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Nervenheilkunde 2004; 23(02): 99-103
DOI: 10.1055/s-0038-1626285
Original- und Übersichtsarbeiten - Original and Review Articles
Schattauer GmbH

Genetik und molekulare Pathogenese der Myoklonus-Dystonie

Genetics and molecular pathogenesis of myoclonus-dystonia
F. Asmus
1   Abteilung für Neurologie mit Schwerpunkt Neurodegenerative Erkrankungen und Hertie-Institut für Klinische Hirnforschung, Zentrum für Neurologie der Universität Tübingen
,
T. Gasser
1   Abteilung für Neurologie mit Schwerpunkt Neurodegenerative Erkrankungen und Hertie-Institut für Klinische Hirnforschung, Zentrum für Neurologie der Universität Tübingen
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Publikationsverlauf

Publikationsdatum:
19. Januar 2018 (online)

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Zusammenfassung

Myoklonus-Dystonie (M-D, DYT11) zählt zu den »Dystonie-Plus-Syndromen«. Patienten zeigen neben fokalen oder segmentalen Dystonien, die sich meist als Schreibkrampf oder zervikale Dystonie manifestieren, v. a. kurz andauernde, »blitzartige« Myoklonien mit Betonung an Hals und oberen Extremitäten. Alkohol bessert die Bewegungsstörung in sehr vielen Fällen drastisch. Heterozygote Mutationen im ɛ-Sarkoglykangen (SGCE) kosegregieren mit der Erkrankung in Familien mit Myoklonus- Dystonie. Dabei handelt es sich in der überwiegenden Mehrzahl um Nonsense- oder Spleißstellenmutationen, die höchstwahrscheinlich zu einem Funktionsverlust des kodierten Proteins führen. Der pathogenetische Mechanismus, durch den ein Fehlen von ɛ-Sarkoglykan im Gehirn M-D auslöst, wurde bisher nicht experimentell aufgeklärt. Für die SGCE-Genregion auf Chromosom 7q21 ist maternales genomisches Imprinting bekannt. Dieser Mechanismus epigenetischer Modifikation führt durch spezifische Methylierung des maternalen SGCE-Promotors zu einer fast ausschließlichen Transkription des paternalen Allels. Dies erklärt die transmissionsspezifische Unterdrückung des M-D-Phänotyps nach Übertragung der Mutation durch die Mutter. M-D ist eine genetisch heterogene Erkrankung. Nur in jeweils einer Familie konnten eine Missense-Mutation im Gen für den D2-Dopamin- Rezeptor bzw. eine Deletion im TorsinA-Gen zusätzlich zu den SGCE-Mutationen nachgewiesen werden. Auf Chromosom 18p wurde bei einer SGCE-negativen M-DFamilie mit typischem Phänotyp ein weiterer Genlocus kartiert (DYT15).

Summary

Myoclonus-dystonia (M-D, DYT11) is a clinical syndrome characterized by predominant brief, “lightning-like” myoclonic jerks mostly of neck and upper limbs. In addition, most patients show focal or segmental dystonia, presenting as cervical dystonia and/or writers cramp. Typically, abnormal movements are responsive to alcohol ingestion. Heterozygous mutations in the gene for ɛ-sarcoglycan (SGCE) have been shown to segregate with the familial form of M-D. In most cases, SGCE-mutations are nonsense or splice site mutations and presumably lead to a loss of function of the encoded protein. The mechanisms by which a loss of functional SGCE protein in CNS causes M-D have not been detected yet. For the 7q21 chromosomal region of SGCE maternal genomic imprinting has been shown. By this epigenetic mechanism the maternal SGCE allele is inactivated by promoter methylation and only paternal alleles are transcribed. This finding could explain the transmission specific suppression of Myoclonus-dystonia symptoms in cases, where the SGCE mutation is inherited maternally. M-D is genetically heterogeneous. In single families, mutations in the D2 dopamine receptor gene or in the TorsinA gene have been reported in addition to SGCE mutations. In one large pedigree with a typical M-D phenotype an additional gene locus on chromosome 18p has been mapped (DYT15).

Schlüsselwörter

Myoklonus-Dystonie - DYT11 - ɛ-Sarkoglykan - Imprinting

Keywords

Myoclonus-dystonia - DYT11 - ɛ-sarcoglycan - imprinting
 

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