Development and validation of the Charcot-Marie-Tooth disease Infant Scale

Abstract

Charcot-Marie-Tooth disease (CMT) is the most commonly inherited neuropathy. Many genetic subtypes of CMT show signs of symptomatic disease during the earliest years of life. This might be the ideal time to intervene before progression of clinical sequelae due to demyelination and axonal loss. No outcome measures have been validated for infants <3 years with CMT, a barrier to conducting trials for disease-modifying interventions, as well as running natural history studies (Chapter One). Existing outcome measures for the assessment of disease severity for infants with neuromuscular disease were systematically reviewed (Chapter Two). No CMT-specific outcome measures were identified, yet several items were appropriate to contribute to a new outcome measure: the CMT Infant Scale (CMTInfS). Peer review by 12 experts in the NIH-funded Inherited Neuropathies Consortium, and pilot testing of 22 infants confirmed the 31-item preliminary CMTInfS to undergo validation studies across 7 international sites (Chapter Three). In Chapter Four, excellent intra-rater and inter-rater reliability of CMTInfS total scores showed acceptable agreement both within (ICC3,1 0.994, 95% CI3,1 0.985 – 0.997) and between (ICC2,10.997, 95% CI 0.993 – 0.999) evaluators. Validation studies were conducted based on data from 128 infants: 26 confirmed CMT cases, 7 ‘at risk’ cases of CMT and 95 healthy controls (Chapter Five). Item, Factor and Rasch analyses produced a psychometrically robust 15-item functional outcome measure. The CMTInfS can be completed in 20min, requiring minimal training for experienced paediatric clinicians/researchers. Using age-matched z-scores to account for normal growth and development, the CMTInfS can discriminate between infants with CMT and controls. There was good agreement with the CMT Pediatric Scale. With further longitudinal data collection of different CMT genetic subtypes (Chapter Six), the CMTInfS will be trial-ready to evaluate potential treatments for CMT.