Search Results (129)

Background: Charcot–Marie–Tooth disease (CMTd) is the most prevalent inherited peripheral neuropathy, often associated with foot deformities and gait and balance impairments. While the structural characteristics of the foot have been extensively investigated, limited data are available regarding the features of the plantar fascia in individuals with CMTd. Aim: To investigate the ultrasound (US) structural characteristics of the plantar fascia in subjects with CMTd and to explore their relations with disease severity and functional outcomes, encompassing lower extremity function, gait, and balance. Methods: A total of 26 individuals with confirmed CMTd underwent clinical and functional assessments. Bilateral ultrasound examination of the plantar fascia was performed to assess thickness, echogenicity, fibrillar pattern, and inflammatory signs (as assessed by US Power Doppler). Correlations between ultrasound findings, clinical data, and functional measures were also evaluated. Results: No pathological increase in plantar fascia thickness was observed, although a significant side-to-side difference was noted (p = 0.031) on ultrasound (US) imaging. No inflammatory signs were also detected. Significant associations were found between fascial alterations and age (p = 0.024), disease severity (CMTES, p = 0.014), and functional performance (10 MWT p = 0.017; SPPB p = 0.039). Conclusions: In individuals with CMT, plantar fascia abnormalities likely reflect chronic structural degeneration rather than acute inflammation. These changes are more evident with an increase in age, disease progression, and functional decline, suggesting the role of US imaging as a valuable tool for clinical and therapeutic strategies. Full article

Charcot–Marie–Tooth disease type 1A (CMT1A) is a hereditary condition caused by the duplication of the PMP22 gene. Overexpression of peripheral myelin protein 22 in Schwann cells leads to myelin sheath defects and axonal loss. We have produced a cell model to facilitate studies of the molecular mechanisms involved in PMP22 accumulation and clearance. Our model is a stably transfected, clonal, immortalised human Schwann cell line with overexpressed levels of PMP22 fusion protein. A control-transfected cell line (vector lacking PMP22) was also produced. PMP22-transfected cells had reduced levels of mitosis, with the PMP22 fusion protein concentrated in punctate aggregates in the cytoplasm and expressed at the plasma membranes, which were often irregular and spindly. In contrast, control cells (control-transfected and parent cell lines) generally had smooth and regular plasma membrane morphology. Culturing in the presence of NRG1 and forskolin lead to upregulation of markers of myelination potential in the control cells. These markers were more variable in the cells stably transfected with PMP22, including decreased levels of transcripts of SOX10, JUN, S100B and NGFR, but increased levels of MPZ and EGR2 compared to controls. Using proximity-dependent biotin identification (BioID2), several hundred proteins were identified in the proximity of the overexpressed PMP22, of which 291 significant proteins were only detected in the proximity of PMP22 and not in that of control pull-downs. Among the most significantly enriched PMP22-interacting proteins were integrins alpha-2 (ITGA2) and alpha-7 (ITGA7), which play a role in myelination via their interactions with the extracellular matrix. The presence of ITGA2 in just the PMP22-transfected fraction was confirmed by western blot. Some of the proteins were associated with several enriched molecular pathways, including molecular transport and protein trafficking, and may represent potential therapeutic targets for CMT1A by promoting the degradation and enhanced trafficking of PMP22. Full article

Neurological disorders significantly affect ocular surface homeostasis, influencing parameters such as blink rate (BR), tear production, corneal nerve density, and sensitivity. This review summarizes recent findings on ocular surface alterations associated with neurological diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Guillain-Barré syndrome (GBS), trigeminal neuralgia (TN), multiple sclerosis (MS), and Charcot–Marie–Tooth disease (CMT). Notably, ocular manifestations such as reduced BR, decreased tear break-up time (TBUT), impaired tear secretion, and corneal nerve fiber loss are consistently reported. In AD, elevated tear amyloid-beta and tau proteins emerge as promising biomarkers for early disease detection. PD patients frequently experience dry eye symptoms attributed to reduced BR and tear film instability. GBS is linked to lagophthalmos and corneal nerve impairment, potentially leading to severe ocular surface damage. TN demonstrates bilateral ocular surface dysfunction despite unilateral neuropathic symptoms. MS is associated with significant ocular surface alterations, reflecting broader neuroinflammatory and autonomic disturbances. Similarly, CMT patients show reduced corneal sensitivity and tear production, underscoring the systemic nature of neurological impacts. Awareness of these ocular manifestations is essential for improving patient care and guiding future research into ocular biomarkers and targeted therapies. Full article

This study proposes a methodology for conducting computational simulations of pathological gait. The literature shows a consensus that biomechanical models for gait analysis should be formulated as control problems. To achieve this, it is common practice to guide the solution using kinematic or kinetic data to prevent temporal instability. The aim of this study is to implement a biomechanical model of the Charcot–Marie–Tooth disease in OpenSim software that enables more comprehensive simulations, which may in future involve the musculoskeletal system of patient and predictive studies. In this way, it will be possible to design specific active assistive devices tailored to each patient. Experimental gait data from six Charcot–Marie–Tooth patients were used. The dataset comprises three-dimensional trajectories of reflective markers placed according to the Davis-Heel protocol. The acquired data allowed a patient-specific adjustment of the biomechanical model. The inverse kinematic was solved, and the results were validated by comparing them with those obtained using the commercial BTS Bioengineering^® software. The results show a strong alignment in ankle kinematics between the OpenSim model and the data generated by BTS Bioengineering^®. Additionally, the kinematic results have been compared with normative curves, allowing the identification of potential areas for intervention using active assistive devices aimed at improving movement patterns of patients. Full article

Background: Charcot–Marie–Tooth (CMT) is a group of inherited diseases impairing the peripheral nervous system. CMT originates from genetic variants that affect proteins fundamental for the myelination of peripheral nerves and survival. Moreover, environmental and humoral factors can impact disease development and evolution. Currently, no therapy is available. Metabolomics is an emerging field of biomedical research that enables the development of novel biomarkers for neurodegenerative diseases by targeting metabolic pathways or metabolites. This study aimed to evaluate the metabolomics profile of CMT disease by comparing patients with healthy individuals. Methods: A total of 22 CMT patients (CMT) were included in this study and were demographically matched with 26 healthy individuals (C). Serum samples were analyzed through Nuclear Magnetic Resonance spectroscopy, and multivariate and univariate statistical analyses were subsequently applied. Results: A supervised model showed a clear separation (R²X = 0.3; R²Y = 0.7; Q² = 0.4; p-value = 0.0004) between the two classes of subjects, and nine metabolites were found to be significantly different (2-hydroxybutyrate, 3-hydroxybutyrate, 3-methyl-2-oxovalerate, choline, citrate, glutamate, isoleucine, lysine, and methyl succinate). The combined ROC curve showed an AUC of 0.94 (CI: 0.9–1). Additional altered metabolic pathways were also identified within the disease context. Conclusion: This study represents a promising starting point, demonstrating the efficacy of metabolomics in evaluating CMT patients and identifying novel potential disease biomarkers. Full article

Background: Charcot–Marie–Tooth disease (CMT) is a genetically and phenotypically heterogeneous hereditary neuropathy. Axonal CMT type 2 (CMT2) subtypes often exhibit overlapping clinical features, which makes molecular genetic analysis essential for accurate diagnosis and subtype differentiation. Methods: This retrospective study included five pediatric patients who presented with gait disturbance, muscle weakness, and foot deformities and were subsequently diagnosed with axonal forms of CMT. Clinical data, electrophysiological studies, neuroimaging, and genetic analyses were evaluated. Whole exome sequencing (WES) was performed in three sporadic cases, while targeted CMT gene panel testing was used for two siblings. Variants were interpreted using ACMG guidelines, supported by public databases (ClinVar, HGMD, and VarSome), and confirmed by Sanger sequencing when available. Results: All had absent deep tendon reflexes and distal muscle weakness; three had intellectual disability. One patient was found to carry a novel homozygous frameshift variant (c.2568_2569del) in the IGHMBP2 gene, consistent with CMT2S. Other variants were identified in the NEFH (CMT2CC), DYNC1H1 (CMT2O), and MPV17 (CMT2EE) genes. Notably, a previously unreported co-occurrence of MPV17 mutation and congenital heart disease was observed in one case. Conclusions: This study expands the clinical and genetic spectrum of pediatric axonal CMT and highlights the role of early physical examination and molecular diagnostics in detecting rare variants. Identification of a novel IGHMBP2 variant and unique phenotypic associations provides new insights for future genotype–phenotype correlation studies. Full article

Background: Charcot-Marie-Tooth (CMT) disease is a hereditary motor and sensory neuropathy that affects foot morphology and gait patterns, potentially leading to abnormal plantar pressure distribution. This systematic review synthesizes the existing literature examining plantar pressure characteristics in CMT patients. Methods: A comprehensive search was conducted across PubMed, Scopus, and Web of Science databases. Risk of bias was assessed using the Newcastle–Ottawa Scale. Results: Six studies comprising 146 patients were included. Four studies employed dynamic baropodometry, and two used in-shoe pressure sensors to evaluate the main plantar pressure parameters. The findings were consistent across different populations and devices, with a characteristic plantar-pressure profile of marked midfoot off-loading with peripheral overload at the forefoot and rearfoot, often accompanied by a lateralized center-of-pressure path and a prolonged pressure–time exposure. These alterations reflect both structural deformities and impaired neuromuscular control. Interventional studies demonstrated a load redistribution of pressure after corrective surgery, though residual lateral overload often persists. Conclusions: Plantar pressure mapping seems to be a valuable tool to identify high-pressure zones of the foot in order to personalize orthotic treatment planning, to objectively monitor disease progression, and to evaluate therapeutic efficacy. Further longitudinal studies with standardized protocols are needed to confirm these results. Full article

Background: This scoping review aims to map and summarise physical therapy interventions specifically targeting gait and balance in individuals with Charcot-Marie-Tooth disease (CMT), highlighting commonly applied strategies, methodological limitations, and clinical implications. Charcot-Marie-Tooth disease (CMT) is a hereditary neuropathy characterised by progressive motor and sensory impairment, often resulting in reduced mobility, muscle weakness, balance deficits, and fatigue. Although pharmacological options remain limited, rehabilitation is increasingly recognised as a key component of disease management. However, the scope, type, and effectiveness of rehabilitative interventions in CMT remain poorly mapped. Methods: This scoping review was conducted in accordance with the Joanna Briggs Institute (JBI) methodology and the PRISMA-ScR guidelines. Five databases (PubMed, Cochrane, PEDro, Scopus, and Web of Science) were systematically searched up to March 2024. Studies were eligible if they involved participants with CMT undergoing rehabilitation interventions aimed at improving functional outcomes. Data extraction focused on study characteristics, methods, outcome measures, and results. Results: Eleven studies met inclusion criteria, comprising case reports, cohort studies, and two randomised controlled trials. Interventions included aerobic training, strength and balance exercises, videogame-based home programmes, and multidisciplinary rehabilitation. Most studies reported improvements in walking capacity (e.g., 6MWT, 10MWT), postural balance (e.g., BBS), and lower limb strength (e.g., MRC, dynamometry). Some also showed positive changes in fatigue and quality of life, though data were limited. Methodological heterogeneity and small sample sizes limited comparability and generalisability. Conclusions: Rehabilitation appears to yield meaningful improvements in key functional domains in people with CMT. Tailored, multimodal interventions show promise, though long-term benefits remain underexplored. Future research should adopt standardised protocols and outcome measures to better define best practices and optimise patient care. Full article

Background: Charcot–Marie–Tooth disease (CMT) is a genetically and clinically heterogeneous group of progressive peripheral neuropathies. Preimplantation genetic testing for monogenic disorders (PGT-M), a well-established assisted reproductive technology used to detect specific genetic mutations in embryos before implantation, has been used in common CMT subtypes (e.g., CMT1A); however, data on its application across rarer subtypes and in de novo cases remain limited. In this study, we aimed to evaluate the effectiveness of PGT-M using karyomapping in achieving clinical pregnancies and healthy births in families affected by various CMT types, including the previously unreported subtypes CMT1B and CMT2. Methods: We analyzed 31 PGT-M cycles from 13 families with genetically confirmed CMT, including cases of previously unreported subtypes CMT1B and CMT2. A total of 150 embryos were biopsied. Through 19 embryo transfer cycles, 21 embryos were transferred. In one de novo case, karyomapping was performed using amniotic fluid from an affected fetus as a reference. Results: Of the 19 embryo transfers, 15 resulted in clinical pregnancies. Prenatal diagnosis confirmed that all fetuses were unaffected, and all pregnancies resulted in healthy live births. Successful phasing using amniotic fluid from an affected fetus enabled accurate embryo selection and led to the birth of healthy twins. Conclusions: PGT-M using karyomapping is a rapid and reliable method for achieving successful pregnancies in families affected by diverse CMT subtypes, including de novo cases, and supports broader applicability to other monogenic disorders. Full article

Background: Primary ciliary dyskinesia (PCD) is a rare hereditary disorder caused by defective motile cilia, predominantly affecting the respiratory system. Conductive hearing loss (CHL) due to chronic otitis media with effusion (OME) is a typical feature of PCD, particularly in childhood. However, the underlying mechanisms contributing to sensorineural hearing loss (SNHL) in patients with PCD remain unclear. Methods: We present the case of a 52-year-old male with a clinical diagnosis of PCD, confirmed by the presence of situs inversus, chronic respiratory symptoms, and ultrastructural ciliary defects. Results: Despite a history of recurrent acute otitis media (AOM), the patient developed severe bilateral SNHL, a relatively uncommon and poorly understood manifestation of PCD. Genetic testing revealed a pathogenic SH3TC2 variant, a gene classically associated with Charcot–Marie–Tooth disease type 4C (CMT4C), raising the possibility of an alternative or contributory genetic etiology for the patient’s auditory dysfunction. Conclusions: This case highlights the importance of comprehensive audiological and genetic evaluations in PCD patients, particularly those presenting with progressive or atypical HL. The presence of a pathogenic SH3TC2 mutation suggests a potential neuropathic component to the patient’s HL, underscoring the need for further research into the intersection between ciliary dysfunction and genetic neuropathies. Early identification and intervention are critical to optimizing auditory outcomes and quality of life in affected individuals. Full article

Background: As the number of individuals diagnosed with neurodegenerative disorders (NDs) rises, there is a growing need to enhance both the quantity and quality of approaches used to treat these debilitating conditions. The progression of NDs can cause muscle weakness in the lower or upper limbs. We particularly focus on the area of the upper limb, specifically grip rehabilitation, by developing a system (VRGrip) that can reliably record electromyography (EMG) events of the hand flexor muscles to control an adaptive and engaging game using grip exertion. The purpose of this study was to determine the feasibility of using the VRGrip system. Methods: We prototyped a three-component wearable system consisting of an e-textile forearm band (E-band), data acquisition module (DAM), and a computer game. This allows participants to play a game by squeezing their dominant hand. A feasibility study was completed with 9 individuals who self-reported an ND (including Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Charcot–Marie–Tooth disease (CMT), spinal muscular atrophy (SMA), and essential tremor (ET)) and 12 individuals who self-reported to be relatively healthy (RH). Each participant completed 15 min of gameplay (three trials of five minutes), where they would squeeze a resistive ball to trigger in-game actions. The user experience was then evaluated via a User Satisfaction Evaluation Questionnaire (USEQ; scored 0–30, with 30 being best). Results: Analysis of the grip detection reliability during the feasibility study resulted in an F1 score of 0.8343 ± 0.1208 for the healthy participant group and 0.8401 ± 0.1034 for the ND participant group. The USEQ (Avg. score: 4.65 ± 0.51) indicated that participants found the system comfortable, engaging, and enjoyable. Additionally, we potentially identified age-related changes in muscle fatigue. Conclusion: The results of this study demonstrate that our VRGrip system could be used for hand grip detection in a virtual environment. In the future, we aim to conduct longitudinal studies to determine if repeated use of the system has merit for grip rehabilitation. Full article

The heat shock protein B8 (HSPB8) is one of the small heat shock proteins (sHSP or HSPB) and is a ubiquitous protein in various organisms, including humans. It is highly expressed in skeletal muscle, heart, and neurons. It plays a crucial role in identifying misfolding proteins and participating in chaperone-assisted selective autophagy (CASA) for the removal of misfolded and damaged, potentially cytotoxic proteins. Mutations in HSPB8 can cause distal hereditary motor neuropathy (dHMN), Charcot–Marie–Tooth (CMT) disease type 2L, or myopathy. The disease can manifest from childhood to mid-adulthood. Most missense mutations in the N-terminal and α-crystallin domains of HSPB8 lead to dHMN or CMT2L. Frameshift mutations in the C-terminal domain (CTD), resulting in elongation of the HSPB8 C-terminal, cause myopathy with myofibrillar pathology and rimmed vacuoles. Myopathy and motor neuropathy can coexist. HSPB8 frameshift mutations in the CTD result in HSPB8 mutant aggregation, which weakens the CASA ability to direct misfolded proteins to autophagic degradation. Cellular and animal models indicate that HSPB8 mutations drive pathogenesis through a toxic gain-of-function mechanism. Currently, no cure is available for HSPB8-associated neuromuscular disorders, but numerous therapeutic strategies are under investigation spanning from small molecules to RNA interference to exogenous HSPB8 delivery. Full article

Chronic pain is a global health problem with major socioeconomic implications. Drug therapy for chronic pain is limited, prompting search for non-pharmacological treatments. One such approach is physical exercise, which has been found to be beneficial for numerous health issues. Research in recent years has yielded considerable evidence for the analgesic actions of exercise in humans and experimental animals, but the underlying mechanisms are far from clear. It was proposed that exercise influences the pain pathways by interacting with the immune system, mainly by reducing inflammatory responses, but the release of endogenous analgesic mediators is another possibility. Exercise acts on neurons and glial cells in both the central and peripheral nervous systems. This review focuses on the periphery, with emphasis on possible glia–neuron interactions. Key topics include interactions of Schwann cells with axons (myelinated and unmyelinated), satellite glial cells in sensory ganglia, enteric glial cells, and the sympathetic nervous system. An attempt is made to highlight several neurological diseases that are associated with pain and the roles that glial cells may play in exercise-induced pain alleviation. Among the diseases are fibromyalgia and Charcot–Marie–Tooth disease. The hypothesis that active skeletal muscles exert their effects on the nervous system by releasing myokines is discussed. Full article

Mitochondrial dynamics, governed by fusion and fission, are crucial for maintaining cellular homeostasis, energy production, and stress adaptation. MFN2 and OPA1, key regulators of mitochondrial fusion, play essential roles beyond their structural functions, influencing bioenergetics, intracellular signaling, and quality control mechanisms such as mitophagy. Disruptions in these processes, often caused by MFN2 or OPA1 mutations, are linked to neurodegenerative diseases like Charcot-Marie-Tooth disease type 2A (CMT2A) and autosomal dominant optic atrophy (ADOA). This review explores the molecular mechanisms underlying mitochondrial fusion, the impact of MFN2 and OPA1 dysfunction on oxidative phosphorylation and autophagy, and their role in disease progression. Additionally, we discuss the divergent cellular responses to MFN2 and OPA1 mutations, particularly in terms of proliferation, senescence, and metabolic signaling. Finally, we highlight emerging therapeutic strategies to restore mitochondrial integrity, including mTOR modulation and autophagy-targeted approaches, with potential implications for neurodegenerative disorders. Full article

Charcot–Marie–Tooth disease (CMT) is the most common hereditary peripheral neuropathy worldwide, presenting clinically as muscle weakness that progresses to impaired ambulation or quadriplegia with age. CMT1A, the most common subtype, is caused by a duplication in PMP22, encoding an essential membrane protein for Schwann cell myelin integrity. While the mechanisms of peripheral neurodegeneration in CMT1A are poorly understood, excessive oxidative stress, particularly lipid peroxidation, is a known pathological feature, and antioxidant therapy has reversed the CMT1A phenotype in a mouse model. For the first time, we define the pathogenic link between CMT1A and ferroptosis, a form of regulated cell death caused by excessive lipid peroxidation and hindered antioxidant defenses. Human-derived CMT1A fibroblasts showed greater susceptibility to RSL3, a pro-ferroptosis agent, compared with controls, alongside several ferroptosis markers, including elevated lipid peroxides and depleted GPX4, a critical anti-ferroptosis repressor. Similarly, transcriptomic analysis of human iPSC-derived Schwann cells revealed elevated ferroptosis activation and cellular stress markers in CMT1A. We propose that chronic, sublethal ferroptotic stress, mediated by lipid peroxide accumulation, depletes antioxidant defenses in CMT1A Schwann cells, leading to decompensation with age, manifesting as symptomatic disease. These results emphasize ferroptosis as a driver of CMT1A pathology, potentially revealing a new therapeutic path. Full article