Quantitative Foot Muscle Magnetic Resonance Imaging Reliably Measures Disease Progression in Children and Adolescents with Charcot-Marie-Tooth Disease Type 1A.

Quantitative muscle fat fraction (FF) responsiveness is lower in younger Charcot-Marie-Tooth disease type 1A (CMT1A) patients with lower baseline calf-level FF. We investigated the practicality, validity, and responsiveness of foot-level FF in this cohort involving 22 CMT1A patients and 14 controls. The mean baseline foot-level FF was 25.9 ± 20.3% in CMT1A patients, and the 365-day FF (n = 15) increased by 2.0 ± 2.4% (p < 0.001 vs controls). Intrinsic foot-level FF demonstrated large responsiveness (12-month standardized response mean (SRM) of 0.86) and correlated with the CMT examination score (ρ = 0.58, P = 0.01). Intrinsic foot-level FF has the potential to be used as a biomarker in future clinical trials involving younger CMT1A patients. ANN NEUROL 2024;96:170-174.

Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study.

Mitofusin-2 (MFN2) is one of two ubiquitously expressed homologous proteins in eukaryote cells, playing a critical role in mitochondrial fusion. Mutations in MFN2 (most commonly autosomal dominant) cause Charcot-Marie-Tooth disease type 2A (CMT2A), the commonest axonal form of CMT, with significant allelic heterogeneity. Previous, moderately-sized, cross sectional genotype-phenotype studies of CMT2A have described the phenotypic spectrum of the disease, but longitudinal natural history studies are lacking. In this large multicentre prospective cohort study of 196 patients with dominant and autosomal recessive CMT2A, we present an in-depth genotype-phenotype study of the baseline characteristics of patients with CMT2A and longitudinal data (1-2 years) to describe the natural history. A childhood onset of autosomal dominant CMT2A is the most predictive marker of significant disease severity and is independent of the disease duration. When compared to adult onset autosomal dominant CMT2A, it is associated with significantly higher rates of use of ankle-foot orthoses, full-time use of wheelchair, dexterity difficulties and also has significantly higher CMT Examination Score (CMTESv2) and CMT Neuropathy Score (CMTNSv2) at initial assessment. Analysis of longitudinal data using the CMTESv2 and its Rasch-weighted counterpart, CMTESv2-R, show that over 1 year, the CMTESv2 increases significantly in autosomal dominant CMT2A (mean change 0.84 ± 2.42; two-tailed paired t-test P = 0.039). Furthermore, over 2 years both the CMTESv2 (mean change 0.97 ± 1.77; two-tailed paired t-test P = 0.003) and the CMTESv2-R (mean change 1.21 ± 2.52; two-tailed paired t-test P = 0.009) increase significantly with respective standardized response means of 0.55 and 0.48. In the paediatric CMT2A population (autosomal dominant and autosomal recessive CMT2A grouped together), the CMT Pediatric Scale increases significantly both over 1 year (mean change 2.24 ± 3.09; two-tailed paired t-test P = 0.009) and over 2 years (mean change 4.00 ± 3.79; two-tailed paired t-test P = 0.031) with respective standardized response means of 0.72 and 1.06. This cross-sectional and longitudinal study of the largest CMT2A cohort reported to date provides guidance for variant interpretation, informs prognosis and also provides natural history data that will guide clinical trial design.

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.

Genotype-phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene.

We aimed to characterize genotype-phenotype correlations and establish baseline clinical data for peripheral neuropathies caused by mutations in the myelin protein zero (MPZ) gene. MPZ mutations are the second leading cause of Charcot-Marie-Tooth disease type 1. Recent research makes clinical trials for patients with MPZ mutations a realistic possibility. However, the clinical severity varies with different mutations and natural history data on progression is sparse. We present cross-sectional data to begin to define the phenotypic spectrum and clinical baseline of patients with these mutations. A cohort of patients with MPZ gene mutations was identified in 13 centres of the Inherited Neuropathies Consortium - Rare Disease Clinical Research Consortium (INC-RDCRC) between 2009 and 2012 and at Wayne State University between 1996 and 2009. Patient phenotypes were quantified by the Charcot-Marie-Tooth disease neuropathy score version 1 or 2 and the Charcot-Marie-Tooth disease paediatric scale outcome instruments. Genetic testing was performed in all patients and/or in first- or second-degree relatives to document mutation in MPZ gene indicating diagnosis of Charcot-Marie-Tooth disease type 1B. There were 103 patients from 71 families with 47 different MPZ mutations with a mean age of 40 years (range 3-84 years). Patients and mutations were separated into infantile, childhood and adult-onset groups. The infantile onset group had higher Charcot-Marie-Tooth disease neuropathy score version 1 or 2 and slower nerve conductions than the other groups, and severity increased with age. Twenty-three patients had no family history of Charcot-Marie-Tooth disease. Sixty-one patients wore foot/ankle orthoses, 19 required walking assistance or support, and 10 required wheelchairs. There was hearing loss in 21 and scoliosis in 17. Forty-two patients did not begin walking until after 15 months of age. Half of the infantile onset patients then required ambulation aids or wheelchairs for ambulation. Our results demonstrate that virtually all MPZ mutations are associated with specific phenotypes. Early onset (infantile and childhood) phenotypes likely represent developmentally impaired myelination, whereas the adult-onset phenotype reflects axonal degeneration without antecedent demyelination. Data from this cohort of patients will provide the baseline data necessary for clinical trials of patients with Charcot-Marie-Tooth disease caused by MPZ gene mutations.

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.

Refining clinical trial inclusion criteria to optimize the standardized response mean of the CMTPedS.

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.

A longitudinal study of CMT1A using Rasch analysis based CMT neuropathy and examination scores.

OBJECTIVE: To evaluate the sensitivity of Rasch analysis-based, weighted Charcot-Marie-Tooth Neuropathy and Examination Scores (CMTNS-R and CMTES-R) to clinical progression in patients with Charcot-Marie-Tooth disease type 1A (CMT1A). METHODS: Patients with CMT1A from 18 sites of the Inherited Neuropathies Consortium were evaluated between 2009 and 2018. Weighted CMTNS and CMTES modified category responses were developed with Rasch analysis of the standard scores. Change from baseline for CMTNS-R and CMTES-R was estimated with longitudinal regression models. RESULTS: Baseline CMTNS-R and CMTES-R scores were available for 517 and 1,177 participants, respectively. Mean ± SD age of participants with available CMTES-R scores was 41 ± 18 (range 4-87) years, and 56% were female. Follow-up CMTES-R assessments at 1, 2, and 3 years were available for 377, 321, and 244 patients. A mixed regression model showed significant change in CMTES-R score at years 2 through 6 compared to baseline (mean change from baseline 0.59 points at 2 years, p = 0.0004, n = 321). Compared to the original CMTES, the CMTES-R revealed a 55% improvement in the standardized response mean (mean change/SD change) at 2 years (0.17 vs 0.11). Change in CMTES-R at 2 years was greatest in mildly to moderately affected patients (1.48-point mean change, 95% confidence interval 0.99-1.97, p < 0.0001, for baseline CMTES-R score 0-9). CONCLUSION: The CMTES-R demonstrates change over time in patients with CMT1A and is more sensitive than the original CMTES. The CMTES-R was most sensitive to change in patients with mild to moderate baseline disease severity and failed to capture progression in patients with severe CMT1A. CLINICALTRIALSGOV IDENTIFIER: NCT01193075.

Stoichiometric alteration of PMP22 protein determines the phenotype of hereditary neuropathy with liability to pressure palsies.

BACKGROUND: Hereditary neuropathy with liability to pressure palsies (HNPP) is caused by a 1.4-megabase deletion at chromosome 17p11.2, which bears the PMP22 gene and other genes. However, whether other genes besides PMP22 contribute to the phenotype is unknown. Whether any mutation within the coding region of the PMP22 gene ultimately causes HNPP by reducing the amount of peripheral myelin protein 22 (PMP22) expressed in myelin is also unknown. OBJECTIVE: To determine whether affected patients develop a phenotype identical to that found in HNPP and whether the leucine 7 frameshift (Leu7fs) mutation reduces PMP22 levels in myelin. DESIGN: We evaluated affected family members by neurological examination, electrophysiology, and skin biopsies. We identified a large family with a Leu7fs mutation of PMP22 (11 affected members across 3 generations) that predicts truncation of the protein prematurely and eliminates PMP22 expression from the mutant allele. RESULTS: We found that PMP22 levels were reduced in peripheral nerve myelin in dermal skin biopsies in patients with an Leu7fs mutation. Through clinical and electrophysiological evaluation, we also found that patients with the Leu7fs mutation were indistinguishable from patients with HNPP caused by deletion. We also found that a length-dependent axonal loss became pronounced in elderly patients with Leu7fs mutations, similar to what has been described in heterozygous knockout mice (pmp22 +/-). CONCLUSIONS: Taken together, these results confirm that the phenotypic expression is identical in patients with Leu7fs mutation and patients with HNPP caused by chromosome 17p11.2 deletion. They also demonstrate that reduction of PMP22 is sufficient to cause the full HNPP phenotype.

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.

Phenotypic clustering in MPZ mutations.

Myelin protein zero (MPZ) is a member of the immunoglobulin gene superfamily with single extracellular, transmembrane and cytoplasmic domains. Homotypic interactions between extracellular domains of MPZ adhere adjacent myelin wraps to each other. MPZ is also necessary for myelin compaction since mice which lack MPZ develop severe dysmyelinating neuropathies in which compaction is dramatically disrupted. MPZ mutations in humans cause the inherited demyelinating neuropathy CMT1B. Some mutations cause the severe neuropathies of infancy designated as Dejerine-Sottas disease, while others cause a 'classical' Charcot-Marie-Tooth (CMT) disease Type 1B (CMT1B) phenotype with normal early milestones but development of disability during the first two decades of life. Still other mutations cause a neuropathy that presents in adults, with normal nerve conduction velocities, designated as a 'CMT2' form of CMT1B. To correlate the phenotype of patients with MPZ mutations with their genotype, we identified and evaluated 13 patients from 12 different families with eight different MPZ mutations. In addition, we re-analysed the clinical data from 64 cases of CMT1B from the literature. Contrary to our expectations, we found that most patients presented with either an early onset neuropathy with signs and symptoms prior to the onset of walking or a late onset neuropathy with signs and symptoms at around age 40 years. Only occasional patients presented with a 'classical' CMT phenotype. Correlation of specific MPZ mutations with their phenotypes demonstrated that addition of either a charged amino acid or altering a cysteine residue in the extracellular domain caused a severe early onset neuropathy. Severe neuropathy was also caused by truncation of the cytoplasmic domain or alteration of an evolutionarily conserved amino acid. Taken together, these data suggest that early onset neuropathy is caused by MPZ mutations that significantly disrupt the tertiary structure of MPZ and thus interfere with MPZ-mediated adhesion and myelin compaction. In contrast, late onset neuropathy is caused by mutations that more subtly alter myelin structure and which probably disrupt Schwann cell-axonal interactions.