Dystrophia Myotonica Type 2 (DM2) in Finland
A Mutation with Extensive Clinical Implications
Acta Universitatis Tamperensis No. 1770


By Tiina Suominen
December 2012
Tampere University Press
Distributed By Coronet Books
ISBN: 9789514489334
152 pages
$87.50 Paper Original

Myotonic dystrophy type 2 (DM2) is a multisystemic genetic disease caused by a repeat expansion of four nucleotides (CCTG) in the first intron of CNBP (previously called ZNF9) gene on chromosome 3q21. The main clinical features include proximal muscle weakness, muscle pain (myalgia) and cataracts. Myotonia, although present in the disease name, is not so prominent and may be absent even when studied by electromyography.

DM2 is clinically variable and especially milder presentations may be easily misdiagnosed or get mingled with usual complaints of elderly persons. The phenotypic variability remains without conclusive explanations, but in some cases it has been suggested that mutations in other genes may affect the phenotype. Some explanations might also come from the pathomechanism of the disease, implicating secondary splicing abnormalities of a number of effector genes. Repeat numbers from 75 to as many as 11,000 have been reported from patients with DM2 disease. Because of the challenges in diagnosing DM2, the disease prevalence has been unknown. Nevertheless, DM2 has been considered much more infrequent than myotonic dystrophy type 1 (DM1), which is reported to have a prevalence of 1 in 8,000. This estimation of DM1 prevalence is based on clinical ascertainment of patients before the genetic discrimination of DM1 and DM2 was available. The repeat number varies widely from patient to patient, but does not correlate with the disease severity.

In this thesis the prevalence of DM2 was studied by investigating the frequency of DM2 mutation in the population. A surprisingly high mutation carrier frequency of 1 in 1,830 was obtained by analyzing over 5,500 Finnish samples. High prevalence was also suggested by the finding of a higher frequency of recessive CLCN1 mutation carriers among currently diagnosed DM2 patients compared to healthy individuals or DM1 patients. Co-segregating heterozygous recessive CLCN1 mutations in combination with DM2 mutation was found to have an aggravating effect on the symptoms and signs, i.e. myotonia. The DM2 phenotype is very variable, and according to our results DM2 can also be misdiagnosed as fibromyalgia, a chronic pain disorder, because of the similarity of the myalgia symptoms in these two disorders. As a result of our ascertainment strategy for DM2 disease, we also identified a new disease type linked to the DM2 repeat expansion. In one family a very short (CCTG)55-61 repeat expansion mutation was identified causing a late onset muscle disease without myotonia. Our preliminary studies on pathomechanism of this new proximal myalgic myopathy suggest that it is caused by a different mechanism compared to DM2 disease.

The results of this study have provided new and more exact information on DM2 disease and mutation prevalence, on the effects of modifying genes, on significant alternatives for differential diagnosis, and even a completely new disease type associated with short DM2 expansion. Clinicians will benefit from this new data by understanding the extent of the disease prevalence and the variability of the phenotype in order to get correct diagnosis and management for the patients. The results will also aid researchers to understand the pathomechanisms associated with specific multisystemic features in DM2.

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