Measuring disease severity in children with Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy, affecting approximately 1 in 1,214 to 2,500 individuals, or approximately 3-6 million people worldwide. It is a progressive disease, characterised by upper and lower limb distal weakness, sensory loss, and foot deformities (e.g. cavovarus, hammer toes). However CMT is phenotypically and genetically diverse with >80 types identified, therefore it is important to measure disease severity and progression both within and between types of CMT. Despite effective therapies to manage the disease, no curative or disease-modifying treatments exist. Reliable, valid and meaningful outcome measures for patients at the earliest stage of disease, namely childhood, are essential to determine the effectiveness of pharmaceutical, surgical and rehabilitative interventions. Therefore, the aim of this thesis was to identify and evaluate the sensitivity and responsiveness of performance-based outcome measures and biomarkers of disease severity in children and adolescents with CMT. To achieve this aim, the objectives of this thesis were to assess the sensitivity of an established outcome measure (CMT Pediatric Scale (CMTPedS)), explore the feasibility of a new biomarker (MRI), and to comprehensively evaluate hand and upper limb function between children with CMT1A and Riboflavin Transporter Deficiency type 2 (a generalised sensory neuropathy with upper limb predominant motor neuropathy), using established and novel outcome measures. The final objective of the thesis was to assess the longitudinal responsiveness of the CMTPedS, both within and between types of CMT, in order to establish the natural history of the disease during childhood. The sensitivity of the CMTPedS was conducted in collaboration with the Inherited Neuropathies Consortium whereby 520 affected children were assessed to determine the range of disease severity and differences between genetic types. The CMTPedS is a well- validated 11-item performance-based outcome measure capturing fine and gross motor function, strength, sensation and balance, with scores ranging from 0 (unaffected) to 44 (severely affected). The main findings were that children with CMT1B, CMT2A and CMT4C were more severely affected than children with the most common form of CMT, CMT1A. Differences existed within certain items of the CMTPedS between types. Namely, children with CMT4C had more impaired hand function, children with CMT2A had lower grip strength and children with both CMT2A and CMT4C had lower foot strength (Chapter Two). This study was published in JAMA Neurology. To explore the feasibility of MRI as a new biomarker for disease severity, a novel technique in Materialise Mimics® Software was used to calculate muscle and intramuscular fat volume in the anterior compartment of the lower leg, responsible for foot dorsiflexion, in 55 affected children. The MRI protocol was shown to be feasible, reliable and sensitive to the magnitude of weakness (hand-held dynamometry), disability (CMTPedS) and walking difficulties (3D gait analysis) in children with CMT. Muscle volume, in particular, might provide an early indication of the safety and efficacy of therapies in trials of affected children. (Chapter Three). In Chapter Four, existing and new upper limb measures of strength, function, fatigue and sensation were evaluated in a pilot study of four children with CMT1A and four children with RTD2 (for an upper limb predominant motor neuropathy comparison) and compared to four age and sex-matched healthy controls. Strength of the small muscles of the hands assessed by hand-held dynamometry and timed functional tasks were the most sensitive items of upper limb impairment in CMT1A and RTD2. Finally, the longitudinal responsiveness of the CMTPedS, both within and between types of CMT, was assessed over 2 years in 206 affected children. The overall rate of disease progression was 2.4±4.9 CMTPedS points over 2 years (14% change from baseline). In CMT1A, the rate of progression was 1.8±4.2 CMTPedS points over 2 years (12% change from baseline). These findings provide important natural history data for designing and powering future clinical trials (Chapter Five). This study was published in Annals of Neurology. The studies in this thesis provide extensive baseline and natural history data for the CMTPedS, supporting its use in therapeutic trials. Further, muscle and fat volume of the anterior compartment of the lower leg measured by MRI was identified as a potentially sensitive biomarker for disease severity, strength and walking ability. However, the responsiveness to change needs to be evaluated in longitudinal studies. Finally, several existing and some new measures of upper limb impairment, particularly in strength and function, were identified as potentially useful outcome measures of rehabilitative therapy in affected children in the future. Overall, this thesis has identified and evaluated several feasible, reliable and valid measures of disease severity in affected children and adolescents for use in clinical trials of the most common types of CMT, such as CMT1A, and further natural history studies of the rarer forms, such as CMTX3, CMT1E, CMTX1 and CMT2D