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.

Download full-text


Available from: Ralf Krahe
  • Source
    • "However, DM2 is usually less severe and develops only in adults, which sometimes makes it difficult to distinguish from normal aging. The mutated alleles containing CCTG repeats are considerably larger than CTG tracts in DM1, but the size of the expansion does not correlate with the age of onset or the severity of the phenotype (Udd and Krahe 2012). The reason for the diverse manifestations of mytonic dystrophies has not been identified. "
    [Show abstract] [Hide abstract]
    ABSTRACT: RNA transcripts that include expanded CCUG repeats are associated with myotonic dystrophy type 2. Crystal structures of two CCUG-containing oligomers show that the RNA strands associate into slipped duplexes that contain noncanonical C-U pairs that have apparently undergone tautomeric transition or protonation resulting in an unusual Watson-Crick-like pairing. The overhanging ends of the duplexes interact forming U-U pairs, which also show tautomerism. Duplexes consisting of CCUG repeats are thermodynamically less stable than the trinucleotide repeats involved in the TRED genetic disorders, but introducing LNA residues increases their stability and raises the melting temperature of the studied oligomers by ∼10°C, allowing detailed crystallographic studies. Quantum mechanical calculations were performed to test the possibility of the tautomeric transitions or protonation within the noncanonical pairs. The results indicate that tautomeric or ionic shifts of nucleobases can manifest themselves in biological systems, supplementing the canonical "rules of engagement."
    Full-text · Article · Nov 2015 · RNA
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Sep 2015 · Biochimica et Biophysica Acta
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Myotonic dystrophy type 1 (DM1 or Steinert’s disease) and type 2 (DM2) are multisystem disorders of genetic origin. Progressive muscular weakness, atrophy and myotonia are the most prominent neuromuscular features of these diseases, while 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) triplet expansion in the 3′ untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) gene, whereas (CCTG)n repeats in the first intron of the Cellular Nucleic acid Binding Protein/Zinc Finger Protein 9 (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.
    Full-text · Article · Jul 2015 · Frontiers in Aging Neuroscience
Show more