Characterization of Fine Motor and Visual Motor Skills in Aicardi-Goutières Syndrome.

Aicardi-Goutières syndrome is a genetic inflammatory disorder resulting in dispersed neurologic dysfunction. Despite a recognition of overall motor impairment, fine and visual motor skills are undercharacterized. We hypothesize that there is a spectrum of fine and visual motor skills in the Aicardi-Goutières syndrome population as captured by a standard outcome measure, the Peabody Developmental Motor Scales (PDMS-2), which will be proportional to overall disease severity.In a cohort of 74 subjects, the Peabody Developmental Motor Scales-2 grasping and visual-motor integration subtests were administered concurrently with the Aicardi-Goutières syndrome Severity Scale (severe [range 0-3], moderate [range 4-8], and attenuated [range 9-11]). The cohort was also compared by genotype and performance as defined by raw scores. The distribution of Peabody Developmental Motor Scales-2 scores within a genotype was assessed by interquartile ranges (IQRs).Peabody Developmental Motor Scales-2 grasping and visual-motor integration performance was the least variable in the TREX1-cohort (IQR: 10.00-12.00) versus the SAMHD1 and IFIH1 cohorts (IQR: 51.00-132.00 and 48.50-134.00, respectively). Neurologic severity highly correlated with both fine and visual motor skills (Spearman correlation: r = 0.87, 0.91, respectively). A floor effect (lowest 10% of possible scores) was observed within the severe cohort (n = 32/35), whereas a ceiling effect (top 10%) was observed in the attenuated cohort (n = 13/17).This study characterized the spectrum of fine and visual motor function in the Aicardi-Goutières syndrome population, which correlated with overall neurologic dysfunction. The Peabody Developmental Motor Scales-2 grasping and visual-motor integration showed promise as potential assessment tools in moderate and attenuated Aicardi-Goutières syndrome cohorts. A better understanding of fine and visual motor function in this population will benefit clinical care and clinical trial design.

Multicenter Validation of the Charcot-Marie-Tooth Functional Outcome Measure.

BACKGROUND AND OBJECTIVES: Charcot-Marie-Tooth disease type 1A (CMT1A), caused by a duplication of PMP22, is the most common hereditary peripheral neuropathy. For participants with CMT1A, few clinical trials have been performed; however, multiple therapies have reached an advanced stage of preclinical development. In preparation for imminent clinical trials in participants with CMT1A, we have produced a Clinical Outcome Assessment (COA), known as the CMT-Functional Outcome Measure (CMT-FOM), in accordance with the FDA Roadmap to Patient-Focused Outcome Measurement to capture the key clinical end point of function. METHODS: Participants were recruited through CMT clinics in the United States (n = 130), the United Kingdom (n = 52), and Italy (n = 32). To derive the most accurate signal with the fewest items to identify a therapeutic response, a series of validation studies were conducted including item and factor analysis, Rasch model analysis and testing of interrater reliability, discriminative ability, and convergent validity. RESULTS: A total of 214 participants aged 18-75 years with CMT1A (58% female) were included in this study. Item, factor, and Rasch analysis supported the viability of the 12-item CMT-FOM as a unidimensional interval scale of function in adults with CMT1A. The CMT-FOM covers strength, upper and lower limb function, balance, and mobility. The 0-100 point scoring system showed good overall model fit, no evidence of misfitting items, and no person misfit, and it was well targeted for adults with CMT1A exhibiting high inter-rater reliability across a range of clinical settings and evaluators. The CMT-FOM was significantly correlated with the CMT Examination Score (r = 0.643; p < 0.001) and the Overall Neuropathy Limitation Scale (r = 0.516; p < 0.001). Significantly higher CMT-FOM total scores were observed in participants self-reporting daily trips and falls, unsteady ankles, hand tremor, and hand weakness (p < 0.05). DISCUSSION: The CMT-FOM is a psychometrically robust multi-item, unidimensional, disease-specific COA covering strength, upper and lower limb function, balance, and mobility to capture how participants with CMT1A function to identify therapeutic efficacy.

Association of Body Mass Index With Disease Progression in Children With Charcot-Marie-Tooth Disease.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the impact of body mass index (BMI) on disease progression over 2 years in children with Charcot-Marie-Tooth disease (CMT). METHODS: BMI was classified in 242 participants aged 3-20 years with CMT enrolled in the Inherited Neuropathy Consortium, using the International Obesity Task Force (based on adult BMI values, kg/m2) criteria. Groups were categorized as severely underweight (BMI <17 kg/m2), underweight (BMI ≥17 to <18.5 kg/m2), healthy weight (BMI ≥18.5 to <25 kg/m2), overweight (BMI ≥25 to <30 kg/m2), and obese (BMI ≥30 kg/m2). Disease severity was assessed using the CMT Pediatric Scale (CMTPedS), a clinical outcome assessment of disability (0-44 points, mild to severe). RESULTS: At baseline, compared with individuals being of a healthy weight (mean CMTPedS 15.48, SD 9.22), children who were severely underweight (mean CMTPedS difference 9.03, 95% CI 0.94-17.12; p = 0.02), underweight (mean CMTPedS difference 5.97, 95% CI 0.62-11.31; p = 0.02), or obese (mean CMTPedS difference 7.96, 95% CI 1.03-14.88; p = 0.015) exhibited greater disability. At 2 years, compared with individuals being of a healthy weight (mean CMTPedS 17.53, SD 9.41), children who were severely underweight exhibited greater disability (mean CMTPedS difference 9.27, 95% CI 0.90-17.64; p = 0.02). Over the 2-year periods, the mean CMTPedS for the whole sample deteriorated by 1.72 points (95% CI 1.09-2.38; p < 0.001), with severely underweight children progressing at the fastest rate (mean CMTPedS change of 2.3, 95% CI 1.53-6.13; p = 0.21). In children who did not have a change in BMI categories over 2 years (69% of sample), CMTPedS scores deteriorated faster in those who were severely underweight (mean CMTPedS change 6.40 points, 95% CI 2.42-10.38; p = 0.01) than those of healthy weight (mean CMTPedS change 1.79 points, 95% CI 0.93-2.69; p < 0.001). For children who changed BMI categories (31% of sample), CMTPedS scores deteriorated faster in children who became overweight/obese (mean CMTPedS change 2.76 points, 95% CI 0.11-5.41; p = 0.031). DISCUSSION: Children with CMT who were severely underweight, underweight, or obese exhibited greater disability at baseline. Over the 2-year period in those whose BMI remained stable, severely underweight children deteriorated at the fastest rate. For children who changed BMI categories over the 2 years, CMTPedS scores deteriorated faster in children who became overweight/obese. Interventions that maintain or improve BMI toward healthy weight may reduce disability in children with CMT.

Validation of the parent-proxy version of the pediatric Charcot-Marie-Tooth disease quality of life instrument for children aged 0-7 years.

OBJECTIVE: To evaluate the parent-proxy version of the pediatric Charcot Marie Tooth specific quality of life (pCMT-QOL) outcome instrument for children aged 7 or younger with CMT. We have previously developed and validated the direct-report pCMT-QOL for children aged 8-18 years and a parent proxy version of the instrument for children 8-18 years old. There is currently no CMT-QOL outcome measure for children aged 0-7 years old. METHODS: Testing was conducted in parents or caregivers of children aged 0-7 years old with CMT evaluated at participating INC sites from the USA, United Kingdom, and Australia. The development of the instrument was iterative, involving identification of relevant domains, item pool generation, prospective pilot testing and clinical assessments, structured focus group interviews, and psychometric testing. The parent-proxy instrument was validated rigorously by examining previously identified domains and undergoing psychometric tests for children aged 0-7. RESULTS: The parent-proxy pCMT-QOL working versions were administered to 128 parents/caregivers of children aged 0-7 years old between 2010 and 2016. The resulting data underwent rigorous psychometric analysis, including factor analysis, internal consistency, and convergent validity, and longitudinal analysis to develop the final parent-proxy version of the pCMT-QOL outcome measure for children aged 0-7 years old. CONCLUSIONS: The parent-proxy version of the pCMT-QOL outcome measure, known as the pCMT-QOL (0-7 years parent-proxy) is a valid and sensitive proxy measure of health-related QOL for children aged 0-7 years with CMT.

Validation of the parent-proxy pediatric Charcot-Marie-Tooth disease quality of life outcome measure.

Charcot-Marie-Tooth disease (CMT) reduces health-related quality of life (QOL) in children. We have previously developed and validated the English and Italian versions of the pediatric CMT-specific QOL outcome measure (pCMT-QOL) for children aged 8 to 18. There is currently no parent-proxy CMT QOL outcome measure for use in clinical trials, which could provide complementary information in these children and adolescents. This study describes the validation studies conducted to develop the parent-proxy version of the pCMT-QOL outcome measure for children aged 8 to 18 years old. Development and validation of the parent-proxy version of the pCMT-QOL outcome measure for children aged 8 to 18 years old was iterative, involving identifying relevant domains, item pool generation, prospective pilot testing and clinical assessments, structured focus-group interviews, and psychometric testing, conducted on parents of children with CMT seen at participating sites from the USA, United Kingdom, and Australia. We utilized previously described methods to develop a working parent-proxy version of the pCMT-QOL measure. From 2010 to 2016, the parent-proxy pCMT-QOL working version was administered to 358 parents of children with CMT aged 8 to 18, seen at the participating study sites of the Inherited Neuropathies Consortium. The resulting data underwent rigorous psychometric analysis, including factor analysis, test-retest reliability, internal consistency, convergent validity, IRT analysis, and longitudinal analysis, to develop the final parent-proxy version of the pCMT-QOL outcome measure for children aged 8 to 18 years old. The parent-proxy version of the pCMT-QOL outcome measure is a reliable, valid, and sensitive proxy measure of health-related QOL for children aged 8 to 18 with CMT.

Clinical practice guideline for the management of paediatric Charcot-Marie-Tooth disease.

BACKGROUND AND OBJECTIVES: Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy and often presents during childhood. Guidelines for the optimal management of common problems experienced by individuals with CMT do not exist, for either children or adults. We formed the Paediatric CMT Best Practice Guidelines Consortium to develop evidence and consensus-based recommendations for the clinical management of children and adolescents with CMT, with the primary objective of promoting optimal, standardised care globally. METHODS: Development of this clinical practice guideline involved a series of systematic reviews covering 10 clinical questions, modified Delphi methodology involving an international panel of clinicians to generate consensus where evidence did not exist, and application of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to evaluate the body of literature and formulate recommendations. RESULTS: The final guideline includes three evidence-based and 31 consensus-based recommendations. They encompass the management of muscle weakness, balance and mobility impairment, sensory symptoms, muscle cramps, impaired upper limb function, respiratory impairment, maintenance of joint range of motion and non-surgical management of joint deformity. Consensus was not achieved in some management areas, reflecting differences in practice between clinicians and healthcare settings, and highlighting the need for further research. CONCLUSIONS: This clinical practice guideline provides practical and implementable guidance on the management of common clinical problems experienced by children with CMT and advocates for improved access to multidisciplinary care. Successful dissemination and implementation of these recommendations will be critical in ensuring their application across multiple healthcare settings.

Association Between Body Mass Index and Disability in Children With Charcot-Marie-Tooth Disease.

BACKGROUND AND OBJECTIVES: This study examined the association between body mass index (BMI) and disability in children with Charcot-Marie-Tooth disease (CMT). METHODS: We conducted a cross-sectional analysis of 477 patients with CMT who were 3 to 20 years of age from the Inherited Neuropathy Consortium and 316 age- and sex-matched healthy children from the 1,000 Norms Project. BMI was categorized according to the International Obesity Task Force (IOTF) criteria, and BMI categorization was compared with healthy children. IOTF categories (adult equivalent BMI cut points) were severely underweight (BMI <17 kg/m2), underweight (BMI ≥17-<18.5 kg/m2), healthy weight (BMI ≥18.5-<25 kg/m2), overweight (BMI ≥25-<30 kg/m2), and obese (BMI ≥30 kg/m2). Scores on the 0 to 44-point CMT Pediatric Scale (CMTPedS), a well-validated measure of disability, were examined in relation to BMI. RESULTS: There was a higher proportion of children with CMT categorized as severely underweight (5.7% vs 0.3%), underweight (10.3% vs 5.1%), and obese (7.3% vs 3.8%) (p < 0.05). Fewer children with CMT were categorized as healthy weight (61.8% vs 74.4%) (p < 0.05), and the proportion of overweight (14.9% vs 16.5%) between groups was similar. CMTPedS scores (mean ± SD) for weight categories were as follows: severely underweight 27 ± 9, underweight 20 ± 8, healthy weight 17 ± 9, overweight 17 ± 9, and obese 22 ± 10. Compared to children with a healthy weight with CMT, being severely underweight was associated with being more disabled (p < 0.001), as was being obese (p = 0.015). DISCUSSION: The proportion of children with CMT who are underweight or obese is higher compared to age- and sex-matched healthy children. In children with CMT, being underweight or obese is associated with greater disability, when compared to children with CMT of healthy weight.

Development and Validation of the Pediatric Charcot-Marie-Tooth Disease Quality of Life Outcome Measure.

OBJECTIVE: Charcot-Marie-Tooth disease (CMT) reduces health-related quality of life (QOL), especially in children. Defining QOL in pediatric CMT can help physicians monitor disease burden clinically and in trials. We identified items pertaining to QOL in children with CMT and conducted validation studies to develop a pediatric CMT-specific QOL outcome measure (pCMT-QOL). METHODS: Development and validation of the pCMT-QOL patient-reported outcome measure were iterative, involving identifying relevant domains, item pool generation, prospective pilot testing and clinical assessments, structured focus-group interviews, and psychometric testing. Testing was conducted in children with CMT seen at participating sites from the USA, United Kingdom, and Australia. RESULTS: We conducted systematic literature reviews and analysis of generic QOL measures to identify 6 domains relevant to QOL in children with CMT. Sixty items corresponding to those domains were developed de novo, or identified from literature review and CMT-specific modification of items from the pediatric Neuro-QOL measures. The draft version underwent prospective feasibility and face content validity assessments to develop a working version of the pCMT-QOL measure. From 2010 to 2016, the pCMT-QOL working version was administered to 398 children aged 8 to 18 years seen at the participating study sites of the Inherited Neuropathies Consortium. The resulting data underwent rigorous psychometric analysis, including factor analysis, test-retest reliability, internal consistency, convergent validity, item response theory analysis, and longitudinal analysis, to develop the final pCMT-QOL patient-reported outcome measure. INTERPRETATION: The pCMT-QOL patient-reported outcome measure is a reliable, valid, and sensitive measure of health-related QOL for children with CMT. ANN NEUROL 2021;89:369-379.

Reliability of the Charcot-Marie-Tooth functional outcome measure.

The CMT-FOM is a 13-item clinical outcome assessment (COA) that measures physical ability in adults with Charcot-Marie-Tooth disease (CMT). Test-retest reliability, internal consistency and convergent validity have been established for the CMT-FOM. This current study sought to establish inter-rater reliability. Following an in-person training of six international clinical evaluators we recruited 10 participants with genetically diagnosed CMT1A, (aged 18-74 years, 6 female). Participants were evaluated using the CMT-FOM over 2 days. Participants were given at least a 3 hour rest between evaluations, and were assessed twice each day. Following the provision of training by master trainers, all 13 items of the CMT-FOM exhibited excellent inter-rater reliability for raw scores (ICC1,1 0.825-0.989) and z-scores (ICC1,1 0.762-0.969). Reliability of the CMT-FOM total score was excellent (ICC1,1 0.983, 95% CI 0.958-0.995). The CMT-FOM is a reliable COA used by clinical evaluators internationally. The next steps are to establish further validation through psychometric evaluation of the CMT-FOM in the Accelerate Clinical Trials in CMT (ACT-CMT) study.

Improving Temporomandibular Range of Motion in People With Duchenne Muscular Dystrophy and Spinal Muscular Atrophy.

IMPORTANCE: People with Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) develop impaired oral function because of reduced temporomandibular joint range of motion (ROM), which affects feeding and oral hygiene activities of daily living (ADLs). OBJECTIVE: To assess whether the TheraBite®, an intraoral stretching device, improves ROM. DESIGN: Case series, with intervention duration varying from 7 to 30 mo. Treatment frequency varied from weekly to consultative (several times per year). SETTING: Varied depending on the ease of transportation for the participant and caregivers. Two participants were treated in an outpatient medical clinic. The other was provided consultative care during multidisciplinary medical clinics and completed a home program. PARTICIPANTS: Two adults with DMD and one with SMA. INTERVENTION: Stretching protocol using the TheraBite. OUTCOMES AND MEASURES: Temporomandibular active ROM (AROM) was determined using a disposable TheraBite oral goniometer. Passive ROM (PROM) was determined using the adhesive scale on the TheraBite. Measures were taken at baseline, each intervention or consultation, and the end of care. ADL participation and caregiver burden were measured at the end of intervention. RESULTS: For participants with DMD, AROM remained unchanged, but PROM increased by 40%-65%. The participant with SMA demonstrated 33% and 47% improvements in AROM and PROM, respectively. Participants or caregivers reported improved feeding function, improved oral hygiene, or reduced fatigue. CONCLUSION: TheraBite may improve temporomandibular PROM in people with DMD and temporomandibular AROM and PROM in people with SMA. It may also improve ADL function and consequently reduce caregiver burden. Further investigation is warranted. WHAT THIS ARTICLE ADDS: Temporomandibular contracture in people with DMD and SMA contributes to reduced lifespan and loss of function. Use of the TheraBite with this population may preserve temporomandibular ROM and improve feeding, hygiene, and quality-of-life outcomes.

Balance impairment in pediatric charcot-marie-tooth disease.

INTRODUCTION: Balance impairment contributes to gait dysfunction, falls, and reduced quality of life in adults with Charcot-Marie-Tooth disease (CMT) but has been minimally examined in pediatric CMT. METHODS: The CMT Pediatric Scale (CMTPedS) was administered to 520 children with CMT. Associations between balance function (Bruininks-Oseretsky Test of Motor Proficiency [BOT-2]) and sensorimotor and gait impairments were investigated. RESULTS: Daily trips/falls were reported by 42.3% of participants. Balance (BOT-2) varied by CMT subtype, was impaired in 42% of 4-year-olds, and declined with age (P < 0.001). Vibration (P < 0.001), pinprick (P < 0.004), ankle dorsiflexion strength (P < 0.001), and foot alignment (P < 0.004) were associated with BOT-2 balance (adjusted R2 = 0.28). The visual dependence of balance increased with age. DISCUSSION: Balance impairment occurs from a young age in children with CMT. Balance intervention studies are required in pediatric CMT and should consider the degree of sensorimotor impairment, foot malalignment, and visual dependence. Muscle Nerve, 2019.

Development and validation of the Charcot-Marie-Tooth Disease Infant Scale.

Many genetic subtypes of Charcot-Marie-Tooth disease (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. In the absence of disease-specific clinical trial outcome measures for CMT during infancy and early childhood the aim of this study was to develop and validate a functional measure of disease severity, known as the Charcot-Marie-Tooth disease Infant Scale (CMTInfS). Development projects involved identification of a preliminary pool of 31 items representing the range of disability in affected patients aged 0-4 years from a systematic review of the literature, peer review by 12 expert clinicians and researchers in the field, design of a scoring algorithm and pilot testing in 22 participants. Subsequently, a series of validation projects were conducted based on 128 assessments of: 26 confirmed cases of inherited neuropathy (17 CMT1A, one CMT1B, one CMT1D, one CMT2C, one CMT2S, two CMT4C, one CMTX3, one Riboflavin Transporter Deficiency Type 2, and one unidentified mutation); seven 'at risk' cases and 95 unaffected healthy controls recruited through the NIH-funded Inherited Neuropathies Consortium. Validation projects included: Item, Factor and Rasch analysis, intra- and inter-rater reliability, discriminant ability and convergent validity with the CMT Pediatric Scale (CMTPedS) for children aged 3-4 years. Development and validation projects produced a psychometrically robust 15-item scale. Rasch analysis supported the viability of the CMTInfS as a unidimensional measure of disease severity and showed good overall model fit, no evidence of misfitting items or persons and was well targeted for affected children. The CMTInfS demonstrated high intra-rater reliability [intraclass correlation coefficient (ICC)3,1 0.999, 95% confidence interval 0.996-1.000) and inter-rater reliability (ICC2,1 0.997, 95% confidence interval 0.992-0.999). The CMTInfS was able to discriminate between the CMT group and controls (P = 0.006), and convergent validity demonstrated good agreement between CMTInfS and CMTPedS scores (r = 0.76, P = 0.01). The final version of the CMTInfS requires 20 min to administer and is a reliable and sensitive functional outcome measure for early onset CMT and related neuropathies.10.1093/brain/awy280_video1awy280media15970672819001.

Use of the Wilmington Robotic Exoskeleton to Improve Upper Extremity Function in Patients With Duchenne Muscular Dystrophy.

Patients with Duchenne muscular dystrophy in their second decade of life present with decreased upper extremity strength and active range of motion (AROM) that limit activities of daily living (ADLs). We evaluated the ability of the Wilmington Robotic Exoskeleton (WREX) to improve AROM and independence with ADLs. A retrospective chart review of 9 patients who trialed the WREX was performed. Patients were classified on the basis of the Brooke Upper Extremity Scale. AROM, strength, and independence with ADLs were assessed before and after a WREX trial. Patients demonstrated increased shoulder flexion and abduction (25°-100°, median = 55°) and elbow flexion (10°-110°, median = 60°). Increased independence with self-feeding, item retrieval, use of phones and tablets, and facial grooming were noted. The WREX allowed for gravity-reduced movement via elastic bands to unweight the upper extremity, enabling increased upper extremity active movement that supported increased independence with ADLs.

Natural history of Charcot-Marie-Tooth disease during childhood.

OBJECTIVE: To determine the rate of disease progression in a longitudinal natural history study of children with Charcot-Marie-Tooth (CMT) disease. METHODS: Two hundred six (103 female) participants aged 3 to 20 years enrolled in the Inherited Neuropathies Consortium were assessed at baseline and 2 years. Demographic, anthropometric, and diagnostic information were collected. Disease progression was assessed with the CMT Pediatric Scale (CMTPedS), a reliable Rasch-built linearly weighted disability scale evaluating fine and gross motor function, strength, sensation, and balance. RESULTS: On average, CMTPedS Total scores progressed at a rate of 2.4 ± 4.9 over 2 years (14% change from baseline; p < 0.001). There was no difference between males and females (mean difference, 0.5; 95% confidence interval [CI], -0.9 to 1.9; p = 0.49). The most responsive CMTPedS items were dorsiflexion strength (z-score change, -0.3; 95% CI, -0.6 to -0.05; p = 0.02), balance (z-score change, -1.0; 95% CI, -1.9 to -0.09; p = 0.03), and long jump (z-score change, -0.4; 95% CI, -0.7 to -0.02; p = 0.04). Of the most common genetic subtypes, 111 participants with CMT1A/PMP22 duplication progressed by 1.8 ± 4.2 (12% change from baseline; p < 0.001), 9 participants with CMT1B/MPZ mutation progressed by 2.2 ± 5.1 (11% change), 6 participants with CMT2A/MFN2 mutation progressed by 6.2 ± 7.9 (23% change), and 7 participants with CMT4C/SH3TC2 mutations progressed by 3.0 ± 4.5 (12% change). Participants with CMT2A progressed faster than CMT1A (mean difference, -4.4; 95% CI, -8.1 to -0.8; p = 0.02). Children with CMT1A progressed consistently through early childhood (3-10 years) and adolescence (11-20 years; mean difference, 1.1; 95% CI, -0.6 to 2.7; p = 0.19), whereas CMT2A appeared to progress faster during early childhood than adolescence (mean difference, 10.0; 95% CI, -2.2 to 22.2; p = 0.08). INTERPRETATION: Using the CMTPedS as an outcome measure of disease severity, children with CMT progress at a significant rate over 2 years. Understanding the rate at which children with CMT deteriorate is essential for adequately powering trials of disease-modifying interventions. Ann Neurol 2017;82:353-359.

Phenotypic Variability of Childhood Charcot-Marie-Tooth Disease.

IMPORTANCE: Disease severity of childhood Charcot-Marie-Tooth disease (CMT) has not been extensively characterized, either within or between types of CMT to date. OBJECTIVE: To assess the variability of disease severity in a large cohort of children and adolescents with CMT. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study was conducted among 520 children and adolescents aged 3 to 20 years at 8 universities and hospitals involved in the Inherited Neuropathies Consortium between August 6, 2009, and July 31, 2014, in Australia, Italy, the United Kingdom, and the United States. Data analysis was conducted from August 1, 2014, to December 1, 2015. MAIN OUTCOMES AND MEASURES: Scores on the Charcot-Marie-Tooth Disease Pediatric Scale (CMTPedS), a well-validated unidimensional clinical outcome measure to assess disease severity. This instrument includes 11 items assessing fine and gross motor function, sensation, and balance to produce a total score ranging from 0 (unaffected) to 44 (severely affected). RESULTS: Among the 520 participants (274 males) aged 3 to 20 years, CMT type 1A (CMT1A) was the most prevalent type (252 [48.5%]), followed by CMT2A (31 [6.0%]), CMT1B (15 [2.9%]), CMT4C (13 [2.5%]), and CMTX1 (10 [1.9%]). Disease severity ranged from 1 to 44 points on the CMTPedS (mean [SD], 21.5 [8.9]), with ankle dorsiflexion strength and functional hand dexterity test being most affected. Participants with CMT1B (mean [SD] CMTPedS score, 24.0 [7.4]), CMT2A (29.7 [7.1]), and CMT4C (29.8 [8.6]) were more severely affected than those with CMT1A (18.9 [7.7]) and CMTX1 (males: 15.3 [7.7]; females: 13.0 [3.6]) (P < .05). Scores on the CMTPedS tended to worsen principally during childhood (ages, 3-10 years) for participants with CMT4C and CMTX1 and predominantly during adolescence for those with CMT1B and CMT2A (ages, 11-20 years), while CMT1A worsened consistently throughout childhood and adolescence. For individual items, participants with CMT4C recorded more affected functional dexterity test scores than did those with all other types of CMT (P < .05). Participants with CMT1A and CMTX1 performed significantly better on the 9-hole peg test and balance test than did those with all other types of CMT (P < .05). Participants with CMT2A had the weakest grip strength (P < .05), while those with CMT2A and CMT4C exhibited the weakest ankle plantarflexion and dorsiflexion strength, as well as the lowest long jump and 6-minute walk test distances (P < .05). Multiple regression modeling identified increasing age (r = 0.356, ß = 0.617, P < .001) height (r = 0.251, ß = 0.309, P = .002), self-reported foot pain (r = 0.162, ß = .114, P = .009), and self-reported hand weakness (r = 0.243, ß = 0.203, P < .001) as independent predictors of disease severity. CONCLUSIONS AND RELEVANCE: These results highlight the phenotypic variability within CMT genotypes and mutation-specific manifestations between types. This study has identified distinct functional limitations and self-reported impairments to target in future therapeutic trials.