Validity of the 6 minute walking test in myotonic dystrophy type 1 in a large scale cross-sectional study

ObjectiveThe goal of the study was to identify brain and functional features associated with premanifest phases of adult-onset myotonic dystrophy type 1 (i.e., PreDM1).MethodsThis cross-sectional study included 68 healthy adults (mean age = 43.4 years, SD = 12.9), 13 individuals with PreDM1 (mean age: 47.4 years, SD = 16.3), and 37 individuals with manifest DM1 (mean age = 45.2 years, SD = 9.3). The primary outcome measures included fractional anisotropy (FA), motor measures (Muscle Impairment Rating Scale, Grooved Pegboard, Finger-Tapping Test, and grip force), general cognitive abilities (Wechsler Adult Intelligence Scales), sleep quality (Scales for Outcomes in Parkinson's Disease–Sleep), and apathy (Apathy Evaluation Scale).ResultsIndividuals with PreDM1 exhibited an intermediate level of white matter FA abnormality, where whole-brain FA was lower relative to healthy controls (difference of the estimated marginal mean [EMMdifference] = 0.02, 95% confidence interval (CI) 0.01–0.03, p < 0.001), but the PreDM1 group had significantly higher FA than did individuals with manifest DM1 (EMMdifference = 0.02, 95% CI 0.009–0.03, p < 0.001). Individuals with PreDM1 exhibited reduced performance on the finger-tapping task relative to control peers (EMMdifference = 5.70, 95% CI 0.51–11.00, p = 0.03), but performance of the PreDM1 group was better than that of the manifest DM1 group (EMMdifference = 5.60, 95% CI 0.11–11.00, p = 0.05). Hypersomnolence in PreDM1 was intermediate between controls (EMMdifference = −1.70, 95% CI −3.10–0.35, p = 0.01) and manifest DM1 (EMMdifference = −2.10, 95% CI −3.50–0.60, p = 0.006).ConclusionsOur findings highlight key CNS and functional deficits associated with PreDM1, offering insight in early disease course.

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A large multicenter study of pediatric myotonic dystrophy type 1 for evidence-based management

Neurology ◽

10.1212/wnl.0000000000006948 ◽

2019 ◽

Vol 92 (8) ◽

pp. e852-e865 ◽

Cited By ~ 15

Author(s):

Emmanuelle Lagrue ◽

Céline Dogan ◽

Marie De Antonio ◽

Frédérique Audic ◽

Nathalie Bach ◽

...

Keyword(s):

Myotonic Dystrophy ◽

Transmission Rate ◽

Gastrointestinal Symptoms ◽

Autism Spectrum ◽

Evidence Based ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

Juvenile Form ◽

Cross Sectional

ObjectiveTo genotypically and phenotypically characterize a large pediatric myotonic dystrophy type 1 (DM1) cohort to provide a solid frame of data for future evidence-based health management.MethodsAmong the 2,697 patients with genetically confirmed DM1 included in the French DM-Scope registry, children were enrolled between January 2010 and February 2016 from 24 centers. Comprehensive cross-sectional analysis of most relevant qualitative and quantitative variables was performed.ResultsWe studied 314 children (52% females, with 55% congenital, 31% infantile, 14% juvenile form). The age at inclusion was inversely correlated with the CTG repeat length. The paternal transmission rate was higher than expected, especially in the congenital form (13%). A continuum of highly prevalent neurodevelopmental alterations was observed, including cognitive slowing (83%), attention deficit (64%), written language (64%), and spoken language (63%) disorders. Five percent exhibited autism spectrum disorders. Overall, musculoskeletal impairment was mild. Despite low prevalence, cardiorespiratory impairment could be life-threatening, and frequently occurred early in the first decade (25.9%). Gastrointestinal symptoms (27%) and cataracts (7%) were more frequent than expected, while endocrine or metabolic disorders were scarce.ConclusionsThe pedDM-Scope study details the main genotype and phenotype characteristics of the 3 DM1 pediatric subgroups. It highlights striking profiles that could be useful in health care management (including transition into adulthood) and health policy planning.

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Recovery in the Myogenic Program of Congenital Myotonic Dystrophy Myoblasts after Excision of the Expanded (CTG)n Repeat

International Journal of Molecular Sciences ◽

10.3390/ijms20225685 ◽

2019 ◽

Vol 20 (22) ◽

pp. 5685 ◽

Cited By ~ 2

Author(s):

Laurène M. André ◽

Remco T.P. van Cruchten ◽

Marieke Willemse ◽

Karel Bezstarosti ◽

Jeroen A.A. Demmers ◽

...

Keyword(s):

Myotonic Dystrophy ◽

Large Scale ◽

Myogenic Differentiation ◽

In Vitro Study ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

Expression Of Genes ◽

Proteome Level

The congenital form of myotonic dystrophy type 1 (cDM) is caused by the large-scale expansion of a (CTG•CAG)n repeat in DMPK and DM1-AS. The production of toxic transcripts with long trinucleotide tracts from these genes results in impairment of the myogenic differentiation capacity as cDM’s most prominent morpho-phenotypic hallmark. In the current in vitro study, we compared the early differentiation programs of isogenic cDM myoblasts with and without a (CTG)2600 repeat obtained by gene editing. We found that excision of the repeat restored the ability of cDM myoblasts to engage in myogenic fusion, preventing the ensuing myotubes from remaining immature. Although the cDM-typical epigenetic status of the DM1 locus and the expression of genes therein were not altered upon removal of the repeat, analyses at the transcriptome and proteome level revealed that early abnormalities in the temporal expression of differentiation regulators, myogenic progression markers, and alternative splicing patterns before and immediately after the onset of differentiation became normalized. Our observation that molecular and cellular features of cDM are reversible in vitro and can be corrected by repeat-directed genome editing in muscle progenitors, when already committed and poised for myogenic differentiation, is important information for the future development of gene therapy for different forms of myotonic dystrophy type 1 (DM1).

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