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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.

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., Competing Interests: Competing interests: MES has received consulting fees or honoraria from Inflectis Bioscience, Passage Biosci and Mitochondria in Motion, Temple University and Albert Einstein Medical College, and is the Chair of the CMT and Related Disorders (CMTR) Consortium of the Peripheral Nerve Society. SR has been employed at the Janssen Pharmaceutical Companies of Johnson & Johnson since January 2021 and has restricted stock options. Her contributions to the paper were made prior to her current employment. IM is a board member of the CMTR Consortium of the Peripheral Nerve Society. CES is a voluntary advisory board member of the CMT Association. EMY, PB, JBa, SKB, NB, KdV, TE, MAF, RSF, JH, RAK, GAN, MaMR, KR, SWY, MPM, MoMR and JBu report no competing interests., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

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 (ICC 1,1 0.825-0.989) and z-scores (ICC 1,1 0.762-0.969). Reliability of the CMT-FOM total score was excellent (ICC 1,1 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., (© 2020 Peripheral Nerve Society.)

The CMT Pediatric Scale (CMTPedS) is a reliable, valid, and responsive clinical outcome measure of disability in children with CMT. The aim of this study was to identify the most responsive patient subset(s), based on the standardized response mean (SRM), to optimize the CMTPedS as a primary outcome measure for upcoming clinical trials. Analysis was based on a 2-year natural history data from 187 children aged 3-20 years with a range of CMT genetic subtypes. Subsets based on age (3-8 years), disability level (CMTPedS score 0-14), and CMT type (CMT1A) increased the SRM of the CMTPedS considerably. Refining the inclusion criteria in clinical trials to younger, mildly affected cases of CMT1A optimizes the responsiveness of the CMTPedS., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

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 R 2 = 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., (© 2019 Wiley Periodicals, Inc.)

Introduction: Biomarkers of disease severity in Charcot-Marie-Tooth disease (CMT) are required to evaluate early responses to treatment. In this study we used magnetic resonance imaging (MRI) to evaluate the relationship between muscle volume and intramuscular fat accumulation with weakness, disability, and impaired gait in affected children and adolescents., Methods: Fifty-five participants underwent MRI of the anterior compartment of the lower leg. Muscle and fat volumes were calculated. Strength was measured using hand-held dynamometry, disability using the CMT Pediatric Scale, and 3-dimensional gait analysis using an 8-camera Vicon Nexus motion capture system., Results: Lower muscle volume was significantly associated with reduced dorsiflexion strength, increased disability, impaired gait profile score, and foot drop. Intramuscular fat accumulation was associated with reduced dorsiflexion strength and impaired gait profile score., Discussion: The MRI protocol described was feasible, reliable, and sensitive to the magnitude of weakness, disability, and walking difficulties in children with CMT. Muscle Nerve 59:213-217, 2019., (© 2018 Wiley Periodicals, Inc.)

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&#95;video1awy280media15970672819001.

Hand function is a problem in patients with Charcot-Marie-Tooth disease type 1A (CMT1A) and Riboflavin Transporter Deficiency type 2 (RTD2). However, a detailed understanding of upper limb involvement in these conditions is lacking. The aim of this pilot study was to compare hand and upper limb function between children with CMT1A, RTD2 and healthy controls using established and novel outcome measures. Three age-and sex-matched groups of four children (5-15 years, 1 male/group) with CMT1A, RTD2, and healthy controls were assessed for function, strength, and sensation. Fatigue and muscle activity of the FDI was also assessed using a submaximal contraction at 40% of the participants' maximal voluntary contraction. Functional measures were most affected in children with RTD2 followed by children with CMT1A, compared to healthy controls. Strength was similarly impaired in CMT1A and RTD2 compared to controls (p < 0.05). Sensation was significantly impaired in RTD2 compared to CMT1A and controls (p = 0.008). While time to fatigue did not differ between groups, a decline in muscle activity while force remained constant showed that controls compensated with other muscles during the fatigue task while children with CMT1A and RTD2 did not have this compensatory ability. Children with CMT1A and RTD2 exhibited marked hand/upper limb impairment. These results suggest the upper limb should be a focus of rehabilitative therapy in affected children using sensitive outcome measures of strength and sensation, as well as functional activities of daily living, which are most relevant to the patient., (© 2017 Peripheral Nerve Society.)

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., (© 2017 American Neurological Association.)

Hand weakness and impaired manual dexterity have been reported in children with Charcot-Marie-Tooth disease type 1A (CMT1A). This early onset of upper limb involvement might explain frequent clinical referrals for assessment and treatment of impaired handwriting performance. The aim of this study was to examine the impact of CMT1A on handwriting speed and legibility, and identify demographic, anthropometric, and physical measures that might relate to handwriting performance. Handwriting speed (Handwriting Speed Test), handwriting legibility (Evaluation Tool of Children's Handwriting-Cursive), and hand strength (hand-held dynamometry of tip pinch, lateral pinch and grip) were assessed in 30 children with CMT1A (aged 8-17 years) and 30 age- and sex-matched controls. Children with CMT1A exhibited 34% slower handwriting speed (p < 0.0001) with 4% reduced legibility (p = 0.001) and 37-48% lower hand strength (p < 0.0001). All measures of strength, age, height, and weight were positively associated with handwriting speed (r = 0.39-0.79, p < 0.01). None of these factors related to handwriting legibility (p > 0.05). Regression modelling identified a diagnosis of CMT1A, lateral pinch weakness and younger age as significant independent predictors of slower handwriting speed, explaining 78% of the variance. Children with CMT1A have considerable handwriting difficulties, primarily with speed, and substantial associated hand and finger weakness. Understanding the cause-effect relationship between strength and function might provide modifiable targets for upper limb intervention., (© 2016 Peripheral Nerve Society.)

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, β = 0.617, P < .001) height (r = 0.251, β = 0.309, P = .002), self-reported foot pain (r = 0.162, β = .114, P = .009), and self-reported hand weakness (r = 0.243, β = 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.

Aim: To investigate parent-reported health status of boys with Duchenne muscular dystrophy (DMD) compared with a large Australian normative population and a cohort of children with Charcot-Marie-Tooth disease type 1A (CMT1A)., Methods: The Child Health Questionnaire parent form (CHQ-PF50) was completed by parents of 34 boys with confirmed DMD. Seventeen parents were followed up at 6 months. CHQ-PF50 data were compared with 2620 age-matched norms and 90 children with CMT1A., Results: All domains of the CHQ-PF50 for the DMD cohort were significantly lower than the general paediatric population, particularly for physical functioning (t = -17.2, P < 0.001) and the child's ability to fulfil school and social roles because of physical limitations (t = -9.4, P < 0.001). Parents experienced greatest emotional impact of their child's DMD around the time of loss of ambulation. Children with DMD had lower health status compared with children with CMT1A with the exception of the behaviour and pain domains. Physical functioning worsened during 6 months (P = 0.04); no other changes in health status were observed at follow-up., Conclusions: Parents report the impact of DMD on health status to be considerably worse when compared with CMT1A. Interventions should target minimising the impact of physical limitations on role functioning., (© 2011 The Authors. Journal of Paediatrics and Child Health © 2011 Paediatrics and Child Health Division (Royal Australasian College of Physicians).)

Charcot-Marie-Tooth disease type 1A (CMT1A), a demyelinating neuropathy characterised by progressive length-dependent muscle weakness and atrophy, is thought to affect the foot and leg first followed some time later by hand weakness and dysfunction. We aimed to characterise hand strength, function and disease-related symptoms in children with CMT1A. Intrinsic and extrinsic hand strength was measured by hand-held dynamometry, function by nine-hole peg test, and disease-related symptoms by interview and examination in 84 affected children aged 2-16 years. Hand weakness and dysfunction was present from the earliest stages of the disease. While hand strength and function measures tended to increase with age throughout childhood, at no point did they reach normal values. Day-to-day hand problems such as poor handwriting, weakness, pain and sensory symptoms also worsened with age. The hand is affected at all ages in children with CMT1A, but may be under-recognised in its early stages, potentially delaying therapy.

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. [ABSTRACT FROM AUTHOR]

Hand function is a problem in patients with Charcot‐Marie‐Tooth disease type 1A (CMT1A) and Riboflavin Transporter Deficiency type 2 (RTD2). However, a detailed understanding of upper limb involvement in these conditions is lacking. The aim of this pilot study was to compare hand and upper limb function between children with CMT1A, RTD2 and healthy controls using established and novel outcome measures. Three age‐and sex‐matched groups of four children (5–15 years, 1 male/group) with CMT1A, RTD2, and healthy controls were assessed for function, strength, and sensation. Fatigue and muscle activity of the FDI was also assessed using a submaximal contraction at 40% of the participants' maximal voluntary contraction. Functional measures were most affected in children with RTD2 followed by children with CMT1A, compared to healthy controls. Strength was similarly impaired in CMT1A and RTD2 compared to controls (p < 0.05). Sensation was significantly impaired in RTD2 compared to CMT1A and controls (p = 0.008). While time to fatigue did not differ between groups, a decline in muscle activity while force remained constant showed that controls compensated with other muscles during the fatigue task while children with CMT1A and RTD2 did not have this compensatory ability. Children with CMT1A and RTD2 exhibited marked hand/upper limb impairment. These results suggest the upper limb should be a focus of rehabilitative therapy in affected children using sensitive outcome measures of strength and sensation, as well as functional activities of daily living, which are most relevant to the patient. [ABSTRACT FROM AUTHOR]