Charcot-Marie-Tooth Research Articles

Computational study of the motor neuron protein KIF5A to identify nsSNPs, bioactive compounds, and its key regulators.

Introduction: Kinesin family member 5A (KIF5A) is a motor neuron protein expressed in neurons and involved in anterograde transportation of organelles, proteins, and RNA. Variations in the KIF5A gene that interfere with axonal transport have emerged as a distinguishing feature in several neurodegenerative disorders, including hereditary spastic paraplegia (HSP10), Charcot-Marie-Tooth disease type 2 (CMT2), and Amyotrophic Lateral Sclerosis (ALS). Methods: In this study, we implemented a computational structural and systems biology approach to uncover the role of KIF5A in ALS. Using the computational structural biology method, we explored the role of non-synonymous Single Nucleotide Polymorphism (nsSNPs) in KIF5A. Further, to identify the potential inhibitory molecule against the highly destabilizing structure variant, we docked 24 plant-derived phytochemicals involved in ALS. Results: We found KIF5AS291F variant showed the most structure destabilizing behavior and the phytocompound "epigallocatechin gallate" showed the highest binding affinity (-9.0Kcal/mol) as compared to wild KIF5A (-8.4Kcal/mol). Further, with the systems biology approach, we constructed the KIF5A protein-protein interaction (PPI) network to identify the associated Kinesin Families (KIFs) proteins, modules, and their function. We also constructed a transcriptional and post-transcriptional regulatory network of KIF5A. With the network topological parameters of PPIN (Degree, Bottleneck, Closeness, and MNC) using CytoHubba and computational knock-out experiment using Network Analyzer, we found KIF1A, 5B, and 5C were the significant proteins. The functional modules were highly enriched with microtubule motor activity, chemical synaptic transmission in neurons, GTP binding, and GABA receptor activity. In regulatory network analysis, we found KIF5A post-transcriptionally down-regulated by miR-107 which is further transcriptionally up-regulated by four TFs (HIF1A, PPARA, SREBF1, and TP53) and down-regulated by three TFs (ZEB1, ZEB2, and LIN28A). Discussion: We concluded our study by finding a crucial variant of KIF5A and its potential therapeutic target (epigallocatechin gallate) and KIF5A associated significant genes with important regulators which could decrypt the novel therapeutics in ALS and other neurodegenerative diseases.

Psychosocial factors and well-being among adults with Charcot-Marie-Tooth disease: A cross-sectional study.

The goal of the current study is to examine the relationships between psychosocial factors and well-being among adults with Charcot-Marie-Tooth (CMT) disease, a progressive neuromuscular disorder. Specifically, we aimed to examine associations between psychosocial factors and sense of purpose as well as the moderating role of sense of purpose on associations between psychosocial factors and two other measures of well-being (life satisfaction and health-related quality of life). In 2021, we recruited 263 U.S. adults with CMT (Mage = 60.15 years, 58.56% female, 92.40% White) to take part in a cross-sectional study. Participants were asked to complete an online survey assessing components of well-being as well as various psychosocial factors. Moderate-to-strong associations were found between most psychosocial factors assessed and sense of purpose in individuals with CMT. In addition, sense of purpose moderated the relationship between multiple psychosocial factors and other measures of well-being. Psychosocial factors may be important to consider when examining well-being among individuals with CMT. Furthermore, sense of purpose may be a beneficial tool for promoting well-being in this population. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A human mitofusin 2 mutation can cause mitophagic cardiomyopathy.

Cardiac muscle has the highest mitochondrial density of any human tissue, but mitochondrial dysfunction is not a recognized cause of isolated cardiomyopathy. Here, we determined that the rare mitofusin (MFN) 2 R400Q mutation is 15-20× over-represented in clinical cardiomyopathy, whereas this specific mutation is not reported as a cause of MFN2 mutant-induced peripheral neuropathy, Charcot-Marie-Tooth disease type 2A (CMT2A). Accordingly, we interrogated the enzymatic, biophysical, and functional characteristics of MFN2 Q400 versus wild-type and CMT2A-causing MFN2 mutants. All MFN2 mutants had impaired mitochondrial fusion, the canonical MFN2 function. Compared to MFN2 T105M that lacked catalytic GTPase activity and exhibited normal activation-induced changes in conformation, MFN2 R400Q and M376A had normal GTPase activity with impaired conformational shifting. MFN2 R400Q did not suppress mitochondrial motility, provoke mitochondrial depolarization, or dominantly suppress mitochondrial respiration like MFN2 T105M. By contrast to MFN2 T105M and M376A, MFN2 R400Q was uniquely defective in recruiting Parkin to mitochondria. CRISPR editing of the R400Q mutation into the mouse Mfn2 gene induced perinatal cardiomyopathy with no other organ involvement; knock-in of Mfn2 T105M or M376V did not affect the heart. RNA sequencing and metabolomics of cardiomyopathic Mfn2 Q/Q400 hearts revealed signature abnormalities recapitulating experimental mitophagic cardiomyopathy. Indeed, cultured cardiomyoblasts and in vivo cardiomyocytes expressing MFN2 Q400 had mitophagy defects with increased sensitivity to doxorubicin. MFN2 R400Q is the first known natural mitophagy-defective MFN2 mutant. Its unique profile of dysfunction evokes mitophagic cardiomyopathy, suggesting a mechanism for enrichment in clinical cardiomyopathy.

Automatic anatomical foot and ankle coordinate toolbox.

Accurate analysis of bone position and orientation in foot and ankle studies relies on anatomical coordinate systems (ACS). Reliable ACSs are necessary for many biomechanical and clinical studies, especially those including weightbearing computed tomography and biplane fluoroscopy. Existing ACS approaches suffer from limitations such as manual input, oversimplifications, or non-physiological methods. To address these shortcomings, we introduce the Automatic Anatomical Foot and Ankle Coordinate Toolbox (AAFACT), a MATLAB-based toolbox that automates the calculation of ACSs for the major fourteen foot and ankle bones. In this manuscript, we present the development and evaluation of AAFACT, aiming to provide a standardized coordinate system toolbox for foot and ankle studies. The AAFACT was evaluated using a dataset of fifty-six models from seven pathological groups: asymptomatic, osteoarthritis, pilon fracture, progressive collapsing foot deformity, clubfoot, Charcot Marie Tooth, and cavovarus. Three analyses were conducted to assess the reliability of AAFACT. Firstly, ACSs were compared between automatically and manually segmented bone models to assess consistency. Secondly, ACSs were compared between individual bones and group mean bones to assess within-population precision. Lastly, ACSs were compared between the overall mean bone and group mean bones to assess the overall accuracy of anatomical representation. Statistical analyses, including statistical shape modeling, were performed to evaluate the reliability, accuracy, and precision of AAFACT. The comparison between automatically and manually segmented bone models showed consistency between the calculated ACSs. Additionally, the comparison between individual bones and group mean bones, as well as the comparison between the overall mean bone and group mean bones, revealed accurate and precise ACSs calculations. The AAFACT offers a practical and reliable solution for foot and ankle studies in clinical and engineering settings. It accommodates various foot and ankle pathologies while accounting for bone morphology and orientation. The automated calculation of ACSs eliminates the limitations associated with manual input and non-physiological methods. The evaluation results demonstrate the robustness and consistency of AAFACT, making it a valuable tool for researchers and clinicians. The standardized coordinate system provided by AAFACT enhances comparability between studies and facilitates advancements in foot and ankle research.

Surgical Treatment of Foot Deformity in Charcot Marie Tooth Syndrome

Surgical Treatment of Foot Deformity in Charcot Marie Tooth Syndrome

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.