Myotone Dystrophien – Phänotypen, Pathogenese, Diagnostik und Therapie

Zusammenfassung

Zwei Formen der myotonen Dystrophie (DM1, DM2) sind bisher beschrieben. 1992 konnte als genetische Ursache der DM1 ein abnorm expandiertes CTG-Triplettrepeat im 3´-UTR (untranslated region) des Dystrophia myotonica Proteinkinasegens (DMPK) auf Chromosom 19 gefunden werden. Die DM2 wurde 1994 durch Ricker und Thornton beschrieben und 2001 konnte ein abnorm expandiertes Tetranukleotid CCTG-Repeat im Intron 1 des Zinkfinger-9-Gens (ZNF-9) auf Chromosom 3q als kausal identifiziert werden. Multisystemische Symptome betreffen Skelettmuskulatur, Gehirn, Auge, Herz und Endokrinum. Der heterogenen Ätiologie mit zwei genetischen Loci liegt pathogenetisch eine RNA-Prozessierungsstörung mit alternativem Spleißen von organspezifischen Genen zugrunde (sogenanntes Konzept der Spleißeopathie).

Unser Symposium umfasste Beiträge zu aktuellen Aspekten der Klinik, Diagnostik, Bildgebung, Geburtshilfe und Schwangerschaft, molekularen RNA-Pathogenese sowie symptomatischen und molekularen Therapieoptionen.

Summary

Myotonic dystrophies cover at least two clinical and molecular distinct forms, the classic (Steinert’s disease; DM1) and the new type (Ricker’s disease, DM2). In 1992, the mutation causing DM1 was identified as a CTG repeat in the DMPK gene on chromosome 19q, and in 2001 the mutation causing DM2 was identified as a CCTG repeat in the ZNF-9 gene on chromosome 3q. The pathogenesis of both forms seems to be based ona gain-of-function RNA mechanism, as multisystemic features are caused by alternative splicing of tissue specific genes. Thus, recently the term spliceopathy was introduced. Our symposium focused on multisystemic clinical features, new diagnostic techniques, new aspects of the molecular pathogenesis and symptomatic treatment options.

Schlüsselwörter

DM1 - DM2 - myotone Dystrophien - Repeat-Erkrankung - Therapie

Keywords

DM1 - DM2 - myotonic dystrophy - repeat disorder - treatment

• Literatur

• 1 Bachinski LL. et al. Confirmation of DM2 (CCTG)n expansion mutation in PROMM/PDM patients of different European origins: a single shared haplotype indicates ancestral founder effects. Am J Hum Genet 2003; 73: 835-48.
• 2 Bhakta D, Lowe MR, Groh WJ. Prevalence of structural cardiac abnormalities in patients with myotonic dystrophy type I. Am Heart J 2004; 147: 224-47.
• 3 Brook JD. et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3’ end of a transcript encoding a protein kinase family member. Cell 1992; 68: 799-808.
• 4 Cho DH, Tapscott SJ. Myotonic dystrophy: Emerging mechanisms for DM1 and DM2. Biochim Biophys Acta. 2006 PMID: 16876389.
• 5 Gaul C. et al. Subtle cognitive dysfunction in adult myotonic dystrophy type 1 (DM1) and type 2 (DM2). Neurology 2006; 67: 350-2.
• 6 George A. et al. Musculoskeletal pain as the most prominent feature in myotonic dystrophy type 2 Schmerz. 2006 PMID: 16758212.
• 7 George A. et al. Musculoskeletal pain in patients with myotonic dystrophy type 2. Arch Neurol 2004; 61: 1938-42.
• 8 Gomes-Pereira M, Monckton DG. Chemical modifiers of unstable expanded simple sequence repeats: what goes up, could come down. Mutat Res 2006; 598: 15-34.
• 9 Harper PS. Myotonic Dystrophy. 3rd edition. London: W. B. Sauders; 2001
• 10 Jakubiczka S. et al. A strategy for reliable diagnosis of PROMM/DM2. Neurogenetics 2004; 05: 55-9.
• 11 Kanadia RN. et al. Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy. Proc Natl Acad Sci USA 2006; 103: 11748-53.
• 12 Kassubek J. et al. Quantification of brain atrophy in patients with myotonic dystrophy and proximal myotonic myopathy: a controlled 3-dimensional magnetic resonance imaging study. Neurosci Lett 2003; 348: 73-6.
• 13 Kornblum C. et al. Distinct neuromuscular phenotypes in myotonic dystrophy types 1 and 2: a whole body highfield MRI study. J Neurol 2006; 253: 753-61.
• 14 Kornblum C. et al. Cranial magnetic resonance imaging in genetically proven myotonic dystrophy type 1 and 2. J Neurol 2004; 251: 710-4.
• 15 Langlois MA. et al. Cytoplasmic and nuclear retained DMPK mRNAs are targets for RNA interference in myotonic dystrophy cells. J Biol Chem 2005; 280: 16949-54.
• 16 Leroy O. et al. ETR-3 represses Tau exons 2/3 inclusion, a splicing event abnormally enhanced in myotonic dystrophy type I. J Neurosci Res 2006; 84: 852-9.
• 17 Liquori CL. et al. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 2001; 293: 864-7.
• 18 Liquori CL. et al. Myotonic Dystrophy Type 2: Human founder haplotype and evolutionary conservation of the repeat tract. Am J Hum Genet 2003; 73: 849-62.
• 19 Mahadevan M. et al. Myotonic dystrophy mutation: an unstable CTG repeat in the 3’ untranslated region of the gene. Science 1992; 255: 1253-5.
• 20 Mahadevan MS. et al. Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy. Nat Genet 2006; 38: 1066-70.
• 21 Margolis JM. et al. DM2 intronic expansions: evidence for CCUG accumulation without flanking sequence or effects on ZNF9 mRNA processing or protein expression. Hum Mol Genet 2006; 15: 1808-15.
• 22 Maurage CA. et al. Similar brain tau pathology in DM2/PROMM and DM1/Steinert disease. Neurology 2005; 65: 1636-8.
• 23 Osborne RJ, Thornton CA. RNA-dominant diseases. Hum Mol Genet 2006; 15: 162-9.
• 24 Ota M. et al. Relationship between diffusion tensor imaging and brain morphology in patients with myotonic dystrophy. Neurosci Lett 2006; 407: 234-9.
• 25 Ranum LP, Cooper TA. RNA-mediated neuromuscular disorders. Annu Rev Neurosci 2006; 29: 259-77.
• 26 Rudnik-Schoneborn S. et al. Outcome and effect of pregnancy in myotonic dystrophy type 2. Neurology 2006; 66: 579-80.
• 27 Ricker K. et al. Proximal myotonic myopathy: a new dominant disorder with myotonia, muscle weakness, and cataracts. Neurology 1994; 44: 1448-52.
• 28 Schara U, Schoser BG. Myotonic dystrophies type 1 and 2: a summary on current aspects. Semin Pediatr Neurol 2006; 13: 71-9.
• 29 Schneider-Gold C. et al. Cardiac and skeletal muscle involvement in myotonic dystrophy type 2 (DM2): a quantitative 31P-MRS and MRI study. Muscle Nerve 2004; 30: 636-44.
• 30 Schoser BG. Myotone Dystrophien – Aktueller Stand der molekularen Pathogenese. Akt Neurol 2005; 32: 324-30.
• 31 Schoser BG. et al. Sudden cardiac death in myotonic dystrophy type 2. Neurology 2004; 63: 2402-4.
• 32 Sergeant N. et al. Dysregulation of human brain microtubule-associated tau mRNA maturation in myotonic dystrophy type 1. Hum Mol Genet 2001; 10: 2143-55.
• 33 Thornton CA, Griggs RC, Moxley RT. 3^rd edition Myotonic dystrophy with no trinucleotide repeat expansion. Ann Neurol 1994; 35: 269-72.
• 34 Timchenko NA. et al. RNA CUG repeats sequester CUGBP1 and alter protein levels and activity of CUGBP1. J Biol Chem 2001; 276: 7820-6.
• 35 Timchenko L. Reversal of fortune. Nat Genet 2006; 38: 976-7.
• 36 Udd B. et al. Report of the 115^th ENMC workshop: DM2/PROMM and other myotonic dystrophies. 3^rd Workshop, 14–16 February 2003, Naarden, The Netherlands. Neuromuscl Disord 2003; 13: 589-96.
• 37 Udd B. et al. 140^th ENMC International Workshop: Myotonic Dystrophy DM2/PROMM and other myotonic dystrophies with guidelines on management. Neuromuscul Disord 2006; 16: 403-13.
• 38 Vielhaber S. et al. Brain 1H magnetic resonance spectroscopic differences in myotonic dystrophy type 2 and type 1. Muscle Nerve 2006; 34: 145-52.