Abstract
Autosomal dominant inherited Myotonic dystrophy type 1 and 2 (DM1 and DM2) are the most frequent muscle dystrophies in the European population and are caused by repeat expansion mutations. For Germany cumulative empiric evidence suggests an estimated prevalence of DM2 of roughly 9 in 100,000, therefore being as prevalent as DM1. In DM2, a (CCTG)n repeat tract located in the first intron of the CNBP gene is expanded. The CCTG repeat tract is part of a complex repeat structure comprising not only CCTG tetraplets but also repeated TG dinucleotides and TCTG tetraplet elements as well as NCTG interruptions. Here, we provide the distribution of normal sized alleles in the German population, which was found to be highly similar to the Slovak population. Sequencing of 34 unexpanded healthy range alleles in DM2 positive patients (heterozygous for a full expansion) revealed that the CCTG repeat tract is usually interrupted by at least three tetraplets which according to current opinion is supposed to render it stable against expansion. Interestingly, only the largest analyzed normal allele had 23 uninterrupted CCTGs and consequently could represent an instable early premutation allele. In our diagnostic history of DM2 cases, a total of 18 premutations were detected in 16 independent cases. Here, we describe two premutation families, one with an expansion from a premutation allele and the other with a contraction of a full expansion down to a premutation allele. Our diagnostic results support the general assumption that the premutation range of unstable CCTG stretches lies obviously between 25 and 75 CCTGs. However, the clinical significance of premutation alleles is still unclear. In the light of the two described families we suggest incomplete penetrance. Thus, as it was proposed for other repeat expansion diseases (e.g., Huntington's disease), a fluid transition of penetrance is more likely rather than a clear cut CCTG number threshold.
Highlights
Myotonic dystrophy type 2 (DM2; PROMM; Ricker syndrome, MIM 602668) is an autosomal dominant multisystemic neuromuscular disorder that occurs in adults [1, 2]
From our own experience in the diagnostic lab, it is obvious that DM2 and DM1 contribute to the myotonic dystrophy phenotype as we detected about the same number of DM2 and DM1 patients by molecular genetic testing over many years (Table 1)
Cumulative empiric evidence suggests that DM2 exhibits quite the same prevalence like DM1 in the German population
Summary
Myotonic dystrophy type 2 (DM2; PROMM; Ricker syndrome, MIM 602668) is an autosomal dominant multisystemic neuromuscular disorder that occurs in adults [1, 2]. DM2 and DM1 share the same core features (progressive muscle weakness and atrophy, myotonia, cataracts) as well as additional symptoms like muscle pain, cardiac arrhythmias, endocrinologic disturbances and hypersomnia, apparent differences exist. There is no congenital form as well as evident anticipation, but myalgic pain is a frequent symptom and muscle weakness is mainly proximal. DM2 is caused by the expansion of an unstable (CCTG)n repeat located in the first intron of the CNBP (cellular retroviral nucleic acid-binding protein) gene in the 3q21.3 chromosomal region [4]. The pre-mRNA contains the repeat expansion and remains unprocessed [5]. It disrupts cellular pathways like RNA splicing, localization and translation through sequestering of important RNA binding proteins. Developmentally inappropriate protein isoforms are expressed in adult tissue
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