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Introduction: Charcot--Marie--Tooth disease type 4C (CMT4C) OMIM#601596 stands out as one of the most prevalent forms of recessive motor sensory neuropathy worldwide. This disorder results from biallelic pathogenic variants in the SH3TC2 gene. Methods: Within a cohort comprising 700 unrelated Russian patients diagnosed with Charcot--Marie--Tooth disease, we conducted a gene panel analysis encompassing 21 genes associated with hereditary neuropathies. Among the cohort, 394 individuals exhibited demyelinating motor and sensory neuropathy. Results and discussion: Notably, 10 cases of CMT4C were identified within this cohort. The prevalence of CMT4C among Russian demyelinating CMT patients lacking the PMP22 duplication is estimated at 2.5%, significantly differing from observations in European populations. In total, 4 novel and 9 previously reported variants in the SH3TC2 gene were identified. No accumulation of amajor variant was detected. Three previously reported variants, c.2860C>Tp. (Arg954*), p. (Arg658Cys) and c.279G>A p. (Lys93Lys), recurrently detected in unrelated families. Nucleotide alteration p. (Arg954*) is present in most of our patients (30%). [ABSTRACT FROM AUTHOR]

Introduction:Charcot–Marie–Tooth disease type 4C (CMT4C) OMIM#601596 stands out as one of the most prevalent forms of recessive motor sensory neuropathy worldwide. This disorder results from biallelic pathogenic variants in the SH3TC2 gene.Methods:Within a cohort comprising 700 unrelated Russian patients diagnosed with Charcot–Marie–Tooth disease, we conducted a gene panel analysis encompassing 21 genes associated with hereditary neuropathies. Among the cohort, 394 individuals exhibited demyelinating motor and sensory neuropathy.Results and discussion:Notably, 10 cases of CMT4C were identified within this cohort. The prevalence of CMT4C among Russian demyelinating CMT patients lacking the PMP22 duplication is estimated at 2.5%, significantly differing from observations in European populations. In total, 4 novel and 9 previously reported variants in the SH3TC2 gene were identified. No accumulation of a major variant was detected. Three previously reported variants, c.2860C>T p. (Arg954*), p. (Arg658Cys) and c.279G>A p. (Lys93Lys), recurrently detected in unrelated families. Nucleotide alteration p. (Arg954*) is present in most of our patients (30%).

Orthotic management of offloading neuropathic foot in hereditary motor and sensory neuropathy (HMSN) is challenging due to motor, sensory and functional deficits which may interfere with weight distribution over the foot. The challenge further becomes difficult with the involvement of the contralateral lower limb with below-knee amputation. This study is regarding challenges in offloading, weight transmission and distribution during the stance phase of gait in the case of a 35-year-old female with a left neuropathic foot due to HMSN with concomitant right transtibial amputation. The energy expenditure and cosmetic issues for the right lower limb and aiming for maximum functional conservation of the left foot, were considered by taking into account the heel pad thickness measured by musculoskeletal ultrasound, dynamic plantar pressure measured by footplate pressure measurement, the integrity of the ankle joint mobility and stability by clinical assessment, the electrophysiological status of the neuropathic foot by nerve conduction study and the weight-bearing capability of the right below-knee stump. The following management measures are planned for effective offloading with therapeutic footwear modification with silicone gel cushion heel and insole and rocker bottom outsole as an alternative to conventional weight-relieving calliper in a government tertiary care set-up, thereby conserving the foot function and morphology. This will help in planning a structured rehabilitation programme which will be beneficial in preventing future foot changes including trophic ulceration and subsequent amputation. Case follow-up after patient education and assessment of disease progression in each visit is being done. A better outcome in terms of quality of life and level of independent ambulation with concomitant bio-functionality of the left neuropathic foot was accomplished with community ambulation.

Objective: Chronic pain is a major problem for patients with Charcot-Marie-Tooth (CMT) disease. This exploratory study examined patient reported efficacy of medical cannabis for pain management in this population. Methods: Participants (N = 56; 71.4% female; Age = 48.9, SD = 14.6; 48.5% CMT1) were recruited though the Hereditary Neuropathy Foundation. The online survey contained 52 multiple choice questions about demographics, medical cannabis use, symptomology, efficacy, and adverse effects. Results: Nearly all (90.9%) of respondents reported experiencing pain, including all (100%) females and 72.7% of males (chi-square P <.05) with 91.7% of respondents indicating cannabis provided at least 50% pain relief. The most frequent response was an 80% reduction in pain. Moreover, 80.0% of respondents reported using less opiates, 69% noted using less sleep medication, and 50.0% reported using less anxiety/antidepressant medications. Negative side effects were noted by 23.5% of respondents. However, almost all (91.7%) of that subgroup did not have plans to stop consuming cannabis. One-third (33.9%) possessed a medical cannabis certificate. Patient perceptions of their physicians' attitudes regarding patient medical cannabis use greatly impacted whether respondents informed their providers of their usage. Conclusion: The vast majority of patients with CMT reported that cannabis was effective to manage pain symptoms. These data support the need for prospective, randomized, controlled trials using standardized dosing protocols to further delineate and optimize the potential use of cannabis to treat pain related to CMT. [ABSTRACT FROM AUTHOR]

We describe five families from different regions in Norway with a late-onset autosomal-dominant hereditary polyneuropathy sharing a heterozygous variant in the SLC12A6 gene. Mutations in the same gene have previously been described in infants with autosomal-recessive hereditary motor and sensory neuropathy with corpus callosum agenesis and mental retardation (Andermann syndrome), and in a few case reports describing dominantly acting de novo mutations, most of them with onset in childhood. The phenotypes in our families demonstrated heterogeneity. Some of our patients only had subtle to moderate symptoms and some individuals even no complaints. None had CNS manifestations. Clinical and neurophysiological evaluations revealed a predominant sensory axonal polyneuropathy with slight to moderate motor components. In all 10 patients the identical SLC12A6 missense variant, NM_001365088.1 c.1655G>A p.(Gly552Asp), was identified. For functional characterization, the mutant potassium chloride cotransporter 3 was modelled in Xenopus oocytes. This revealed a significant reduction in potassium influx for the p.(Gly552Asp) substitution. Our findings further expand the spectrum of SLC12A6 disease, from biallelic hereditary motor and sensory neuropathy with corpus callosum agenesis and mental retardation and monoallelic early-onset hereditary motor and sensory neuropathy caused by de novo mutations, to late-onset autosomal-dominant axonal neuropathy with predominant sensory deficits. [ABSTRACT FROM AUTHOR]

Abstract Background Waardenburg syndrome (WS) is a rare genetic disorder characterized by musculoskeletal abnormalities, deafness and hypopigmentation of hair and skin. This article’s aim is to investigate clinical and genetic characteristics of WS in three unrelated Caucasian individuals. Case presentation The first patient was a 25-year-old female with congenital bilateral hearing loss, bright-blue-eyes, hypopigmentation of hair and skin, megacolon, language retardation, tenosynovitis and neuromas. The second case was an infant symptomatic from birth, with dysphagia, Hirschsprung disease and neurological abnormalities. The third patient was a 14-year-old boy with congenital bilateral hearing loss and ileocolic Hirschsprung disease. In order to identify variants in potentially causal genes of the patients’ phenotype, genetical testing was conducted: targeted clinical exome, targeted exome and trio exome, respectively. We identified three novel variants spread throughout the coding sequence of SOX10. The c.395C>G variant identified de novo in patient 1 was a single nucleotide substitution in exon 2. The c.850G>T variant identified as heterozygous in patient 2 was a loss-of-function variant that generated a premature stop codon. The c.966dupT variant identified in patient 3 was a duplication that generated a premature stop codon. It had been identified in his father, arising a possible germinal mosaicism. According to in silico predictors the variant identified in patient 1 was considered as pathogenic, whereas the other two were classified as likely pathogenic. Conclusions An exact description of the mutations responsible for WS provides useful information to explain clinical features of WS and contributes to better genetic counselling of WS patients.

Background: Waardenburg syndrome (WS) is a rare genetic disorder characterized by musculoskeletal abnormalities, deafness and hypopigmentation of hair and skin. This article's aim is to investigate clinical and genetic characteristics of WS in three unrelated Caucasian individuals. Case presentation: The first patient was a 25-year-old female with congenital bilateral hearing loss, bright-blue-eyes, hypopigmentation of hair and skin, megacolon, language retardation, tenosynovitis and neuromas. The second case was an infant symptomatic from birth, with dysphagia, Hirschsprung disease and neurological abnormalities. The third patient was a 14-year-old boy with congenital bilateral hearing loss and ileocolic Hirschsprung disease. In order to identify variants in potentially causal genes of the patients' phenotype, genetical testing was conducted: targeted clinical exome, targeted exome and trio exome, respectively. We identified three novel variants spread throughout the coding sequence of SOX10. The c.395C>G variant identified de novo in patient 1 was a single nucleotide substitution in exon 2. The c.850G>T variant identified as heterozygous in patient 2 was a loss-of-function variant that generated a premature stop codon. The c.966dupT variant identified in patient 3 was a duplication that generated a premature stop codon. It had been identified in his father, arising a possible germinal mosaicism. According to in silico predictors the variant identified in patient 1 was considered as pathogenic, whereas the other two were classified as likely pathogenic. Conclusions: An exact description of the mutations responsible for WS provides useful information to explain clinical features of WS and contributes to better genetic counselling of WS patients. [ABSTRACT FROM AUTHOR]

Introduction. Hereditary motor and sensory neuropathies, a highly genetic heterogeneous group of disorders, have a phenotype caused by peripheral nerve damage.Purpose of the study – to assess the extent of genetic heterogeneity of hereditary motor and sensory neuropathies in Russian patients and to evaluate the diagnostic effectiveness of using full-exome research methods to find the genetic cause of hereditary motor and sensory neuropathies.Materials and methods. The material for the study was DNA samples from 51 patients and their family members referred for whole exome sequencing to the DNA-diagnostics laboratory of Research Centre for Medical Genetics in 2017–2019. Methods: whole exome sequencing, Sanger sequencing, restriction fragment length polymorphism.Results. Whole exome sequencing in combination with segregation analysis of the pathogenic variants in families allowed to determine the cause of the disease in 41 % of cases. In another 16 % of cases, candidate genetic variants as a possible cause of the disease were revealed, but additional studies are needed to confirm it. The most frequently mutated gene was MFN2 caused neuropathy in 6 unrelated families. MPZ gene mutations were detected in two families, AARS gene mutations were revealed in another two families, and mutations in GJB1, HINT1, INF2, LRSAM1, LITAF, MME, NEFL, WWOX were detected once. Among the causal variants, mutations in B4GALNT1 caused spastic paraplegia, in COL6A1 led to Bethlem’s congenital muscular dystrophy, and in SYT2 caused congenital myasthenic syndrome indicating difficulties in differential diagnosis of inherited neuromuscular disorders. A PMP22 duplication was detected in 2 families prior to whole exome sequencing.Conclusion. Whole exome sequencing is very important for finding the molecular cause of hereditary motor and sensory neuropathies. In most cases, additional methods should be used to clarify the pathogenicity of variants detected by whole exome sequencing. However, it is necessary to remember that the most common cause of the disease is a large duplication of the region 17p11.2.

Background: Implementing scientific knowledge in clinical practice is a challenge. In this context, the effective dissemination of scientific findings is of utmost importance., Objective: The aim of this study was to develop a Practice Brief in Portuguese, Spanish and English based on a previously published Clinical Practice Guideline to promote safe and effective exercise for children and young people with Charcot-Marie-Tooth disease and related neuropathies (CMT)., Methods: The Practice Brief was developed by eight health professionals from Brazil and Australia with English, Portuguese, and Spanish translations. The target audience chosen were the medical and allied health professionals involved in the rehabilitation of paediatric CMT. The content was based on the world first "Clinical Practice Guideline for the management of paediatric Charcot-Marie-Tooth disease" [1]. The layout of the Practice Brief was designed according to the criteria for the development of educational materials. The disclosure plan for the Practice Brief involves its publication on University and Hospital websites, www.ClinicalOutcomeMeasures.org and through social media platforms such as ResearchGate, Instagram, Facebook and Twitter, as well as in print format for CMT patient care centres., Results: The English, Portuguese and Spanish versions of the Practice Brief is organised into six sections about assessment, exercise and physical rehabilitation, of which one is focused on progressive resistance exercises for the foot dorsiflexor muscles., Conclusion: We developed a Practice Brief in three languages (English, Portuguese and Spanish), synthesising the main recommendations for exercise and related rehabilitative therapies for paediatric CMT from a published clinical guideline., Competing Interests: Conflict of interest statement The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Abstract Background Physical activity is associated with positive health effects, but individuals with neuromuscular disease (NMD) may experience constraints being physically active. There is a gap in the literature on the activity level of people with NMDs, and therefore we did a study to determine the physical activity level in people with Limb-Girdle muscular dystrophy (LGMD) and Charcot-Marie-Tooth disease (CMT). Methods This study used a cross-sectional design to obtain self-reported physical activity and sitting time among individuals with LGMD and CMT who were recruited from the Norwegian registry for hereditary and congenital neuromuscular diseases. Results A total of 127 respondents who filled out questionnaires about either physical activity or sitting time were included in the analysis. Seventy (55.1%) had a diagnosis of CMT and 57 (44.9%) had a diagnosis of LGMD. Seventy-three (57.5%) respondents were female and 54 (42.5%) were male. Among the 108 respondents with available physical activity data, 44.4% reported being physically inactive. Among the 109 respondents with available sitting time data, the average sitting time was 8.6 h. Longer sitting time was associated with higher physical inactivity. Conclusion Among people with LGMD and CMT in our study, 55.6% reported being physically active. Respondents with LGMD and CMT reported longer sitting time and less physical activity compared with healthy respondents in other studies. Further research should explore variables and measures that can promote physical activity among people with neuromuscular conditions.

Abstract Objective To estimate the prevalence and significance of cranial nerve (CN) imaging abnormalities in patients with hereditary neuropathy and discuss clinical implications. Methods We retrospectively analyzed data from patients at four tertiary academic medical centers with hereditary neuropathy diagnoses who had undergone gadolinium‐enhanced magnetic resonance imaging (MRI) of the brain or skull base between 2004 and 2018. MRI scans, as well as computed tomography imaging when available, were reviewed and bivariable analysis was performed to identify predictors of CN abnormalities on imaging. Results Among 39 patients meeting study criteria, 11 had clinical CN deficits (28%) and 8 had CN abnormalities on imaging (21%). Of the patients with CN abnormalities on imaging, half had CN deficits (4/8) and only a quarter had imaging abnormalities of the CNs with the deficits (2/8). Imaging abnormalities were found in varied CNs, including CNs III, V, VII, and the VII/VIII complex in the internal auditory canal. MRI obtained for the purpose of evaluating CN deficits had a statistically significant increased likelihood of containing CN imaging abnormalities. However, CN deficits themselves were not predictive of imaging abnormalities. Conclusion Thickening and enhancement of CNs on MRI may be found in approximately 1/5 of patients with hereditary neuropathies and are inconsistently associated with clinical deficits. These imaging findings should not be mistaken for neoplastic and infectious processes as they may be manifestations of the patients' underlying genetic neuropathy. Level of Evidence 4.

This study aimed to describe the clinical, genetic, and epidemiological features of Charcot‐Marie‐Tooth disease (CMT) in Brazilian patients from a tertiary center, and to compare our data with previously published findings. This retrospective observational study conducted between February 2015 and July 2020 evaluated 503 patients (94 families and 192 unrelated individuals), diagnosed with CMT. Clinical and neurophysiological data were obtained from electronic medical records and blood samples were used for genetic analyses. Multiplex ligation‐dependent probe amplification was used to assess duplications/deletions in PMP22. Sanger sequencing of GJB1 was performed in cases of suspected demyelinating CMT. Targeted gene panel sequencing was used for the remaining negative demyelinating cases and all axonal CMT cases. The first decade of life was the most common period of disease onset. In all, 353 patients had demyelinating CMT, 39 had intermediate CMT, and 111 had axonal CMT. Pathogenic or likely pathogenic variants were identified in 197 index cases. The most common causative genes among probands were PMP22 (duplication) (n = 116, 58.88%), GJB1 (n = 23, 11.67%), MFN2 (n = 12, 6.09%), GDAP1 (n = 7, 3.55%), MPZ (n = 6, 3.05%), PMP22 (point mutation) (n = 6, 3.05%), NEFL (n = 3, 1.52%), SBF2 (n = 3, 1.52%), and SH3TC2 (n = 3, 1.52%). Other identified variants were ≤1% of index cases. This study provides further data on the frequency of CMT subtypes in a Brazilian clinical‐based population and highlights the importance of rarer and previously undiagnosed variants in clinical practice. [ABSTRACT FROM AUTHOR]

Background. Hereditary motor and sensory neuropathies (HMSN) are a genetically diverse group of disorders of the peripheral nerves characterized by gradual development of weakness, muscular hypo-/atrophy, sensory disturbances in distal areas of the extremities. Currently among the recessive forms, the most prevalent HMSN is associated with the ganglioside-induced differentiation associated-protein 1 (GDAP1) gene (GDAP1-HMSN).The objective is to present an observation of a family case of HMSN type IVA with unusual genealogy.Materials and methods. Clinical, electrophysiological, and genetic characteristics of a Russian family with GDAP1-HMSN were examined.Results. We describe a family with autosomal recessive HMSN and unusual genealogy due to homozygous and compound heterozygous mutations of GDAP1.Conclusion. The particularity of the described family case is the unusual genealogy with the patients in two non-consecutive generations. This type of inheritance is caused by presence of mutations in compound heterozygous state in the proband's grandson which was confirmed by genetic analysis. The presented case demonstrates the importance and necessity of full analysis of the GDAP1 gene or identification of 2 mutations in trans-position in the proband and subsequent assessment of possible risks for future generations. Multiple stroke-like episodes in the 2 affected members of the family are described that have not been previously reported for GDAP1-HMSN. Stroke has been presented in HMSN associated with mitofusin-2 gene which also as GDAP1, affects mitochondrial function in the neurons.

Inherited peripheral neuropathy is the most common hereditary neuromuscular disease with a prevalence of about 1:2,500. The most frequent form is Charcot-Marie-Tooth disease (CMT, or hereditary motor and sensory neuropathy [HMSN]). Other clinical entities are hereditary neuropathy with liability to pressure palsies (HNPP), distal hereditary motor neuropathies (dHMN), and hereditary sensory and autonomic neuropathies (HSAN). With the exception of HNPP, which is almost always caused by defects of the PMP22 gene, all other forms show genetic heterogeneity with altogether more than 100 genes involved. Mutation detection rates vary considerably, reaching up to 80 % in demyelinating CMT (CMT1) but are still as low as 10–30 % in axonal CMT (CMT2), dHMN, and HSAN. Based on current information, analysis of only four genes (PMP22, GJB1, MPZ, MFN2) identifies 80–90 % of CMT-causing mutations that can be detected in all known disease genes. For the remaining patients, parallel analysis of multiple neuropathy genes using next-generation sequencing is now replacing phenotype-oriented multistep gene-by-gene sequencing. Such approaches tend to generate a wealth of genetic information that requires comprehensive evaluation of the pathogenic relevance of identified variants. In this review, we present current classification systems, specific phenotypic clues, and diagnostic yields in the different subgroups of hereditary CMT and motor neuropathies. [ABSTRACT FROM AUTHOR]

Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by recurrent sensory and motor neuropathy in individual nerves starting in adolescence or young adulthood, focal conduction abnormalities at entrapment sites on nerve conduction studies, and sausage-like swellings (tomacula) of the myelin sheaths by nerve biopsy. It is characterized genetically by the deletion of the chromosome 17p11.2–p12 region including the peripheral myelin protein-22 gene in the overwhelming majority of cases. HNPP may be frequently underdiagnosed or misdiagnosed owing to the heterogeneity of clinical and electrophysiological appearance. The main objective of this review is to describe clinical manifestations, paraclinical features such as electrodiagnostic, pathological, radiological and genetics findings, and possible treatments. [ABSTRACT FROM AUTHOR]

The majority of patients with spinal muscular atrophy (SMA) identified to date harbor a biallelic exonic deletion of SMN1. However, there have been reports of SMA‐like disorders that are independent of SMN1, including those due to pathogenic variants in the glycyl‐tRNA synthetase gene (GARS1). We report three unrelated patients with de novo variants in GARS1 that are associated with infantile‐onset SMA (iSMA). Patients were ascertained during inpatient hospital evaluations for complications of neuropathy. Evaluations were completed as indicated for clinical care and management and informed consent for publication was obtained. One newly identified, disease‐associated GARS1 variant, identified in two out of three patients, was analyzed by functional studies in yeast complementation assays. Genomic analyses by exome and/or gene panel and SMN1 copy number analysis of three patients identified two previously undescribed de novo missense variants in GARS1 and excluded SMN1 as the causative gene. Functional studies in yeast revealed that one of the de novoGARS1 variants results in a loss‐of‐function effect, consistent with other pathogenic GARS1 alleles. In sum, the patients' clinical presentation, assessments of previously identified GARS1 variants and functional assays in yeast suggest that the GARS1 variants described here cause iSMA. GARS1 variants have been previously associated with Charcot–Marie–Tooth disease (CMT2D) and distal SMA type V (dSMAV). Our findings expand the allelic heterogeneity of GARS‐associated disease and support that severe early‐onset SMA can be caused by variants in this gene. Distinguishing the SMA phenotype caused by SMN1 variants from that due to pathogenic variants in other genes such as GARS1 significantly alters approaches to treatment. [ABSTRACT FROM AUTHOR]

Background: Physical activity is associated with positive health effects, but individuals with neuromuscular disease (NMD) may experience constraints being physically active. There is a gap in the literature on the activity level of people with NMDs, and therefore we did a study to determine the physical activity level in people with Limb-Girdle muscular dystrophy (LGMD) and Charcot-Marie-Tooth disease (CMT).Methods: This study used a cross-sectional design to obtain self-reported physical activity and sitting time among individuals with LGMD and CMT who were recruited from the Norwegian registry for hereditary and congenital neuromuscular diseases.Results: A total of 127 respondents who filled out questionnaires about either physical activity or sitting time were included in the analysis. Seventy (55.1%) had a diagnosis of CMT and 57 (44.9%) had a diagnosis of LGMD. Seventy-three (57.5%) respondents were female and 54 (42.5%) were male. Among the 108 respondents with available physical activity data, 44.4% reported being physically inactive. Among the 109 respondents with available sitting time data, the average sitting time was 8.6 h. Longer sitting time was associated with higher physical inactivity.Conclusion: Among people with LGMD and CMT in our study, 55.6% reported being physically active. Respondents with LGMD and CMT reported longer sitting time and less physical activity compared with healthy respondents in other studies. Further research should explore variables and measures that can promote physical activity among people with neuromuscular conditions. [ABSTRACT FROM AUTHOR]

Objective: To estimate the prevalence and significance of cranial nerve (CN) imaging abnormalities in patients with hereditary neuropathy and discuss clinical implications. Methods: We retrospectively analyzed data from patients at four tertiary academic medical centers with hereditary neuropathy diagnoses who had undergone gadolinium‐enhanced magnetic resonance imaging (MRI) of the brain or skull base between 2004 and 2018. MRI scans, as well as computed tomography imaging when available, were reviewed and bivariable analysis was performed to identify predictors of CN abnormalities on imaging. Results: Among 39 patients meeting study criteria, 11 had clinical CN deficits (28%) and 8 had CN abnormalities on imaging (21%). Of the patients with CN abnormalities on imaging, half had CN deficits (4/8) and only a quarter had imaging abnormalities of the CNs with the deficits (2/8). Imaging abnormalities were found in varied CNs, including CNs III, V, VII, and the VII/VIII complex in the internal auditory canal. MRI obtained for the purpose of evaluating CN deficits had a statistically significant increased likelihood of containing CN imaging abnormalities. However, CN deficits themselves were not predictive of imaging abnormalities. Conclusion: Thickening and enhancement of CNs on MRI may be found in approximately 1/5 of patients with hereditary neuropathies and are inconsistently associated with clinical deficits. These imaging findings should not be mistaken for neoplastic and infectious processes as they may be manifestations of the patients' underlying genetic neuropathy. Level of Evidence: 4. [ABSTRACT FROM AUTHOR]

Pathogenic variants in the HINT1 gene lead to hereditary axonopathy with neuromyotonia. However, many studies show that neuromyotonia may remain undiagnosed, while axonopathy is the major clinical finding. The most common cause of neuromyotonia and axonopathy, especially in patients of Slavic origin, is a c.110G>C (p.Arg37Pro) pathogenic variant in homozygous or compound heterozygous state. In this study, we analyzed a peripheral neuropathy caused by pathogenic variants in the HINT1 gene and evaluated its contribution to the hereditary neuropathy structure. The studied group included 1596 non-related families diagnosed with hereditary motor and sensory neuropathy (HMSN). The results show that HINT1 gene pathogenic variants make a significant contribution to the hereditary neuropathy epidemiology in Russian patients. They account for at least 1.9% of all HMSN cases and 9% of axonopathy cases. The most common HINT1 pathogenic variant in Russian patients is the c.110G>C (p.Arg37Pro) substitution. Its allelic frequency is 0.2% (95% CI 0.19–0.21%), carrier frequency is 1 in 250 people in Russian Federation, and the estimated disease incidence is 1 in 234,000 individuals. It was determined that the cause of this pathogenic variant's prevalence is the founder effect. [ABSTRACT FROM AUTHOR]

Background. Hereditary motor and sensory neuropathies (HMSN, Charcot–Marie–Tooth disease) form genetically heterogenous and clinically polymorphic group of diseases which predominantly affect peripheral nervous system. Correct primary diagnostics of these diseases is a starting point for planning subsequent molecular and genetic diagnostics.Objective. Analysis of primary diagnostics of HMSN for subsequent improvement of specialized medical and genetic help for patients and their families.Materials and methods. We analyzed 260 primary diagnoses of patients referred to a neurogeneticist for consultation and registered in the Genetics Consultation Clinic with the diagnosis of HMSN between 1970 and 2016.Results. A total of 17 variants of referral diagnoses of patients with HMSN were identified. They can be divided into 3 subgroups: hereditary diseases of the nervous and neuromuscular systems, other diseases of the nervous system, diseases of other systems. A correct diagnosis was listed in a little more than half (58.1 %) of all cases of primary referrals. The most common (10.8 %) erroneous referral diagnosis of patients with HMSN was Friedreich’s ataxia. Most of erroneous referral diagnoses could be confidently ruled out at the stage of primary clinical diagnosis and after electroneuromyography. Altogether, in the observed period percentage of correct referral diagnoses increased while the specter of erroneous diagnoses decreased significantly which attests to increased doctors’ awareness of HMSN.Conclusion. In order to improve HMSN diagnostics doctors should pay more attention to analysis of family medical history and perform a clinical examination of all proband’s available relatives.

The article presents the results of ultrasound studies inpatients with hereditary motor and sensory neuropathy, orCharcot-Marie-Tooth disease (CMT). Based on standardelectroneuromiography, the patients were divided into two groupswith demyelinating (n=25) or axonal (n=31) process, CMT1 andCMT2 respectively. Demyelinating forms were characterized byspecific prolonged sonographic changes with uniform thickeningof all studied nerves and abnormalities of their cable structure.In axonal forms the character of structural changes was not assevere and specific as in CMT1, but symmetrical prolongationof the nerve structure was seen in this type of CMT as well. Thedescription of genetically confirmed familial cases of HMSN type1X in male relatives is presented, which demonstrates modernpotential of unltrasound studies in diagnosing the involvementof peripheral nerves in patients from a heterogeneous group ofhereditary neuropahies.

In this study, clinical manifestations of hereditary motor andsensory neuropathy type IIA (HMSN IIA, orCharcotMarieTooth disease type 2A) were analyzed in 22patients with the disease caused by different mutations of theMFN2 gene. Molecular genetic analysis showed that in theexamined cohort of Russian families with axonal form of hereditary motor and sensory neuropathy, HMSN IIA accounted for17% cases. Eighteen from 22 patients under observation weremembers of three large families with the disease segregating intwo or more generations, which enabled us to determine thescope of clinical polymorphism of HMSN IIA, as well as toassess intra and interfamilial variability of clinical features andfollow up the dynamics of clinical phenotype formation uponthe disease progression.

UNLABELLED: The aim of this work was to assess the hearing impairment in patients with hereditary motor and sensory neuropathy (HMSN). Elevation of pure tone thresholds in the presence of preserved inner ear function as suggested by cochlear microphonics (CM), absent or markedly abnormal brainstem auditory evoked potentials (BAEP), and elevation of speech perception out of proportion to the pure tone loss were found in the patients. From 28 members of a Gypsy family, we examined two siblings aged 31 and 30 years and their nephew aged 20 years, all suffering from HMSN that was associated with auditory neuropathy. All three affected members with difficulty of understanding speech had following investigations: pure tone and speech audiograms, BAEP, cochlear microphonics, and nerve conduction studies (NCV). RESULTS: the older two siblings had a flat 80 dB audiogram, whereas the younger one has flat 20 dB audiogram on the Lt. ear and 30 dB audiogram on the Rt. ear. All had no speech comprehension and no BAEP. Two patients had preserved cochlear microphonics on one ear. Peripheral nerves were electrically not elicitable, however, at the beginning of the disease nerve conduction was slow. CONCLUSION: in all three affected members with distinct clinical picture of HMSN their hearing impairment was proved to be due to severe auditory neuropathy in the presence of preserved inner ear function.

UNLABELLED: The aim of this work was to assess the hearing impairment in patients with hereditary motor and sensory neuropathy (HMSN). Elevation of pure tone thresholds in the presence of preserved inner ear function as suggested by cochlear microphonics (CM), absent or markedly abnormal brainstem auditory evoked potentials (BAEP), and elevation of speech perception out of proportion to the pure tone loss were found in the patients. From 28 members of a Gypsy family, we examined two siblings aged 31 and 30 years and their nephew aged 20 years, all suffering from HMSN that was associated with auditory neuropathy. All three affected members with difficulty of understanding speech had following investigations: pure tone and speech audiograms, BAEP, cochlear microphonics, and nerve conduction studies (NCV). RESULTS: the older two siblings had a flat 80 dB audiogram, whereas the younger one has flat 20 dB audiogram on the Lt. ear and 30 dB audiogram on the Rt. ear. All had no speech comprehension and no BAEP. Two patients had preserved cochlear microphonics on one ear. Peripheral nerves were electrically not elicitable, however, at the beginning of the disease nerve conduction was slow. CONCLUSION: in all three affected members with distinct clinical picture of HMSN their hearing impairment was proved to be due to severe auditory neuropathy in the presence of preserved inner ear function.

The inherited neuropathies are a common and heterogeneous group of slowly progressive disorders affecting motor, sensory, and autonomic nerves. These hereditary conditions can be confined to the peripheral nervous system, termed the primary hereditary neuropathies, or can occur as part of a multisystem disease. Identification of systemic involvement is necessary to distinguish the primary and secondary hereditary neuropathies to prevent the misdiagnosis of potentially treatable entities. Recent genetic and technological advances have dramatically improved our understanding of the underlying pathophysiology of these inherited neuropathies and hence provide the correct milieu for the future development of disease-modifying therapies. This review provides clinical, neurophysiological, genetic, pathophysiological, and treatment insights into the primary inherited neuropathies, and those associated with multisystem diseases, including porphyria and mitochondrial disorders. [ABSTRACT FROM AUTHOR]

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Vincristine (VCR), a microtubule inhibitor that arrests the cell cycle by blocking metaphase of mitosis, is unique among the vinca alkaloids for causing polyneuropathy. Patients with increased risk of VCR neurotoxicity include the elderly and those with prior history of neuropathy-prone medical conditions. Identifying such risk factors prior to the development of neurotoxicity should be a goal prior to VCR administration. Clinicians should obtain a thorough medical and family history of neuropathies in any child scheduled to receive neurotoxic medications to avoid exacerbating an underlying disorder. We report a case of a young child with newly diagnosed medulloblastoma who started treatment on a VCR-containing chemotherapy regimen following surgery and craniospinal radiation. She subsequently developed severe peripheral polyneuropathy and new enhancement of the cranial and nerve roots following a relatively low cumulative dose of VCR and was diagnosed with previously unidentified Charcot–Marie–Tooth disease (CMTD) Type 1A. This case highlights that an evaluation of risk factors should be completed prior to initiation of neurotoxic chemotherapies and advocates for testing for inherited neuropathies such as CMTD even in asymptomatic patients when hereditary neuropathy is suspected. [ABSTRACT FROM AUTHOR]

Background. In the recent years interest towards nerve sonography has largely increased, specifically in terms of differentiating types of hereditary motor and sensory neuropathy (HMSN). The diagnostic possibilities of high-resolution ultrasound (HRUS) compared to standard neurophysiological tools in the peripheral nerve disorders is still a matter of debate.Objectives. Analysis of quantitative and qualitative ultrasound changes of limb nerves in patients with HMSN type 1 and its comparison with anthropometric and nerve conduction study data.Materials and methods. 44 HMSN patients were analyzed: 16 men, mean age 35,9 ± 6,8 years; 16 (37 %) with autosomal dominant type 1А, 11 (25 %) – with 1В type and 17 (38 %) with Х-linked inheritance. Control group included 44 subjects, 16 male; mean age 35,9 ± 6,8 years. HRUS parameters were analyzed bilaterally on the selected levels: cross-sectional area (CSA), visual cross sectional and longitudinal patterns of the median and ulnar nerves, C5, C6, C7 spinal nerves, tibial, peroneal and sciatic nerves. HRUS parameters were compared to standard anthropometric data, nerve conduction velocity and CMAP amplitude.Results. In all HMSN cases CSA was enlarged compared to healthy controls. Greater changes were found in patients with autosomal dominant inheritance. CSA enlargement in С5, С6, С7 spinal nerves was found in patients with HMSN 1A, С6, С7 – in HMSN 1В, С6 – in HMSN 1X, confirming the necessity to include those nerves in the sonographic protocol in patients with HMSN. Three qualitative cross sectional and longitudinal patterns of the investigated arm nerves were identified, distinct for each of the HMSN type. Absence of significant differences in CSA of the upper limb nerves among analyzed types of HMSN makes it unreliable as the differential parameter, opposite to the defined sonographic patterns. Methodological issues and absence of significant quantitative and qualitative data from the lower limb nerves makes it possible to exclude those from HRUS protocol in HMSN.Conclusions. Nerve sonography of the upper limbs could be a useful additional tool in the differential diagnosis of HMSN type 1 when applying described qualitative HRUS patterns.

The clinical and genetic features of hereditary motor and sensory neuropathy (HMSN; Charcot–Marie–Tooth disease, CMT) caused by newly identified missense mutation s.65G>T (p.Pro22His) in NEFL gene located on the chromosome 8р21.2 are described. The disease was diagnosed in a large family from Ust-Dzhegutinsky district of the Karachay-Cherkess Republic with the segregation of the disease in four generations. The prevalence of the HMSN in that district was found to be 1:4340 persons, including 1:3376 among Karachays. The clinical picture of the disease was characterized by onset at the age of 11–14 years, weakness in foot muscles and steppage gait. The specific features in the majority of patients were the absence of major sensory disturbances, as well as long-term preserved distal arm muscles. Nerve conduction velocity in the median nerve varied from 30 to 42 m/s, which corresponds to values in patients with CMT2E, previously described.

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is a rare hereditary motor and sensory neuropathy. This is a report of a pilot with this condition with a discussion of the challenges for the regulator in the assessment for medical certification of pilots with a neurological disability. CASE REPORT: A pilot with CMTX1 declared his condition to the United Kingdom Civil Aviation Authority when his brother was diagnosed with the same condition. Apart from high arched feet and some difficulty playing sports, he had no problems until his mid-forties, when he very slowly developed increasing weakness with foot dorsiflexion and later wasting and weakness of the small hand muscles. He reported no problems with any flying activity. On clinical examination, it seemed likely that the disability would have an impact on his ability to undertake all the flying tasks of a commercial pilot, including those required in emergencies. DISCUSSION: A modified Medical Flight Test (MFT) specifically tailored by the regulator to test areas of functional impairment allowed the successful certificatory assessment of a pilot with this condition; an approach which could apply to any pilot with a rare neurological disability. [ABSTRACT FROM AUTHOR]

Introduction: This study analyzes and describes atypical presentations of Charcot-Marie-Tooth disease type 4C (CMT4C).Methods: We present clinical and physiologic features of 5 patients with CMT4C caused by biallelic private mutations of SH3TC2.Results: All patients manifested scoliosis, and nerve conduction study indicated results in the demyelinating range. All patients exhibited signs of motor impairment within the first years of life. We describe 2 or more different genetic diseases in the same patient, atypical presentations of CMT, and 3 new mutations in CMT4C patients.Discussion: A new era of unbiased genetic testing has led to this small case series of individuals with CMT4C and highlights the recognition of different genetic diseases in CMT4C patients for accurate diagnosis, genetic risk identification, and therapeutic intervention. The phenotype of CMT4C, in addition, appears to be enriched by a number of features unusual for the broad CMT category. Muscle Nerve 57: 749-755, 2018. [ABSTRACT FROM AUTHOR]

Abstract: Histidyl‐tRNA synthetase (HARS) ligates histidine to cognate tRNA molecules, which is required for protein translation. Mutations in HARS cause the dominant axonal peripheral neuropathy Charcot‐Marie‐Tooth disease type 2W (CMT2W); however, the precise molecular mechanism remains undefined. Here, we investigated three HARS missense mutations associated with CMT2W (p.Tyr330Cys, p.Ser356Asn, and p.Val155Gly). The three mutations localize to the HARS catalytic domain and failed to complement deletion of the yeast ortholog (HTS1). Enzyme kinetics, differential scanning fluorimetry (DSF), and analytical ultracentrifugation (AUC) were employed to assess the effect of these substitutions on primary aminoacylation function and overall dimeric structure. Notably, the p.Tyr330Cys, p.Ser356Asn, and p.Val155Gly HARS substitutions all led to reduced aminoacylation, providing a direct connection between CMT2W‐linked HARS mutations and loss of canonical ARS function. While DSF assays revealed that only one of the variants (p.Val155Gly) was less thermally stable relative to wild‐type, all three HARS mutants formed stable dimers, as measured by AUC. Our work represents the first biochemical analysis of CMT‐associated HARS mutations and underscores how loss of the primary aminoacylation function can contribute to disease pathology. [ABSTRACT FROM AUTHOR]

The inherited peripheral neuropathies (IPNs) are characterized by marked clinical and genetic heterogeneity and include relatively frequent presentations such as Charcot‐Marie‐Tooth disease and hereditary motor neuropathy, as well as more rare conditions where peripheral neuropathy is associated with additional features. There are over 250 genes known to cause IPN‐related disorders but it is estimated that in approximately 50% of affected individuals a molecular diagnosis is not achieved. In this study, we examine the diagnostic utility of whole‐exome sequencing (WES) in a cohort of 50 families with 1 or more affected individuals with a molecularly undiagnosed IPN with or without additional features. Pathogenic or likely pathogenic variants in genes known to cause IPN were identified in 24% (12/50) of the families. A further 22% (11/50) of families carried sequence variants in IPN genes in which the significance remains unclear. An additional 12% (6/50) of families had variants in novel IPN candidate genes, 3 of which have been published thus far as novel discoveries (KIF1A, TBCK, and MCM3AP). This study highlights the use of WES in the molecular diagnostic approach of highly heterogeneous disorders, such as IPNs, places it in context of other published neuropathy cohorts, while further highlighting associated benefits for discovery. [ABSTRACT FROM AUTHOR]

Copyright of Operative Orthopädie und Traumatologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective This study aims to compare mechanography, measuring force in jumping, and rising, with the 6-minute walk test (6MWT) and time function tests in pediatric patients with hereditary motor and sensory neuropathies. Methods A cohort of 23 patients performed the 6MWT and time function tests (time to run 10 m, to rise from a supine position, and to climb four stairs), as well as the chair rising test (CRT) and the single two-legged jump (S2LJ) on a mechanography ground reaction force platform. Results were correlated calculating linear regression. Results Correlation revealed high or moderate correlation between mechanography and the 6MWT and the time function tests: S2LJ/6MWT = 0.64; CRT/6MWT = 0.52; S2LJ/rising from floor = 0.63; CRT/rising from floor = 0.67; S2LJ/10 m run = 0.74; CRT/10 m run = 0.66; S2LJ/climb four stairs = 0.56; CRT/climb four stairs = 0.47. Conclusion Jumping mechanography is a good additional tool for the assessment of pediatric patients with Charcot-Marie-Tooth disease and might be used for primary outcome measures. It was not feasible in more advanced stages of the disease. In less disabled children, the S2LJ, which quantifies force generated by proximal and distal muscles, might be superior to other tests. [ABSTRACT FROM AUTHOR]

Waardenburg syndrome (WS) is a rare disorder comprising sensorineural deafness and pigmentation abnormalities. Four distinct subtypes are defined based on the presence or absence of additional symptoms. Mutations in six genes have been described in WS. SOX10 mutations are usually associated with a more severe phenotype of WS with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, and Hirschsprung disease. Here we report a 32-year-old man with a novel heterozygous missense variant in SOX10 gene, who presented with congenital deafness, Hirschsprung disease, iris heterochromia, foot deformity, and intermediate conduction velocity length-dependent sensorimotor neuropathy. This case highlights that the presence of other non-neuropathic features in a patient with presumed hereditary neuropathy should alert the clinician to possible atypical rare causes. [ABSTRACT FROM AUTHOR]

Hereditary neuropathy is an umbrella term for a group of nonsyndromic conditions with a prevalence of approximately 1:2,500. In addition to the most frequent form, Charcot-Marie-Tooth's disease (CMT, or hereditary motor and sensory neuropathy), there are additional entities such as hereditary neuropathy with liability to pressure palsies (HNPP), hereditary motor neuropathies (HMNs), and hereditary sensory and autonomic neuropathies (HSANs). With the exception of HNPP, which is almost always caused by defects of the PMP22 gene, all other forms show genetic heterogeneity with altogether close to 100 genes involved. Mutation detection rates vary considerably, reaching up to 80% in demyelinating CMT (CMT1) but are still as low as 10 to 30% in axonal CMT (CMT2), HMN, and HSAN. Based on current information, analysis of only four genes (PMP22, GJB1, MPZ, MFN2) identifies 80 to 90% of CMT-causing mutations that can be detected in all known disease genes. For the remaining patients, parallel analysis of multiple neuropathy genes using next-generation sequencing is now replacing phenotype-oriented multistep gene-by-gene sequencing. Such approaches tend to generate a wealth of genetic information that requires comprehensive evaluation of the pathogenic relevance of identified variants. In this review, we present current classification systems, specific phenotypic clues, and genetic testing algorithms in the different subgroups of hereditary neuropathies. [ABSTRACT FROM AUTHOR]

Charcot-Marie-Tooth (CMT) is a rare inherited peripheral neuropathy in which quality of life (QoL) is reduced compared with the general population. This paper investigates the relationship between QoL and physical performance in people with CMT with the aim of identifying avenues for future research into rehabilitation strategies. Cross-sectional data was obtained from 10 participants (5 men, 5 women, age 46 ± 13 years, height 1.7 ± 0.1 m, body mass 77 ± 17 kg) with CMT (CMT1A n = 5; CMT-X n = 3; unknown genetic origin n = 2). Participants were evaluated for QoL, falls efficacy (FES), balance, mobility, muscle strength, and power. Physical component score (PCS) of the Short Form-36 (SF-36) was significantly and directly related to higher leg press power (r = 0.75, p = 0.02). Better FES scores were significantly related to faster habitual gait speed (r = −0.70, p = 0.02), left hip abduction, and seated row strength (r = −0.68, p = 0.03; r = −0.73, p = 0.03, respectively). Future research should aim to substantiate these preliminary findings in a larger cohort and investigate whether interventions targeting muscle strength and power can improve QoL and mobility outcomes in people with CMT. [ABSTRACT FROM AUTHOR]

We report 2 members of a family with gene mutations for both X‐linked dominant Charcot–Marie–Tooth disease and myotonic dystrophy type 1. The father shows symptoms of hereditary motor and sensory neuropathy, while his daughter has symptoms of myotonic dystrophy. Detailed clinical manifestations in both cases are described. [ABSTRACT FROM AUTHOR]

Introduction Charcot-Marie-Tooth neuropathy ( CMT) is a genetically heterogeneous group of peripheral neuropathies. In addition to the classical clinical phenotype, additional features can occur. Methods We studied a wide range of additional features in a cohort of 49 genetically confirmed CMT patients and performed a systematic literature revision. Results Patients harbored a PMP22 gene alteration ( n = 28) or a mutation in MPZ ( n = 11), GJB1 ( n = 4), LITAF ( n = 2), MFN2 ( n = 2), INF2 ( n = 1), NEFL ( n = 1). We identified four novel mutations (3 MPZ, 1 GJB1). A total of 88% presented at least one additional feature. In MPZ patients, we detected hypertrophic nerve roots in 3/4 cases that underwent spinal MRI, and pupillary abnormalities in 27%. In our cohort, restless legs syndrome ( RLS) was present in 18%. We describe for the first time RLS associated with LITAF or MFN2 and predominant upper limb involvement with LITAF. Cold-induced hand cramps occurred in 10% ( PMP22, MPZ, MFN2), and autonomous nervous system involvement in 18% ( PMP22, MPZ, LITAF, MFN2). RLS and respiratory insufficiency were mostly associated with severe neuropathy, and pupillary abnormalities with mild to moderate neuropathy. Conclusions In CMT patients, additional features occur frequently. Some of them might be helpful in orienting genetic diagnosis. Our data broaden the clinical spectrum and genotype-phenotype associations with CMT. [ABSTRACT FROM AUTHOR]