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Aims Advances in genetic technology and small molecule drug development have paved the way for clinical trials in Charcot-Marie-Tooth disease (CMT), however, the current FDA-approved clinical trial outcome measures are insensitive to detect a meaningful clinical response. There is therefore a need to identify sensitive outcome measures or clinically relevant biomarkers. The aim of this study was to further evaluate plasma neurofilament light chain (NFL) as a disease biomarker in CMT. Methods Plasma NFL was measured using SIMOA technology in both a cross sectional study of a US cohort of CMT patients and longitudinally over six years in a UK CMT cohort. In addition, plasma NFL was measured longitudinally in two mouse models of CMT2D. Results Plasma concentrations of NFL were increased in a US cohort of patients with CMT1B, CMT1X and CMT2A but not CMT2E compared with controls. In a separate UK cohort, over a six-year interval, there was no significant change in plasma NFL concentration in CMT1A or HSN1, but a small but significant reduction in patients with CMT1X. Plasma NFL was increased in wild type compared to GARSC201R mice. There was no significant difference in plasma NFL in GARSP278KY compared to wild type mice. Conclusion In patients with CMT1A, the small difference in cross sectional NFL concentration versus healthy controls and the lack of change over time suggests that plasma NFL may lack sufficient sensitivity to detect a clinically meaningful treatment response in adulthood. This article is protected by copyright. All rights reserved.

Charcot Marie Tooth disease (CMT) is the most common inherited neuropathy and is also called Hereditary Motor Sensory Neuropathy (HMSN). Whilst both motor and sensory deficits are present, motor deficits tend to predominate over sensory deficits. Charcot neuroarthropathic joints occur in conditions, most commonly diabetes nowadays, where joints are destroyed in association with reduced protective sensation, pain in particular. Three cases of development of Charcot joint disorders in patients with CMT are discussed and the literature is reviewed. Orthopaedic surgeons should be aware that Charcot joints can occur in CMT and surgery can be complicated by Charcot joints.

X-linked Charcot Marie Tooth disease type 1 (CMTX1) is a clinically heterogenous X-linked hereditary neuropathy caused by mutation of the gene encoding gap junction beta 1 protein (GJB1). Typical clinical manifestations of CMTX1 are progressive weakness or sensory disturbance due to peripheral neuropathy. However, there have been some CMTX1 cases with accompanying central nervous system (CNS) manifestations. We report the case of a genetically confirmed CMTX1 patient who presented recurrent transient CNS symptoms without any symptom or sign of peripheral nervous system involvement.

Background: Hip dysplasia is a lack of femoral head coverage and disruption of hip and acetabular alignment and congruency, with severity ranging from mild subluxation in nascent at-risk hips to complete dislocation. Presentation of hip dysplasia in neuromuscular conditions can be sub-clinical or associated with a limp with or without hip pain, abductor and flexor weakness and reduced hip range of motion. Untreated hip dysplasia leads to early onset osteoarthritis requiring hip arthroplasty in early adulthood. Hip dysplasia occurs in 6–20% of children with Charcot-Marie-Tooth disease, however little is known about the reliability and sensitivity of detection on plain film pelvic radiographs. Methods: 14 common measures of hip dysplasia on anteroposterior pelvis radiographs were independently assessed by 2 orthopaedic specialists in 30 ambulant children with Charcot-Marie-Tooth disease. Hip health was also categorised based on clinical impression to assess the sensitivity of radiographic measures to identify hip dysplasia status. Results: 8 measures (acetabular index, head width, lateral centre-edge angle, lateral uncoverage, medial joint width, migration percentage, neck shaft angle, triradiate status) exhibited ‘excellent’ reliability between clinical evaluators. 5 of the 30 patients (17%) were identified as having nascent hip dysplasia. Reliable radiographic measures that significantly distinguished between nascent hip dysplasia and healthy hips were acetabular index, lateral centre edge angle, medial joint width and migration percentage. Conclusions: We have identified a subset of reliable and sensitive radiographic hip measures in children with Charcot-Marie-Tooth disease to prioritise during hip screening to mitigate the deleterious effects of hip dysplasia, pain and disability in adulthood.

X-linked Charcot-Marie-Tooth (CMT) disease type I (CMTX1) is the second most frequent type of CMT disease caused by pathogenic variants in the GJB1 gene. We described 2 extended cases (families) with CMTX1 with identified pathogenic variants – p.Val139Met and p.Arg215Trp. In both the families, neurological symptoms started earlier in male than in female patients. In some family members, molecular diagnostics was performed prior to neurological investigation due to family cascade screening. There was variable neurological phenotype representing CMT. Conclusions: There is a large clinical heterogeneity in CMTX, even amongst the family members.

Introduction: Charcot-Marie-Tooth disease (CMT) and related neuropathies represent the most prevalent inherited neuromuscular disorders. Nonetheless, there is still no pharmacological treatment available for any CMT type. However, the landscape is rapidly evolving and several novel approaches are providing encouraging results in preclinical studies and leading to clinical trials.Areas covered: The authors review the most promising therapies under study and the ongoing/planned clinical trials. Several approaches to address PMP22 overexpression underlying CMT1A, the most frequent subtype, are being tested. Gene silencing, targeting PMP22, and gene therapy, to introduce specific genes or to substitute or modulate defective ones, are being experimented in animal models. Compounds acting on ER stress, unfolded protein response, neuregulin pathways, phosphoinositides metabolism, axonal transport and degeneration, inflammation, polyol pathway, deoxysphingolipid metabolism, purine nucleotide pool are potential therapeutic candidates for different forms of CMT and related neuropathies.Expert opinion: We are getting closer to find effective therapies for CMT, but are far behind the exciting examples of other genetic neuromuscular disorders. The authors analyze the possible reasons for this gap and the way to fill it. Preclinical and clinical research is ongoing with coordinated efforts and they are confident that in the next few years we will see the first effective treatments.

Background/aims High-intensity power training has been shown to be effective in improving muscular capabilities, functional performance and health-related quality of life in populations with physical impairments. However, the effectiveness of high-intensity power training in people with Charcot–Marie–Tooth disease remains uncertain. This case series investigated the effects of high-intensity power training on muscle performance, function and health-related quality of life in middle-aged women with Charcot-Marie-Tooth disease. Methods Four women (age 51–58 years) with Charcot–Marie–Tooth disease type 1A participated in 8 weeks of supervised high-intensity power training. Results All participants improved strength of the right hip abductors (46.7–109.7%) and left hip abductors (27.3–128.6%), maximal gait speed (2.3–9.1%), static balance (0.7–4.9%), tandem walk (−3.3 to −58.5%), and mental component scores on the Short Form 36 Health Status Survey (0.8–27.6%). Adherence to high-intensity power training was 100% and only one minor adverse event related to the intervention was reported. Conclusions Although promising, larger controlled studies are indicated to confirm the safety and efficacy of high-intensity progressive resistance and power training in this cohort.

Objective This work aims to expand knowledge regarding the genetic spectrum of HSPB1‐related diseases. HSPB1 is a gene encoding heat shock protein 27, and mutations in HSPB1 have been identified as the cause of axonal Charcot–Marie–Tooth (CMT) disease type 2F and distal hereditary motor neuropathy (dHMN). Methods Two patients with axonal sensorimotor neuropathy underwent detailed clinical examinations, neurophysiological studies, and next‐generation sequencing with subsequent bioinformatic prioritization of genetic variants and in silico analysis of the likely causal mutation. Results The HSPB1 p.S135F and p.R136L mutations were identified in homozygosis in the two affected individuals. Both mutations affect the highly conserved alpha‐crystallin domain and have been previously described as the cause of severe CMT2F/dHMN, showing a strictly dominant inheritance pattern. Interpretation Thus, we report for the first time two cases of biallelic HSPB1 p.S135F and p.R136L mutations in two families.

Charcot-Marie-Tooth disease is a heterogenous group of genetic disorders, presenting the phenotype of a chronic progressive neuropathy affecting both the motor nerves, and thesensitive ones. The disease generally develops before the age of 20 years in the lower limbs. The evolution is chronic and progresses slowly. Charcot-Marie-Tooth disease is one of most commonly inherited neurological disorders, affecting about one in 2,500 people in the United States and 2,8 million people around the world. The present paper intends to be a contribution to improving kinetic treatment programme for Charcot-Marie-Tooth during adolescence. For the research purposes we have monitored an adolescent male patient who benefited from a customized kinetic treatment for six months. The analysis of our recorded data highlighted the progress made (increased joint mobility, improvement of dynamic balance, pain reduction, improvement of foot aesthetics, as well as increase of the quality of life).

Two patients with auditory neuropathy spectrum disorder (ANSD) considered to be associated with Charcot-Marie-Tooth (CMT) are reported. In case 1, a 23-year-old man presented with progressive bilateral sensorineural hearing loss (SNHL) from 10 years of age and was diagnosed with ANSD. He was later diagnosed with CMT by neurological testing. In case 2, a 16-year-old girl, the younger sister of the patient in case 1, presented with progressive SNHL with similar auditory findings since 6 years of age as those of her brother. Both cases underwent bilateral cochlear implantation. In case 1, the maximum discrimination score improved to 45% 24 months after the first side of cochlear implantation from 5% before the surgery. In case 2, the score was 5% 10 months after cochlear implant (CI) surgery from 0% before the surgery. CI treatment for CMT patients has been considered difficult because of both failure in synchronization of nerve conduction due to demyelination and axonal failure of the auditory nerve. Though slower progress compared to the average subset of patients receiving CI was seen, significant improvement was gradually observed in the present patients after bilateral cochlear implantations. CI is thus a viable option for rehabilitation of SNHL in CMT patients.

Fatigue is common in people with Charcot-Marie-Tooth (pwCMT) disease. However, no studies have characterized performance fatigability during gait in this population. Characterizing performance fatigability during gait, and assessing its relation to life satisfaction could improve understanding and treatment of mobility challenges in pwCMT.How do gait outcomes change with fatigue in pwCMT? Do these changes relate to life satisfaction?31 pwCMT completed a 6-minute, fast-as-possible walk while gait outcomes were captured via inertial sensors. Gait outcomes were separated into six sequential bins of equal size. The mean value, variability, and asymmetry (step time only) of outcomes were calculated for each bin. Perceived fatigue and general life satisfaction were assessed via questionnaire.Of the five mean gait outcomes measured, four showed statistically significant changes over the 6-minute fast-as-possible walk: velocity (reduced; p = 0.008); cadence (reduced; p 0.001), step time (increased; p 0.001), and trunk ROM (increased; p = 0.032). Of the four variability and one asymmetry outcomes, only stride length variability changed during the walking task (p = 0.015), decreasing from bins 1-2, and remaining stable for bins 2-6. Changes in velocity, cadence, step time were related to general life satisfaction (0.038 ps0.04), but not perceived fatigue (ps0.343).pwCMT exhibit statistically significant changes in mean gait outcomes, but not variability outcomes, across a 6-minute, fast-as-possible walking bout. Changes correlated to life satisfaction, suggesting performance fatigability during gait could be a target for rehabilitation for pwCMT. Perceived fatigue did not correlate to gait fatigue, underscoring the differentiation between perceived fatigue and performance fatigability.

International audience; Next-generation sequencing (NGS) allows the detection of mutations in inherited genetic diseases, like the Charcot-Marie-Tooth disease (CMT) which is the most common hereditary peripheral neuropathy. The majority of mutations detected by NGS are single nucleotide variants (SNVs) or small indels, while structural variants (SVs) are often underdiagnosed. PMP22 was the first gene described as being involved in CMT via a SV of duplication type. To date, more than 90 genes are known to be involved in CMT, with mainly SNVs and short indels described. Herein targeted NGS and the CovCopCan bioinformatic tool were used in two unrelated families, both presenting with typical CMT symptoms with pyramidal involvement. We have discovered two large SVs in KIF5A, a gene known to cause axonal forms of CMT (CMT2) in which no SVs have yet been described. In the first family, the patient presented with a large deletion of 12 kb in KIF5A from Chr12:57,956,278 to Chr12:57,968,335 including exons 2-15, that could lead to mutation c.(130-943_c.1717-533del), p.(Gly44_Leu572del). In the second family, two cases presented with a large deletion of 3 kb in KIF5A from Chr12:57,974,133 to Chr12:57,977,210 including exons 24-28, that could lead to mutation c.(2539-605_*36 + 211del), p.(Leu847_Ser1032delins33). In addition, bioinformatic sequence analysis revealed that a NAHR (Non-Allelic-Homologous-Recombination) mechanism, such as those in the PMP22 duplication, could be responsible for one of the KIF5A SVs and could potentially be present in a number of other patients. This study reveals that large KIF5A deletions can cause CMT2 and highlights the importance of analyzing not only the SNVs but also the SVs during diagnosis of neuropathies.

Charcot‐Marie‐Tooth disease (CMT) is one of the most common inherited neurodegenerative disorders with an increasing number of CMT‐associated variants identified as causative factors, however, there has been no effective therapy for CMT to date. Aminoacyl‐tRNA synthetases (aaRS) are essential enzymes in translation by charging amino acids onto their cognate tRNAs during protein synthesis. Dominant monoallelic variants of aaRSs have been largely implicated in CMT. Some aaRSs variants affect enzymatic activity, demonstrating a loss‐of‐function property. In contrast, loss of aminoacylation activity is neither necessary nor sufficient for some aaRSs variants to cause CMT. Instead, accumulating evidence from CMT patient samples, animal genetic studies or protein conformational analysis has pinpointed toxic gain‐of‐function of aaRSs variants in CMT, suggesting complicated mechanisms underlying the pathogenesis of CMT. In this review, we summarize the latest advances in studies on CMT‐linked aaRSs, with a particular focus on their functions. The current challenges, future direction and the promising candidates for potential treatment of CMT are also discussed., Variants of some aminoacyl‐tRNA synthetases (aaRS) are strongly associated with Charcot–Marie–Tooth disease (CMT), one of the most common inherited neuromuscular disorders. Some variants affect enzymatic activity, showing loss‐of‐function effects. In contrast, evidence from CMT patient samples, animal genetic studies or protein conformational analysis has confirmed toxic gain‐of‐function of some aaRSs variants in CMT outside of aminoacylation. In this review, we will discuss the latest advances in studies on CMT‐associated aaRSs, with a particular focus on the complicated mechanisms in the pathogenesis of CMT.

Biallelic mutations in the sorbitol dehydrogenase (SORD) encoding gene were recently identified as a common genetic cause in autosomal‐recessive CMT patients. Here, we investigated the clinical, genetic, and electrophysiological characteristics of three CMT patients with biallelic SORD mutations from a Chinese cohort. Two patients harbored c.757delG (p.A253Qfs*27) homozygous mutations, and one patient carried both c.757delG (p.A253Qfs*27) and c.625C>T (p.R209X) compound heterozygous mutations. Interestingly, the two patients homozygous for the c.757delG mutation exhibited positive responses for pinprick test. In conclusion, we confirmed SORD mutations as causative for CMT and further expanded the mutational and phenotypic spectrum of SORD‐related CMT.

Charcot Marie Tooth disease (CMT) is a progressive motor and sensory polyneuropathy, it is characterized by a very heterogeneous molecular basis and phenotype. MFN2 and GDAP1 participate in mitochondrial energy metabolism and the rare coinheritance of its pathogenic variants has been associated with a cumulative effect in the observed phenotype. We describe a patient with a severe axonal CMT and inherited heterozygous MFN2 (p.Leu741Val) and GDAP1 (p.Gln163*) variants. In accordance with a possible digenic inheritance, none of the heterozygous carriers in his family were symptomatic or exhibited electrophysiological abnormalities. We also review all of the previously reported patients with coinheritance of variants in these two genes; similar to our patient, all exhibit a predominantly axonal severe CMT phenotype. Our findings expand the genotypic spectrum of CMT and further support that digenic inheritance should be considered for analyzing and counseling CMT patients.

This scientific commentary refers to ‘Induced pluripotent stem cell-derived motor neurons of CMT type 2 patients reveal progressive mitochondrial dysfunction’, by Van Lent et al. (doi:10.1093/brain/awab226).

There are several examples of single mutations that lead to a well-defined disease through a well-known mechanism. In other cases, a collection of mutations of the same protein produces a pathology with different degrees of severity. The accompanying work by Uusitalo et al. studies several mutants of the fatty acid binding protein P2 of the peripheral nervous system myelin. They conserve the native tertiary structure but a remarkable difference in the capacity to interact with lipids. This could be a clue to unravel the complex way in which these mutations affect myelin structure and function in a variant of Charcot-Marie-Tooth disease. Comment on: https://doi.org/10.1111/febs.16079.

Aims/ Objectives: To study the importance of electrophysiological tests in diagnosing hereditary motor sensory neuropathy in absence of genetic studies. Study Design: Cross-sectional study. Place and Duration of Study: Department of Physiology, Pt. B.D. Sharma Post Graduate Institute of Medical Sciences, Rohtak, Haryana, India. Methodology: The patients were referred from the Department of Medicine to the Department of Physiology for nerve conduction, F-wave, EMG, VEP & BERA studies. Results: On electrophysiological examination, there was symmetrical decreased motor conduction velocity of median nerve (less than 38 m/sec), ulnar, tibial and peroneal nerves except in the first patient where the left peroneal nerve conduction velocity was not recordable with decreased amplitude and increased distal motor latencies. Sensory conduction velocities for bilateral median nerves were also decreased with increased latency and decreased amplitude in both the patients. Sensory conduction velocity and amplitudes of bilateral sural nerves were decreased in the first patient with increased latencies. However, sensory conduction velocity wasn’t recordable for bilateral sural nerves in the other patient. EMG shows decrease in recruitment of motor unit potentials, amplitude in bilateral tibial, peroneous, abductor digiti minimi & 1st dorsal interosseus muscle in the first patient. In proximal upper & lower limb muscles, EMG showed features of denervation. In the second patient, EMG was not advised. VEP in one patient had increased latency of P100 wave & other had normal VEP. Brainstem auditory evoked potential was normal in both patients. Conclusion: The paper highlights the importance of electrophysiological studies in diagnosis of motor sensory neuropathy in absence of genetic studies. Marked slowing of conduction velocity is the hallmark of CMDT1 [demylinating type].

Purpose of review This article provides an overview of Charcot-Marie-Tooth disease (CMT) and other inherited neuropathies. These disorders encompass a broad spectrum with variable motor, sensory, autonomic, and other organ system involvement. Considerable overlap exists, both phenotypically and genetically, among these separate categories, all eventually exhibiting axonal injury and neurologic impairment. Depending on the specific neural and non-neural localizations, patients experience varying morbidity and mortality. Neurologic evaluations, including neurophysiologic testing, can help diagnose and predict patient disabilities. Diagnosis is often complex, especially when genetic and acquired components overlap. Recent findings Next-generation sequencing has greatly improved genetic diagnosis, with many third-party reimbursement parties now embracing phenotype-based panel evaluations. Through the advent of comprehensive gene panels, symptoms previously labeled as idiopathic or atypical now have a better chance to receive a specific diagnosis. A definitive molecular diagnosis affords patients improved care and counsel. The new classification scheme for inherited neuropathies emphasizes the causal gene names. A specific genetic diagnosis is important as considerable advances are being made in gene-specific therapeutics. Emerging therapeutic approaches include small molecule chaperones, antisense oligonucleotides, RNA interference, and viral gene delivery therapies. New therapies for hereditary transthyretin amyloidosis and Fabry disease are discussed. Summary Comprehensive genetic testing through a next-generation sequencing approach is simplifying diagnostic algorithms and affords significantly improved decision-making processes in neuropathy care. Genetic diagnosis is essential for pathogenic understanding and for gene therapy development. Gene-targeted therapies have begun entering the clinic. Currently, for most inherited neuropathy categories, specific symptomatic management and family counseling remain the mainstays of therapy.

The purpose of this study is to assess how Charcot-Marie-Tooth disease, a group of inherited peripheral neuropathies that result in distal weakness, affects walking velocity over time in comparison to age-matched controls. Comprehensive gait analysis of 57 children (mean age 12.0, SD 3.7 years) compared to 76 age-matched controls (mean age 10.1, SD 3.4 years) demonstrated slower walking velocity (p0.001) due to both shorter stride length (p0.001) and diminished cadence (p=0.01). There was higher walking velocity (p0.001), stride length (p=0.002) and cadence (p0.001) in patients with dorsiflexor strength ≥3 and higher walking velocity (p=0.001) and cadence (p=0.03) in patients plantar flexor strength ≥4. Analysis of Charcot-Marie-Tooth type 1 and type 2 subgroups showed that walking velocity increased significantly with age in controls (p=0.001) but did not increase in children with either subtype (p0.54). Stride length increased significantly with age in all groups (p0.001) but at a slower rate in type 1 and 2 compared to controls. These differences contributed to increasing deficits in walking velocity and stride length with age in type 1 and 2 in comparison to controls, with deficits appearing earlier in type 2. Since the slower walking velocity in children with Charcot-Marie-Tooth disease is primarily due to short stride length, treatments that enable improved stride length, such as plantar flexor strengthening and bracing, may improve walking velocity and associated gait function.

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.

Background Ankle foot orthoses (AFOs) are commonly prescribed to individuals with Charcot-Marie-Tooth disease (CMT). The aim of this study was to evaluate patient reported satisfaction with orthotic devices and services in individuals with CMT to provide preliminary data for advancing AFO development and improving clinical care. Methods The Orthotics and Prosthetics Users Survey was distributed via e-mail through the Inherited Neuropathy Consortium (INC) Contact Registry and includes 11 device-specific questions and 10 service-related questions. Participants were also asked open-ended questions about their experiences with AFOs. Results Three hundred and fourteen individuals completed the survey. Over one-third of participants provided negative responses, including dislike of AFO appearance, discomfort, abrasions or irritations, and pain. Ratings of orthotic services were generally positive. Conclusions Lower scores related to discomfort, abrasions and pain identified areas for AFO improvement. Continued research in these areas will be beneficial to informing and advancing AFO development and improving clinical care.

Introduction. Charcot–Marie–Tooth disease type 4D is a hereditary demyelinating neuropathy, that occurs with the high frequency in patients of Roma origin. It is characterized by early onset at the age of 2–10 years and hearing impairment, manifested by the 3rd decade of life.Aim of the study. To describe the clinical and genetic characteristics of Charcot–Marie–Tooth disease type 4D in Russian patients of Roma origin.Materials and methods. For 14 probands from unrelated families of Roma origin with a clinical diagnosis of Charcot–Marie–Tooth disease, genetic tests for the pathogenic variants c. 442C>T in the NDRG1 gene and c. 3325C>T in the SH3TC2 gene was carried out. For 8 patients with Charcot–Marie–Tooth disease type 4D, detailed clinical and electrophysiological examination was performed.Results. In 11 families of Roma origin, the c. 442C>T pathogenic variant in the NDRG1 gene in a homozygous state was detected, which accounted for 79 % all observed Roma patients with Charcot–Marie–Tooth disease. There are 12 of the 14 tested families live in the European part of Russia, 7 of them are from nearby regions. The average age of onset was 3.3 years. The first symptom in 7 of 8 patients was gait disturbances. At the time of examination (age range 6–19 years), all patients showed marked hypotrophy and weakness of the feet, lower leg, hands muscles, feet deformities, reduction or loss of tendon reflexes.Discussion. Due to the detection of only one pathogenic variant in most Russian patients of Roma origin with Charcot–Marie–Tooth disease, the knowledge of the ethnicity of a proband with early myelinopathy can significantly simplify the confirmation of the diagnosis on the molecular level.

Background and purpose Systematic research on the effect of Charcot-Marie-Tooth (CMT) disease on the outcome of pregnancy and conversely the effect of pregnancy on neuropathy is still sparse. Methods A clinical cohort study and cross-sectional study within the German CMT-NET was conducted between 2016 and 2019. Inclusion criteria were a confirmed diagnosis of CMT and at least one completed pregnancy after 1990. All participants agreed to fill in questionnaires and have their medical files reviewed. Results The study group comprised 54 women with a total of 98 pregnancies. The mean age at onset of CMT disease was 12.6 years (range 0-37 years). Fifty (92%) patients had autosomal dominant CMT; two patients each (4%) had X-linked and autosomal recessive CMT. Forty patients (74%) had a PMP22 gene duplication (CMT1A). Obstetric complications did not differ significantly from a German reference population, neither in the whole group nor in the CMT1A group. Overall there was no increased newborn morbidity and mortality. About one-third of patients reported exacerbation of CMT disease in or after pregnancy. No adverse effects of anaesthesia were reported. Most participants stressed a positive attitude and awareness of challenges associated with pregnancy. Important issues were assistance and support in caring for the family. Discussion In line with findings from our previous study undertaken in the 1990s, there were no increased complication rates for pregnancy and delivery. These results are reassuring for the vast majority of CMT patients and are important for family planning and clinical care.

Background: Charcot-Marie-Tooth (CMT) disease is a hereditary motor-sensory neuropathy that is often associated with a cavovarus foot deformity. Limited evidence exists for the orthopedic management of these patients. Our goal was to develop consensus guidelines based upon the clinical experiences and practices of an expert group of foot and ankle surgeons. Methods: Thirteen experienced, board-certified orthopedic foot and ankle surgeons and a neurologist specializing in CMT disease convened at a 1-day meeting. The group discussed clinical and surgical considerations based upon existing literature and individual experience. After extensive debate, conclusion statements were deemed “consensus” if 85% of the group were in agreement and “unanimous” if 100% were in support. Conclusions: The group defined consensus terminology, agreed upon standardized templates for history and physical examination, and recommended a comprehensive approach to surgery. Early in the course of the disease, an orthopedic foot and ankle surgeon should be part of the care team. This consensus statement by a team of experienced orthopedic foot and ankle surgeons provides a comprehensive approach to the management of CMT cavovarus deformity. Level of Evidence: Level V, expert opinion.

Charcot Marie Tooth disease is a is a very chronic progressive hereditarymotor and sensory neuropathy characterized by progressive weakness andloss of touch sensation across various parts of the body. There are no curative or effective medical therapies that can ameliorate the disability associated with Charcot Marie Tooth disease. The aim of this paper is to describe the safe novel use of cerebrolysin in an Iraqi patient with Charcot Marie Tooth disease. Patients and Methods A boy who was born on the seventh of November, 2009, and was first seen on 29th of January, 2018 at the Children Teaching Hospital of Baghdad Medical City and had Charcot Marie Tooth disease was observed. He had difficulty in walking and abnormal gait that made him left first grade primary school. The nerve conduction study and electromyography study supported the clinical diagnosis of chronic symmetric sensori-motor polyneuropathy of moderated severity. The boy was treated with a safe novel therapy for one month. He receivedten doses of 3 ml intra-muscular cerebrolysin every three days. Results The short term effect of the therapy was dramatic with noticeable improvement that has never been reported before with this condition. Conclusion Further studies enrolling more patients are highly recommended.

ObjectiveTo investigate the effectiveness of targeted next-generation sequencing (NGS) panels in achieving a molecular diagnosis in Charcot-Marie-Tooth disease (CMT) and related disorders in a clinical setting.MethodsWe prospectively enrolled 220 patients from 2 tertiary referral centers, one in London, United Kingdom (n = 120), and one in Iowa (n = 100), in whom a targeted CMT NGS panel had been requested as a diagnostic test.PMP22duplication/deletion was previously excluded in demyelinating cases. We reviewed the genetic and clinical data upon completion of the diagnostic process.ResultsAfter targeted NGS sequencing, a definite molecular diagnosis, defined as a pathogenic or likely pathogenic variant, was reached in 30% of cases (n = 67). The diagnostic rate was similar in London (32%) and Iowa (29%). Variants of unknown significance were found in an additional 33% of cases. Mutations inGJB1,MFN2, andMPZaccounted for 39% of cases that received genetic confirmation, while the remainder of positive cases had mutations in diverse genes, includingSH3TC2,GDAP1,IGHMBP2,LRSAM1,FDG4, andGARS, and another 12 less common genes. Copy number changes inPMP22,MPZ,MFN2,SH3TC2, andFDG4were also accurately detected. A definite genetic diagnosis was more likely in cases with an early onset, a positive family history of neuropathy or consanguinity, and a demyelinating neuropathy.ConclusionsNGS panels are effective tools in the diagnosis of CMT, leading to genetic confirmation in one-third of cases negative forPMP22duplication/deletion, thus highlighting how rarer and previously undiagnosed subtypes represent a relevant part of the genetic landscape of CMT.

We found a p.Ala406Val (c.1217C > T) mutation in MORC2 in three individuals, from two families. All three individuals were evaluated and clinical electrophysiology was completed. The neuropathy began in childhood to early adulthood, with distal weakness progressing to proximal weakness. Vinblastine (for Hodgkin lymphoma) acutely worsened the weakness in one patient. This finding confirms that that the p.Ala406Val mutation in MORC2 causes severe neuropathy. In addition, we report the first case of vinblastine neurotoxicity in Charcot-Marie-Tooth disease type 2Z.

Background and ObjectivesThis study examined the association between body mass index (BMI) and disability in children with Charcot-Marie-Tooth disease (CMT).MethodsWe conducted a cross-sectional analysis of 477 patients with CMT who were 3 to 20 years of age from the Inherited Neuropathy Consortium and 316 age- and sex-matched healthy children from the 1,000 Norms Project. BMI was categorized according to the International Obesity Task Force (IOTF) criteria, and BMI categorization was compared with healthy children. IOTF categories (adult equivalent BMI cut points) were severely underweight (BMI 2), underweight (BMI ≥17–2), healthy weight (BMI ≥18.5–2), overweight (BMI ≥25–2), and obese (BMI ≥30 kg/m2). Scores on the 0 to 44–point CMT Pediatric Scale (CMTPedS), a well-validated measure of disability, were examined in relation to BMI.ResultsThere was a higher proportion of children with CMT categorized as severely underweight (5.7% vs 0.3%), underweight (10.3% vs 5.1%), and obese (7.3% vs 3.8%) (p< 0.05). Fewer children with CMT were categorized as healthy weight (61.8% vs 74.4%) (p< 0.05), and the proportion of overweight (14.9% vs 16.5%) between groups was similar. CMTPedS scores (mean ± SD) for weight categories were as follows: severely underweight 27 ± 9, underweight 20 ± 8, healthy weight 17 ± 9, overweight 17 ± 9, and obese 22 ± 10. Compared to children with a healthy weight with CMT, being severely underweight was associated with being more disabled (p< 0.001), as was being obese (p= 0.015).DiscussionThe proportion of children with CMT who are underweight or obese is higher compared to age- and sex-matched healthy children. In children with CMT, being underweight or obese is associated with greater disability, when compared to children with CMT of healthy weight.