Myotonic dystrophy (DM) is the most common adult muscular dystrophy, characterized by autosomal dominant progressive myopathy, myotonia and multiorgan involvement. To date two distinct forms caused ...by similar mutations have been identified. Myotonic dystrophy type 1 (DM1, Steinert's disease) is caused by a (CTG)n expansion in DMPK, while myotonic dystrophy type 2 (DM2) is caused by a (CCTG)n expansion in ZNF9/CNBP. When transcribed into CUG/CCUG-containing RNA, mutant transcripts aggregate as nuclear foci that sequester RNA-binding proteins, resulting in spliceopathy of downstream effector genes. However, it is now clear that additional pathogenic mechanism like changes in gene expression, protein translation and micro-RNA metabolism may also contribute to disease pathology. Despite clinical and genetic similarities, DM1 and DM2 are distinct disorders requiring different diagnostic and management strategies. This review is an update on the recent advances in the understanding of the molecular mechanisms behind myotonic dystrophies. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.
•Recent advances in the pathomolecular mechanisms•Clinical features, genetics, pathology and animal models•Diagnosis and management
Myotonic dystrophies are multisystemic diseases characterized not only by muscle and heart dysfunction but also by CNS alteration. They are now recognized as brain diseases affecting newborns and ...children for myotonic dystrophy type 1 and adults for both myotonic dystrophy type 1 and type 2. In the past two decades, much progress has been made in understanding the mechanisms underlying the DM symptoms allowing development of new molecular therapeutic tools with the ultimate aim of curing the disease. This review describes the state of the art for the characterization of CNS related symptoms, the development of molecular strategies to target the CNS as well as the available tools for screening and testing new possible treatments.
Myotonic dystrophy types 1 (DM1) and 2 (DM2) are similar yet distinct autosomal‐dominant disorders characterized by muscle weakness, myotonia, cataracts, and multiple organ involvement, including the ...brain. One key difference between DM1 and DM2 is that a congenital form has been described for DM1 only. Expression of RNA transcripts containing pathogenic repeat lengths produces defects in alternative splicing of multiple RNAs, sequesters specific repeat‐binding proteins, and ultimately leads to developmentally inappropriate splice products for a particular tissue. Whether brain pathology in its entirety in adult DM1 and DM2 is caused by interference in RNA processing remains to be determined. This review focuses on the similarities and differences between DM1 and DM2 with respect to neuropsychological, neuropathological, and neuroimaging data relating to cerebral involvement, with special emphasis on the clinical relevance and social consequences of such involvement. Muscle Nerve, 2007
Myotonic dystrophy (DM) is the most common adult muscular dystrophy, characterized by autosomal dominant progressive myopathy, myotonia, and multiorgan involvement. To date, two distinct forms caused ...by similar mutations in two different genes have been identified: myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2). Aberrant transcription and mRNA processing of multiple genes due to RNA-mediated toxic gain-of function has been suggested to cause the complex phenotype in DM1 and DM2. However, despite clinical and genetic similarities, DM1 and DM2 may be considered as distinct disorders. This review is an update on the latest findings specific to DM2, including explanations for the differences in clinical manifestations and pathophysiology between the two forms of myotonic dystrophies.
Myotonic dystrophy type 1 (DM1) is one of the most variable monogenic diseases at phenotypic, genetic, and epigenetic level. The disease is multi-systemic with the age at onset ranging from birth to ...late age. The underlying mutation is an unstable expansion of CTG repeats in the
gene, varying in size from 50 to >1000 repeats. Generally, large expansions are associated with an earlier age at onset. Additionally, the most severe, congenital DM1 form is typically associated with local DNA methylation. Genetic variability of DM1 mutation is further increased by its structural variations due to presence of other repeats (e.g., CCG, CTC, CAG). These variant repeats or repeat interruptions seem to confer an additional level of epigenetic variability since local DNA methylation is frequently associated with variant CCG repeats independently of the expansion size. The effect of repeat interruptions on DM1 molecular pathogenesis is not investigated enough. Studies on patients indicate their stabilizing effect on
expansions because no congenital cases were described in patients with repeat interruptions, and the age at onset is frequently later than expected. Here, we review the clinical relevance of repeat interruptions in DM1 and genetic and epigenetic characteristics of interrupted
expansions based on patient studies.
The objective of our study was to perform a randomized controlled trial (RCT) aimed to evaluate the effects of three strictly monitored exercise programs (SMEP) compared to “usual care” (UCP) in a ...cohort of ALS patients. We included patients with definite and probable ALS and disease duration ≤24 months. Patients were randomized to receive a SMEPs or a UCP. SMEPs included three subgroups of treatment: active exercises associated with cycloergometer activity (1A), only active (1B) and passive (1C) exercises, respectively. Moreover, SMEP patients and their caregivers were trained to a daily home-based passive exercise program. The UCP group was treated with passive and stretching exercises twice weekly. The treatment period for both groups was 6 months (T180), and patients were assessed by revised ALS Functional Rating Scale (ALSFRS-R), % Forced Vital Capacity (FVC %), and McGill Quality of Life (MGQoL) questionnaire. ALSFRS-R score was also evaluated at 6 months after the treatment period (T360). Sixty ALS patients were randomly assigned to one of two arms: SMEP Group included 30 patients, ten subjects for each subgroup (1A, 1B, and 1C); 30 patients were included in the UCP Group. At T180 and T360, SMEPs group had significantly higher ALSFRS-R score compared to the UCP group (32.8 ± 6.5 vs 28.7 ± 7.5,
p
= 0.0298; 27.5 ± 7.6 vs 23.3 ± 7.6,
p
= 0.0338, respectively). No effects of SMEPs on survival, respiratory decline and MGQol were found. In conclusion, although no effect on survival was demonstrated, our data suggest that a strictly monitored exercise program may significantly reduce motor deterioration in ALS patients.
Myotonic dystrophy type-1 (DM1) is a genetic multi-systemic disorder involving several organs including the brain. Despite the heterogeneity of this condition, some patients with non-congenital DM1 ...can present with minimal cognitive impairment on formal testing but with severe difficulties in daily-living activities including social interactions. One explanation for this paradoxical mismatch can be found in patients' dysfunctional social cognition, which can be assessed in the framework of the Theory of Mind (ToM). We hypothesize here that specific disease driven abnormalities in DM1 brains may result in ToM impairments. We recruited 20 DM1 patients who underwent the "Reading the Mind in the Eyes" and the ToM-story tests. These patients, together with 18 healthy controls, also underwent resting-state functional MRI. A composite Theory of Mind score was computed for all recruited patients and correlated with their brain functional connectivity. This analysis provided the patients' "Theory of Mind-network", which was compared, for its topological properties, with that of healthy controls. We found that DM1 patients showed deficits in both tests assessing ToM. These deficits were associated with specific patterns of abnormal connectivity between the left inferior temporal and fronto-cerebellar nodes in DM1 brains. The results confirm the previous suggestions of ToM dysfunctions in patients with DM1 and support the hypothesis that difficulties in social interactions and personal relationships are a direct consequence of brain abnormalities, and not a reaction symptom. This is relevant not only for a better pathophysiological comprehension of DM1, but also for non-pharmacological interventions to improve clinical aspects and impact on patients' success in life.
Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant multisystemic disorders linked to two different genetic loci and characterized by several features including myotonia, muscle ...atrophy and insulin resistance. The aberrant alternative splicing of insulin receptor (IR) gene and post-receptor signalling abnormalities have been associated with insulin resistance, however the precise molecular defects that cause metabolic dysfunctions are still unknown. Thus, the aims of this study were to investigate in DM skeletal muscle biopsies if beyond INSR missplicing, altered IR protein expression could play a role in insulin resistance and to verify if the lack of insulin pathway activation could contribute to skeletal muscle wasting. Our analysis showed that DM skeletal muscle exhibits a lower expression of the insulin receptor in type 1 fibers which can contribute to the defective activation of the insulin pathway. Moreover, the aberrant insulin signalling activation leads to a lower activation of mTOR and to an increase in MuRF1 and Atrogin-1/MAFbx expression, possible explaining DM skeletal muscle fiber atrophy. Taken together our data indicate that the defective insulin signalling activation can contribute to skeletal muscle features in DM patients and are probably linked to an aberrant specific-fiber type expression of the insulin receptor.
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