Workshop report
140th ENMC International Workshop: Myotonic Dystrophy DM2/PROMM and other myotonic dystrophies with guidelines on management

To the memory of Dr Ken Ricker
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Introduction: ‘Then and Now for myotonic dystrophy type 2’

Myotonic dystrophy is the combination of progressive myotonic myopathy, multiorgan involvement and autosomal dominant inheritance. Currently, two distinct entities of myotonic dystrophy are characterized and defined by their underlying molecular genetic cause. Myotonic dystrophy type 1 (DM1, Steinert's disease) is considered to be the most frequent muscular dystrophy in adults [1]. Starting in 1994 publications of another disorder with similar core features but lacking the DM1 mutation have

Frequency and origin of the DM2 mutation

Ralf Krahe (TX, USA) started the scientific sessions by reporting on DM2 mutation studies in patients and 93 DM2 kindreds of various ethnic populations from Europe and the USA. The mutation itself is a repeat expansion in the microsatellite CL3N58 (from hereon referred to as the DM2 repeat) in the first intron of the ZNF9 gene that has a complex structure: (TG)14–25(TCTG)4–10(CCTG)11–26. When mutated the (CCTG)n portion of the repeat tract is expanded to repeat lengths approximately between 75

The clinical spectrum of symptoms and signs in patients with DM2 mutation

Guillaume Bassez (France) presented experience from the testing lab and the clinical setting in Paris. During the last 13 years the average number of DM1 analyses has been 170/year with an average of 75 positive results each year. During the last 3 years the lab has analyzed 98 samples for DM2 mutation out of which 45 were positive. Many of the DM2 negative samples proved later to have CLC1 mutation. The group also analyzed 74 stored biopsies with chromogenic in situ hybridization (CISH) [14]

Molecular pathomechanisms of DM2

Charles Thornton (USA) started the highly interesting session by discussing the effects of retained mutant ZNF9-transcript and the consequences of Muscleblind (MBLN1, 2 and 3) protein sequestration. MBLN normally binds target RNAs and mediates control of splicing events of pre-mRNA. When MBLN is sequestered by mutant (CAGG)n the net effect is loss of MBLN function [24], [25]. There are basically two types of RNA-binding proteins: the MBLN-family and the CUG-BP/CELF-family with different modes

Gene expression profiling results in DM2

Ralf Krahe (USA). Extensive microarray studies using the Affymetrix GeneChip platform have been conducted during the last years comparing DM2 with DM1 and with myotonic myopathy patients negative for both DM1 and DM2 mutations (from hereon referred to as DMx patients) and two other muscular dystrophies (TMD titinopathy and dystrophinopathies). Using a 2-fold threshold for dysregulation, all three DM groups showed some 800–1000 genes differentially expressed relative to controls. Among these

Animal models for DM2

Laura Ranum (USA) described transgenic models they are developing to explore the RNA toxicity of CCUG expansion transcripts and the effects that expression pattern plays on the phenotypic similarities between DM1 and DM2. Transgenic lines expressing (CCUG)300 and (CCUG)5 transcripts have been generated and are currently being characterized. The conditional expression of this non-coding CCUG transcript will allow the evaluation of RNA toxicity, reversibility and variable expression. Initial

Myotonic dystrophy type 3 (DM3) and other non-DM1/DM2-families

In 2004, a large French family with myotonic dystrophy phenotype combined with late FTD was published a possible DM3 family with suggestive linkage for a locus on Chr 15 [31]. However, in late 2005 Bjarne Udd was notified by the corresponding author of the paper that the family was not a DM3 candidate because linkage was incorrect and they had identified changes of Paget disease in the family and also identified the mutation in the VCP gene in the family [32]. This message was announced by Udd

Therapy and practical management

Richard Moxley (USA) presented a comprehensive and careful overview on the current issues regarding therapeutic options and practical management of patients with DM2. The recommendations below in the Guidelines section are based on the presentation and the result of discussions during the presentation and accepted by the workshop.

Benedikt Schoser (Germany) referred a recent retrospective study on the outcome of pregnancies and deliveries in 42 German DM2 women from 37 families. Results were

Conclusions and measures for diagnostics and research

Wolfram Kress (Germany) summarized discussions during the workshop to increase availability and accuracy of genetic DNA-tests in DM2 as the only reliable diagnostic definition. The workshop agreed on Guidelines for DNA Genetic Testing (see below) to ensure a lower threshold for requesting DNA tests. In addition, the represented European labs providing these DNA-tests agreed on regular sharing of samples with difficult results as a measure of continuous quality control. The system is already

Guidelines no. 1: indications for genetic DM2 testing

Increasing numbers of patients without the full range of multi-organ symptoms associated with myotonic dystrophy have been verified with DM2 mutation. In the single patient, none of the common clinical key features: proximal weakness, myotonia, cataracts, elevated CK-values or established family history is absolutely mandatory for DM2 disease:

  • the threshold for genetic testing of DM2 based on clinical findings should generally be lower than that usually required for DM1 genetic testing,

Acknowledgements

This Workshop was made possible thanks to the financial support of the European Neuromuscular Centre (ENMC) and ENMC main sponsors:

  • Association Française contre les Myopathies (France)

  • Deutsche Gesellschaft für Muskelkranke (Germany)

  • Telethon Foundation (Italy)

  • Muscular Dystrophy Campaign (UK)

  • Muskelsvindfonden (Denmark)

  • Prinses Beatrix Fonds (The Netherlands)

  • Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (Switzerland)

  • Österreichische Muskelforschung (Austria)

  • Vereniging Spierziekten

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