12-Month progression of motor and functional outcomes in congenital myotonic dystrophy.
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ABSTRACT: Background
We aim to describe 12-mo functional and motor outcome performance in a cohort of participants with congenital myotonic dystrophy (CDM).Methods
CDM participants performed the 6 Minute Walk Test (6MWT), 10 Meter Run, 4 Stair Climb, Grip Strength, and Lip Force at baseline and 12-mo visits. Parents completed the Vineland Adaptive Behavior Scale.Results
Forty-seven participants, aged 0 to 13 y old, with CDM were enrolled. 6MWT, 10 Meter Run, and 4 Stair Climb were completed in >85% of eligible participants. The only significant difference between mean baseline and 12-mo performance was an improvement in 6MWT in children 3-6 y old (P = .008). This age group also had the largest mean % improvement in performance in all other timed functional testing. In children >7 y, the slope of change on timed functional tests decreased or plateaued, with further reductions in performance in children ≥10 y. Participants with CTG repeat lengths <500 did not perform differently than those with repeat lengths >1000.Conclusions
The 6MWT, 10 Meter Run, and 4 Stair Climb were the most feasible measures. Our findings are consistent with the clinical profile and prior cross-sectional data, helping to establish reasonable expectations of functional trajectories in this population as well as identifying points in which therapeutic interventions may be best studied. Further study of outcomes in children >10 y old and <3 y is warranted, but this new information will assist planning of clinical trials in the CDM population.
SUBMITTER: Quigg KH
PROVIDER: S-EPMC8038871 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveHerein, we describe the disease burden and age-related changes of congenital-onset myotonic dystrophy (CDM) in childhood.MethodsChildren with CDM and age-matched controls aged 0 to 13 years were enrolled. Participants were divided into cohorts based on the following age groups: 0-2, 3-6, and 7-13 years. Each cohort received age-appropriate evaluations including functional testing, oral facial strength testing, neuropsychological testing, quality-of-life measurements, and ECG. Independent-samples t test or Wilcoxon 2-sample test was used to compare the differences between children with CDM and controls. Probability values less than 0.05 are reported as significant.ResultsForty-one participants with CDM and 29 healthy controls were enrolled. The 6-minute walk was significantly different between CDM (258.3 m [SD 176.0]) and control participants (568.2 m [SD 73.2]). The mean lip force strength was significantly different in CDM (2.1 N [SD 2.8)] compared to control participants (17.8 N [SD 7.6]). In participants with CDM, the mean IQ (65.8; SD 18.4) was 3 SDs below the mean compared to standardized norms. Measurements of grip strength, sleep quality, and quality of life were also significantly different. Strength measures (oral facial strength, grip strength, and 6-minute walk) correlated with each other but not with participant IQ.ConclusionsThis work identifies important phenotypes associated with CDM during childhood. Several measures of strength and function were significantly different between participants with CDM and controls and may be useful during future therapeutic trials.
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Project description:Myotonic dystrophy types 1 (DM1) and 2 (DM2) are dominantly inherited neuromuscular disorders caused by a toxic gain of function of expanded CUG and CCUG repeats, respectively. Although both disorders are clinically similar, congenital myotonic dystrophy (CDM), a severe DM form, is found only in DM1. CDM is also characterized by muscle fiber immaturity not observed in adult DM, suggesting specific pathological mechanisms. Here, we revealed upregulation of the interleukin-6 (IL-6) myokine signaling pathway in CDM muscles. We also found a correlation between muscle immaturity and not only IL-6 expression but also expanded CTG repeat length and CpG methylation status upstream of the repeats. Aberrant CpG methylation was associated with transcriptional dysregulation at the repeat locus, increasing the toxic RNA burden that upregulates IL-6. Because the IL-6 pathway is involved in myocyte maturation and muscle atrophy, our results indicate that enhanced RNA toxicity contributes to severe CDM phenotypes through aberrant IL-6 signaling.
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Project description:INTRODUCTION:Herein we present an exploratory study of orofacial function in children with congenital myotonic dystrophy (CDM) vs. healthy controls. METHODS:We evaluated 41 children with CDM and 29 healthy controls for speech and swallow function and for lingual and labial strength. RESULTS:The Iowa Oral Performance Instrument (IOPI), measuring tongue strength, and a lip force meter (LFM), measuring lip strength, had excellent interrater reliability with intraclass correlation coefficients (ICCs) of 0.75 (n?=?19, P?<?0.001) and 0.96 (n?=?20, P?<?0.001), respectively. Mean overall lingual strength was 3.5-fold less and labial strength was about 7-fold less in CDM patients than in healthy controls. Eighteen of 24 children with CDM demonstrated dysarthria and an additional 11 participants were nonverbal. Dysarthria correlated moderately with lingual strength, age, and dysphagia. Strength measures correlated moderately with dysphagia. DISCUSSION:Children with CDM have impaired orofacial functioning that affects communication and swallowing. Reliability of strength measures may be useful for future therapeutic trials. Muscle Nerve 58: 413-417, 2018.
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Project description:Myotonic dystrophy type 1 (DM1) is a CTG microsatellite expansion (CTGexp) disorder caused by expression of CUGexp RNAs. These mutant RNAs alter the activities of RNA processing factors, including MBNL proteins, leading to re-expression of fetal isoforms in adult tissues and DM1 pathology. While this pathogenesis model accounts for adult-onset disease, the molecular basis of congenital DM (CDM) is unknown. Here, we test the hypothesis that disruption of developmentally regulated RNA alternative processing pathways contributes to CDM disease. We identify prominent alternative splicing and polyadenylation abnormalities in infant CDM muscle, and, although most are also misregulated in adult-onset DM1, dysregulation is significantly more severe in CDM. Furthermore, analysis of alternative splicing during human myogenesis reveals that CDM-relevant exons undergo prenatal RNA isoform transitions and are predicted to be disrupted by CUGexp-associated mechanisms in utero. To test this possibility and the contribution of MBNLs to CDM pathogenesis, we generated mouse Mbnl double (Mbnl1; Mbnl2) and triple (Mbnl1; Mbnl2; Mbnl3) muscle-specific knockout models that recapitulate the congenital myopathy, gene expression, and spliceopathy defects characteristic of CDM. This study demonstrates that RNA misprocessing is a major pathogenic factor in CDM and provides novel mouse models to further examine roles for cotranscriptional/post-transcriptional gene regulation during development.
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Project description:Introduction: Myotonic dystrophy type 2 (DM2) lacks disease-specific, validated, motor outcome measures (OMs), and patients' reported outcomes (PROs). This represents a limit for the monitoring of disease progression and treatment response. Our aim was to identify the most appropriate OMs to be translated in clinical practice and clinical trials on DM2. This study has been registered on clinicaltrials.gov NCT03603171 (https://clinicaltrials.gov/ct2/show/NCT03603171). Methods: Sixty-six patients with genetically confirmed DM2 underwent a baseline and a follow-up visit after 1 year. The tested OMs included: hand opening time, pressure pain threshold (PPT), manual muscle testing (MMT), hand held dynamometry (HHD), scale for the assessment and rating of ataxia (SARA), quantitative motor function test (QMFT), gait stairs Gowers chair (GSGC), 30-s sit to stand test, functional index 2 (FI-2) and 6MWT. The PROs included DM1-Active-C, Rasch-built Pompe-specific activity scale (R-Pact), fatigue and daytime sleepiness (FDSS), brief pain inventory short form (BPI-sf), myotonia behavior scale (MBS), and the McGill pain questionnaire. Results: All patients completed the MBS and the results correlated well with the hand-opening time. The PPT showed a low reliability, no correlation with pain questionnaires, and did not differentiate patients with or without myalgia. Both muscle strength assessments, MMT and HHD, showed good construct validity. The QMFT showed an acceptable ceiling effect (14.5%), good convergent and differential validity and performed overall better than GSGC. The SARA score showed high flooring effect and is not useful in DM2. 6MWT proved a valid outcome measure in DM2. The 30-s sit to stand is a feasible test with good convergent validity, showing a flooring effect of 20% as it cannot be used in more severely affected patients. The FI-2 is time-consuming and has a high ceiling effect. At the 1-year visit the only assessments able to detect a worsening of DM2 were HHD, QMFT, and 6MWT, which are the most sensitive to change, and therefore clinically meaningful OMs in DM2. Conclusion: The clinical meaningful motor outcome measures that best depict the multifaceted phenotype of DM2 and its slow progression are MBS, MMT, or HHD (depending on the clinical setting), QMFT, and the 6MWT.
| S-EPMC7186332 | biostudies-literature
Project description:Myotonic dystrophy type 1 (DM1) is a CTG microsatellite expansion (CTGexp) disorder caused by expression of CUGexp RNAs. These mutant RNAs alter the activities of RNA processing factors, including MBNL proteins, leading to reversion to specific fetal isoforms in adult tissues and DM1 pathology. While this pathogenesis model accounts for adult-onset disease, the molecular basis of congenital DM (CDM) is unknown. Here, we test the hypothesis that disruption of developmentally regulated RNA alternative processing pathways contributes to CDM disease. Analysis of alternative splicing (AS) transitions during human myogenesis reveals hundreds of AS events that undergo prenatal isoform transitions and both AS and alternative polyadenylation abnormalities are prominently detectable in infant CDM muscle biopsies. While the majority of RNA targets are also mis-regulated in adult-onset DM1, splicing dysregulation is significantly more severe in CDM. Since many of these mis-processing events are MBNL-regulated, we generated mouse Mbnl double (Mbnl1; Mbnl2) and triple (Mbnl1; Mbnl2; Mbnl3) muscle-specific knockout models that recapitulate the congenital myopathy, gene expression and spliceopathy defects characteristic of CDM. This study demonstrates RNA mis-processing is a major pathogenic factor in CDM and provides novel mouse models to further examine roles for co/post-transcriptional gene regulation during tissue development.
2017-07-12 | GSE97806 | GEO