Charcot-Marie-Tooth Research Articles

O-GlcNAcylation regulates neurofilament-light assembly and function and is perturbed by Charcot-Marie-Tooth disease mutations

The neurofilament (NF) cytoskeleton is critical for neuronal morphology and function. In particular, the neurofilament-light (NF-L) subunit is required for NF assembly in vivo and is mutated in subtypes of Charcot-Marie-Tooth (CMT) disease. NFs are highly dynamic, and the regulation of NF assembly state is incompletely understood. Here, we demonstrate that human NF-L is modified in a nutrient-sensitive manner by O-linked-β-N-acetylglucosamine (O-GlcNAc), a ubiquitous form of intracellular glycosylation. We identify five NF-L O-GlcNAc sites and show that they regulate NF assembly state. NF-L engages in O-GlcNAc-mediated protein-protein interactions with itself and with the NF component α-internexin, implying that O-GlcNAc may be a general regulator of NF architecture. We further show that NF-L O-GlcNAcylation is required for normal organelle trafficking in primary neurons. Finally, several CMT-causative NF-L mutants exhibit perturbed O-GlcNAc levels and resist the effects of O-GlcNAcylation on NF assembly state, suggesting a potential link between dysregulated O-GlcNAcylation and pathological NF aggregation. Our results demonstrate that site-specific glycosylation regulates NF-L assembly and function, and aberrant NF O-GlcNAcylation may contribute to CMT and other neurodegenerative disorders.

Charcot-Marie-Tooth Disease with a Novel Variant in Gap Junction Protein Beta 1 Presenting with Visual Field Defects.

Pathogenic variants in Gap Junction Protein Beta 1 (GJB1) cause X-linked Charcot-Marie-Tooth (CMT) disease type 1 (CMTX1), which is a common hereditary motor and sensory neuropathy. A 45-year-old man presented with progressive muscle weakness, atrophy, sensory disturbance of all limbs from childhood, and visual field defects in both eyes at 40 years old. A segregation analysis revealed a novel variant, c.173C>A (p.P58H), in the GJB1 gene. Patients with variants at codon 58 in GJB1 showed clinically varied phenotypes, ranging from demyelinating neuropathy to cerebellar ataxia. This patient may represent one of the various clinical phenotypes of GJB1 variants.

Neuron-Schwann cell interactions in peripheral nervous system homeostasis, disease, and preclinical treatment.

Schwann cells (SCs) have a critical role in the peripheral nervous system. These cells are able to support axons during homeostasis and after injury. However, mutations in genes associated with the SCs repair program or myelination result in dysfunctional SCs. Several neuropathies such as Charcot-Marie-Tooth (CMT) disease, diabetic neuropathy and Guillain-Barré syndrome show abnormal SC functions and an impaired regeneration process. Thus, understanding SCs-axon interaction and the nerve environment in the context of homeostasis as well as post-injury and disease onset is necessary. Several neurotrophic factors, cytokines, and regulators of signaling pathways associated with proliferation, survival and regeneration are involved in this process. Preclinical studies have focused on the discovery of therapeutic targets for peripheral neuropathies and injuries. To study the effect of new therapeutic targets, modeling neuropathies and peripheral nerve injuries (PNIs) in vitro and in vivo are useful tools. Furthermore, several in vitro protocols have been designed using SCs and neuron cell lines to evaluate these targets in the regeneration process. SCs lines have been used to generate effective myelinating SCs without success. Alternative options have been investigated using direct conversion from somatic cells to SCs or SCs derived from pluripotent stem cells to generate functional SCs. This review will go over the advantages of these systems and the problems associated with them. In addition, there have been challenges in establishing adequate and reproducible protocols in vitro to recapitulate repair SC-neuron interactions observed in vivo. So, we also discuss the mechanisms of repair SCs-axon interactions in the context of peripheral neuropathies and nerve injury (PNI) in vitro and in vivo. Finally, we summarize current preclinical studies evaluating transgenes, drug, and novel compounds with translational potential into clinical studies.

Gait Pattern in Charcot-Marie-Tooth Disease Type 1A According to Disease Severity.

The aim of this study was to evaluate the characteristics of gait patterns in Charcot-Marie-Tooth disease type 1A (CMT1A) patients according to disease severity. Twenty-two CMT1A patients were enrolled and classified into two groups, according to the disease severity. The healthy control group consisted of 22 subjects with no gait impairment. Full barefoot three-dimensional gait analysis with temporospatial, kinematic, and kinetic data was performed among the mild and moderate CMT1A group and the control group. Minimal hip abduction, maximal hip extension generation, peak knee flexion moment at stance, ankle dorsiflexion at initial contact, maximal ankle plantarflexion at push-off and maximal ankle rotation moment at stance in the CMT1A group showed a significant difference compared to the control group (p < 0.05). In the moderate group, there were greater maximal hip flexion angles in swing, and smaller dorsiflexion angles at initial contact compared to the control group and mild group. CMT patients had typical gait characteristics and their gait patterns were different according to severity. The analysis of gait patterns in patients with CMT1A will help to understand gait function and provide important information for the treatment of patients with CMT in the future.

Proposal of physical exercises for charcot marie tooth disease patients: a tailored approach

Background: Charcot-Marie-Tooth disease (CMT) is a neurological condition of genetic etiology classified among rare diseases.Methods: The aim of the study was to subject two CMT-1A patient sisters to an ad-hoc training program of 6 weeks (18 sessions) and to record and obtain improvements in proprioception, stability, balance, mobility, and strength.Results: The study showed positive results on the following scales: Romberg test; 6 MWT; 30-ACT; 30 CST; TUG; Q-Walk-12, and Q-SF-36.Conclusion: The study aimed to underline the importance of an early disease training approach to limit its progression. The study demonstrated a positive impact of a 6-week gym training program based on monopodalic standing and quadrupedal exercises on proprioceptive abilities, postural stability, and improved balance.

Homozygous Mutations in GDAP1 and MFN2 Genes Resulted in Autosomal Recessive Forms of Charcot-Marie-Tooth Disease in Consanguineous Pakistani Families.

Charcot-Marie-Tooth disease (CMT) is a heritable neurodegenerative disease of peripheral nervous system diseases in which more than 100 genes and their mutations are associated. Two consanguineous families Dera Ghazi Khan (PAK-CMT1-DG KHAN) and Layyah (PAK-CMT2-LAYYAH) with multiple CMT-affected subjects were enrolled from Punjab province in Pakistan. Basic epidemiological data were collected for the subjects. Nerve conduction study (NCS) and electromyography (EMG) were performed for the patients. Whole-exome sequencing (WES) followed by Sanger sequencing was applied to report the genetic basic of CMT. The NCS findings revealed that sensory and motor nerve conduction velocities for both families were <38 m/s. EMG presented denervation, neuropathic motor unit potential, and reduced interference pattern of peripheral nerves. WES identified that a novel nonsense mutation (c. 226 G>T) in GADP1 gene and a previously known missense mutation in MFN2 gene (c. 334 G>A) cause CMT4A (Charcot-Marie-Tooth disease type 4A) in the PAK-CMT1-DG KHAN family and CMT2A (Charcot-Marie-Tooth disease type 2A) in the PAK-CMT2-LAYYAH family, respectively. Mutations followed Mendelian pattern with autosomal recessive mode of inheritance. Multiple sequence alignment by Clustal Omega indicated that mutation-containing domain in both genes is highly conserved, and in situ analysis revealed that both mutations are likely to be pathogenic. We reported that a novel nonsense mutation and a previously known missense mutation in GAPD1 gene and MFN2 gene, respectively, cause CMT in consanguineous Pakistani families.

P442 Charcot Marie Tooth disease type 4J and FIG4 compound heterozygous mutation

P442 Charcot Marie Tooth disease type 4J and FIG4 compound heterozygous mutation

Intravenous Administration of an AAV9 Vector Ubiquitously Expressing C1orf194 Gene Improved CMT-Like Neuropathy in C1orf194-/- Mice

Charcot-Marie-Tooth (CMT) disease, also known as hereditary motor sensory neuropathy, is a group of rare genetically heterogenous diseases characterized by progressive muscle weakness and atrophy, along with sensory deficits. Despite extensive pre-clinical and clinical research, no FDA-approved therapy is available for any CMT type. We previously identified C1ORF194, a novel causative gene for CMT, and found that both C1orf194 knock-in (I121N) and knockout mice developed clinical phenotypes similar to those in patients with CMT. Encouraging results of adeno-associated virus (AAV)-mediated gene therapy for spinal muscular atrophy have stimulated the use of AAVs as vehicles for CMT gene therapy. Here, we present a gene therapy approach to restore C1orf194 expression in a knockout background. We used C1orf194-/- mice treated with AAV serotype 9 (AAV9) vector carrying a codon-optimized WT human C1ORF194 cDNA whose expression was driven by a ubiquitously expressed chicken β-actin promoter with a CMV enhancer. Our preclinical evaluation demonstrated the efficacy of AAV-mediated gene therapy in improving sensory and motor abilities, thus achieving largely normal gross motor performance and minimal signs of neuropathy, on the basis of neurophysiological and histopathological evaluation in C1orf194-/- mice administered AAV gene therapy. Our findings advance the techniques for delivering therapeutic interventions to individuals with CMT.

The Importance of Rebalancing Foot Biomechanics by Computerized Podoscopic Assessment - Study in Charcot Marie Tooth Syndroms

Abstract Charcot–Marie–Tooth disease (CMT) is one of the hereditary motor and sensory neuropathies, a group of varied inherited disorders of the peripheral nervous system characterized by progressive loss of muscle tissue and touch sensation across various parts of the body. Currently incurable, this disease is the most commonly inherited neurological disorder, and affects about one in 2,500 people. A CMT diagnosis involves clinical evaluation of muscle function and atrophy, testing of sensory responses, and electromyography and nerve conduction studies. Often, the most important goal for patients with CMT is to maintain movement, muscle strength, and flexibility. Therefore, an interprofessional team approach with occupational therapy, physical therapy, orthotics, podiatrist, and orthopedic surgeon is recommended. Physical therapy should be involved in designing an exercise program that fits a person’s personal strengths and flexibility, but also in a god evaluation podoscopic assessment. Due to the lack of good sensory reception in the feet, CMT patients need to see a physical therapist in order to stabilize their feet or correct progressive problems by rebalancing the biomechanics of the foot. The procedure involves a computerized assessment, the realization of the plant footprint in the foam and the creation of plantatory therapeutics on the mold. These plantar orthoses help control foot drop and ankle instability and often provide a better sense of balance for patient. Appropriate footwear is also very important for CMT case, but often with difficulty finding well-fitting shoes because of their high arched feet and hammer toes. The patient will use these plantatory proponents in the right shoes in order to: increase of planting support surface, reduction of varus, slowing down the retraction tendency of plant aponeurosis

Charcot-Marie-Tooth Hastalığında Bilateral Pençe-Elin Düzeltilmesi İçin Ortez : Olgu Sunumu

Charcot-Marie-Tooth (CMT) is a common inherited peripheral nerve disorder. Although lower extremity deformities are more common in patients with CMT, claw-hand deformities and monkey hand deformities are also frequently seen. If these deformities are not corrected, they impair the biomechanics of the hand. Orthoses made of thermoplastic material are often used to correct these deformities. In this case, the results of the lumbrical bar orthosis applied to the bilateral claw-hand deformity in a patient with CMT are presented. Before and after orthosis use, dexterity was evaluated with the Purdue Pegboard test, hand grip strength was evaluated with a manual hand dynamometer, and pinch strength was evaluated with a pinchmeter. As a result of the evaluations, it was seen that the lumbrical bar orthosis corrected the claw-hand deformity, but did not cause improvements in hand grip strength, pinch strength and dexterity.

Phenotype-driven reanalysis reveals five novel pathogenic variants in 40 exome-negative families with Charcot-Marie-Tooth Disease.

To identify genetic causes in 40 whole exome sequencing (WES)-negative Charcot-Marie-Tooth (CMT) families and provide a summary of the clinical and genetic features of the diagnosed patients. The clinical information and sequencing data of 40 WES-negative families out of 131 CMT families were collected, and phenotype-driven reanalysis was conducted using the Exomiser software. The molecular diagnosis was regained in 4 families, increasing the overall diagnosis rate by 3.0%. One family with adolescent-onset pure CMT1 was diagnosed [POLR3B: c.2810G>A (p.R937Q)] due to the novel genotype-phenotype association. One infantile-onset, severe CMT1 family with deep sensory disturbance was diagnosed by screening the BAM file and harbored c.1174C>T (p.R392*) and 875_927delinsCTGCCCACTCTGCCCACTCTGCCCACTCTG (p.V292Afs53) of PRX. Two families were diagnosed due to characteristic phenotypes, including an infantile-onset ICMT family with renal dysfunction harboring c.213_233delinsGAGGAGCA (p.S72Rfs34) of INF2 and an adolescent-onset CMT2 family with optic atrophy harboring c.560C>T (p.P187L) and c.616A>G (p.K206E) of SLC25A46. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the variants of POLR3B and SLC25A46 were classified as likely pathogenic, and the variants of INF2 and PRX were pathogenic. All these variants were first reported worldwide except for p.R392* of PRX. We identified five novel pathogenic variants in POLR3B, PRX, INF2, and SLC25A46, which broaden their phenotypic and genotypic spectrums. Regular phenotype-driven reanalysis is a powerful strategy for increasing the diagnostic yield of WES-negative CMT patients, and long-term follow-up and screening BAM files for contiguous deletion and missense variants are both essential for reanalysis.

Clinical trials in Charcot-Marie-Tooth disorders: a retrospective and preclinical assessment.

This study aimed to evaluate the progression of clinical and preclinical trials in Charcot-Marie-Tooth (CMT) disorders. CMT has historically been managed symptomatically and with genetic counseling. The evolution of molecular and pathologic understanding holds a therapeutic promise in gene-targeted therapies. ClinicalTrials.gov from December 1999 to June 2022 was data extracted for CMT with preclinical animal gene therapy trials also reviewed by PubMed search. The number of active trials was 1 in 1999 and 286 in 2022. Academic settings accounted for 91% and pharmaceutical companies 9%. Of the pharmaceutical and academic trials, 38% and 28%, respectively, were controlled, randomized, and double-blinded. Thirty-two countries participated: the United States accounted for 26% (75/286). In total, 86% of the trials were classified as therapeutic: 50% procedural (21% wrist/elbow surgery; 22% shock wave and hydrodissection therapy), 23% investigational drugs, 15% devices, and 11% physical therapy. Sixty-seven therapeutic trials (49%) were designated phases 1-2 and 51% phases 3-4. The remaining 14% represent non-therapeutic trials: diagnostic testing (3%), functional outcomes (4%), natural history (4%), and standard of care (3%). One-hundred and three (36%) resulted in publications. Phase I human pharmaceutical trials are focusing on the safety of small molecule therapies (n = 8) and AAV and non-viral gene therapy (n = 3). Preclinical animal gene therapy studies include 11 different CMT forms including viral, CRISPR-Cas9, and nanoparticle delivery. Current CMT trials are exploring procedural and molecular therapeutic options with substantial participation of the pharmaceutical industry worldwide. Emerging drug therapies directed at molecular pathogenesis are being advanced in human clinical trials; however, the majority remain within animal investigations.

Novel variant in CADM3 causes Charcot–Marie–Tooth disease

Abstract CADM3 has been recently reported causing a rare axonal Charcot–Marie–Tooth disease in three independent Caucasian families carrying a recurrent change. We describe the first alternative causative mutation in CADM3 in a family from black African and also observed de novo in a patient of Caucasian ancestry. The disease inheritance was consistent with autosomal dominant and sporadic patterns, respectively. Eight patients and their relatives were enroled from both families. The mean age at diagnosis was 33.9 years, and walking difficulty was commonly the first symptom. Neurological examination showed distal muscle weakness and atrophy, sensory loss and foot and hand deformities. A high clinical variability was noted, but as seen in CADM3-associated neuropathy, symptoms were more pronounced in the arms in some patients. Nerve conduction studies showed no response in most of the examined nerves, and an axonal type of neuropathy, where recorded. Whole exome sequencing revealed a novel missense variant (c.1102G&amp;gt;T; Gly368Cys) in CADM3, segregating with the disease. Functional analyses showed a significant decrease in CADM3-Gly368Cys protein levels in the membrane and major structural changes in its predicted secondary structure. Therefore, we extend the genotype spectrum of CADM3, underlining the need for genetic studies in underrepresented populations like in Africa.

Re-survey of 16 Japanese patients with advanced-stage hereditary motor sensory neuropathy with proximal dominant involvement (HMSN-P): Painful muscle cramps for early diagnosis.

Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is an intractable neurological disease with autosomal dominant inheritance, four-limb weakness, sensory impairment, and a slowly progressive course. HMSN-P patients develop four-limb paralysis at the advanced-stage, as in amyotrophic lateral sclerosis (ALS). There is a natural 20- to 30-year course from initial painful muscle cramps and four-limb paralysis to respiratory dysfunction. A delay in the diagnosis of HMSN-P occurs due to the 20- to 30-year span from the initial symptom(s) to typical quadriplegia. Its early diagnosis is important, but the involvement of painful muscle cramps as an early symptom has not been clear. Following our earlier survey, we conducted a re-survey focusing on painful muscle cramps, assistive-device use, and hope for specific therapies in 16 Japanese patients with advanced-stage HMSN-P. Fifteen patients presented painful muscle cramps as the initial symptom, and muscle cramps in the lower abdomen including the flank were described by 10 of the patients. The presence of painful muscle cramps including those in the abdominal region may be a clue for the early diagnosis of HMSN-P. Painful abdominal cramps have not described in related diseases, e.g., ALS, spinal muscular atrophy, and Charcot-Marie-Tooth disease. Recent patient-welfare improvements and advances in assistive devices including robot-suit assistive limbs are delaying the terminal state of HMSN-P. Regarding specific therapies for HMSN-P, many patients choose both nucleic acid medicine and the application of induced pluripotent stem cells as a specific therapy for HMSN-P.

Genetic study of inherited peripheral neuropathy disease (Charcot–Marie Tooth) disease

Background Charcot-Marie-Tooth disease (CMT) is the most common hereditary neuromuscular disorder. Charcot-Marie-Tooth disease can be caused by mutations in many different genes. These genes provide instructions for making proteins involved in the functioning of the peripheral nerves of the feet, legs, and hands. Peripheral myelin protein 22 (PMP22) related neuropathies account for over 50% of inherited peripheral neuropathies. Agene copy variation results in CMT1A (duplication of 17p11.2.p12) and hereditary neuropathy with liability to pressure palsies (HNPP; single deletion). Point mutation comprise both phenotypes. The underlying pathological mechanisms are incompletely understood and biallilic mutations of PMP22 are very rare. Objective To study clinical characteristics of a cohort of Egyptian patients with CMT; frequency of PMP22 gene duplication and deletion by MLPA and molecular diagnosis. Methodology We applied our study on 97 Egyptian patients from 70 unrelated families with suspected CMT disease, patients were referred from different provinces to Ain Shams neuromuscular outpatient clinic. After an informed and written consent, all patients were examined neurologically and systemically. Diagnosis was based on clinical symptoms, electromyography and genetic study. Results Clinical classification of our patients revealed high incidence rate of AR CMT type patients (43.3%) and sporadic cases (39.3%), while AD CMT type represents (17.5%), the cause of the high rate of negative family history of same disease affection may be for many reasons mild subclinical expression in other family members, autosomal recessive inheritance, or a de novo heterozygous pathogenic variant in a gene associated with autosomal dominant inheritance. Neurophysiological classification according to median NCV shows that 53 patients (51.5%) have axonal sensory-motor affection with median NCV &amp;lt;38 m/s, 26 patients (26.8%) have demyelinating CMT type, and 19 patients (19.6%) have intermediate type (mixed axonal and demyelinating affection with median NCV range between 35 m/s to 45 m/s. Thus the commonest form is CMT 2 (axonal AR type) followed by CMT 4 (demyelinating AR type) with lower incidence of CMT 1 (demyelinating AD type). Conclusion from our study we concluded that (AR CMT type) is not uncommon in Egypt because of the high prevalence of consanguinity, and that PMP22 duplication is not a common cause of Egyptian inherited neuropathy disease.

Orthopedic footwear has a positive influence on gait adaptability in individuals with hereditary motor and sensory neuropathy

BackgroundIndividuals with Hereditary Motor and Sensory Neuropathy (HMSN) are commonly provided with orthopedic footwear to improve gait. Although orthopedic footwear has shown to improve walking speed and spatiotemporal parameters, its effect on gait adaptability has not been established. Research questionWhat is the effect of orthopedic footwear on gait adaptability in individuals with HMSN? MethodsFifteen individuals with HMSN performed a precision stepping task on an instrumented treadmill projecting visual targets, while wearing either custom-made orthopedic or standardized footwear (i.e. minimally supportive, flexible sneakers). Primary measure of gait adaptability was the absolute Euclidean distance [mm] between the target center and the middle of the foot (absolute error). Secondary outcomes included the relative and variable error [mm] in both anterior-posterior (AP) and medial-lateral (ML) directions. Dynamic balance was assessed by the prediction of ML foot placement based on the ML center of mass position and velocity, using linear regression. Dynamic balance was primarily determined by foot placement deviation in terms of root mean square error. Another aspect of dynamic balance was foot placement adherence in terms of the coefficient of determination (R2). Differences between the footwear conditions were analyzed with a paired t-test or Wilcoxon signed-rank test (α = 0.05). ResultsThe absolute error, relative error (AP) and variable error (AP and ML) decreased with orthopedic footwear, whereas the relative error in ML-direction slightly increased. As for dynamic balance, no effect on foot placement deviation or adherence was found. SignificanceGait adaptability improved with orthopedic compared to standardized footwear in people with HMSN, as indicated by improved precision stepping. Dynamic balance, as a possible underlying mechanism, was not affected by orthopedic footwear.

Charcot-Marie-Tooth disease: A Case Report

Charcot-Marie-Tooth (CMT) disease is one of the most common genetically inherited neuromuscular disorder causing peripheral neuropathies. More than 60 different gene mutations are causing this disease and affecting approximately 1 in every 2500 people. We report a case of previously healthy 14-year-old male presented to the OPD with progressive walking difficulty since 4 years of age. Electromyography showed senori-motor axonal peripheral neuropathy compatible with CMT type 2. Patients with Charcot Marie Tooth should invariably be part of an ongoing multidisciplinary plan of care in regards to their functional impairments.

Effects of intensive rehabilitation on functioning in patients with mild and moderate Charcot-Marie-Tooth disease: a real-practice retrospective study.

Charcot-Marie-Tooth (CMT) disease is one of the most common inherited neuropathies and can lead to progressive muscular weakness, pes cavus, loss of deep tendon reflexes, distal sensory loss, and gait impairment. There are still no effective drugs or surgical therapies for CMT, and supportive treatment is limited to rehabilitative therapy and surgical treatment of skeletal deformities. Many rehabilitative therapeutic approaches have been proposed, but timing and cadence of rehabilitative intervention are not clearly defined, and long-term follow-up is lacking in literature. The aim of this real-practice retrospective study was to assess the effectiveness of an intensive neurorehabilitation protocol on muscle strength and functioning in CMT patients. We analyzed data of patients with diagnosis of mild to moderate CMT. The rehabilitation program lasted 2-4 h a day, 5 days a week, for 3 weeks and consisted of manual treatments, strengthening exercises, stretching, core stability, balance and resistance training, aerobic exercises, and tailored self-care training. Data were collected at baseline (T0), after treatment (T1), and at the 12-month mark (T2) in terms of the following outcome measures: muscle strength, pain, fatigue, cramps, balance, walking speed, and ability. We included 37 CMT patients with a median age of 50.72 ± 13.31 years, with different forms: demyelinating (n = 28), axonal (n = 8), and mixed (n = 1). After intensive rehabilitation treatment, all outcomes significantly improved. This improvement was lost at the 1-year mark. Taken together, these findings suggest that an intensive rehabilitation program improves short-term symptoms and functional outcomes in a cohort of inpatients affected by mild to moderate CMT.

Genetic research of inherited peripheral neuropathies

AbstractBackgroundOur department has been conducting genetic research on hereditary neuropathies, with a focus on the Charcot–Marie–Tooth (CMT) disease and other inherited peripheral neuropathies for the past 20 years. The CMT disease is an untreatable disease characterized by progressive muscle weakness, atrophy, and sensory impairment, primarily affecting the peripheral nerves.Materials and MethodsIn our institution, we collected blood samples from patients with the CMT disease, nationwide, and performed comprehensive genetic testing to elucidate its underlying causes.ResultUsing next‐generation sequencing (NGS), we successfully discovered two novel causative genes of the CMT disease, membrane metalloendopeptidase (MME), and cytochrome c oxidase assembly factor 7, via whole exome analysis of previously unidentified cases. These findings, combined with the comprehensive analysis enabled by NGS, have significantly improved the diagnostic rate of this disease.ConclusionNotably, the MME gene has been reported as the most frequent causative gene for autosomal recessive CMT disease, attracting global attention and subsequent research efforts. Accurate genetic diagnosis for each patient serves as a crucial first step toward understanding hereditary diseases. The identification of new causes of the CMT disease can assist in elucidating the molecular mechanisms involved completely, further contributing to the development of effective treatment approaches, including gene therapies.

Daytime sleepiness and sleep quality in Charcot–Marie–Tooth disease

BackgroundSleep abnormalities have been reported in Charcot–Marie–Tooth disease (CMT), but data are scanty. We investigated their presence and correlation in a large CMT patients’ series.MethodsEpworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI) were administered to CMT patients of the Italian registry and controls. ESS score > 10 indicated abnormal daytime somnolence, PSQI score > 5 bad sleep quality. We analyzed correlation with disease severity and characteristics, Hospital Anxiety and Depression Scale (HADS), Modified Fatigue Impact Scale (MFIS), Body Mass Index, drug use.ResultsESS and PSQI questionnaires were filled by 257 and 253 CMT patients, respectively, and 58 controls. Median PSQI score was higher in CMT patients than controls (6 vs 4, p = 0.006), with no difference for ESS score. Abnormal somnolence and poor sleep quality occurred in 23% and 56% of patients; such patients had more frequently anxiety/depression, abnormal fatigue, and positive sensory symptoms than those with normal ESS/PSQI. Moreover, patients with PSQI score > 5 had more severe disease (median CMT Examination Score, CMTES, 8 vs 6, p = 0.006) and more frequent use of anxiolytic/antidepressant drugs (29% vs 7%, p < 0.001).ConclusionsBad sleep quality and daytime sleepiness are frequent in CMT and correlated with anxiety, depression and fatigue, confirming that different components affect sleep. Sleep disorders, such as sleep apnea and restless leg syndrome, not specifically investigated here, are other factors known to impact on sleep quality and somnolence. CMT patients’ management must include sleep behavior assessment and evaluation of its correlated factors, including general distress and fatigue.