The myotonic dystrophies: Molecular, clinical, and therapeutic challenges

Neuromuscular Research Unit, Tampere University and University Hospital, Tampere, Finland. Electronic address: .
The Lancet Neurology (Impact Factor: 21.9). 10/2012; 11(10):891-905. DOI: 10.1016/S1474-4422(12)70204-1
Source: PubMed


Myotonic dystrophy is the most common type of muscular dystrophy in adults and is characterised by progressive myopathy, myotonia, and multiorgan involvement. Two genetically distinct entities have been identified. Myotonic dystrophy type 1 (also known as Steinert's disease) was first described more than 100 years ago, whereas myotonic dystrophy type 2 was identified only 18 years ago, after genetic testing for type 1 disease could be applied. Both diseases are caused by autosomal dominant nucleotide repeat expansions. In patients with myotonic dystrophy type 1, a (CTG)(n) expansion is present in DMPK, whereas in patients with type 2 disease, there is a (CCTG)(n) expansion in CNBP. When transcribed into CUG-containing RNA, mutant transcripts aggregate as nuclear foci that sequester RNA-binding proteins, resulting in a spliceopathy of downstream effector genes. The prevailing paradigm therefore is that both disorders are toxic RNA diseases. However, research indicates several additional pathogenic effects take place with respect to protein translation and turnover. Despite clinical and genetic similarities, myotonic dystrophy type 1 and type 2 are distinct disorders requiring different diagnostic and management strategies.

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    • "In addition to " spliceopathy, " RNA toxicity in DM1 may trigger different pathogenic mechanisms including dysregulation of transcription and microRNA metabolism, defects in protein translation/turnover and activation of cellular stress and apoptotic pathways [11] [12] [13] [14]. A role for epigenetic alterations in DM1 has also been proposed, either as a mechanism to explain intergenerational or somatic repeat instability or as an explanation for the altered expression of the DMPK transcript itself and of adjacent genes [15]. "
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    ABSTRACT: A differential CpGmethylation profile upstreamof the expanded CTG array at the DMPK locus has been reported in patientswithmyotonic dystrophy type 1 (DM1), suggesting that hypermethylationmightmodulate DM1 phenotype, possibly affecting expression levels of DMPK and/or flanking genes. To clarify this issue,we characterized by methylation sensitive high resolution melting (MS-HRM) the CpG methylation pattern of DNA sequences flanking the pathological CTG expansion in 13 childhood-onset, 37 juvenile/adult-onset, 7 congenital DM1 pa- tients carrying uninterrupted CTG expansions and in 9 DM1 patients carrying variant expansions vs 30 controls. Association of methylation status with disease features (nCTG, age, sex, MIRS, disease duration) was also assessed. Finally, DMPK and SIX5 expression levels were evaluated in leukocytes from controls, methylated and unmethylated DM1 patients. We found hypermethylation involving upstreamsequences of DM1 locus in patientswith uninterrupted CTG ex- pansions N1000 CTG and affected by a congenital or childhood onset form. Besides the n(CTG) and early disease onset, hypermethylation was also significantly associated with maternal transmission. On the other hand, hypermethylation involved the 3' of the CTG array in DM1 patients carrying variant expan-sions. DMPK and SIX5 expression did not significantly differ in methylated vs unmethylated DM1 patients. Our results suggest that either the inherited size of the expanded allele and the presence of interruptions at the 3' end are associated with a highly polarized pattern of CpGmethylation at the DM1 locus and that, at least in leukocytes, DM1 locus hypermethylation would not significantly affect DMPK or SIX5 expression.
    Biochimica et Biophysica Acta 09/2015; 1852(12). DOI:10.1016/j.bbadis.2015.09.007 · 4.66 Impact Factor
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    • "Consistent with this, congenital and childhood-onset forms of DM2 are absent, and the disease phenotype ranges from early adult-onset severe forms to very late-onset mild forms (Day et al., 2003). The prevalence of this disorder has yet to be clearly defined but it is estimated to be similar to DM1 in Northern European Countries (Udd and Krahe, 2012). However, very late-onset FIGURE 1 | Representation of the DM-causing genes, the location of the tandem repeats and their neighboring genes. "
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    ABSTRACT: Myotonic dystrophy type I (DM1 or Steinert’s disease) and type II (DM2) are multisystem disorders of genetic origin. Progressive muscular weakness, atrophy and myotonia are the most prominent neuromuscular features of these diseases, and other clinical manifestations such as cardiomyopathy, insulin-resistance and cataracts are also common. From a clinical perspective, most DM symptoms are interpreted as a result of an accelerated aging (cataracts, muscular weakness and atrophy, cognitive decline, metabolic dysfunction, etc.), including an increased risk of developing tumors. From this point of view, DM1 could be described as a progeroid syndrome since a notable age-dependent dysfunction of all systems occurs. The underlying molecular disorder in DM1 consists of the existence of a pathological (CTG)n triplet expansion in the 3’ untranslated region of the DMPK gene, whereas (CCTG)n repeats in the first intron of the CNBP/ZNF9 gene cause DM2. The expansions are transcribed into (CUG)n and (CCUG)n-containing RNA, respectively, which form secondary structures and sequester RNA-binding proteins, such as the splicing factor muscleblind-like protein (MBNL), forming nuclear aggregates known as foci. Other splicing factors, such as CUGBP, are also disrupted, leading to a spliceopathy of a large number of downstream genes linked to the clinical features of these diseases. Skeletal muscle regeneration relies on muscle progenitor cells, known as satellite cells, which are activated after muscle damage, and which proliferate and differentiate to muscle cells, thus regenerating the damaged tissue. Satellite cell dysfunction seems to be a common feature of both age-dependent muscle degeneration (sarcopenia) and muscle wasting in DM and other muscle degenerative diseases. This review aims to describe the cellular, molecular and macrostructural processes involved in the muscular degeneration seen in DM patients, highlighting the similarities found with muscle aging.
    Frontiers in Aging Neuroscience 07/2015; 7:125. DOI:10.3389/fnagi.2015.00125 · 4.00 Impact Factor
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    • "When transcribed into CUG-containing RNA, mutant transcripts aggregate as nuclear foci that sequester RNA-binding proteins, resulting in a spliceopathy of down stream effector proteins (troponin, insulin receptor, etc.). DM1 may be considered as a toxic RNA disease [6] [7] "
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    ABSTRACT: Abstract In this case report we study the dynamics of the SMR band in a subject affected from Facioscapulohumeral Muscular Dystrophy and subjected to Ken Ware Neuro Physics treatment. We use the Generalized Mutual Information (GMI) to analyze in detail the SMR band at rest during the treatment. Brain dynamics responds to a chaotic-deterministic regime with a complex behaviour that constantly self-rearranges and self-organizes such dynamics in function of the outside require- ments. We demonstrate that the SMR chaotic dynamics responds directly to such regime and that also decreasing in EEG during muscular activity really increases its ability of self-arrangement and self-organization in brain. The proposed novel method of the GMI is arranged by us so that it may be used in several cases of clinical interest. In the case of muscular dystrophy here examined, GMI enables us to quantify with accuracy the improvement that the subject realizes during such treatment. Keywords Ken Ware Neuro Physics Treatment, SMR Band, Generalized Mutual Information, Chaotic Brain Dynamics
    World Journal of Neuroscience 03/2015;
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