine Sottas Syndrome [DSS] and CMT4) and axonal (CMT2) types. About 70% of patients of a demyelinating neuropathy carry a 1.4 Mb tandem duplication in chromosome 17p11.2-12 (CMT type 1A). A reciprocal deletion leads to the hereditary neuropathy with liability to pressure palsies (HNPP, synonymous tomaculous neuropathy). Both diseases are due to a vice-versa gene dosage effect of the peripheral myelin protein 22 (PMP22) gene. The intensive research efforts of the last 11 years revealed about 10 genes and more as 30 associated loci. This growing knowledge about the associated genes leads simultanously to a more differentiated understanding of the often intermingled demyelinating-axonal phenotypes. The analysis of these genes and the encoded proteins will lead to additional insights into the molecular and cellular basis of neuronal metabolism and peripheral neuropathies.

Schlüsselwörter

Charcot-Marie-Tooth-Erkrankungen (CMT) - hereditäre motorisch-sensible Neuropathien (HMSN) - tomakulöse Neuropathie (HNPP) - Duplikation - Deletion

Keywords

Charcot-Marie-Tooth diseases (CMT) - hereditary motor and sensory neuropathy (HMSN) - tomaculous neuropathy (HNPP) - duplication - deletion

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