Charcot-Marie-Tooth Research Articles

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.

An integrative analysis of genotype-phenotype correlation in Charcot Marie Tooth type 2A disease with MFN2 variants: A case and systematic review

Dominant genetic variants in the mitofusin 2 (MFN2) gene lead to Charcot-Marie-Tooth type 2A (CMT2A), a neurodegenerative disease caused by genetic defects that directly damage axons. In this study, we reported a proband with a pathogenic variant in the GTPase domain of MFN2, c.494A > G (p.His165Arg). To date, at least 184 distinct MFN2 variants identified in 944 independent probands have been reported in 131 references. However, the field of medical genetics has long been challenged by how genetic variation in the MFN2 gene is associated with disease phenotypes. Here, by collating the MFN2 variant data and patient clinical information from Leiden Open Variant Database 3.0, NCBI clinvar database, and available related references in PubMed, we determined the mutation frequency, age of onset, sex ratio, and geographical distribution. Furthermore, the results of an analysis examining the relationship between variants and phenotypes from multiple genetic perspectives indicated that insertion and deletions (indels), copy number variants (CNVs), duplication variants, and nonsense mutations in single nucleotide variants (SNVs) tend to be pathogenic, and the results emphasized the importance of the GTPase domain to the structure and function of MFN2. Overall, three reliable classification methods of MFN2 genotype-phenotype associations provide insights into the prediction of CMT2A disease severity. Of course, there are still many MFN2 variants that have not been given clear clinical significance, which requires clinicians to make more accurate clinical diagnoses.

Characterization of cytoskeletal and structural effects of INF2 variants causing glomerulopathy and neuropathy

Focal segmental glomerulosclerosis (FSGS) is a common glomerular injury leading to end-stage renal disease. Monogenic FSGS is primarily ascribed to decreased podocyte integrity. Variants between residues 184 and 245 of INF2, an actin assembly factor, produce the monogenic FSGS phenotype. Meanwhile, variants between residues 57 and 184 cause a dual-faceted disease involving peripheral neurons and podocytes (Charcot–Marie–Tooth CMT/FSGS). To understand the molecular basis for INF2 disorders, we compared structural and cytoskeletal effects of INF2 variants classified into two subgroups: One (G73D, V108D) causes the CMT/FSGS phenotype, and the other (T161N, N202S) produces monogenic FSGS. Molecular dynamics analysis revealed that all INF2 variants show distinct flexibility compared to the wild-type INF2 and could affect stability of an intramolecular interaction between their N- and C-terminal segments. Immunocytochemistry of cells expressing INF2 variants showed fewer actin stress fibers, and disorganization of cytoplasmic microtubule arrays. Notably, CMT/FSGS variants caused more prominent changes in mitochondrial distribution and fragmentation than FSGS variants and these changes correlated with the severity of cytoskeletal disruption. Our results indicate that CMT/FSGS variants are associated with more severe global cellular defects caused by disrupted cytoskeleton-organelle interactions than are FSGS variants. Further study is needed to clarify tissue-specific pathways and/or cellular functions implicated in FSGS and CMT phenotypes

Pediatric Charcot-Marie-Tooth disease: A case report and diagnostic challenges

Charcot-Marie-Tooth (CMT) disease is a hereditary motor sensory neuropathy affecting about one in 2500 individuals that is characterized by progressive weakness and loss of touch sensation affecting different parts of the body. Despite its significant genetic heterogeneity, CMT is rarely reported in the Indian literature. We report a 10-year-old boy with CMT presented with severe calf pain, bilateral pes cavus deformity, and areflexia. His mother also had similar symptoms, and the diagnosis was confirmed by neuroimaging and nerve conduction studies. This highlights the importance of considering CMT disease in patients with progressive muscle weakness and deformities, especially with a family history of similar symptoms.

Amlexanox: Readthrough Induction and Nonsense-Mediated mRNA Decay Inhibition in a Charcot-Marie-Tooth Model of hiPSCs-Derived Neuronal Cells Harboring a Nonsense Mutation in GDAP1 Gene.

Nonsense mutations are involved in multiple peripheral neuropathies. These mutations induce the presence of a premature termination codon (PTC) at the mRNA level. As a result, a dysfunctional or truncated protein is synthesized, or even absent linked to nonsense-mediated mRNA degradation (NMD) system activation. Readthrough molecules or NMD inhibitors could be innovative therapies in these hereditary neuropathies, particularly molecules harboring the dual activity as amlexanox. Charcot-Marie-Tooth (CMT) is the most common inherited pathology of the peripheral nervous system, affecting 1 in 2500 people worldwide. Nonsense mutations in the GDAP1 gene have been associated with a severe form of CMT, prompting us to investigate the effect of readthrough and NMD inhibitor molecules. Although not clearly defined, GDAP1 could be involved in mitochondrial functions, such as mitophagy. We focused on the homozygous c.581C>G (p.Ser194*) mutation inducing CMT2H using patient human induced pluripotent stem cell (hiPSC)-derived neuronal cells. Treatment during 20 h with 100 µM of amlexanox on this cell model stabilized GDAP1 mRNAs carrying UGA-PTC and induced a restoration of the mitochondrial morphology. These results highlight the potential of readthrough molecules associated to NMD inhibitors for the treatment of genetic alterations in CMT, opening the way for future investigations and a potential therapy.

The Surgical Correction of Cavovarus Deformity in Charcot-Marie-Tooth Disease.

Charcot-Marie-Tooth (CMT) disease is the most commonly inherited neuropathy. CMT disease is a motor-sensory neuropathy with multiple genotypes. By comparison, the phenotypic expression is more uniform, with two main presentations. Most patients who need surgical care have progressive cavovarus foot deformity, with muscle imbalance causing a nonplantigrade foot, soft-tissue contractures, and abnormal bone morphology. Surgical treatment can be life-changing for these patients, allowing them to walk potentially brace free with more endurance and less pain. Early realignment procedures may reduce progression of joint arthritis. A minority of patients have diffuse paralysis below the knee. These patients are best treated with ground-reaction ankle-foot orthoses. This review article is based on the senior author's extensive experience with CMT, along with the limited evidenced-based literature.

A Novel ENU-Induced Mfn2 Mutation Causes Motor Deficits in Mice without Causing Peripheral Neuropathy.

Mitochondrial fission and fusion are required for maintaining functional mitochondria. The mitofusins (MFN1 and MFN2) are known for their roles in mediating mitochondrial fusion. Recently, MFN2 has been implicated in other important cellular functions, such as mitophagy, mitochondrial motility, and coordinating endoplasmic reticulum-mitochondria communication. In humans, over 100 MFN2 mutations are associated with a form of inherited peripheral neuropathy, Charcot-Marie-Tooth disease type 2A (CMT2A). Here we describe an ENU-induced mutant mouse line with a recessive neuromuscular phenotype. Behavioral screening showed progressive weight loss and rapid deterioration of motor function beginning at 8 weeks. Mapping and sequencing revealed a missense mutation in exon 18 of Mfn2 (T1928C; Leu643Pro), within the transmembrane domain. Compared to wild-type and heterozygous littermates, Mfn2L643P/L643P mice exhibited diminished rotarod performance and decreases in activity in the open field test, muscular endurance, mean mitochondrial diameter, sensory tests, mitochondrial DNA content, and MFN2 protein levels. However, tests of peripheral nerve physiology and histology were largely normal. Mutant leg bones had reduced cortical bone thickness and bone area fraction. Together, our data indicate that Mfn2L643P causes a recessive motor phenotype with mild bone and mitochondrial defects in mice. Lack of apparent nerve pathology notwithstanding, this is the first reported mouse model with a mutation in the transmembrane domain of the protein, which may be valuable for researchers studying MFN2 biology.

The Current State of Charcot–Marie–Tooth Disease Treatment

Charcot–Marie–Tooth disease (CMT) and associated neuropathies are the most predominant genetically transmitted neuromuscular conditions; however, effective pharmacological treatments have not established. The extensive genetic heterogeneity of CMT, which impacts the peripheral nerves and causes lifelong disability, presents a significant barrier to the development of comprehensive treatments. An estimated 100 loci within the human genome are linked to various forms of CMT and its related inherited neuropathies. This review delves into prospective therapeutic strategies used for the most frequently encountered CMT variants, namely CMT1A, CMT1B, CMTX1, and CMT2A. Compounds such as PXT3003, which are being clinically and preclinically investigated, and a broad array of therapeutic agents and their corresponding mechanisms are discussed. Furthermore, the progress in established gene therapy techniques, including gene replacement via viral vectors, exon skipping using antisense oligonucleotides, splicing modification, and gene knockdown, are appraised. Each of these gene therapies has the potential for substantial advancements in future research.

Bone Health in Pediatric Charcot-Marie-Tooth (CMT) Patients: The Baseline Experience in a Multidisciplinary Neuromuscular Program at a Pediatric Tertiary Care Center

Bone Health in Pediatric Charcot-Marie-Tooth (CMT) Patients: The Baseline Experience in a Multidisciplinary Neuromuscular Program at a Pediatric Tertiary Care Center

Charcot-Marie-Tooth Disease: Updates in Diagnosis and Treatment Guidelines Pertaining to the Lower Extremity and Case Study

Diagnosis and treatment of Charcot-Marie-Tooth (CMT) can present as a challenging issue. Several published studies have demonstrated the complexity of diagnosis and treatment with an increasing role of genetics in diagnosis.

Evaluation of the median nerve by shear wave elastography in patients with Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease type 1A (CMT1A) is characterized by enlargement and stiffness of peripheral nerves due to edema with large numbers of "onion bulbs" in the endoneurium. Ultrasound elastography seems to be an ideal method to detect this condition. The aim of this study was to analyze the shear wave elastography (SWE) features of peripheral nerves in patients with CMT1A. We included 24 CMT1A patients with a mean age of 28 years, along with 24 age- and gender-matched controls. All patients presented with mutations of the PMP22 gene and showed length-dependent polyneuropathy. The motor nerve conduction velocity (MNCV) of the median nerve ranged from 5.2 to 37.4 m/s. SWE and cross-sectional area (CSA) were used to evaluate the bilateral median nerves at predefined sites in both patients and con-trols. The average elastography value (EV) of the median nerve was 73.5±11.7 kPa in patients with CMT1A and 37.5±6.1 kPa in control subjects. The difference between the two groups was statistically significant (P<0.05). In CMT1A pa-tients, the average EV at the proximal and distal parts of the median nerve were 81.4±9.4 kPa and 65.2±8.1 kPa, respectively. The average CSAs at the proximal and distal parts of the median nerve were 0.29±0.06 cm2 and 0.20±0.05 cm2, respectively. The EV on SWE was positively correlated with CSA (p< 0.01) and negatively correlated with MNCV in the median nerve (p< 0.01). Peripheral nerve stiffness dramatically increases in CMT1A and is correlated with the severity of nerve involvement.

Thoracic synovial cyst as cause of cord compression in a patient with Charcot-Marie-Tooth disease.

An 80-year-old male patient affected by Charcot-Marie-Tooth (CMT) disease came to our attention in July 2020, for the occurrence of low back pain and lower limb weakness, and also saddle anesthesia, urinary and faecal retention were referred. His diagnosis of CMT is dated back to 1955 and through the years, the clinical picture slowly worsened but never got particularly severe. The quick symptoms outbreak and the presence of urinary disturbances were red flags, which lead us to direct the diagnostic orientation elsewhere. A Magnetic Resonance Imaging of the thoraco-lumbar spinal cord was then performed and it was suggestive for synovial cyst at T10-T11. The patient underwent a decompression with laminectomy and then stabilized through arthrodesis. In the very next days after the surgery, the patient showed a sudden and significant improvement of his condition. At the last visit, he showed a remarkable relief of the symptoms, walking by himself.

The Therapeutic Potential of Vitamins B1, B3 and B6 in Charcot-Marie-Tooth Disease with the Compromised Status of Vitamin-Dependent Processes.

Understanding the molecular mechanisms of neurological disorders is necessary for the development of personalized medicine. When the diagnosis considers not only the disease symptoms, but also their molecular basis, treatments tailored to individual patients may be suggested. Vitamin-responsive neurological disorders are induced by deficiencies in vitamin-dependent processes. These deficiencies may occur due to genetic impairments of proteins whose functions are involved with the vitamins. This review considers the enzymes encoded by the DHTKD1, PDK3 and PDXK genes, whose mutations are observed in patients with Charcot-Marie-Tooth (CMT) disease. The enzymes bind or produce the coenzyme forms of vitamins B1 (thiamine diphosphate, ThDP) and B6 (pyridoxal-5'-phosphate, PLP). Alleviation of such disorders through administration of the lacking vitamin or its derivative calls for a better introduction of mechanistic knowledge to medical diagnostics and therapies. Recent data on lower levels of the vitamin B3 derivative, NAD+, in the blood of patients with CMT disease vs. control subjects are also considered in view of the NAD-dependent mechanisms of pathological axonal degeneration, suggesting the therapeutic potential of vitamin B3 in these patients. Thus, improved diagnostics of the underlying causes of CMT disease may allow patients with vitamin-responsive disease forms to benefit from the administration of the vitamins B1, B3, B6, their natural derivatives, or their pharmacological forms.

Canine models of Charcot-Marie-Tooth: MTMR2, MPZ, and SH3TC2 variants in golden retrievers with congenital hypomyelinating polyneuropathy

Congenital hypomyelinating polyneuropathy (HPN) restricted to the peripheral nervous system was reported in 1989 in two Golden Retriever (GR) littermates. Recently, four additional cases of congenital HPN in young, unrelated GRs were diagnosed via neurological examination, electrodiagnostic evaluation, and peripheral nerve pathology. Whole-genome sequencing was performed on all four GRs, and variants from each dog were compared to variants found across >1,000 other dogs, all presumably unaffected with HPN. Likely causative variants were identified for each HPN-affected GR. Two cases shared a homozygous splice donor site variant in MTMR2, with a stop codon introduced within six codons following the inclusion of the intron. One case had a heterozygous MPZ isoleucine to threonine substitution. The last case had a homozygous SH3TC2 nonsense variant predicted to truncate approximately one-half of the protein. Haplotype analysis using 524 GR established the novelty of the identified variants. Each variant occurs within genes that are associated with the human Charcot-Marie-Tooth (CMT) group of heterogeneous diseases, affecting the peripheral nervous system. Testing a large GR population (n = >200) did not identify any dogs with these variants. Although these variants are rare within the general GR population, breeders should be cautious to avoid propagating these alleles.

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

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

Quantitative sensory testing in a large cohort of neuropathy patients

Background:&#x0D; Quantitative sensory testing (QST) is a subjective but reliable and quantifiable method to detect patient thresholds to different sensory stimuli. QST is used to measure small- and large-fiber nerve function and can be used in conjunction with other diagnostic modalities in the evaluation of peripheral neuropathy (PN). The utility of QST to distinguish among different types of PN, however, has not been explored. The objective of the study was to evaluate if different patterns of QST abnormalities could distinguish between PN types.&#x0D; Methods:&#x0D; This single-center retrospective cohort study evaluated the frequency of QST abnormalities to vibratory, cold and heat detection thresholds in a large population of PN cases evaluated at the University of Texas Southwestern Medical Center peripheral neuropathy clinic between 1995-2000. PN was categorized by etiology.&#x0D; Results:&#x0D; A total of 559 QST studies were performed in this study. The average age of patients (n=557) was 60 years with a male-to-female ratio of 1:1. The most common diagnosis was cryptogenic sensory polyneuropathy (CSPN, n=294), followed by Charcot–Marie–Tooth disease (n=84)). Meta-regression of vibration and cold indicate that the expected proportion of abnormal responses is less for the vibration test (p = 0.0002), relative to the cold test. However, no differences were observed between diagnoses.&#x0D; Conclusions:&#x0D; Though abnormal QST thresholds were seen in most patients with PN, patterns of QST abnormalities do not distinguish between different types of PN. The routine clinical utility of QST is likely limited.