Pediatric Natural History

Virginia Commonwealth University, Richmond VA

Investigators

Abstract

Modified Project Summary/Abstract Section When myotonic dystrophy type 1 (DM1) begins at birth, known as congenital myotonic dystrophy (CDM), or prior to the age of 10, known as childhood onset myotonic dystrophy (ChDM) it represents the most severe forms of myotonic dystrophy. Children with CDM experience hypotonia, respiratory failure, and feeding problems at birth. Both children with CDM and ChDM experience learning difficulty and intellectual impairment in childhood. Nearly 90% of parents with children who have CDM and ChDM reported they were unable to achieve independence. Our Center has followed children with CDM through three prior natural history studies and described a triphasic pattern of progression in childhood with severe motor symptoms in infancy that naturally improve and then regress in adolescence. Interestingly, these clinical changes are reflected in the degree of RNA mis-splicing, the biological signature of DM1. Given the wide age range of participants previously enrolled, additional observations at individual ages will confirm these observations and the study will be enriched by additional longitudinal observations. Children with ChDM have not previously enrolled in natural history studies. Additionally, the degree of RNA mis-splicing in ChDM is unknown. In adults with DM1, the toxic RNA CUG repeat expansion sequesters RNA binding proteins and dysregulates RNA splicing. These changes in RNA splicing are strongly associated with motor function in adults with DM1. Similarly, changes in RNA splicing are associated with changes in function in CDM. The degree of RNA mis-splicing in ChDM is unknown. Here we will enroll 75 children with CDM and 75 children with ChDM for a 24-month observational study, leveraging our prior natural history participants and multinational research network to speed enrollment, described in Aim 1. Children will have longitudinal assessments of motor function, strength, language, cognition, and quality of life. In Aim 2, we will enroll a subset of children with ChDM (n=30) for a cross-sectional muscle biopsy to validate the splice index, a composite measure of RNA dysregulation in DM1, in this population. In the entire cohort we will validate the DEXA as a marker of lean muscle mass and explore blood based proteomic measures that are associated with cognition. In Aim 3, we will seek to build a longitudinal disease progression model of pediatric myotonic dystrophy. We will leverage our three prior studies in pediatric DM1 which include 127 prior participant observations and shared clinical assessments. We will use machine learning techniques to create a model of disease progression across childhood. At the completion of this project, we will have validated the clinical and molecular course of CDM/ChDM disease progression across pediatric development. By better understanding the progression we both allow access of these children to forthcoming disease modifying therapies in myotonic dystrophy.