Foot surgery for adults with Charcot-Marie-Tooth disease.

People with Charcot-Marie-Tooth (CMT) disease often undergo foot and ankle surgery, as foot deformities are common and cause a degree of functional limitations impairing quality of life. Surgical approaches are variable and there are no evidence-based guidelines. A multidisciplinary approach involving neurology, physical therapy and orthopaedic surgery is ideal to provide guidance on when to refer for surgical opinion and when to intervene. This review outlines the range of foot deformities associated with CMT, their clinical assessment, and their conservative and surgical and postoperative management.

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.

Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT) is one of the most common and genetically heterogeneous inherited neurological diseases, with more than 130 disease-causing genes. Whole genome sequencing (WGS) has improved diagnosis across genetic diseases, but the diagnostic impact in CMT is yet to be fully reported. We present the diagnostic results from a single specialist inherited neuropathy centre, including the impact of WGS diagnostic testing. Patients were assessed at our specialist inherited neuropathy centre from 2009-2023. Genetic testing was performed using single gene testing, next-generation sequencing targeted panels, research whole exome and whole genome sequencing (WGS), and latterly WGS through the UK National Health Service. Variants were assessed using the American College of Medical Genetics and Genomics and Association for Clinical Genomic Science criteria. Excluding patients with hereditary ATTR amyloidosis, 1515 patients with a clinical diagnosis of CMT and related disorders were recruited. 621 patients had CMT1 (41.0%), 294 CMT2 (19.4%), 205 intermediate CMT (CMTi, 13.5%), 139 hereditary motor neuropathy (HMN, 9.2%), 93 hereditary sensory neuropathy (HSN, 6.1%), 38 sensory ataxic neuropathy (2.5%), 72 hereditary neuropathy with liability to pressure palsies (HNPP, 4.8%) and 53 'complex' neuropathy (3.5%). Overall, a genetic diagnosis was reached in 76.9% (1165/1515). A diagnosis was most likely in CMT1 (96.8%, 601/621), followed by CMTi (81.0%, 166/205) and then HSN (69.9%, 65/93). Diagnostic rates remained less than 50% in CMT2, HMN and complex neuropathies. The most common genetic diagnosis was PMP22 duplication (CMT1A; 505/1165, 43.3%), then GJB1 (CMTX1; 151/1165, 13.0%), PMP22 deletion (HNPP; 72/1165, 6.2%) and MFN2 (CMT2A; 46/1165, 3.9%). We recruited 233 cases to the UK 100,000 Genomes Project (100KGP), of which 74 (31.8%) achieved a diagnosis; 28 had been otherwise diagnosed since recruitment leaving a true diagnostic rate of WGS through the 100KGP of 19.7% (46/233). However, almost half of the solved cases (35/74) received a negative report from the study, and the diagnosis was made through our research access to the WGS data. The overall diagnostic uplift of WGS for the entire cohort was 3.5%. Our diagnostic rate is the highest reported from a single centre, and has benefitted from the use of WGS, particularly access to the raw data. However, almost one quarter of all cases remain unsolved, and a new reference genome and novel technologies will be important to narrow the 'diagnostic gap'.

Intermediate conduction velocity in two cases of Charcot-Marie-Tooth disease type 1A.

BACKGROUND AND PURPOSE: Charcot-Marie-Tooth disease type 1A (CMT1A) is the most prevalent hereditary neuropathy worldwide and classically has slow nerve conduction velocity (NCV), in most cases below 38 m/s. Two unrelated patients with motor NCVs in the upper limbs above 38 m/s are reported. METHOD: Case report. RESULTS: Two genetically confirmed CMT1A patients are presented, from two unrelated families (one of British origin and the other of Brazilian origin). Both individuals had upper limb motor NCVs above 38 m/s, with values ranging from 41.9 to 45 m/s in the median nerve and from 42 to 42.3 m/s in the ulnar nerve. They presented with a very mild phenotype, with CMT Neuropathy Score version 2 (CMTNSv2) of 6 and 5, respectively. In contrast, affected family members within both kinships exhibited a classical phenotype with more severe disease manifestation (CMTNSv2 ranging from 12 to 20) and motor NCVs below 30 m/s. CONCLUSION: These cases, although very rare, highlight the importance of testing PMP22 duplication in patients with intermediate conduction velocities.

Lower limb muscle MRI fat fraction is a responsive outcome measure in CMT X1, 1B and 2A.

OBJECTIVE: With potential therapies for many forms of Charcot-Marie-Tooth disease (CMT), responsive outcome measures are urgently needed for clinical trials. Quantitative lower limb MRI demonstrated progressive calf intramuscular fat accumulation in the commonest form, CMT1A with large responsiveness. In this study, we evaluated the responsiveness and validity in the three other common forms, due to variants in GJB1 (CMTX1), MPZ (CMT1B) and MFN2 (CMT2A). METHODS: 22 CMTX1, 21 CMT1B and 21 CMT2A patients and matched controls were assessed at a 1-year interval. Intramuscular fat fraction (FF) was evaluated using three-point Dixon MRI at thigh and calf level along with clinical measures including CMT examination score, clinical strength assessment, CMT-HI and plasma neurofilament light chain. RESULTS: All patient groups had elevated muscle fat fraction at thigh and calf levels, with highest thigh FF and atrophy in CMT2A. There was moderate correlation between calf muscle FF and clinical measures (CMTESv2 rho = 0.405; p = 0.001, ankle MRC strength rho = -0.481; p < 0.001). Significant annualised progression in calf muscle FF was seen in all patient groups (CMTX1 2.0 ± 2.0%, p < 0.001, CMT1B 1.6 ± 2.1% p = 0.004 and CMT2A 1.6 ± 2.1% p = 0.002). Greatest increase was seen in patients with 10-70% FF at baseline (calf 2.7 ± 2.3%, p < 0.0001 and thigh 1.7 ± 2.1%, p = 0.01). INTERPRETATION: Our results confirm that calf muscle FF is highly responsive over 12 months in three additional common forms of CMT which together with CMT1A account for 90% of genetically confirmed cases. Calf muscle MRI FF should be a valuable outcome measure in upcoming CMT clinical trials.

Mutations in alpha-B-crystallin cause autosomal dominant axonal Charcot-Marie-Tooth disease with congenital cataracts.

BACKGROUND AND PURPOSE: Mutations in the alpha-B-crystallin (CRYAB) gene have initially been associated with myofibrillar myopathy, dilated cardiomyopathy and cataracts. For the first time, peripheral neuropathy is reported here as a novel phenotype associated with CRYAB. METHODS: Whole-exome sequencing was performed in two unrelated families with genetically unsolved axonal Charcot-Marie-Tooth disease (CMT2), assessing clinical, neurophysiological and radiological features. RESULTS: The pathogenic CRYAB variant c.358A>G;p.Arg120Gly was segregated in all affected patients from two unrelated families. The disease presented as late onset CMT2 (onset over 40 years) with distal sensory and motor impairment and congenital cataracts. Muscle involvement was probably associated in cases showing mild axial and diaphragmatic weakness. In all cases, nerve conduction studies demonstrated the presence of an axonal sensorimotor neuropathy along with chronic neurogenic changes on needle examination. DISCUSSION: In cases with late onset autosomal dominant CMT2 and congenital cataracts, it is recommended that CRYAB is considered for genetic testing. The identification of CRYAB mutations causing CMT2 further supports a continuous spectrum of expressivity, from myopathic to neuropathic and mixed forms, of a growing number of genes involved in protein degradation and chaperone-assisted autophagy.

Home-based multi-sensory and proximal strengthening program to improve balance in Charcot-Marie-Tooth disease Type 1A: A proof of concept study.

INTRODUCTION/AIMS: People with Charcot-Marie-Tooth Disease (CMT) frequently report problems with balance, which lead to an increased risk of falls. Evidence is emerging of training interventions to improve balance for people with CMT, but to date all have relied on clinic-based treatment and equipment. This proof-of-concept study explored whether a multi-modal program of proprioceptive rehabilitation and strength training can be delivered at home, to improve balance performance in people with CMT Type 1A. METHODS: Fourteen participants with CMT Type 1A were recruited into this randomized, two-arm study. Baseline assessments included measures of disease severity, posturography, physical function, and patient-reported outcome measurements. All participants received one falls education session. Participants were randomized to either 12 weeks of balance training or 12 weeks of usual activities. The intervention comprised a home-based, multi-sensory balance training and proximal strengthening program, supported by three home visits from a physiotherapist. RESULTS: Thirteen participants completed the study. The intervention was successfully implemented and well tolerated, with high participation levels. Functional measures of balance and walking showed strong effect sizes in favor of the training group. Posturography testing demonstrated moderate improvements in postural stability favoring the intervention group. Inconsistent changes were seen in lower limb strength measures. DISCUSSION: The intervention was feasible to implement and safe, with some evidence of improvement in balance performance. This supports future studies to expand this intervention to larger trials of pragmatic, home-delivered programs through current community rehabilitation services and supported self-management pathways.

Digenic FLNA and UCHL1 variants resulting in a complex phenotype.

AIM: X-linked variants in Filamin A (FLNA) are associated with the Ehlers-Danlos-syndrome-variant form of periventricular heterotopia, and autosomal dominant variants in ubiquitin C-terminal hydrolase L1 (UCHL1) are associated with a late-onset spastic ataxia, peripheral neuropathy and optic atrophy. Here we present a rare case involving both a novel heterozygous whole-gene deletion of UCHL1 and a heterozygous frameshift variant in the FLNA gene resulting in a complex phenotype. METHODS: A 67-year-old female with a confirmed pathogenic variant in the FLNA gene, resulting in an enlarged aorta and joint pains, presented with a 4-year history of severe sensory ataxia, upper motor neuron signs, eye movement abnormalities and severe sensory loss. RESULTS: Neurophysiology including Somatosensory-evoked potentials confirmed the sensory loss as predominantly preganglionic with denervation. Genetic testing revealed a digenic cause of her complex presentation, confirming a pathogenic frameshift variant in the FLNA gene and a heterozygous loss of function deletion in the UCHL1 gene. CONCLUSIONS: To the best of our knowledge, this is the first case with concomitant pathogenic variants in the FLNA and UCHL1 genes which explain the complex phenotype. The severe preganglionic sensory loss is also a rare finding and expands the phenotype of UCHL1 variants.

Quantitative MRI outcome measures in CMT1A using automated lower limb muscle segmentation.

BACKGROUND: Lower limb muscle magnetic resonance imaging (MRI) obtained fat fraction (FF) can detect disease progression in patients with Charcot-Marie-Tooth disease 1A (CMT1A). However, analysis is time-consuming and requires manual segmentation of lower limb muscles. We aimed to assess the responsiveness, efficiency and accuracy of acquiring FF MRI using an artificial intelligence-enabled automated segmentation technique. METHODS: We recruited 20 CMT1A patients and 7 controls for assessment at baseline and 12 months. The three-point-Dixon fat water separation technique was used to determine thigh-level and calf-level muscle FF at a single slice using regions of interest defined using Musclesense, a trained artificial neural network for lower limb muscle image segmentation. A quality control (QC) check and correction of the automated segmentations was undertaken by a trained observer. RESULTS: The QC check took on average 30 seconds per slice to complete. Using QC checked segmentations, the mean calf-level FF increased significantly in CMT1A patients from baseline over an average follow-up of 12.5 months (1.15%±1.77%, paired t-test p=0.016). Standardised response mean (SRM) in patients was 0.65. Without QC checks, the mean FF change between baseline and follow-up, at 1.15%±1.68% (paired t-test p=0.01), was almost identical to that seen in the corrected data, with a similar overall SRM at 0.69. CONCLUSIONS: Using automated image segmentation for the first time in a longitudinal study in CMT, we have demonstrated that calf FF has similar responsiveness to previously published data, is efficient with minimal time needed for QC checks and is accurate with minimal corrections needed.

Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies.

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies.

Muscle magnetic resonance imaging of a large cohort of distal hereditary motor neuropathies reveals characteristic features useful for diagnosis.

Distal motor neuropathies (dHMN) are an heterogenous group of diseases characterized by progressive muscle weakness affecting predominantly the distal muscles of the lower and upper limbs. Our aim was to study the imaging features and pattern of muscle involvement in muscle magnetic resonance imaging (MRI) in dHMN patients of suspected genetic origin (dHMN). We conducted a retrospective study collecting clinical, genetic and muscle imaging data. Muscle MRI included T1-weighted and T2 weighted Short Tau Inversion Recovery images (STIR-T2w) sequences. Muscle replacement by fat was quantified using the Mercuri score. Identification of selective patterns of involvement was performed using hierarchical clustering. Eighty-four patients with diagnosis of dHMN were studied. Fat replacement was predominant in the distal lower leg muscles (82/84 cases), although also affected thigh and pelvis muscles. Asymmetric involvement was present in 29% of patients. The superficial posterior compartment of the leg, including the soleus and gastrocnemius muscles, was the most affected area (77/84). We observed a reticular pattern of fatty replacement progressing towards what is commonly known as "muscle islands" in 79.8%. Hyperintensities in STIR-T2w were observed in 78.6% patients mainly in distal leg muscles. Besides features common to all individuals, we identified and describe a pattern of muscle fat replacement characteristic of BICD2, HSPB1 and DYNC1H1 patients. We conclude that muscle MRI of patients with suspected dHMN reveals common features helpful in diagnosis process.

Pregnancy and delivery in patients with Charcot-Marie-Tooth disease and related disorders.

Background: Charcot-Marie-Tooth disease is the most common inherited peripheral neuropathy and many patients with Charcot-Marie-Tooth are women of childbearing age. Guidelines for managing pregnancy in Charcot-Marie-Tooth are lacking. Aims: To assess the impact of pregnancy on Charcot-Marie-Tooth and how Charcot-Marie-Tooth affects pregnancy, delivery and postnatal care. Methods: A retrospective questionnaire exploring disease course during pregnancy, delivery, pregnancy complications, anaesthetic management and puerperium was administered to 92 patients with Charcot-Marie-Tooth and related disorders. Results: Worsening of Charcot-Marie-Tooth symptoms were reported in 37% of pregnant patients which resolved after delivery in half of the patients. No significant increase in pregnancy, delivery and anaesthetic complications were observed and the type of delivery did not significantly differ from the normal population. Conclusions: While these results are reassuring, ideally an international prospective study should be done to confirm these results and to develop practice guidelines on the management of pregnancy in Charcot-Marie-Tooth.

Genetic analysis and natural history of Charcot-Marie-Tooth disease CMTX1 due to GJB1 variants.

Charcot-Marie-Tooth disease (CMT) due to GJB1 variants (CMTX1) is the second most common form of CMT. It is an X-linked disorder characterized by progressive sensory and motor neuropathy with males affected more severely than females. Many reported GJB1 variants remain classified as variants of uncertain significance (VUS). In this large, international, multicentre study we prospectively collected demographic, clinical and genetic data on patients with CMT associated with GJB1 variants. Pathogenicity for each variant was defined using adapted American College of Medical Genetics criteria. Baseline and longitudinal analyses were conducted to study genotype-phenotype correlations, to calculate longitudinal change using the CMT Examination Score (CMTES), to compare males versus females, and pathogenic/likely pathogenic (P/LP) variants versus VUS. We present 387 patients from 295 families harbouring 154 variants in GJB1. Of these, 319 patients (82.4%) were deemed to have P/LP variants, 65 had VUS (16.8%) and three benign variants (0.8%; excluded from analysis); an increased proportion of patients with P/LP variants compared with using ClinVar's classification (74.6%). Male patients (166/319, 52.0%, P/LP only) were more severely affected at baseline. Baseline measures in patients with P/LP variants and VUS showed no significant differences, and regression analysis suggested the disease groups were near identical at baseline. Genotype-phenotype analysis suggested c.-17G>A produces the most severe phenotype of the five most common variants, and missense variants in the intracellular domain are less severe than other domains. Progression of disease was seen with increasing CMTES over time up to 8 years follow-up. Standard response mean (SRM), a measure of outcome responsiveness, peaked at 3 years with moderate responsiveness [change in CMTES (ΔCMTES) = 1.3 ± 2.6, P = 0.00016, SRM = 0.50]. Males and females progressed similarly up to 8 years, but baseline regression analysis suggested that over a longer period, females progress more slowly. Progression was most pronounced for mild phenotypes (CMTES = 0-7; 3-year ΔCMTES = 2.3 ± 2.5, P = 0.001, SRM = 0.90). Enhanced variant interpretation has yielded an increased proportion of GJB1 variants classified as P/LP and will aid future variant interpretation in this gene. Baseline and longitudinal analysis of this large cohort of CMTX1 patients describes the natural history of the disease including the rate of progression; CMTES showed moderate responsiveness for the whole group at 3 years and higher responsiveness for the mild group at 3, 4 and 5 years. These results have implications for patient selection for upcoming clinical trials.

Post-transcriptional microRNA repression of PMP22 dose in severe Charcot-Marie-Tooth disease type 1.

Copy number variation (CNV) may lead to pathological traits, and Charcot-Marie-Tooth disease type 1A (CMT1A), the commonest inherited peripheral neuropathy, is due to a genomic duplication encompassing the dosage-sensitive PMP22 gene. MicroRNAs act as repressors on post-transcriptional regulation of gene expression and in rodent models of CMT1A, overexpression of one such microRNA (miR-29a) has been shown to reduce the PMP22 transcript and protein level. Here we present genomic and functional evidence, for the first time in a human CNV-associated phenotype, of the 3' untranslated region (3'-UTR)-mediated role of microRNA repression on gene expression. The proband of the family presented with an early-onset, severe sensorimotor demyelinating neuropathy and harboured a novel de novo deletion in the PMP22 3'-UTR. The deletion is predicted to include the miR-29a seed binding site and transcript analysis of dermal myelinated nerve fibres using a novel platform, revealed a marked increase in PMP22 transcript levels. Functional evidence from Schwann cell lines harbouring the wild-type and mutant 3'-UTR showed significantly increased reporter assay activity in the latter, which was not ameliorated by overexpression of a miR-29a mimic. This shows the importance of miR-29a in regulating PMP22 expression and opens an avenue for therapeutic drug development.

Incidence and risk factors for patellofemoral dislocation in adults with Charcot-Marie-Tooth disease: An observational study.

BACKGROUND AND PURPOSE: Patellofemoral (PF) dislocation is frequently encountered in clinical practice among people with Charcot-Marie-Tooth disease (CMT), but the frequency and risk factors for PF dislocation in adults with CMT are unknown. This study aimed to establish the incidence of PF dislocation in adults with CMT and to explore the risk factors associated with PF dislocation. METHODS: This is a cross-sectional study involving adults with a diagnosis of CMT, attending their outpatient clinics at a specialist neuromuscular centre in the United Kingdom. Eighty-one individuals were interviewed about any PF dislocation and underwent a lower-limb assessment, with a focussed knee examination, to identify possible risk factors for PF dislocation. The incidence of PF dislocation was expressed as a percentage (number of individuals with a positive history of patellar dislocation/overall sample) and the association between different risk factors and PF dislocation was explored using logistic regression analysis. RESULTS: The incidence of PF dislocation was 22.2% (18/81). PF dislocation was associated with a younger age at the time of the assessment (p = 0.038) and earlier disease onset (p = 0.025). All people bar two who dislocated had CMT1A (88.9%), but there was no difference in terms of CMT distribution with the non-dislocation group (p = 0.101). No association was found between PF dislocation and CMT severity measured by CMTSS (p = 0.379) and CMTES (p = 0.534). Patella alta (p = 0.0001), J-sign (p = 0.004), lateral patellar glide (p = 0.0001), generalised joint hypermobility (p = 0.001) and knee flexors weakness (p = 0.008) were associated with an increased risk of dislocation. Patella alta (p = 0.010) and lateral patellar glide (p = 0.028) were independent PF dislocation predictors. CONCLUSIONS: PF dislocation was common in this cohort with CMT and was associated with multiple risk factors. Future studies should be conducted to confirm the present findings so that the identified risk factors may be addressed by clinicians through preventive, supportive and corrective measures.

Disease Progression in Charcot-Marie-Tooth Disease Related to MPZ Mutations: A Longitudinal Study.

OBJECTIVE: The paucity of longitudinal natural history studies in MPZ neuropathy remains a barrier to clinical trials. We have completed a longitudinal natural history study in patients with MPZ neuropathies across 13 sites of the Inherited Neuropathies Consortium. METHODS: Change in Charcot-Marie-Tooth Examination Score (CMTES) and Rasch modified CMTES (CMTES-R) were evaluated using longitudinal regression over a 5-year period in subjects with MPZ neuropathy. Data from 139 patients with MPZ neuropathy were examined. RESULTS: The average baseline CMTES and CMTES-R were 10.84 (standard deviation [SD] = 6.0, range = 0-28) and 14.60 (SD = 7.56, range = 0-32), respectively. A mixed regression model showed significant change in CMTES at years 2-5 (mean change from baseline of 0.87 points at 2 years, p = 0.008). Subgroup analysis revealed greater change in CMTES at 2 years in subjects with axonal as compared to demyelinating neuropathy (mean change of 1.30 points [p = 0.016] vs 0.06 points [p = 0.889]). Patients with a moderate baseline neuropathy severity also showed more notable change, by estimate, than those with mild or severe neuropathy (mean 2-year change of 1.14 for baseline CMTES 8-14 [p = 0.025] vs -0.03 for baseline CMTES 0-7 [p = 0.958] and 0.25 for baseline CMTES ≥ 15 [p = 0.6897]). The progression in patients harboring specific MPZ mutations was highly variable. INTERPRETATION: CMTES is sensitive to change over time in adult patients with axonal but not demyelinating forms of MPZ neuropathy. Change in CMTES was greatest in patients with moderate baseline disease severity. These findings will inform future clinical trials of MPZ neuropathies. ANN NEUROL 2023;93:563-576.

Virtual Charcot-Marie-Tooth Examination Score: A Validated Virtual Evaluation for People With Charcot-Marie-Tooth Disease.

Background and Objectives: The Charcot-Marie-Tooth Examination Score (CMTES) has been used since 2005 in clinics to measure impairment in patients with CMT and has provided natural history data for patients with CMT1A, CMT1B, CMTX1, CMT2A, and many other subtypes. However, the CMTES requires an in-person visit, and many individuals are unable to travel to CMT centers because of the distance from the clinic or physical disability or more recently because of COVID-19 restrictions. We therefore developed the virtual CMTES (vCMTES) as outlined below. The aim of this study is to create a remote clinical outcome assessment to measure impairment in patients with CMT. Methods: We modified the CMTESv2 replacing the pinprick and vibration items with light touch and position sense, which can be performed remotely by the patient or the patient with an assistant while being observed by the clinic evaluator. Motor evaluations were performed similar to CMTESv2 by the assistant or the patient, while being observed remotely. We developed a standardized protocol to be used with Zoom or a similar format, a training and certification program, and enabled the vCMTES data to be housed in the Inherited Neuropathy Consortium databases. Patients were evaluated in person and remotely for interexaminer and intraexaminer studies. Results: Sixty-four patients with genetically confirmed CMT were evaluated by vCMTES and CMTESv2; 53 patients were evaluated virtually 3 weeks after their initial examination. Ten patients were evaluated with the vCMTES by different examiners 5 days apart. CMTESv2 correlates strongly with the vCMTES in person and virtually (p < 0.0001). There was a strong correlation between the vCMTES made in person and virtually (p < 0.0001). Similar results were obtained comparing symptoms score items, sensory items, and motor items. Interclass correlation coefficients (ICCs) were ≥0.92. Discussion: Statistical analyses demonstrated that the vCMTES was reproducible and reliable as a clinical outcome assessment for CMT. Further studies are needed to test responsiveness to change and progression in different subtypes. The vCMTES also offers the potential to reach diverse populations that do not have access to CMT centers.