Pharmacologically increasing cGMP improves proteostasis and reduces neuropathy in mouse models of CMT1.

Increasing cyclic GMP activates 26S proteasomes via phosphorylation by Protein Kinase G and stimulates the intracellular degradation of misfolded proteins. Therefore, agents that raise cGMP may be useful therapeutics against neurodegenerative diseases and other diseases in which protein degradation is reduced and misfolded proteins accumulate, including Charcot Marie Tooth 1A and 1B peripheral neuropathies, for which there are no treatments. Here we increased cGMP in the S63del mouse model of CMT1B by treating for three weeks with either the phosphodiesterase 5 inhibitor tadalafil, or the brain-penetrant soluble guanylyl cyclase stimulator CYR119. Both molecules activated proteasomes in the affected peripheral nerves, reduced polyubiquitinated proteins, and improved myelin thickness and nerve conduction. CYR119 increased cGMP more than tadalafil in the peripheral nerves of S63del mice and elicited greater biochemical and functional improvements. To determine whether raising cGMP could be beneficial in other neuropathies, we first showed that polyubiquitinated proteins and the disease-causing protein accumulate in the sciatic nerves of the C3 mouse model of CMT1A. Treatment of these mice with CYR119 reduced the levels of polyubiquitinated proteins and the disease-causing protein, presumably by increasing their degradation, and improved myelination, nerve conduction, and motor coordination. Thus, pharmacological agents that increase cGMP are promising treatments for CMT1 neuropathies and may be useful against other proteotoxic and neurodegenerative diseases.

Characterization of a novel heterozygous variant in the histidyl-tRNA synthetase gene associated with Charcot-Marie-Tooth disease type 2W.

Heterozygous pathogenic variants in the histidyl-tRNA synthetase (HARS) gene are associated with Charcot-Marie-Tooth (CMT) type 2W disease, classified as an axonal peripheral neuropathy. To date, at least 60 variants causing CMT symptoms have been identified in seven different aminoacyl-tRNA synthetases, with eight being found in the catalytic domain of HARS. The genetic data clearly show a causative role of aminoacyl-tRNA synthetases in CMT; however, the cellular mechanisms leading to pathology can vary widely and are unknown in the case of most identified variants. Here we describe a novel HARS variant, c.412T>C; p.Y138H, identified through a CMT gene panel in a patient with peripheral neuropathy. To determine the effect of p.Y138H we employed a humanized HARS yeast model and recombinant protein biochemistry, which identified a deficiency in protein dimerization and a growth defect which shows mild but significant improvement with histidine supplementation. This raises the potential for a clinical trial of histidine.

Patient-reported disease burden in the Accelerate Clinical Trials in Charcot-Marie-Tooth Disease Study.

BACKGROUND AND AIMS: The Charcot-Marie-Tooth Disease Health Index (CMT-HI) is a disease-specific, patient-reported disease burden measure. As part of an international clinical trial readiness study, individuals with CMT1A (ages 18-75 years) underwent clinical outcome assessments (COAs), including the CMT-HI, to capture their longitudinal perspective on the disease burden. METHODS: Two hundred and fifteen participants underwent serial COAs including the CMT-HI, CMT Functional Outcome Measure (CMT-FOM), CMT Neuropathy Score (CMTNSv2R), and CMT Exam Score (CMTES/CMTES-R). Correlations between the total and subscale scores for the CMT-HI and other COAs were determined. Changes in the CMT-HI scores over 12 months were assessed using paired t-tests. The minimum clinically important difference (MCID) for the CMT-HI and its subscales were calculated by anchoring to a participant global impression of change scale. RESULTS: At baseline, CMT1A participants were 44.5 ± 15 years old (range: 18-75) and 58% were women. The mean CMT-HI was 25.7 ± 18.8 (range: 0-91.9; 100 reflecting maximal disease burden). The CMT-HI correlated with the CMT-FOM (r = .54, p < .0001), CMTNSv2R (r = .48, p < .0001), and CMTES/CMTES-R (r = .52/r = .54, p < .0001). Disease burden was greater in women than in men (CMT-HI 29.1 ± 19.1 vs. 21.2 ± 17.3, p = .001). Over 12 months, there was a nonsignificant mean increase in CMT-HI of 0.40 ± 10.0 (n = 189, p = .89). The MCID for the CMT-HI total score was 3.8 points (95% CI: 1.7-5.9). DISCUSSION: Patient-reported disease burden in CMT1A as measured by the CMT-HI is associated with measures of neurologic impairment and physical functioning. Women reported a higher disease burden than men. These data will inform the design of clinical trials in CMT1A.

3D-printed custom ankle braces for people with Charcot-Marie-Tooth disease: A pilot study.

INTRODUCTION: Charcot-Marie-Tooth disease (CMT) is a neurodegenerative condition resulting in footdrop, ankle instability and impaired balance and gait. This study aimed to determine (1) whether 3D-printed custom ankle braces improve function and balance in people with CMT and (2) whether this is an acceptable device for use in this population. METHODS: A within-subject comparison pragmatic/pilot study was undertaken. Ten people with CMT (mean [SD] age 48 [14] years, 60% male) were fitted with 3D-printed ankle braces. Following a 4-week wear-in period, walking and balance tests and patient-reported outcomes were assessed in two experimental conditions: (i) usual shoes and (ii) usual shoes with 3D-printed custom ankle braces. Differences in outcome measures between experimental conditions were analysed using linear mixed models. Comfort, aesthetics and overall satisfaction of the brace were assessed via 100-mm visual analogue scale (VAS). Adverse events and tripping/falls associated with the brace during the wear-in period were also recorded by participants using daily diaries. RESULTS: A significant improvement was seen during single-leg balance with eyes open (p = 0.026, Cohen's d = 0.55) and a significant reduction in foot pain (p = 0.045, Cohen's d = 0.82), with use of the ankle brace. Mean (SD) 100 mm VAS scores were 62.7 mm (17.9) for overall comfort and 73.9 mm (21.2) for overall satisfaction. Subjective data from the daily dairies showed that one participant found the brace too firm around the ankle due to loss of soft tissue mass and two participants found it challenging to don and doff the brace due to loss of hand dexterity. CONCLUSION: This pilot study suggests that a 3D-printed custom ankle brace may improve balance and reduce foot pain in people with CMT; however, larger-scale trials are needed to further explore the impact of this brace on function and balance. Further customisation of the brace may also be required to improve acceptability for some people.

Congenital Insensitivity to Pain: A Case Study of a Rare Genetic Disorder.

Congenital insensitivity to pain (CIP) is an exceedingly rare autosomal recessive condition caused by SCN9A Nav1.7 loss-of-function mutations. We present a case of a patient with clinical symptoms compatible with CIP who had a homozygous SCN9A probable pathogenic variation, which results in a premature stop codon. According to the recommendations of the American College of Medical Genetics and Genomics, it is classified as probable pathogenic (class 2). Early detection and treatment may aid in reducing mortality and morbidity as the signs and symptoms of CIP with dysmorphic features manifest early, typically at birth or during infancy. However, with careful medical attention, affected individuals can have longer life expectancies.

Charcot's interest in faith healing.

Jean-Martin Charcot believed that "miraculous" cures followed the rules of nature and that the resolution of physical stigmata after pilgrimages to shrines followed the laws of physiology. He acknowledged that some of the patients he had failed to improve at La Salpêtrière had subsequently been cured by the "faith cure" at Lourdes, but he believed their recovery had occurred through "autosuggestion." Although this term is more commonly associated with his collaborator Pierre Janet, it is clearly expressed in Charcot's final pronouncements. Charcot's recognition of the neurological origin of hysteria is central to contemporary ideas about the cause of functional neurological disorders, and even some components of his once derided treatment approach-including mental training, graded exercise, and medical hypnotism-are in vogue.

Lower limb nerve ultrasound: A four-way comparison of acquired and inherited axonopathy, inherited neuronopathy and healthy controls.

INTRODUCTION/AIMS: In a recent study, we showed that nerve ultrasound of the upper limbs could distinguish inherited sensory neuronopathy from inherited axonopathy; surprisingly, no differences were found in the lower limb nerves. In this study, we compared lower limb nerve ultrasound measurements in inherited neuronopathy, inherited axonopathy, and acquired axonopathy. METHODS: Tibial and sural nerve ultrasound cross-sectional areas (CSAs) of 34 healthy controls were retrospectively compared with those of three patient groups: 17 with cerebellar ataxia with neuronopathy and vestibular areflexia syndrome (CANVAS), 18 with Charcot-Marie-Tooth type 2 (CMT2), and 18 with acquired length-dependent sensorimotor axonal neuropathy, using ANOVA with post-hoc Tukey honestly significance difference (HSD) (significance level set at p < .05). RESULTS: The nerve CSAs of CANVAS and CMT2 patients were not significantly different. Both the tibial and the sural nerve CSAs were significantly smaller in CANVAS and CMT2 compared with the acquired axonal neuropathy group. Tibial nerve CSAs of CANVAS and CMT2 were significantly smaller than controls. Tibial and sural nerve CSAs of the acquired axonal neuropathy group were also significantly larger than the controls'. DISCUSSION: Ultrasound of the lower limb nerves distinguished inherited from acquired axonopathy with the nerve size respectively reduced and increased in these two groups. This has potential implication for the differential diagnosis of these diseases in clinical practice.

Navigating the Landscape of CMT1B: Understanding Genetic Pathways, Disease Models, and Potential Therapeutic Approaches.

Charcot-Marie-Tooth type 1B (CMT1B) is a peripheral neuropathy caused by mutations in the gene encoding myelin protein zero (MPZ), a key component of the myelin sheath in Schwann cells. Mutations in the MPZ gene can lead to protein misfolding, unfolded protein response (UPR), endoplasmic reticulum (ER) stress, or protein mistrafficking. Despite significant progress in understanding the disease mechanisms, there is currently no effective treatment for CMT1B, with therapeutic strategies primarily focused on supportive care. Gene therapy represents a promising therapeutic approach for treating CMT1B. To develop a treatment and better design preclinical studies, an in-depth understanding of the pathophysiological mechanisms and animal models is essential. In this review, we present a comprehensive overview of the disease mechanisms, preclinical models, and recent advancements in therapeutic research for CMT1B, while also addressing the existing challenges in the field. This review aims to deepen the understanding of CMT1B and to encourage further research towards the development of effective treatments for CMT1B patients.

Optical Genome Mapping Identifies a Second Xq27.1 Rearrangement Associated With Charcot-Marie-Tooth Neuropathy CMTX3.

BACKGROUND: X-linked recessive type 3 Charcot-Marie-Tooth (CMTX3) is a rare subtype of childhood-onset CMT. To date, all reported CMTX3 patients share a common founder 78 kb insertion from chromosome 8 into the Xq27.1 palindrome region. METHODS: We conducted patient-parent trio optical genome mapping (OGM) on a male patient presenting with clinically diagnosed Dejerine-Sottas disease for whom initial standard diagnostic genetic tests, including whole-genome sequencing (WGS), yielded negative results. RESULTS: OGM analysis revealed a maternally inherited interchromosomal insertion from chromosome region 7q31.1 into Xq27.1. Coupled with manual reassessment of WGS data, this confirmed the molecular diagnosis of atypical CMTX3 and showed that the 122.4 kb inserted fragment contained DLD and partially LAMB1. Subsequent analyses confirmed that the rearrangement had arisen de novo in the proband's mother. CONCLUSION: We report the second Xq27.1 rearrangement associated with CMTX3, providing novel clinical insights into its phenotypic and genotypic spectrum. Our findings highlight the importance of including genomic rearrangement analysis of Xq27.1 in standard diagnostic pipelines for childhood-onset CMT. Given the overlap in polyneuropathy phenotypes resulting from insertions from chromosomes 7 and 8 into the same Xq27.1 palindrome region, the pathogenic mechanism underlying peripheral neuropathy in CMTX3 likely involves dysregulation of genes within this region.

Charcot and hallucinations: A study in insight and blindness.

Jean-Martin Charcot (1825-1893) showed little interest in mental disorders, the domain of nineteenth-century alienists. But hallucinations are not confined to the field of psychiatry, and Charcot, who had once tested the hallucinogenic effects of hashish in his youth, went on to describe hallucinations in the course of various neurological conditions as just another semiological element. Most of his or his disciples' writings on hallucinations can be found in his work on hysteria. Hallucinations and delusions were part of "grand hysteria" and occurred at the end of the attack (third or fourth phase). Hypnosis or chemical agents could also induce hallucinations. Charcot and his disciples did not go so far as to emphasize the importance of hallucinations when they evoked past trauma, especially sexual trauma. Charcot's materialistic orientation led him and his disciples-especially D. M. Bourneville (1840-1909), G. Gilles de la Tourette (1857-1904), and the neurologist and artist P. Richer (1849-1833)-to seek hysteria in artistic representations of "possessed women" and in the visions of nuns and mystics. Finally, Charcot recognized the importance of hallucinations in neurological semiology, by means of precise and relevant observations scattered throughout his work. Preoccupied with linking hysteria to neurology, Charcot only scratched the surface of the possible significance of hallucinations in this context, paving the way for the work of his students Pierre Janet (1859-1947) and Sigmund Freud (1856-1939).

Charcot-Marie-Tooth type 2CC misdiagnosed as Chronic Inflammatory Demyelinating Polyradiculoneuropathy.

BACKGROUND AND AIMS: Charcot-Marie-Tooth (CMT) is a heterogeneous group of genetic neuropathies and is typically characterized by distal muscle weakness, sensory loss, pes cavus and areflexia. Herein we describe a case of CMT2CC presenting with proximal muscle weakness and equivocal electrophysiological features, that was misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP). CASE REPORT: A 30-year-old woman complained of proximal muscle weakness with difficulty climbing stairs. Neurological examination showed weakness in lower limb (LL) muscles, that was marked proximally and mild distally, and absence of deep tendon reflexes in the ankles. Nerve conduction studies (NCS) showed sensory-motor neuropathy with non-uniform NC velocity and a partial conduction block (CBs) in peroneal nerve and tibial nerves. Thus, a diagnosis of CIDP was entertained and the patient underwent ineffective treatment with intravenous immunoglobulins. At electrophysiological revaluation CB in peroneal nerve was undetectable as also distal CMAP had decreased whereas the CBs persisted in tibial nerves. Hypothesizing a hereditary neuropathy, we examined the proband's son, who presented mild weakness of distal and proximal muscles at lower limbs. Neurophysiological investigation showed findings consistent with an intermediate-axonal electrophysiological pattern. A targeted-NGS including 136 CMT genes showed the heterozygous frameshift mutation (c.3057dupG; p.K1020fs*43) in the NEFH gene, coding for the neurofilament heavy chain and causing CMT2CC. INTERPRETATION: Diagnosis of a genetic neuropathy may be challenging when clinical features are atypical and/or electrophysiological features are misleading. The most common misdiagnosis is CIDP. Our report suggests that also CMT2CC patients with proximal muscle weakness and equivocal electrophysiological features might be misdiagnosed as CIDP.

Charcot neuro-osteoarthropathy: a review of key concepts and an evidence-based surgical management algorithm.

Charcot neuro-osteoarthropathy (CNO), mainly as a result of diabetic neuropathy, is a complex problem which carries significant morbidity, and is an increasing burden on healthcare as demographics change globally. A multi-disciplinary team (MDT) is necessary to treat the multiple facets of this disease. The multifactorial and non-homogenous nature of this condition and its management, has prevented the development of comprehensive guidelines based on level 1 evidence. Although there is a trend to surgically treat these patients in tertiary centres, the increasing prevalence of CNO necessitates the capability of all units to manage this condition to an extent locally. This article conducted a thorough literature search of Pubmed and Embase from 2003 to 2023 including the following search terms; "Charcot" "neuroarthropathy" "diabetic foot" "management" "surgery" "treatment" "reconstruction". The results of this review have been summarised and synthesised into an evidence-based algorithm to aid in the surgical decision-making process, and improve the understanding of surgical management by the whole MDT.

Risk factors for Charcot foot development in individuals with diabetes mellitus.

AIMS/HYPOTHESIS: Charcot foot is a complication of diabetes mellitus that has potentially disastrous consequences. Although it was first described in 1868 and found to be associated with diabetes in 1936, there is still uncertainty about the risk factors affecting the development of the condition. Here, we aim to identify risk factors for Charcot foot in a nationwide cohort study. METHODS: A retrospective register-based cohort study was performed for the period 2001-2016, using nationwide registries. Individuals with diabetes and Charcot foot were identified and matched by diabetes type and with similar diabetes duration with individuals with diabetes but not Charcot foot. Logistic regression analyses were used to identify risk factors. RESULTS: A total of 3397 participants with diabetes mellitus and Charcot foot and 27,662 control participants with diabetes but without Charcot foot were included. HbA1c, duration of diabetes, micro- and macroalbuminuria, retinopathy and atherosclerosis (general and peripheral) were identified as risk factors for Charcot foot in participants with type 1 diabetes and participants with type 2 diabetes. CONCLUSIONS/INTERPRETATION: In the most extensive study on Charcot foot to date, we identified distinctive and common risk factors associated with the development of Charcot foot in individuals with type 1 diabetes and type 2 diabetes.

A Case of Charcot-Marie-Tooth Disease Causing Colitis and Electrolyte Imbalances.

Peripheral nerve injury is a result of the rare and crippling Charcot-Marie-Tooth (CMT) disease. Although it can happen at any age, progressive muscle weakening is most obvious in adolescence or the early stages of adulthood. We present a case of an 81-year-old female with recurrent urinary tract infections (UTIs), complaints of abdominal pain and constipation, as well as dysuria with abnormal electrolyte levels. This case serves as an effective symptomatic treatment plan for a patient with this rare neuromuscular disorder.

The recovery cycle of excitability assessed by a conventional electrodiagnostic machine: A study in healthy volunteers and in Charcot-Marie-Tooth 1A patients.

OBJECTIVE: To validate the 'paired pulses' technique with a conventional electrodiagnostic machine (CEM) for studying the axonal excitability recovery cycle (ERC). METHODS: Paired pulses, with a variable inter-stimulus interval, were delivered at the wrist along the median nerve. The CEM repeatability was verified in a group of 15 healthy volunteers (test/retest analysis). ERC was then applied in 40 healthy volunteers and 10 patients with Charcot-Marie-Tooth type 1A (CMT1A), using both the threshold tracking (TT) reference method and CEM (basal condition, during and after ischemia). RESULTS: CEM parameters evaluating absolute refractory and supernormal periods were reproducible (interclass correlation coefficient > 0.75). CEM results were consistent with TT method and literature data. In CMT1A, refractory and superexcitable periods were significantly reduced. According to receiving operator characteristic analysis, the CEM supernormal period area was the most relevant parameter for discriminating CMT1A from healthy volunteers (area under the curve = 0.98). CONCLUSIONS: CEM was a valid procedure for studying ERC. CMT1A patients exhibited ERC alterations due to modifications in passive membrane properties and of nodal ion channel distribution resulting from demyelination. SIGNIFICANCE: Studying ERC with CEM could be performed in routine practice in patients with peripheral neuropathies to provide information on motor axonal excitability.

The effect of ankle-foot orthoses on gait characteristics in people with Charcot-Marie-Tooth disease: A systematic review and meta-analysis.

INTRODUCTION: Ankle-foot orthoses (AFOs) are commonly prescribed for people with Charcot-Marie-Tooth disease (CMT) to improve gait efficiency and reduce the occurrence of tripping and falls. The aim of this study was to systematically review evidence on the effects of AFOs on gait kinematics and kinetics and postural stability/balance in people with CMT. METHODS: Studies were identified from electronic databases and screened for inclusion online using Rayyan. Data from all eligible studies were extracted into a standardised Excel spreadsheet. Methodological quality was assessed using the Joanna Briggs Institute Critical Appraisal Checklists. Where available, continuous outcomes were pooled to estimate standardised mean differences in random-effects meta-analyses. RESULTS: A total of 15 studies were included with variable methodological quality. Sample sizes ranged from 1 to 32 with significant variability in participant characteristics, AFO designs and testing procedures. Data from eight studies were available for meta-analysis. Although AFOs impacted walking velocity, stride length, step length, cadence, ankle dorsiflexion, plantarflexion, knee and hip flexion and ankle plantarflexion and dorsiflexion moments, the effect sizes were small-to-moderate and non-significant. There were insufficient data available for pooled analyses of outcomes related to postural stability/balance. CONCLUSION: Although AFOs positively affect a number of gait and balance parameters, the small participant numbers, variability in participant characteristics, AFO designs and testing procedures adopted by the available studies resulted in the absence of statistically significant effects when data were pooled. The results from this review also highlight the importance of device customisation based on the individual needs of people with CMT and their degree of gait impairment.

Jean-Martin Charcot: Pioneer of Neurology.

Jean-Martin Charcot, born on November 29, 1825, in Paris, France, is known as the father of neurology. During a time when neurology was not yet a recognized medical specialty, Charcot's pioneering contributions significantly advanced the field. Charcot's use of the anatomo-clinical method, which correlates clinical symptoms with anatomical findings, led to the discovery and characterization of numerous neurological conditions, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Charcot's joint, and Charcot-Marie-Tooth (CMT) disease. His methodical approach to documenting clinical signs and conducting post-mortem examinations revolutionized neurological research and diagnosis, laying the groundwork for modern neurology. The anatomo-clinical methods continue to be a vital tool in neurological research and practice today. Charcot's work extended beyond clinical practice, influencing the study of neurology through his role as an educator and mentor to many, including Sigmund Freud. Despite some controversies and a reputation for being difficult to work with, Charcot's legacy endures, with his initial discoveries fostering greater awareness and the development of therapies for various neurological disorders.

Syringomyelia-induced wrist Charcot neuroarthropathy.

We present a rare case of wrist Charcot neuroarthropathy secondary to post-tuberculosis syringomyelia.Level of evidence: V.

Hereditary spastic paraplegia and extensive leukoencephalopathy: a case report of a unique phenotype associated with a GJB1/Cx32 p.Pro174Ser variant.

BACKGROUND: Pathogenic variants in Gap junction protein beta 1 (GJB1), which encodes Connexin 32, are known to cause X-linked Charcot-Marie-Tooth disease (CMTX), the second most common form of CMT. CMTX presents with the following five central nervous systems (CNS) phenotypes: subclinical electrophysiological abnormalities, mild fixed abnormalities on neurological examination and/or imaging, transient CNS dysfunction, cognitive impairment, and persistent CNS manifestations. CASE PRESENTATION: A 40-year-old Japanese male showed CNS symptoms, including nystagmus, prominent spastic paraplegia, and mild cerebellar ataxia, accompanied by subclinical peripheral neuropathy. Brain magnetic resonance imaging revealed hyperintensities in diffusion-weighted images of the white matter, particularly along the pyramidal tract, which had persisted since childhood. Nerve conduction assessment showed a mild decrease in motor conduction velocity, and auditory brainstem responses beyond wave II were absent. Peripheral and central conduction times in somatosensory evoked potentials elicited by stimulation of the median nerve were prolonged. Genetic analysis identified a hemizygous GJB1 variant, NM_000166.6:c.520C > T p.Pro174Ser. CONCLUSIONS: The patient in the case described here, with a GJB1 p.Pro174Ser variant, presented with a unique CNS-dominant phenotype, characterized by spastic paraplegia and persistent extensive leukoencephalopathy, rather than CMTX. Similar phenotypes have also been observed in patients with GJC2 and CLCN2 variants, likely because of the common function of these genes in regulating ion and water balance, which is essential for maintaining white matter function. CMTX should be considered within the spectrum of GJB1-related disorders, which can include patients with predominant CNS symptoms, some of which can potentially be classified as a new type of spastic paraplegia.

Trigeminal neuralgia, demyelinating polyneuropathy, and central nervous system involvement in a patient with an SH3TC2 mutation.

BACKGROUND: Charcot-Marie-Tooth type 4C (CMT4C) is a slowly progressive, autosomal recessive, sensorimotor polyneuropathy characterized by demyelination and distinct clinical features, including cranial nerve involvement. CMT4C is associated with pathogenic mutations in the SH3TC2 gene. METHODS: A patient presenting with gait instability due to demyelinating polyneuropathy and refractory trigeminal neuralgia underwent comprehensive evaluation. Nerve conduction studies, magnetic resonance imaging (MRI) of the brain, cervical spine, and thoracic spine, lumbar puncture, and genetic test through next generation sequencing were performed. RESULTS: The genetic test found an Arg1109Stop mutation in the SH3TC2 gene, associated with demyelinating polyneuropathy and cranial neuropathy. Interestingly, brain MRI showed multiple, nonenhancing white matter hyperintensities. This is the first case of CMT4C associated with white matter lesions. CONCLUSION: Any patient with slowly progressive peripheral nervous system symptoms and disproportionally abnormal nerve conduction study findings should be tested for an inherited polyneuropathy and brain imaging for screening of possible central nervous system involvement should be performed. Further investigation is needed to elucidate the pathogenetic basis of CMT4C and a possible association with white matter lesions.