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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. [ABSTRACT FROM AUTHOR]

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. [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]

Objectives: Dysregulated RNA alternative splicing is the hallmark of myotonic dystrophy type 1 (DM1). However, the association between RNA mis-splicing and physical function in children with the most severe form of disease, congenital myotonic dystrophy (CDM), is unknown., Methods: 82 participants (42 DM1 adults & 40 CDM children) with muscle biopsies and measures of myotonia, motor function, and strength were combined from five observational studies. Data were normalized and correlated with an aggregate measure of alternative splicing dysregulation, [MBNL] inferred in skeletal muscle biopsies. Multiple linear regression analysis was performed to predict [MBNL] inferred using clinical outcome measures alone. Similar analyses were performed to predict 12-month physical function using baseline metrics., Results: Myotonia (measured via vHOT) was significantly correlated with RNA mis-splicing in our cross-sectional population of all DM1 individuals; CDM participants alone displayed no myotonia despite a similar range of RNA mis-splicing. Measures of motor performance and muscle strength were significantly associated with [MBNL] inferred in our cohort of all DM1 individuals and when assessing CDM children independently. Multiple linear regression analyses yielded two models capable of predicting [MBNL] inferred from select clinical outcome assessments alone in all subjects (adjusted R 2 = 0.6723) or exclusively in CDM children (adjusted R 2 = 0.5875)., Interpretation: Our findings establish significant correlations between skeletal muscle performance and a composite measure of alternative splicing dysregulation, [MBNL] inferred, in DM1. The strength of these correlations and the development of the predictive models will assist in designing efficacious clinical trials for individuals with DM1, particularly CDM.

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: 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/m 2 ), underweight (BMI ≥17-<18.5 kg/m 2 ), healthy weight (BMI ≥18.5-<25 kg/m 2 ), overweight (BMI ≥25-<30 kg/m 2 ), and obese (BMI ≥30 kg/m 2 ). 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., (© 2021 American Academy of Neurology.)

Introduction: The 6-minute walk test (6MWT) is a well-established clinical assessment of functional endurance, validated as a measure of walking ability in spinal muscular atrophy (SMA). The current availability of disease-modifying therapies for SMA indicates a growing need for normative reference data to compare SMA patients with healthy controls., Methods: The literature was searched in two scientific databases. Studies were evaluated and selected based on adherence to American Thoracic Society guidelines for administering the 6MWT. Reference equations from the selected studies were applied to 6MWT data collected from SMA patients to calculate and compare % predicted values., Results: Three pediatric and six adult studies were selected for comparison. The % predicted values using the pediatric and adult equations ranged from 47.7 ± 18.2% to 67.6 ± 26.2% and 43.0 ± 17.9% to 59.5 ± 26.2%, respectively, and were significantly different (P < 0.001)., Discussion: Results suggest significant variability between % predicted values derived from published reference equations in children and adults, despite adherence to 6MWT standardization., (© 2019 Wiley Periodicals, Inc.)

Charcot-Marie-Tooth disease (CMT) causes disabling cavovarus foot deformity. Orthopaedic surgery is performed in severe cases; however few studies have investigated whether surgery improves health outcomes during childhood. This study investigated the impact of cavovarus surgery on validated physical, functional, parent/self-reported and biomechanical measures in 21 consecutive patients (mean age at surgery 12.5 years, SD 2.7) evaluated before and after surgery (mean duration 15.7 months, SD 5.9), and compared to natural history data from 206 children with CMT. Measures from the CMT Pediatric Scale evaluated foot alignment (Foot Posture Index), ankle flexibility (lunge test), strength (foot dorsiflexion/plantarflexion by hand-held dynamometry), function (balance, long jump, 6-minute walk test) and self-reported symptoms. Quality of life (Child Health Questionnaire) and gait (pressure loading) were also assessed. Foot Posture Index and lunge improved with surgery by 6.0 points (SD 3.2) and 6.1° (SD 7.3) respectively (p< 0.01), and differed to the natural course of the disease (p< 0.005). Self-reported daily trips/falls reduced from 60% to 13% (p = 0.016). Pressure improved beneath the rearfoot and midfoot (p = 0.043). Surgery had no effect on strength, function or quality of life, which generally mirrored the natural course. Cavovarus surgery improved foot alignment, ankle flexibility and self-reported trips/falls in children with CMT., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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.)