TREAT-CDM

Principal Investigator: Nicholas Johnson
Keywords: neuromuscular , Congenital Myotonic Dystrophy Department: Neurology
IRB Number: 00094914 Co Investigator: Russell Butterfield
Specialty: Neurology, Neurology
Sub Specialties: Neuromuscular Diseases, Muscular Dystrophy
Recruitment Status: Recruiting

Contact Information

Becky  Crockett
bcrockett@genetics.utah.edu
801-585-1676

Brief Summary

This proposal will utilize the established subject cohorts at the University of Utah and University of Western Ontario, and will include the NEMO Clinical Center (Neuromuscular Omnicomprehensive Clinical Center - Milan, Italy).  We will further establish our experienced clinical network to be able to conduct clinical trials in CDM.  We hypothesize that a combination of right grip strength, lip force, and a disease specific patient reported outcome, the CCMDHI, will prove appropriate endpoints in CDM.  The mean muscle mass of the right arm and leg as measured by DEXA, and RNA splicing changes will provide appropriate biomarkers.  We will enroll 100 children with CDM between ages 0-15 and 50 healthy children between ages 0-15 with visits at baseline and one year to test the following Specific Aims:

 

1.  To evaluate appropriate physical functional outcomes for children with CDM.  Based on cross sectional data, two outcome measures hold promise as primary endpoints, right grip strength and lip force.  Other measures of strength and function, such as the 6-minute walk distance will be evaluated.  Outcome measures will be evaluated for responsiveness to change.  The CDM cohort will be evaluated for a time interval of more rapid disease progression.

2.  To evaluate appropriate measures of cognitive function and quality of life in children with CDM.  We hypothesize that the BRIEF, a measure of executive function, will be the most sensitive cognitive endpoint and that the CCMDHI, a disease specific patient and parent reported outcome measure will be the most sensitive measure of quality of life.  Other exploratory cognitive measures, such as adaptive function will be evaluated.  Analyses for cohort disease progression and measure responsiveness will be evaluated, similar to Aim 1.

3.  Correlate the functional outcome measures with potential biomarkers (DEXA and muscle RNA splicing) in CDM. We will pursue fine needle muscle biopsies at baseline to evaluate known RNA splicing events correlated with adult DM1.  In the cross sectional data, lean muscle mass of the right arm and leg, as measured by DEXA, correlated with a number of functional outcome measures. These outcomes are critical to evaluate the correlation between the underlying pathophysiology with the clinical outcomes. 

 

Completion of these Specific Aims will extend the understanding of disease progression in CDM and will provide the requisite information for successful therapeutic trials in children with DM.  Such information is imminently needed given ongoing therapeutic trials in adults with DM1.  In addition, the evaluation of RNA splicing changes in CDM will provide a greater understanding of the underlying pathophysiology in childhood.

Inclusion Criteria

Inclusion criteria, CDM group: 

  1. Participants rolling over from HELP-CDM (IRB_00066988): Age 1-15 years, 11 months at enrollment/roll-over visit
  2. New participants enrolling: Age 0-14 years, 11 months at enrollment. 
  3. A diagnosis of CDM, which is defined as children having symptoms of myotonic dystrophy in the newborn period (<30 days), such as hypotonia, feeding or respiratory difficulty, requiring hospitalization to a ward or to the neonatal intensive care unit for more than 72 hours; and a genetic test confirming an expanded trinucleotide (CTG) repeat in the DMPK gene in the child or mother. An expanded CTG repeat size in the child is considered greater than 200 repeats or E1–E4 classification (E1= 200–500, E2=500–1,000, E3=1,000–1,500, E4>1,500).

Inclusion criteria, controls:

  1. Participants rolling over from HELP-CDM: Age 1-15 years, 11 months at enrollment
  2. New participants enrolling: Age 0-14 years, 11 months at enrollment. 
  3. Healthy children on no medication

 

 

Exclusion Criteria

Exclusion criteria, CDM group:

  1. Any other non-DM1 illness that would interfere with the ability or results of the study in the opinion of the site investigator
  2. Significant trauma within one month
  3. Internal metal or devices (exclusion for DEXA component)

Exclusion criteria, controls:

  1. Any illness or social situation that, in the opinion of the site investigator, has the possibility to interfere with study procedures
  1. DM types 1 and 2