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.

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.

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.

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.

Pediatric Charcot-Marie-Tooth disease and peripheral nerve blocks: a retrospective cohort study of 25 patients.

PURPOSE: Charcot-Marie-Tooth (CMT) disease is an inherited neurologic disorder characterized by progressive peripheral neuropathies. The use of peripheral nerve blocks (PNB) in patients with CMT disease has been controversial because of concerns about exacerbating existing neurologic impairments and the "double hit" hypothesis. We aimed to assess the use of PNB in pediatric patients with CMT disease undergoing orthopedic surgery to address the limited data available in the literature on this topic. METHODS: In this retrospective cohort study, we included all pediatric patients with CMT disease scheduled for orthopedic surgery receiving PNB at our centre. All of the patients had preoperative neurologic exams and received one or more ultrasound-guided regional anesthesia techniques. Data extracted included details of anesthesia technique, surgical procedure, opioid consumption, and pain scores during the first three postoperative days. We also reviewed any complications such as neurologic deficits and local anesthetic toxicity. We used descriptive statistics to summarize the findings. RESULTS: We included 25 patients, 14 of whom (56%) presented with pre-existing neurologic deficits, primarily in the lower extremities. Postoperative assessments revealed no new neurologic impairments in 24/25 (96%) patients, with only one patient experiencing a nerve injury possibly related to the surgical procedure. Opioid consumption was low in the postanesthesia care unit and on the day of surgery. No additional complications were noted in the first 72 hr after surgery. CONCLUSION: Despite concerns, PNB showed favourable outcomes in a pediatric cohort with CMT disease, with low opioid consumption and pain scores and minimal complications during follow-up. These findings match previous reports of adult patients with CMT disease and suggest that the benefits of PNB may outweigh the perceived risks in pediatric patients with CMT disease.

RéSUMé: OBJECTIF: La maladie de Charcot-Marie-Tooth (CMT) est une maladie neurologique héréditaire caractérisée par des neuropathies périphériques progressives. L'utilisation de blocs nerveux périphériques (BNP) chez la patientèle atteinte de CMT est controversée en raison des inquiétudes concernant l'exacerbation des déficiences neurologiques existantes et de l'hypothèse d'une « double insulte ¼. Notre objectif était d'évaluer l'utilisation de BNP chez les patient·es pédiatriques atteint·es de CMT bénéficiant d'une chirurgie orthopédique afin de pallier les données limitées disponibles dans la littérature à ce sujet. MéTHODE: Dans cette étude de cohorte rétrospective, nous avons inclus tou·tes les patient·es pédiatriques atteint·es de CMT devant bénéficier d'une chirurgie orthopédique et recevant un BNP dans notre centre. Tou·tes ont bénéficié d'examens neurologiques préopératoires et ont reçu une ou plusieurs techniques d'anesthésie régionale échoguidées. Les données extraites comprenaient des détails sur la technique d'anesthésie, l'intervention chirurgicale, la consommation d'opioïdes et les scores de douleur au cours des trois premiers jours postopératoires. Nous avons également examiné toutes les complications telles que les déficits neurologiques et la toxicité des anesthésiques locaux. Nous avons utilisé des statistiques descriptives pour résumer les résultats. RéSULTATS: Nous avons inclus 25 patient·es, dont 14 (56 %) présentaient des déficits neurologiques préexistants, principalement dans les membres inférieurs. Les évaluations postopératoires n'ont révélé aucune nouvelle déficience neurologique chez 24 patient·es sur 25 (96 %), une seule personne ayant subi une lésion nerveuse possiblement liée à l'intervention chirurgicale. La consommation d'opioïdes était faible en salle de réveil et le jour de l'opération. Aucune complication supplémentaire n'a été notée dans les 72 premières heures après la chirurgie. CONCLUSION: Malgré les inquiétudes, le BNP a montré des résultats favorables dans une cohorte pédiatrique atteinte de CMT, avec une faible consommation d'opioïdes et des scores de douleur et des complications minimes pendant le suivi. Ces résultats correspondent à des comptes rendus antérieurs de patient·es adultes atteint·es de CMT et suggèrent que les avantages des BNP pourraient l'emporter sur les risques perçus chez la patientèle pédiatrique atteinte de CMT.

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.

Current Treatment Methods for Charcot-Marie-Tooth Diseases.

Charcot-Marie-Tooth (CMT) disease, the most common inherited neuromuscular disorder, exhibits a wide phenotypic range, genetic heterogeneity, and a variable disease course. The diverse molecular genetic mechanisms of CMT were discovered over the past three decades with the development of molecular biology and gene sequencing technologies. These methods have brought new options for CMT reclassification and led to an exciting era of treatment target discovery for this incurable disease. Currently, there are no approved disease management methods that can fully cure patients with CMT, and rehabilitation, orthotics, and surgery are the only available treatments to ameliorate symptoms. Considerable research attention has been given to disease-modifying therapies, including gene silencing, gene addition, and gene editing, but most treatments that reach clinical trials are drug treatments, while currently, only gene therapies for CMT2S have reached the clinical trial stage. In this review, we highlight the pathogenic mechanisms and therapeutic investigations of different subtypes of CMT, and promising therapeutic approaches are also discussed.

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 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.

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.

Outcomes of Charcot-Marie-Tooth Disease Cavovarus Surgical Reconstruction.

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is a progressive inherited neurologic disorder causing muscle weakness and lower extremity deformity. The goal of foot and ankle surgical treatment is to create a stable, plantigrade foot, with the potential elimination of brace-wear for ambulation. The aim of this study was to report baseline CMT patient function and subsequent outcome improvement from surgical treatment, as determined by PROMIS physical function (PF), pain interference (PI), and mental health/depression (D) scores. METHODS: Retrospective data were collected on consecutive CMT patients older than 18 years receiving surgical treatment by a single surgeon from 2018 to 2022 with minimum 1-year follow-up. Each patient prospectively completed PROMIS preoperatively and postoperatively after all planned surgical treatment was completed. Prospective clinical and radiographic data were collected to describe complications and correlation to outcome. RESULTS: Ninety-five feet in 64 patients older than 18 years were included for analysis. Mean follow-up was 21 months (range, 12-31) with 100% minimum 1-year follow-up. CMT patients had worse preoperative and baseline scores in all domains except PROMIS-D compared with population normal PROMIS scores. Significant improvements were identified in all PROMIS domains following surgical treatment. The mean PROMIS-PF score increased (40 to 45, delta = 4.9, P < .001), the mean PROMIS-PI score decreased (59 to 52, delta = 7.1, P < .001), and the mean PROMIS-D score decreased (50 to 47, delta = 3.0, P = .004). Subgroup analysis was performed for patients with severe radiographic deformity and those treated with arthrodesis in an attempt to demonstrate the impact of disease severity on outcome. Subgroup analysis demonstrated that arthrodesis led to worse overall PROMIS-PF outcome with the same change score. CONCLUSION: Surgical treatment for CMT patients provides significant clinical improvement in all measured outcome domains. CMT patients can be restored to normal population physical function and pain interference outcome scores. Patients with more severe deformity have similar improvement from surgical treatment, although their ultimate functional improvement is blunted due to a lower baseline.

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.

Pharmacological Doses of Thiamine Benefit Patients with the Charcot-Marie-Tooth Neuropathy by Changing Thiamine Diphosphate Levels and Affecting Regulation of Thiamine-Dependent Enzymes.

Charcot-Marie-Tooth (CMT) neuropathy is a polygenic disorder of peripheral nerves with no effective cure. Thiamine (vitamin B1) is a neurotropic compound that improves neuropathies. Our pilot study characterizes therapeutic potential of daily oral administration of thiamine (100 mg) in CMT neuropathy and its molecular mechanisms. The patient hand grip strength was determined before and after thiamine administration along with the blood levels of the thiamine coenzyme form (thiamine diphosphate, ThDP), activities of endogenous holo-transketolase (without ThDP in the assay medium) and total transketolase (with ThDP in the assay medium), and transketolase activation by ThDP [1 - (holo-transketolase/total transketolase),%], corresponding to the fraction of ThDP-free apo-transketolase. Single cases of administration of sulbutiamine (200 mg) or benfotiamine (150 mg) reveal their effects on the assayed parameters within those of thiamine. Administration of thiamine or its pharmacological forms increased the hand grip strength in the CMT patients. Comparison of the thiamin status in patients with different forms of CMT disease to that of control subjects without diagnosed pathologies revealed no significant differences in the average levels of ThDP, holo-transketolase, or relative content of holo and apo forms of transketolase. However, the regulation of transketolase by thiamine/ThDP differed in the control and CMT groups: in the assay, ThDP activated transketolase from the control individuals, but not from CMT patients. Thiamine administration paradoxically decreased endogenous holo-transketolase in CMT patients; this effect was not observed in the control group. Correlation analysis revealed sex-specific differences in the relationship between the parameters of thiamine status in both the control subjects and patients with the CMT disease. Thus, our findings link physiological benefits of thiamine administration in CMT patients to changes in their thiamine status, in particular, the blood levels of ThDP and transketolase regulation.

A Novel m.1636A > G Variant in Mitochondrial TV Gene Might Cause New Phenotype of Mitochondrial Disease in a 2-Year Old Chinese Boy.

Pathogenic variants of mitochondrial DNA (mtDNA) are associated with a large number of heterogeneous diseases involving multiple systems with which patients may present with a wide range of clinical phenotypes. Clinical data of the proband and his family members were gathered in a retrospective study. Whole-exome sequencing and full-length sequencing of the mitochondrial genome that was performed on peripheral blood, urine, and oral mucosa cells were applied for genetic analysis. In this study, we describe a 2-year-old Chinese boy with global developmental delay, Charcot-Marie-Tooth (CMT) disease, progressive myoclonic epilepsy, paroxysmal arrhythmia, and brain atrophy with elevated blood lactate levels. The clinical manifestations of the patient were improved after metabolic therapy, but the development regressed after infection. The molecular finding of whole-exome sequencing is unremarkable, but the mtDNA genome sequencing of the proband and his monther revealed a de novo novel heteroplasmic variant, m.1636A > G, located next to the highly conserved anticodon loop of tRNA Val (MT-TV) gene. Moreover, the higher levels of mutational load in urinary epithelial cells (19.05%) and oral mucosa cells (20.8%) were detected than that in blood (17.4%). Combined with the phenotypic and molecular genetics analysis of this family, this novel variation was currently considered to be a likely pathogenic variant. Our results added evidence that the de novo m.1636A > G variation in the highly conserved sequence of MT-TV appears to suggest a childhood-onset mitochondrial phenotype of a 2-year-old patient, thus broaden the genotypic interpretation of mitochondrial DNA-related disease.

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.

Corrigendum: Case report: Chronic inflammatory demyelinating polyneuropathy superimposed on Charcot-Marie-tooth type 1A disease after SARS-CoV-2 vaccination and COVID-19 infection.

[This corrects the article DOI: 10.3389/fneur.2024.1358881.].

Identification and Characterization of Novel Founder Mutations in NDRG1: Refining the Genetic Landscape of Charcot-Marie-Tooth Disease Type 4D in Bulgaria.

Charcot-Marie-Tooth neuropathy type 4D (CMT4D) is a rare genetic disorder of the peripheral nervous system caused by biallelic mutations in the N-Myc Downstream Regulated 1 gene (NDRG1). Patients present with an early onset demyelinating peripheral neuropathy causing severe distal muscle weakness and sensory loss, leading to loss of ambulation and progressive sensorineural hearing loss. The disorder was initially described in the Roma community due to a common founder mutation, and only a handful of disease-causing variants have been described in this gene so far. Here, we present genetic and clinical findings from a large Bulgarian cohort of demyelinating CMT patients harboring recurrent and novel variants in the NDRG1 gene. Notably, two splice-site variants are exclusive to Bulgarian Muslims and reside in ancestral haplotypes, suggesting a founder effect. Functional characterization of these novel variants implicates a loss-of-function mechanism due to shorter gene products. Our findings contribute to a deeper understanding of the genetic and clinical heterogeneity of CMT4D and highlight novel founder mutations in the ethnic minority of Bulgarian Muslims.

Neurofilaments in neurologic disease.

Neurofilaments (NFs), major cytoskeletal constituents of neurons, have emerged as universal biomarkers of neuronal injury. Neuroaxonal damage underlies permanent disability in various neurological conditions. It is crucial to accurately quantify and longitudinally monitor this damage to evaluate disease progression, evaluate treatment effectiveness, contribute to novel treatment development, and offer prognostic insights. Neurofilaments show promise for this purpose, as their levels increase with neuroaxonal damage in both cerebrospinal fluid and blood, independent of specific causal pathways. New assays with high sensitivity allow reliable measurement of neurofilaments in body fluids and open avenues to investigate their role in neurological disorders. This book chapter will delve into the evolving landscape of neurofilaments, starting with their structure and cellular functions within neurons. It will then provide a comprehensive overview of their broad clinical value as biomarkers in diseases affecting the central or peripheral nervous system.

Charcot-Marie-Tooth Disease With Leukodystrophy: An Atypical Presentation.

This case report presents a 23-year-old male diagnosed with Charcot-Marie-Tooth (CMT) disease, who exhibited additional neurological symptoms suggestive of leukodystrophy. The patient experienced recurrent episodes of slurred speech, imbalance, and a recent tonic-clonic seizure, prompting admission. Neurological examination and imaging revealed bilateral white matter changes, raising suspicion of leukoencephalopathy. Further investigations confirmed a nonsense mutation c.64C>T (p.Arg22*) in the gap junction beta 1 (GJB1) gene. This case underscores the complexity of Charcot-Marie-Tooth disease type 1 (CMTX1) with atypical central nervous system (CNS) manifestations, highlighting the importance of comprehensive diagnostic evaluations and a multidisciplinary approach to management.