We propose to longitudinally characterize the symptoms and functional outcomes associated with CDM disease progression in early and late childhood to develop a model for symptom development and progression. This study will enroll sixty children with CDM and 30 control subjects with stratified recruitment into four cohorts (birth to 2 years, 11 months; 3 years to 5 years, 11 months; 6 years to 8 years, 11 months; and 9 years to 13 years, 11 months) in order to address the following Specific Aims.
To determine in a prospective manner important clinical endpoints for children with CDM and establish reliability, validity, and responsiveness of these endpoints at differing stages of the disease. These endpoints include medical morbidity and mortality, neuropsychological function, oral facial weakness, muscle weakness, respiratory function, gastrointestinal function, and cardiac conduction. These endpoints will be evaluated for feasibility, test-retest reliability, and responsiveness to change. Determining these profiles will provide accurate and impactful endpoints that may be extended to therapeutic trials.
To validate the disease specific, patient reported outcome measure developed for CDM by assessing its correlation with generic quality of life measures and functional outcome measures using the cross sectional and longitudinal data obtained in Aim 1. This validation process will assess the test-retest reliability, responsiveness of the patient-reported outcome measure-to-measure change, and the validity of the measurement compared to functional outcome measures and generic quality of life scores. In addition, analysis of the patient and parent proxy instruments completed by both parents and educators will assess the ability of various proxies to measure symptom impact and concordance between the proxy and patient instruments. At the completion of this Aim we will have a reliable, valid, and responsive patient reported outcome measure capable of measuring the aggregate symptom impact in this multi-system disease.
To evaluate potential biomarkers, including RNA splicing ratios, PGE2 levels, and lean muscle mass. Prior RNA splicing biomarkers may not be practical in young children. We will assess the ability to obtain accurate RNA splicing ratios and microRNA differences in blood samples. We will extend prior work evaluating a potential difference in PGE2 levels in CDM samples by assessing in vivo PGE2 levels in blood and urine. Lean body mass, as measured by DEXA, will be determined in a subset of children able to cooperate with this procedure. This imaging modality, which has been used commonly in other pediatric NM conditions, may be an important imaging biomarker reflecting muscle mass and may be responsive to change over time and change due to intervention.
Principal Investigator: Nicholas Johnson
Co Investigator: Amy Powell
Co Investigator: Heather Hayes
Co Investigator: Sara Woltz
Co Investigator: Melissa Dixon
Co Investigator: Sandar Reyna-Merida
Co Investigator: Robert Burr
Co Investigator: Russell Butterfield