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Fortschr Neurol Psychiatr 2015; 83(1): 9-17
DOI: 10.1055/s-0034-1385734
Übersicht
© Georg Thieme Verlag KG Stuttgart · New York

Myotone Dystrophien: Klinik, Pathogenese, Diagnostik und Therapie

Myotonic Dystrophies: Clinical Presentation, Pathogenesis, Diagnostics and Therapy
J. Finsterer
1   Krankenanstalt Rudolfstiftung, Wien
,
S. Rudnik-Schöneborn
2   Institut für Humangenetik, Uniklinik RWTH Aachen
› Author Affiliations
Further Information

Publication History

09 April 2014

07 November 2014

Publication Date:
20 January 2015 (online)

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Zusammenfassung

Die autosomal dominanten dystrophischen Myotonien dystrophia myotonica Typ-1 (DM1, Curschmann-Steinert-Erkrankung) und dystrophia myotonica Typ-2 (DM2, proximale myotone Myopathie (PROMM)), sind im Gegensatz zu den nicht-dystrophischen Myotonien progressive Multisystem-Erkrankungen. DM1 und DM2 gelten als die häufigsten Muskeldystrophien. Am stärksten ist bei beiden der Skelettmuskel betroffen (Parese, Atrophie, Myotonie, Myalgie). Zusätzlich manifestiert sich die Erkrankung am Auge, Herzmuskel, Hirn, endokrinen Drüsen, Gastrointestinaltrakt, Skelett, Haut bzw. Hautanhangsgebilden und peripheren Nerven. Bei der DM1 werden eine kongenitale, juvenile, klassische und eine spät manifestierende Form unterschieden. Die DM2 ist eine Erkrankung des mittleren und höheren Erwachsenenalters und verläuft in der Regel milder als die DM1. Ursache der DM1 ist eine CTG-Repeat-Expansion auf > 50 Repeats im 3‘ nicht-kodierenden Ende des DMPK-Gens. Ursache der DM2 ist eine CCTG-Repeat-Expansion auf 75 – 11 000 Repeats in Intron 1 des CNBP/ZNF9 Gens. Die mutierte prä-mRNA beider Gene akkumuliert im Kern, setzt RNA-bindende Proteine frei und führt zu einer veränderten Proteinexpression über alternatives Spleißen von nachgeordneten Genen (toxische RNA-Erkrankungen). Bei der DM1 kommt es zu einer Repeatvermehrung von Generation zu Generation. Die DM1 verläuft umso schwerer, je höher die Repeat-Anzahl (Antizipation) ist. Bei der DM2 korrelieren die Schwere der Symptome und das Alter bei Beginn nicht mit der Repeat-Anzahl.

Abstract

The autosomal-dominant myotonic dystrophies dystrophia myotonica type-1 (DM1, Curschmann-Steinert disease) and dystrophia myotonica type-2 (DM2, proximal myotonic myopathy (PROMM)), are, contrary to the non-dystrophic myotonias, progressive multisystem disorders. DM1 and DM2 are the most frequent of the muscular dystrophies. In both diseases the skeletal muscle is the most severely affected organ (weakness, wasting, myotonia, myalgia). Additionally, they manifest in the eye, heart, brain, endocrine glands, gastrointestinal tract, skin, skeleton, and peripheral nerves. Phenotypes of DM1 may be classified as congenital, juvenile, classical, or late onset. DM2 is a disorder of the middle or older age and usually has a milder course compared to DM1. DM1 is due to a CTG-repeat expansion > 50 repeats in the non-coding 3' UTR of the DMPK-gene. DM2 is caused by a CCTG-repeat expansion to 75 – 11 000 repeats in intron-1 of the CNBP/ZNF9 gene. Mutant pre-mRNAs of both genes aggregate within the nucleus (nuclear foci), which sequester RNA-binding proteins and result in an abnormal protein expression via alternative splicing in downstream effector genes (toxic RNA diseases). Other mechanisms seem to play an additional pathogenetic role. Clinical severity of DM1 increases from generation to generation (anticipation). The higher the repeat expansion the more severe the DM1 phenotype. In DM2 severity of symptoms and age at onset do not correlate with the expansion size. Contrary to DM2, there is a congenital form and anticipation in DM1.

Schlüsselwörter

Myopathie - Muskeldystrophie - Myotonie - myotone Dystrophie

Key words

myopathy - muscular dystrophy - myotonia - myotonic dystrophy
 

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