Introduction The prevalence and impact of symptoms affecting individuals with pediatric forms of myotonic dystrophy type‐1 (DM1) are not well understood. Methods Patients from the United States, Canada, and Sweden completed a survey that investigated 20 themes associated with pediatric‐onset DM1. Participants reported the prevalence and importance of each theme affecting their lives. Surveys from participants were matched with surveys from their caregivers for additional analysis. Results The most prevalent symptomatic themes included problems with hands or fingers (79%) and gastrointestinal issues (75%). Problems with urinary/bowel control and gastrointestinal issues were reported to have the greatest impact on patients’ lives. Responses from participants and their caregivers had varying levels of agreement among symptomatic themes. Discussion Many symptoms have meaningful impact on disease burden. The highest levels of agreement between caregivers and individuals with pediatric forms of myotonic dystrophy were found for physical activity themes.
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.
Myotonic dystrophy type 1 (DM1) is a multi-systemic disorder caused by expansion of CTG microsatellite repeats within DMPK. The most severe form, congenital myotonic dystrophy (CDM), has symptom onset at birth due to large intergenerational repeat expansions. Despite a common mutation, CDM individuals present with a distinct clinical phenotype and absence of common DM1 symptoms. Given the clinical divergence, it is unknown if the hallmark of DM1 pathology, dysregulation of alternative splicing (AS) due to sequestration of MBNL proteins within toxic CUG repeat RNAs, contributes to disease throughout pediatric development. To evaluate global transcriptomic dysregulation RNA-seq was performed on 36 CDM skeletal muscle biopsies ages 2 weeks to 16 years, including two longitudinal samples. 50 DM1 and adult/pediatric controls were also sequenced as comparative groups. Despite a large CTG expansion and shared age of onset, CDM individuals presented with a heterogenous, MBNL-dependent mis-splicing signature. Estimation of intracellular MBNL concentrations from splicing responses of select events correlated with total spliceopathy and revealed a distinct, triphasic pattern of AS dysregulation across pediatric development. CDM infants (< 2 years) possess severe mis-splicing which significantly improves in early childhood (2–8 years) independent of sex or CTG repeat load. Adolescent individuals (8–16 years) stratified into two populations with a full range of global splicing dysregulation. DMPK expression changes correlated with alterations in splicing severity during development. This study reveals the complex dynamics of the CDM muscle transcriptome and provides insights into new therapeutic strategies, timing of therapeutic intervention, and biomarker development.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.