Disease burden and functional outcomes in congenital myotonic dystrophy

Abstract

Objective: Herein, we describe the disease burden and age-related changes of congenital-onset myotonic dystrophy (CDM) in childhood.Methods: Children 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. Myotonic dystrophy type 1 (DM1) is an autosomal dominant, multisystemic disorder that is caused by a CTG n repeat in the DMPK gene. Results:1-3 Congenital myotonic dystrophy (CDM) represents the most severe form of myotonic dystrophy and results from a large expansion of the CTG n repeat between parent and child. Symptoms are present at birth and include severe hypotonia, respiratory failure, gastroparesis, and talipes equinovarus. 4,5 These symptoms are distinct from those described in adults with DM1, who typically present with distal weakness, myotonia, and early-onset cataracts. During the first year of life, there is a 30% mortality for those infants ventilated for greater than 3 months. 6 Beyond the first year of life, there is limited information about the natural history of CDM.Clinically, children with CDM are observed to have significant improvement in respiratory and motor areas; however, as patients get older, myotonia, cardiac arrhythmias, and other features typical of adult-onset DM1 emerge. Both intellectual impairment and oral facial weakness cause significant burden during childhood. 7,8 In addition to intellectual impairment, there is evidence of autism spectrum disorder and attention-deficit/hyperactivity disorder. 7,9 A prior cross-sectional survey study identified difficulty with communication and problems with hands From the Departments of Neurology

Physical function and mobility in children with congenital myotonic dystrophy

“…The total 6MWT distance has been previously reported . Behavioral difficulties prevented some participants (11%) from completing the full 6MWT, but all participants were able to complete at least the first 2 minutes.…”

Body composition in patients with congenital myotonic dystrophy

“…Thirty‐five patients (15 boys and 20 girls) with a diagnosis of CDM and ranging in age from 3 to 13 years were enrolled at 2 different sites, The University of Utah and the University of Western Ontario, as part of the HELP‐CDM (Health Endpoints and Longitudinal Progression in Congenital Myotonic Dystrophy) study . The institutional review boards at both institutions approved all study procedures, and informed consent was obtained from parents or legal guardians of all participants; assent was obtained from patients older than 8 years that were cognitively able to do so.…”

“…The pathophysiology suggests that CDM may be a disorder of muscle immaturity, with the splicing dysfunction forcing proteins into more fetal isoforms . Both clinical observation and the pathophysiology suggest that one might see a gradual improvement in muscle mass (relative to their peers) as the child ages …”

Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy

“…CTG copy numbers as few as 750, but typically >1000, are associated with CDM (Tsilfidis et al 1992;Joseph et al 1997), and mutant DMPK transcripts are expressed in a variety of affected tissues throughout embryogenesis (Wong and Ashizawa 1997). Prenatal symptoms of CDM include polyhydramnios and reduced fetal movement, while newborn infants display muscle immaturity, hypotonia, and life-threatening respiratory insufficiency (Ho et al 2015;Johnson et al 2016). Adult-onset DM (DM1) patients are asymptomatic at birth and experience symptoms in later life likely due to postnatal somatic CTG repeat expansion (Wong et al 1995).…”