A Gap in Understanding

The CNS consequences of early-onset DM1 represent critical components of the burden of disease. Cognitive impairment is considered to be one of the most common and challenging manifestations of childhood DM1. This patient group exhibits significant cognitive and adaptive impairments consistent with intellectual disability. Improving upon developmental knowledge of cognitive functioning and adaptive capability in this DM1 population would serve multiple purposes, including readiness for clinical trials, improving patient management, and aiding the transition from pediatric to adult medical care. To date, relatively modest attention has been given to these critical features of pediatric-onset DM1.

New Longitudinal Study of Congenital/Childhood DM1

Following up on their prior cross-sectional study (Ekström et al., 2009), Dr. Anne-Berit Ekström (Queen Silvia Children’s Hospital) and colleagues have completed a prospective longitudinal study of individuals with a genetic diagnosis of pediatric DM1 (Lindeblad et al., 2019), including severe congenital (n – 16), mild congenital (n = 17), and childhood (n = 18) subtypes. Mean elapsed time between initial assessment and follow-up was 8 2/3 years. The study focused on assessment of subject’s cognitive function (Wechsler scales) and adaptive skill (Vineland Adaptive Behavioral Scales).

Progression of intellectual disability in the severe CDM group was modest—19% showed decreased function over the study period, while 6% showed an improvement. Comparable intellectual function change values for the mild CDM and childhood groups were 35% decreased/12% improved and 22% decreased/22% improved, respectively. Regarding adaptive function, the research team observed longitudinal changes in scores reflecting the domains of communication, socialization, and daily living. Predictors of change over time were patient age and level of intellectual ability at the study's second time point. However, a critically important finding was that subjects did not exhibit an actual regression of any key adaptive skills over the ~8-year study period. By contrast, there was evidence for improvement in some aspects of adaptive functioning.

Patient management in congenital and childhood DM1 draws much from practices/experience in adult patients. Given the severity of the CNS phenotype in pediatric patients, advances in clinical practice must be informed by rigorous, longitudinal assessments of both the natural history of cognitive impairment as well as the adaptive capacity of these patients. A tendency toward decline in cognitive and adaptive ability was seen in severe and mild CDM, but not in childhood DM1. The researchers also offered insights into proper use and caveats of the Vineland Adaptive Behavioral Scales in pediatric DM1.

Taken together, this study highlights the slowed development of individuals living with congenital and childhood DM1, but also the lack of an absolute decline in cognitive and adaptive abilities over time. These data should aid design and implementation of CNS endpoints in interventional clinical trials and improvement of management of patients with pediatric-onset DM1. Going forward, measures capable of detecting changes over shorter timeframes should be explored in this patient population.

References:

Cognition and adaptive skills in myotonic dystrophy type 1: a study of 55 individuals with congenital and childhood forms.
Ekström AB, Hakenäs-Plate L, Tulinius M, Wentz E.
Dev Med Child Neurol. 2009 Dec;51(12):982-90. doi: 10.1111/j.1469-8749.2009.03300.x. Epub 2009 Apr 21.

Cognitive and adaptive functioning in congenital and childhood forms of myotonic dystrophy type 1: a longitudinal study.
Lindeblad G, Kroksmark AK, Ekström AB.
Dev Med Child Neurol. 2019 Jan 31. doi: 10.1111/dmcn.14161. [Epub ahead of print]