Population frequency of myotonic dystrophy: higher than expected frequency of myotonic dystrophy type 2 (DM2) mutation in Finland. Eur J Hum Gen

Neuromuscular Research Unit, Medical School, University of Tampere, Tampere, Finland.
European journal of human genetics: EJHG (Impact Factor: 4.35). 03/2011; 19(7):776-82. DOI: 10.1038/ejhg.2011.23
Source: PubMed


Myotonic dystrophy (DM) is the most common adult-onset muscular dystrophy with an estimated prevalence of 1/8000. There are two genetically distinct types, DM1 and DM2. DM2 is generally milder with more phenotypic variability than the classic DM1. Our previous data on co-segregation of heterozygous recessive CLCN1 mutations in DM2 patients indicated a higher than expected DM2 prevalence. The aim of this study was to determine the DM2 and DM1 frequency in the general population, and to explore whether the DM2 mutation functions as a modifier in other neuromuscular diseases (NMD) to account for unexplained phenotypic variability. We genotyped 5535 Finnish individuals: 4532 normal blood donors, 606 patients with various non-myotonic NMD, 221 tibial muscular dystrophy patients and their 176 healthy relatives for the DM2 and DM1 mutations. We also genotyped an Italian idiopathic non-myotonic proximal myopathy cohort (n = 93) for the DM2 mutation. In 5496 samples analyzed for DM2, we found three DM2 mutations and two premutations. In 5511 samples analyzed for DM1, we found two DM1 mutations and two premutations. In the Italian cohort, we identified one patient with a DM2 mutation. We conclude that the DM2 mutation frequency is significantly higher in the general population (1/1830; P-value = 0.0326) than previously estimated. The identification of DM2 mutations in NMD patients with clinical phenotypes not previously associated with DM2 is of particular interest and is in accord with the high overall prevalence. On the basis of our results, DM2 appears more frequent than DM1, with most DM2 patients currently undiagnosed with symptoms frequently occurring in the elderly population.

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    • "It affects approximately 1 in 7500 individual worldwide (Harper, 1989). The incidence for DM2 seems to be much lower than for DM1 and appears to be population dependent, reaching a higher incidence in Germany and Finland (Suominen et al., 2011). The disorder shows a phenomenon of genetic anticipation in which affected individuals in succeeding generations have an earlier age of onset and a more severe clinical course (Howeler et al., 1989) due to the expansion of the repeat number during gametogenesis. "
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    ABSTRACT: DM1 is caused by CTG repeat expansion in the 3′-UTR of the DMPK gene. DM1 patients have expansions of greater than 50 repeats and up to many thousands. The intention of the present study is the establishment of reliable and rapid polymerase chain reaction methodology in early screening of DM1 patients and their family members. PCR followed by TP-PCR was assessed for screening of 27 cases (from 26 families) and 75 family members and 300 control samples. All patients had CTG repeat expansion while forty seven (63%) and twenty eight (37%), out of seventy five family members were heterozygous and homozygous respectively. Similarly, two hundred thirty (76.77%) and seventy (23.33%), out of three hundred control subjects were heterozygous and homozygous respectively and the number of repeats varied from 5 to 35. Thirteen complete family screenings were done. Thus, TP-PCR is a reliable and rapid molecular technique for the detection of CTG repeat expansion in DM1.
    Meta Gene 12/2014; 2(1):106–113. DOI:10.1016/j.mgene.2013.12.001
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    • "The more frequent and severe DM form is the DM1-Steinert’s disease (OMIM 160900), which affects 1:8000 individuals worldwide, and is caused by an expanded (CTG)n nucleotide sequence in the 3′ untranslated region of the Dystrophia Myotonic Protein Kinase (DMPK) gene (OMIM 605377) on chromosome 19q13.7–9 In 1999, a second DM form displaying a milder clinical phenotype has been identified:10 it has been essentially described in European Countries and has been called DM2 (OMIM 602688); it is much less frequent than DM1 since it affects 1:20000 individuals, although a recent genotypic study on Finnish patients11 suggested that DM2 frequency could be much higher than previously estimated; it is caused by the expansion of the tetranucleotidic repeat (CCTG)n in the first intron of the Zinc Finger Protein (ZNF-9) gene (OMIM 116955)12 on chromosome 3q21.13 "
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    ABSTRACT: Myotonic dystrophy type 2 (DM2) is an autosomal dominant disorder caused by the expansion of the tetranucleotidic repeat (CCTG)n in the first intron of the Zinc Finger Protein-9 gene. In DM2 tissues, the expanded mutant transcripts accumulate in nuclear focal aggregates where splicing factors are sequestered, thus affecting mRNA processing. Interestingly, the ultrastructural alterations in the splicing machinery observed in the myonuclei of DM2 skeletal muscles are reminiscent of the nuclear changes occurring in age-related muscle atrophy. Here, we investigated in vitro structural and functional features of satellite cell-derived myoblasts from biceps brachii, in the attempt to investigate cell senescence indices in DM2 patients by ultrastructural cytochemistry. We observed that in satellite cell-derived DM2 myoblasts, cell-senescence alterations such as cytoplasmic vacuolization, reduction of the proteosynthetic apparatus, accumulation of heterochromatin and impairment of the pre-mRNA maturation pathways occur earlier than in myoblasts from healthy patients. These results, together with preliminary in vitro observations on the early onset of defective structural features in DM2 myoblast derived-myotubes, suggest that the regeneration capability of DM2 satellite cells may be impaired, thus contributing to the muscular dystrophy in DM2 patients.
    European journal of histochemistry: EJH 09/2011; 55(3):e26. DOI:10.4081/ejh.2011.e26 · 2.04 Impact Factor
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    • "The basic cohort consisted of 4532 samples from healthy blood donors and was supplemented by additional cohorts of 827 patients diagnosed with other non-myotonic neuromuscular diseases and their 127 healthy relatives. The results show a surprisingly high frequency 1/1830 of the DM2 mutation in the Finnish population, which is >4-fold higher than any previous estimates of the prevalence of the disease prevalence for DM1 and DM2 combined [12]. The study raised many questions, such as how well the Finnish population may reflect the mutation frequency in other European populations and whether the mutation in fact is 100% penetrant in all circumstances. "
    Neuromuscular Disorders 06/2011; 21(6):443-50. DOI:10.1016/j.nmd.2011.03.013 · 2.64 Impact Factor
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