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Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is a rare autosomal recessive condition characterised by early-onset severe progressive neuropathy, variable degrees of ACC and cognitive impairment. Mutations in

Background: The cavovarus deformity of Charcot-Marie-Tooth (CMT) disease is often characterized by a paradoxical relationship of hindfoot varus and forefoot valgus. The configuration of the midfoot, which links these deformities, is poorly understood. Accurate assessment of 3-dimensional alignment under physiologic loadbearing conditions is possible using weightbearing computed tomography (WBCT). This is the first study to examine the rotational deformity in the midfoot of CMT patients and, thus, provide key insights to successful correction of CMT cavovarus foot. Methods: A total of 27 WBCT scans from 21 CMT patients were compared to control WBCTs from 20 healthy unmatched adults. CMT patients with a history of bony surgery, severe degenerative joint disease, or open physes in the foot were excluded. Scans were analyzed using 3-dimensional software. Anatomic alignment of the tarsal bones was calculated relative to the anterior-posterior axis of the tibial plafond in the axial plane, and weightbearing surface in the coronal plane. Results: Maximal rotational deformity in CMT patients occurred at the transverse tarsal joints, averaging 61 degrees of external rotation (supination), compared to 34 degrees among controls ( P < .01). The talonavicular joint was also the site of peak adduction deformity in the midfoot, with an average talonavicular coverage angle measuring 12 degrees compared with −11 degrees in controls ( P < .01). Conclusion: This 3-dimensional WBCT analysis is the first to isolate and quantify the multiplanar rotational deformity in the midfoot of CMT patients. Compared with healthy unmatched control cases, CMT patients demonstrated increased axial plane adduction and coronal plane rotation at the talonavicular (TN) joint. These findings support performing soft tissue release at the TN joint to abduct and derotate the midfoot as a first step for targeted deformity correction. Level of Evidence: Level III, retrospective case-control study.

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.

Background Charcot–Marie–Tooth disease type 4F (CMT4F) is an autosomal recessive disorder with symptoms presenting in early adulthood. This clinical case series demonstrates atypical findings in cervical and ocular vestibular evoked myogenic potentials (VEMP) in siblings with CMT4F. Purpose The aim of this study was to highlight the audiovestibular test findings in CMT4F. Research Design Case series study sample: 4 siblings, 3 of whom diagnosed with CMT4F. Data Collection and Analysis Audiological test battery and electrophysiological tests comprising auditory brainstem response (ABR) and VEMP (both cervical and ocular) were performed in our patient population. Results Older siblings, in whom the hearing loss was present, manifested prolonged peak V latencies in ABR. Three out of four siblings with CMT4F showed prolongation of latencies on cervical and ocular VEMP. Conclusions In many neurodegenerative conditions, prolongation of ABR peak latencies has often been reported in the literature. There have also been a few reports of prolonged VEMP peak latencies. This article reports prolongation of only VEMP peak latencies (in both cervical and ocular recordings). The youngest sibling had prolongation of VEMP latencies, with ABR peak latencies being normal. The assumption we put forth that CMT4F may affect the vestibular pathway first requires to be tested on a larger sample and by longitudinally studying the individuals with disease condition.

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous group of peripheral neuropathies most of which are associated with mutations in four genes including peripheral myelin protein-22 (

Charcot-Marie-Tooth disease (CMT) is a highly heterogeneous genetic disorder. To date, more than 90 genes have been implicated in the pathogenesis of CMT. Here, we report the identification of a rare causative mutation in a Chinese family with CMT and a pregnant patient underwent prenatal diagnosis.A 33-year-old woman with 21 + 6 weeks of pregnancy presented with progressive weakness of distal extremities after 23 years of age. A total of 8 individuals in 4 generations of her family had similar muscle weakness. On proband whole-exome sequencing (WES), a rare c.121G A variant in the GJB1 gene was identified.Based on the clinical and genetic findings, this patient was finally diagnosed with CMT.The prenatal diagnosis was performed on the proband fetus.The fetus did not carry this rare variant, and the pregnancy continued.Our findings provide the first clinical evidence for the causative role of GJB1 c.121G A variant in CMT. WES is a valuable method for diagnosing patients with CMT.

Background Single-center clinical series provide important information on genetic distribution that can guide genetic testing. However, there are few such studies on pediatric populations with inherited peripheral neuropathies (IPNs). Methods Thorough genetic testing was performed on IPN patients under 20 years of age from a geographically well-defined Mediterranean area (Valencian Community, Spain), annually assessed with the Charcot-Marie-Tooth disease Pediatric Scale (CMTPedS). Results From 86 families with IPNs, 99 patients (59 males) were identified, 85 with sensorimotor neuropathy or CMT (2/3 demyelinating form) and 14 with distal hereditary motor neuropathy (dHMN). Genetic diagnosis was achieved in 79.5% families, with a similar mutation detection rate in the demyelinating (88.7%) and axonal (89.5%) forms, significantly higher than in the dHMN families (27.3%). CMT1A was the most common subtype, followed by those carrying heterozygous mutations in either the GDAP1 or GJB1 genes. Mutations in 15 other genes were identified, including a new pathogenic variant in the ATP1A gene. The CMTPedS detected significant disease progression in all genetic subtypes of CMT, at a rate of 1.84 (+/- 3.7) over 1 year (p < 0.0005, n = 62) and a 2-year rate of 3.6 (+/- 4.4: p < 0.0005, n = 45). Significant disease worsening was also detected for CMT1A over 1 (1.7 +/- 3.6, p < 0.05) and 2 years (4.2 +/- 4.3, p < 0.0005). Conclusions This study highlights the unique spectrum of IPN gene frequencies among pediatric patients in this specific geographic region, identifying the CMTPedS as a sensitive tool to detect significant disease worsening over 1 year that could help optimize the design of clinical trials.

ObjectiveTo determine whether microRNAs (miRs) are elevated in the plasma of individuals with the inherited peripheral neuropathy Charcot-Marie-Tooth disease type 1A (CMT1A), miR profiling was employed to compare control and CMT1A plasma.MethodsWe performed a screen of CMT1A and control plasma samples to identify miRs that are elevated in CMT1A using next-generation sequencing, followed by validation of selected miRs by quantitative PCR, and correlation with protein biomarkers and clinical data: Rasch-modified CMT Examination and Neuropathy Scores, ulnar compound muscle action potentials, and motor nerve conduction velocities.ResultsAfter an initial pilot screen, a broader screen confirmed elevated levels of several muscle-associated miRNAs (miR1, -133a, -133b, and -206, known as myomiRs) along with a set of miRs that are highly expressed in Schwann cells of peripheral nerve. Comparison to other candidate biomarkers for CMT1A (e.g., neurofilament light) measured on the same sample set shows a comparable elevation of several miRs (e.g., miR133a, -206, -223) and ability to discriminate cases from controls. Neurofilament light levels were most highly correlated with miR133a. In addition, the putative Schwann cell miRs (e.g., miR223, -199a, -328, -409, -431) correlate with the recently described transmembrane protease serine 5 (TMPRSS5) protein biomarker that is most highly expressed in Schwann cells and also elevated in CMT1A plasma.ConclusionsThese studies identify a set of miRs that are candidate biomarkers for clinical trials in CMT1A. Some of the miRs may reflect Schwann cell processes that underlie the pathogenesis of the disease.Classification of EvidenceThis study provides Class III evidence that a set of plasma miRs are elevated in patients with CMT1A.

We aimed to establish the cross-sectional area (CSA) reference values for peripheral nerves of lower extremities in a healthy Chinese population, and to determine their diagnostic values for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Charcot-Marie-Tooth disease type1A (CMT1A). One hundred eleven healthy subjects, 15–70 years of age, as well as 104 CIDP patients and 26 CMT1A patients were recruited. CSA at predetermined sites of the tibial, fibular, sciatic and sural nerves was measured. The CSA of the tibial nerve ranged from 10.2 ± 1.9 to 20.7 ± 3.6 mm2, and for fibular nerve from 8.4 ± 1.8 to 9.5 ± 1.9 mm2. 86% CIDP patients had upper limb nerve enlargement, while only 67% had lower limb nerve enlargement. In CIDP patients with normal upper limb ultrasound, 56% (5/9) would have lower limb nerve enlargement. All CMT1A patients had both upper and lower limb nerve enlargement. Addition of lower limb nerve ultrasound showed no added value in diagnosis of CMT1A, but could be supplementary for CIDP when upper limb ultrasound is normal.

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.

Objective To study the pathophysiology of Charcot-Marie-Tooth disease (CMT) with auditory neuropathy (AN) and to follow up cochlear implant or hearing aid use over the long term. Study design Clinical capsule report. Patients Two adult CMT patients with AN. Intervention Cochlear implantation for case 1 and hearing aid use for case 2. Result Case 1 was a 50-year-old man who was diagnosed as having CMT at 15 years of age. He noted his hearing impairment at the age of 22. We considered that he had AN as a complication on the basis of the findings of normal distortion product otoacoustic emission and the absence of auditory brainstem response on both ears. We performed cochlear implantation for his progressive hearing loss when he was 41 years old. His postoperative discrimination scores for words and sentences in the CI-2004 test 4 years after cochlear implantation were 80% and 93%, respectively. His sound discrimination scores were 23/24 in the test with picture matching and 9/24 in that without picture matching 8 years after cochlear implantation.Case 2 was a 38-year-old woman who was neurologically diagnosed as having CMT with AN as a complication on the basis of auditory brainstem response and distortion product otoacoustic emission test findings. During 15 years of follow-up, her discrimination score decreased gradually. She is currently wearing a hearing aid. Conclusions We found a significant improvement in case 1 and a slight increase in hearing level in case 2. The pathoneurological findings of CMT might be either demyelination or axonal degeneration depending on the type of genetic abnormality (e.g., PMP22 and MPZ mutations). The symptoms and courses vary among patients with CMT. Therefore, the selection of an appropriate intervention for hearing loss depending on the severity and course is very important.

More than 80 genes are known to be associated with Charcot-Marie-Tooth disease (CMT). Mutations of LRSAM1 were identified as a rare cause and define the subgroup of axonal neuropathy CMT2P. We identified additional 14 patients out of 12 families. Clinical and electrophysiological data confirm a late-onset axonal neuropathy with a predominance of sensorimotor impairment. The patients harbored ten different variants in LRSAM1, seven of which were novel. Due to variable inheritance patterns and clustering of pathogenic variants in 3´-prime exons, interpretation of genetic variants in LRSAM1 is challenging. The majority follows dominant inheritance, whereas recessive inheritance has been described for one variant. Variants at the 3`end may or may not escape from nonsense-mediated decay, thereby defining the pattern of inheritance. Our data emphasize the importance of the C-terminal RING domain, which exerts a dominant-negative effect on protein function, whenever affected by an altered or truncated protein. In conclusion, CMT2P is a rare, but nevertheless relevant cause of adult-onset axonal and painful neuropathy. ACMG (American College of Medical Genetics and genomics) criteria should be carefully applied in variant interpretation, with special attention to premature termination codon-introducing variants and their location within the gene.

Charcot-Marie-Tooth disease (CMT) represents a phenotypically and genetically heterogeneous disorder of the peripheral nervous system. Biallelic variants in SLC12A6 have been reported as the cause of autosomal-recessive (AR) hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC). Here we identified an autosomal-dominant (AD) heterozygous mutation in SLC12A6 in a Chinese patient with intermediate CMT. The patient presented with slowly progressive distal muscle weakness and atrophy. Electrophysiological examination showed a mixed axonal/demyelinating neuropathy. Cognition and brain MRI were normal. A single heterozygous missense mutation c.620G>A (p.R207H) in exon 5 of SLC12A6 was identified as the likely pathogenic mutation by whole-exome sequencing consistent with two previously published cases. It affects evolutionarily highly conserved amino acid residue and is predicted to be deleterious by using in silico tools. Modelling of the mutant KCC3 cotransporter showed altered formation of hydrogen bonds and weakened interaction force between the mutated site and its surrounding amino acid residues. Our findings expand the genotypic and phenotypic spectrum associated with SLC12A6 mutations from AR-HMSN/ACC to AD-CMT. The differences in the inheritance pattern might be associated with a dominant-negative pathomechanism.

Previous studies showed that being unemployed is associated with lower quality of life in patients with Charcot-Marie-Tooth type 1A (CMT1A). The aim of this study was to assess the differences between CMT1A patients capable of working and CMT1A patients incapable of working due to CMT1A. Forty-four patients with genetically confirmed CMT1A were included. Medical Research Council (MRC) Sum Score, Charcot-Marie-Tooth Neuropathy Score (CMTNS), CMT Examination Score (CMTES), Overall Neuropathy Limitations Scale (ONLS), Beck Depression Inventory (BDI), Krupp’s Fatigue Severity Scale (FSS), and Falls Efficacy Score (FES) were used. Whole cohort was divided into two groups: 1. CMT1A patients capable of working (employed and unemployed not due to CMT) and 2. CMT1A patients incapable of working due to CMT1A (unemployed due to CMT and retired due to CMT). At time of testing, 38.6% patients were employed, 13.6% were unemployed due to CMT, 6.8% were unemployed but not due to CMT, and 40.9% were retired early due to disability caused by CMT. Patients retired due to CMT1A at the age of 43 ± 10 years. ONLS total score and physical work appeared as significant independent predictors of being incapable of working due to CMT1A. Patients incapable of working were almost four times more likely to have fatigue (OR = 3.7, 95% CI 1.0–13.1, p

We describe the clinical, electrodiagnostic, and genetic findings of three homozygous FIG4‐c.122T>C patients suffering from Charcot‐Marie‐Tooth disease type 4J (AR‐CMT‐FIG4). This syndrome usually involves compound heterozygosity associating FIG4‐c.122T>C, a hypomorphic allele coding an unstable FIG4‐p.Ile41Thr protein, and a null allele. While the compound heterozygous patients presenting with early onset usually show rapid progression, the homozygous patients described here show the signs of relative clinical stability. As FIG4 activity is known to be dose dependent, these patients’ observations could suggest that the therapeutic perspective of increasing levels of the protein to improve the phenotype of AR‐CMT‐FIG4‐patients might be efficient.

Recessive mutations in SLC12A6 have been linked to hereditary motor sensory neuropathy with agenesis of the corpus callosum. Patients with early-onset peripheral neuropathy associated with SLC12A6 heterozygous variants were reported in 2016. Only five families and three variants have been reported to date, and the spectrum is unclear. Here, we aim to describe the clinical and mutation spectra of SLC12A6-related Charcot-Marie-Tooth (CMT) disease in Japanese patients.We extracted SLC12A6 variants from our DNA microarray and targeted resequencing data obtained from 2598 patients with clinically suspected CMT who were referred to our genetic laboratory by neurological or neuropediatric departments across Japan. And we summarized the clinical and genetic features of these patients.In seven unrelated families, we identified one previously reported and three novel likely pathogenic SLC12A6 heterozygous variants, as well as two variants of uncertain significance. The mean age of onset for these patients was 17.5 ± 16.1 years. Regarding electrophysiology, the median motor nerve conduction velocity was 39.6 ± 9.5 m/sec. For the first time, we observed intellectual disability in three patients. One patient developed epilepsy, and her brain MRI revealed frontal and temporal lobe atrophy without changes in white matter and corpus callosum.Screening for the SLC12A6 gene should be considered in patients with CMT, particularly those with central nervous system lesions, such as cognitive impairment and epilepsy, regardless of the CMT subtype.

Dejerine-Sottas syndrome (DSS) is the earlier onset, more severe form of Charcot-Marie-Tooth (CMT) disease with heterogenous neurologic manifestations in addition to the peripheral neuropathy depending not only on the underlying causative gene but also the specific mutation. The Trembler mutation is an uncommon missense mutation in the PMP22 gene, the most commonly mutated gene responsible for CMT. We report two cases of DSS in a mother and son with the Trembler mutation, with associated findings of hearing loss and cognitive impairment. The mother had developmental gait abnormalities and became wheelchair bound in adolescence. She displayed impairment on cognitive and audiologic testing. Her son had similar developmental gait abnormalities and became wheelchair bound at age 19. Cognitive function showed an earlier decline in the son as compared to his mother. This report extends the clinical spectrum of the Trembler mutation in humans to include associated hearing loss with cognitive impairment.

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.

Objective To identify and characterize the pathogenicity of novel variants in Chinese patients with Charcot–Marie–Tooth disease. Methods Multiplex ligation‐dependent probe amplification (MLPA) and whole‐exome sequencing (WES) were performed in 30 unrelated CMT patients. Minigene assay was used to verify the effect of a novel splicing variant (c.694+1G>A) on pre‐mRNA. Primary fibroblast cell lines were established from skin biopsies to characterize the biological effects of the novel variants p.L26R and p.S169fs. The mitochondrial structure was observed by an electron microscope. The expression level of protein was analyzed by Western Blotting. Mitochondrial dynamics and mitochondrial membrane potential (MMP, Δψm) were analyzed via immunofluorescence study. Mitochondrial ATP levels were analyzed via bioluminescence assay. The rate of oxygen consumption was measured with a Seahorse Bioscience XF‐96 extracellular flux analyzer. Results We identified 10 pathogenic variants in three known CMT related genes, including three novel variants (p.L26R, p.S169fs, c.694+1G>A) and one known pathogenic variant (p.R120W) in GDAP1. Further, we described the clinical features of patients carrying pathogenic variants in GDAP1 and found that almost all Chinese CMT patients with GDAP1 variants present axonal type. The effect of c.694+1G>A on pre‐mRNA was verified via minigene splice assay. Cellular biological effects showed ultrastructure damage of mitochondrial, reduced protein levels, different patterns of mitochondrial dynamics, decreased mitochondrial membrane potential (Δψm), ATP content, and defects in respiratory capacity in the patient carrying p.L26R and p.S169fs in GDAP1. Interpretation Our results broaden the genetic spectrum of GDAP1 and provided functional evidence for mitochondrial pathways in the pathogenesis of GDAP1 variants.

We aimed to reveal the genetic features associated with MPZ variants in Japan. From April 2007 to August 2017, 64 patients with 23 reported MPZ variants and 21 patients with 17 novel MPZ variants were investigated retrospectively. Variation in MPZ variants and the pathogenicity of novel variants was examined according to the American College of Medical Genetics standards and guidelines. Age of onset, cranial nerve involvement, serum creatine kinase (CK), and cerebrospinal fluid (CSF) protein were also analyzed. We identified 64 CMT patients with reported MPZ variants. The common variants observed in Japan were different from those observed in other countries. We identified 11 novel pathogenic variants from 13 patients. Six novel MPZ variants in eight patients were classified as likely benign or uncertain significance. Cranial nerve involvement was confirmed in 20 patients. Of 30 patients in whom serum CK levels were evaluated, eight had elevated levels. Most of the patients had age of onset >20 years. In another subset of 30 patients, 18 had elevated CSF protein levels; four of these patients had spinal diseases and two had enlarged nerve root or cauda equina. Our results suggest genetic diversity across patients with MPZ variants., Genetic spectrum of MPZ variants was confirmed in this study.

OBJECTIVE: ITPR3, encoding inositol 1,4,5-trisphosphate receptor type 3, was previously reported as a potential candidate disease gene for Charcot-Marie-Tooth neuropathy. Here, we present genetic and functional evidence that ITPR3 is a Charcot-Marie-Tooth disease gene. METHODS: Whole-exome sequencing of four affected individuals in an autosomal dominant family and one individual who was the only affected individual in his family was used to identify disease-causing variants. Skin fibroblasts from two individuals of the autosomal dominant family were analyzed functionally by western blotting, quantitative reverse transcription PCR, and Ca2+ imaging. RESULTS: Affected individuals in the autosomal dominant family had onset of symmetrical neuropathy with demyelinating and secondary axonal features at around age 30, showing signs of gradual progression with severe distal leg weakness and hand involvement in the proband at age 64. Exome sequencing identified a heterozygous ITPR3 p.Val615Met variant segregating with the disease. The individual who was the only affected in his family had disease onset at age 4 with demyelinating neuropathy. His condition was progressive, leading to severe muscle atrophy below knees and atrophy of proximal leg and hand muscles by age 16. Trio exome sequencing identified a de novo ITPR3 variant p.Arg2524Cys. Altered Ca2+ -transients in p.Val615Met patient fibroblasts suggested that the variant has a dominant-negative effect on inositol 1,4,5-trisphosphate receptor type 3 function. INTERPRETATION: Together with two previously identified variants, our report adds further evidence that ITPR3 is a disease-causing gene for CMT and indicates altered Ca2+ homeostasis in disease pathogenesis. ispartof: ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY vol:7 issue:10 pages:1962-1972 ispartof: location:United States status: published

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.

Objective The myelin impairment in demyelinating Charcot-Marie-Tooth (CMT) disease leads to various degrees of axonal degeneration, the ultimate cause of disability. We aimed to assess the pathophysiological changes in axonal function related to the neuropathy severity in hypo-/demyelinating CMT patients associated with myelin protein zero gene (MPZ) deficiency. Methods We investigated four family members (two parents and two sons) harboring a frameshift mutation (c.306delA, p.Asp104ThrfsTer14) in the MPZ gene, predicted to result in a nonfunctional P0, by conventional conduction studies and multiple measures of motor axon excitability. In addition to the conventional excitability studies of the median nerve at the wrist, we tested the spinal accessory nerves. Control measures were obtained from 14 healthy volunteers. Results The heterozygous parents (aged 56 and 63) had a mild CMT1B whereas their two homozygous sons (aged 31 and 39 years) had a severe Dejerine-Sottas disease phenotype. The spinal accessory nerve excitability could be measured in all patients. The sons showed reduced deviations during depolarizing threshold electrotonus and other depolarizing features which were not apparent in the accessory and median nerve studies of the parents. Mathematical modeling indicated impairment in voltage-gated sodium channels. This interpretation was supported by comparative modeling of excitability measurements in MPZ deficient mice. Conclusion Our data suggest that axonal depolarization in the context of abnormal voltage-gated sodium channels precedes axonal degeneration in severely hypo-/demyelinating CMT as previously reported in the mouse models. Significance Measures of the accessory nerve excitability could provide pathophysiological markers of neurotoxicity in severe demyelinating neuropathies.

Diseases related to peripheral myelin protein 22 (PMP22) have been implicated to involve the central nervous system (CNS). This study aimed to detect central nerve impairment using somatosensory evoked potentials (SSEPs) in patients with Charcot-Marie-Tooth disease (CMT) 1A. A total of 30 CMT1A patients and 26 healthy volunteers were included. Baseline characteristics, brain MRI and segmental SSEPs were collected from the participants. The peak latencies of N9, N13 and N20 were recorded, and central conduction velocity (CCT) was calculated and compared between groups. Significant differences were found in the peak latencies and amplitudes of N9, N13 and N20 between the two groups. CCT was significantly prolonged in the CMT group (7.05 ± 2.09 ms) compared to the control group (5.40 ± 1.79 ms) (p = 0.003). Six of 30 CMT patients had abnormal MRI signals, but no correlation with CCT was found. The central somatosensory pathway that carries SSEPs was impaired in CMT1A patients, which implies an important underlying role of PMP22 in the CNS.

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.

Background: Inherited peripheral neuropathies (IPNs) are a group of neuropathies affecting peripheral motor and sensory neurons. Charcot-Marie-Tooth (CMT) disease is the most common disease in this group. With recent advances in next-generation sequencing (NGS) technologies, more than 100 genes have been implicated for different types of CMT and other clinically and genetically inherited neuropathies. There are also a number of genes where neuropathy is a major feature of the disease such as spinocerebellar ataxia (SCA) and hereditary spastic paraplegia (HSP). We aimed to determine the genetic causes underlying IPNs in Iranian families. Methods: We performed whole exome sequencing (WES) for 58 PMP22 deletion-/duplication-negative unrelated Iranian patients with a spectrum of phenotypes and with a preliminary diagnosis of hereditary neuropathies. Results: Twenty-seven (46.6%) of the cases were genetically diagnosed with pathogenic or likely pathogenic variants. In this study, we identified genetically strong variants within genes not previously linked to any established disease phenotype in five (8.6%) patients. Conclusion: Our results highlight the advantage of using WES for genetic diagnosis in highly heterogeneous diseases such as IPNs. Moreover, functional analysis is required for novel and uncertain variants.

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.

Objective To identify the genetic cause of complex neuropathy in two siblings from a consanguineous family. Methods The patients were recruited from our clinic. Muscle biopsy and whole-exome sequencing (WES) were performed. Fibroblasts cell lines from the index patient, unaffected parents, and three normal controls were used for cDNA analysis and western blot. Results The index patient was a 29-year-old male with clinical phenotype of syndactyly, pes cavus, swallowing difficulties, vision problem, imbalance, and muscle weakness. The sibling had similar, but milder symptoms. Nerve conduction studies and electromyography of both patients suggested sensory-motor axonal neuropathy. Muscle biopsy showed a feature of necklace fibres. WES identified a novel homozygous frameshift deletion (c.5477-5478del; p.1826-1826del) in exon 40 of the SBF1 gene in the two siblings, while both parents and the unaffected sibling were heterozygous carriers. Functional analysis showed a markedly reduced level of MTMR5 protein encoded by SBF1 in the index case. The levels of MTMR5 protein in unaffected parents were similar to those found in controls. Conclusion A novel homozygous frameshift deletion in SBF1 was identified in this family. Sensory-motor axonal neuropathy and necklace fibres in biopsy were the major features expanding the phenotypic spectrum of SBF1-related recessive syndromic neuropathy.

Aims Infected and deformed neuropathic feet and ankles are serious challenges for surgical management. In this study we present our experience in performing ankle arthrodesis in a closed manner, without surgical preparation of the joint surfaces by cartilaginous debridement, but instead using an Ilizarov ring fixator (IRF) for deformity correction and facilitating fusion, in arthritic neuropathic ankles with associated osteomyelitis. Methods We retrospectively reviewed all the patients who underwent closed ankle arthrodesis (CAA) in Ilizarov Scientific Centre from 2013 to 2018 (Group A) and compared them with a similar group of patients (Group B) who underwent open ankle arthrodesis (OAA). We then divided the neuropathic patients into three arthritic subgroups: Charcot joint, Charcot-Maire-Tooth disease, and post-traumatic arthritis. All arthrodeses were performed by using an Ilizarov ring fixator. All patients were followed up clinically and radiologically for a minimum of 12 months to assess union and function. Results The union rate for Group A was 81% (17/21) while it was 84.6% (33/39) for Group B. All the nonunions in Group A underwent revision with an open technique and achieved 100% union. Mean duration of IRF was 71.5 days (59 to 82) in Group A and 69 days (64.8 to 77.7) in Group B. The American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot score was similar in both groups. The postoperative hospital stay was shorter in Group A (21 days (SD 8)) than Group B (28 days (SD 9)). In the latter Group there were more problems with wound healing and greater requirement for antibiotic treatment. The mean operating time was 40 minutes (SD 9) in Group A compared to 80 minutes (SD 13) in Group B. Recurrence of infection occurred in 19% (4/21) and 15.5% (6/39) for Group A and Group B respectively. Conclusion We found CAA using an IRF to be an effective method for ankle arthrodesis in infected neuropathic foot and ankle cases and afforded comparable results to open methods. Due to its great advantages, Ilizarov method of CAA should always be considered for neuropathic ankles in suitable patients. Cite this article: Bone Joint J 2020;102-B(4):470–477.

Heterozygous mutations in the Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene have been reported with different clinical phenotypes including Silver syndrome (SS)/spastic paraplegia 17 (SPG17), distal hereditary motor neuropathy type V (dHMN-V), and Charcot-Marie-Tooth (CMT) disease type 2. We screened 407 Japanese patients who were clinically suspected of having CMT by exome sequencing and searched mutations in BSCL2. As a result, we identified five patients with heterozygous mutations in BSCL2. We confirmed three cases of known mutations (p.N88S and p.S90L) and two cases of novel mutations (p.N88T and p.S141A). The clinical features of the cases with known mutations in Japan were similar to those previously reported in other countries. In particular, there were many cases with sensory disturbance. The case with p.N88T mutation showed severe phenotype such as early onset age and prominent vocal cord paresis. The case with p.S141A mutation showed characteristics of demyelinating neuropathy such as CMT disease type 1 by electrophysiological examination. In this article, we report the clinical features and spread of cases with BSCL2 mutation in a Japanese cohort.

BackgroundCharcot-Marie-Tooth disease (CMT) is one of the most commonly inherited neurological disorders. A growing number of genes, involved in glial and neuronal functions, have been associated with different subtypes of CMT leading to improved diagnostics and understanding of pathophysiological mechanisms. However, some patients and families remain genetically unsolved.MethodsWe report on a German family including four affected members over three generations with a CMT phenotype accompanied by cognitive deficits, predominantly with regard to visual abilities and episodic memory.ResultsA comprehensive clinical characterization followed by a sequential diagnostic approach disclosed a heterozygous rare SEPT9 missense variant c.1406 T > C, p.(Val469Ala), that segregates with disease. SEPT9 has been linked to various intracellular functions, such as cytokinesis and membrane trafficking. Interestingly, SEPT9-mutations are known to cause hereditary neuralgic amyotrophy (HNA), a recurrent focal peripheral neuropathy.ConclusionWe, for the first time, present a SEPT9 variant associated to a CMT phenotype and suggest SEPT9 as new sufficient candidate gene in CMT.

The Charcot-Marie-Tooth Pediatric Scale (CMTPedS) is a validated and change-sensitive tool for assessing the severity of neuropathy in children and adolescents between 3 and 20 years of age. The aim of this article is to translate and validate a Spanish version of the CMTPedS in order to disseminate its use in Spanish-speaking countries.The process used to translate the CMTPedS into Spanish was the reverse parallel translation method based on the principles of good practice for translation and the cultural adaptation process of the Food and Drug Administration Guidelines. A direct translation of the original source of the CMTPedS into Spanish was performed first and reviewed by experts in Charcot-Marie-Tooth (CMT) disease trained in the use of the CMTPedS tool. The Spanish version was then translated back into English by a linguist specialised in translation.The preliminary Spanish version of the CMTPedS was evaluated in 18 children with CMT aged 6-20 years (mean: 13.27). The scale was well tolerated and easy for children to understand and easy for clinicians to apply. None of the patients had any difficulty completing the scale.The Spanish version of the CMTPedS can be used for monitoring and conducting clinical trials in the Spanish population and in Spanish-speaking countries.Validación de la versión española de la Charcot-Marie-Tooth Disease Pediatric Scale (CMTPedS).Introducción y objetivos. La Charcot-Marie-Tooth Pediatric Scale (CMTPedS) es una herramienta validada y sensible al cambio para evaluar la gravedad de la neuropatía en niños y adolescentes entre 3 y 20 años. El objetivo de este artículo es traducir y validar una versión española de la CMTPedS para difundir su utilización en países de habla hispana. Material y métodos. El proceso para la traducción al español de la CMTPedS ha sido el método de traducción paralela invertida basado en los principios de buena práctica para la traducción y el proceso de adaptación cultural de las Food and Drug Administration Guidelines. Se realizó primero una traducción directa de la fuente original de la CMTPedS al español que fue revisada por expertos en la enfermedad de Charcot-Marie-Tooth (CMT) formados en la utilización de la herramienta CMTPedS. La versión española fue traducida de nuevo al inglés por un lingüista especialista de la traducción. Resultados. La versión preliminar en español de la CMTPedS se evaluó en 18 niños con CMT entre 6 y 20 años (media: 13,27). La escala fue bien tolerada y fácil de comprender en los niños y fácil de aplicar para los clínicos. Ningún paciente tuvo dificultad en completar la escala. Conclusiones. La versión española de la CMTPedS se puede utilizar para el seguimiento y la realización de ensayos clínicos en población española y países de habla hispana.

Background and objectivesCharcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy and often presents during childhood. Guidelines for the optimal management of common problems experienced by individuals with CMT do not exist, for either children or adults. We formed the Paediatric CMT Best Practice Guidelines Consortium to develop evidence and consensus-based recommendations for the clinical management of children and adolescents with CMT, with the primary objective of promoting optimal, standardised care globally.MethodsDevelopment of this clinical practice guideline involved a series of systematic reviews covering 10 clinical questions, modified Delphi methodology involving an international panel of clinicians to generate consensus where evidence did not exist, and application of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to evaluate the body of literature and formulate recommendations.ResultsThe final guideline includes three evidence-based and 31 consensus-based recommendations. They encompass the management of muscle weakness, balance and mobility impairment, sensory symptoms, muscle cramps, impaired upper limb function, respiratory impairment, maintenance of joint range of motion and non-surgical management of joint deformity. Consensus was not achieved in some management areas, reflecting differences in practice between clinicians and healthcare settings, and highlighting the need for further research.ConclusionsThis clinical practice guideline provides practical and implementable guidance on the management of common clinical problems experienced by children with CMT and advocates for improved access to multidisciplinary care. Successful dissemination and implementation of these recommendations will be critical in ensuring their application across multiple healthcare settings.

This study aims to explore the impact of Charcot-Marie-Tooth disease type 1A (CMT1A) and its treatment on patients in European (France, Germany, Italy, Spain, and the United Kingdom) and US real-world practice.Adults with CMT1A (n = 937) were recruited to an ongoing observational study exploring the impact of CMT. Data were collected via CMTMe, an app through which participants completed patient-reported outcome measures.Symptoms ranked with highest importance were weakness in the extremities, difficulty in walking, and fatigue. Almost half of participants experienced a worsening of symptom severity since diagnosis. Anxiety and depression were each reported by over one-third of participants. Use of rehabilitative interventions, medications, and orthotics/walking aids was high.Patient-reported burden of CMT1A is high, influenced by difficulties in using limbs, fatigue, pain, and impaired quality of life. Burden severity appears to differ across the population, possibly driven by differences in rehabilitative and prescription-based interventions, and country-specific health care variability.

The objectives of this study were to assess the fat fraction (FF) and cross-sectional area (CSA) of the sciatic nerve in Charcot-Marie-Tooth disease type 1A (CMT1A) patients using Dixon-based proton density fat quantification MRI and to elucidate its potential association with clinical parameters. Thigh MRIs of 18 CMT1A patients and 18 age- and sex-matched volunteers enrolled for a previous study were reviewed. Analyses for FF and CSA of the sciatic nerve were performed at three levels (proximal to distal). CSA and FF were compared between the two groups and among the different levels within each group. The relationship between the MRI parameters and clinical data were assessed in the CMT1A patients. The CMT1A patients showed significantly higher FF at level 3 (p = 0.0217) and significantly larger CSA at all three levels compared with the control participants (p < 0.0001). Comparisons among levels showed significantly higher FF for levels 2 and 3 than for level 1 and significantly larger CSA for level 2 compared with level 1 in CMT1A patients. CSA at level 3 correlated positively with the CMT Neuropathy Score version 2 (CMTNSv2). In conclusion, the sciatic nerve FF of CMT1A patients was significantly higher on level 3 compared with both the controls and the measurements taken on more proximal levels, suggesting the possibility of increased intraepineurial fat within the sciatic nerves of CMT1A patients, with a possible distal tendency. Sciatic nerve CSA at level 3 correlated significantly and positively with CMTNSv2, suggesting its potential value as an imaging marker for clinical severity.

Background: Clinical and molecular data on the occurrence and frequency of inherited neuromuscular disorders (NMD) in the Lebanese population is scarce. Objective: This study aims to provide a retrospective overview of hereditary NMDs based on our clinical consultations in Lebanon. Methods: Clinical and molecular data of patients referred to a multi-disciplinary consultation for neuromuscular disorders over a 20-year period (1999–2019) was reviewed. Results: A total of 506 patients were diagnosed with 62 different disorders encompassing 10 classes of NMDs. 103 variants in 49 genes were identified. In this cohort, 81.4% of patients were diagnosed with motor neuron diseases and muscular dystrophies, with almost half of these described with spinal muscular atrophy (SMA) (40.3% of patients). We estimate a high SMA incidence of 1 in 7,500 births in Lebanon. Duchenne and Becker muscular dystrophy were the second most frequently diagnosed NMDs (17% of patients). These disorders were associated with the highest number of variants (39) identified in this study. A highly heterogeneous presentation of Limb Girdle Muscular Dystrophy and Charcot-Marie-Tooth disease was notably identified. The least common disorders (5.5% of patients) involved congenital, metabolic, and mitochondrial myopathies, congenital myasthenic syndromes, and myotonic dystrophies. A review of the literature for selected NMDs in Lebanon is provided. Conclusions: Our study indicates a high prevalence and underreporting of heterogeneous forms of NMDs in Lebanon- a major challenge with many novel NMD treatments in the pipeline. This report calls for a regional NMD patient registry.

Background Charcot-Marie-Tooth (CMT) disease is a group of inherited peripheral neuropathies, which are subdivided into demyelinating and axonal forms. Biallelic mutations in POLR3B are the well-established cause of hypomyelinating leukodystrophy, which is characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. To date, only one study has reported the demyelinating peripheral neuropathy phenotype caused by heterozygous POLR3B variants. Case presentation A 19-year-old male patient was referred to our hospital for progressive muscle weakness of the lower extremities. Physical examination showed muscle atrophy, sensory loss and deformities of the extremities. Nerve conduction studies and electromyography tests revealed sensorimotor demyelinating polyneuropathy with secondary axonal loss. Trio whole-exome sequencing revealed a de novo variant in POLR3B (c.3137G > A). Conclusions In this study, we report the case of a Chinese patient with a de novo variant in POLR3B (c.3137G > A), who manifested demyelinating CMT phenotype without additional neurological or extra-neurological involvement. This work is the second report on POLR3B-related CMT.

Objective This study was undertaken to establish by a multicentric approach the reliability of a new technique evaluating motor axon excitability. Methods The minimal threshold, the lowest stimulus intensity allowing a maximal response by 1 mA increments (iUP) and then by 0.1 mA adjustments (iMAX) were prospectively derived from three nerves (median, ulnar, fibular) in four university centers (Liege, Marseille, Fraiture, Nice). iMAX procedure was applied in 28 healthy volunteers (twice) and 32 patients with Charcot-Marie-Tooth (CMT1a), chronic inflammatory demyelinating polyneuropathy (CIDP), Guillain-Barre syndrome (SGB) or axonal neuropathy. Results Healthy volunteers results were not significantly different between centers. Correlation coefficients between test and retest were moderate (> 0.5). Upper limits of normal were established using the 95th percentile. Comparison of volunteers and patient groups indicated significant increases in iMAX parameters especially for the CMT1a and CIDP groups. In CMT1a, iMAX abnormalities were homogeneous at the three stimulation sites, which was not the case for CIDP. Conclusions The iMAX procedure is reliable and allows the monitoring of motor axon excitability disorders. Significance The iMAX technique should prove useful to monitor motor axonal excitability in routine clinical practice as it is a fast, non-invasive procedure, easily applicable without specific software or devices.

The CMT Pediatric Scale (CMTPedS) is a reliable, valid, and responsive clinical outcome measure of disability in children with CMT. The aim of this study was to identify the most responsive patient subset(s), based on the standardized response mean (SRM), to optimize the CMTPedS as a primary outcome measure for upcoming clinical trials. Analysis was based on a 2‐year natural history data from 187 children aged 3–20 years with a range of CMT genetic subtypes. Subsets based on age (3–8 years), disability level (CMTPedS score 0–14), and CMT type (CMT1A) increased the SRM of the CMTPedS considerably. Refining the inclusion criteria in clinical trials to younger, mildly affected cases of CMT1A optimizes the responsiveness of the CMTPedS.

Bcl2-associated athanogene 3 (BAG3) gene mutations cause dilated cardiomyopathy and myofibrillar myopathy. Recently, a novel c.625C>T (p.Pro209Ser) mutation in BAG3 was reported to cause axonal Charcot-Marie-Tooth (CMT) disease in three families. Here, we describe two patients with adult-onset and moderate CMT in a Chinese family. Nerve conduction velocity studies revealed an axonal sensorimotor neuropathy, which was supported by sural nerve biopsy. Lower limb magnetic resonance imaging (MRI) revealed fatty infiltration more severe in the soleus and deep posterior compartment muscles than in the medial gastrocnemius and anterior compartment muscles. Whole exome sequencing identified the same c.625C>T (p.Pro209Ser) mutation in BAG3, which co-segregated with the CMT disease in this family. This study further enforces the association between BAG3 gene and CMT disease, indicating that BAG3 should be considered in the genetic testing for CMT. The p.Pro209Ser mutation with different ethnic origins might be another hotspot mutation of BAG3. MRI is helpful to detect accurate extent of muscle involvement.

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.

Only several studies analyzed the characteristics of neuropathic pain (NeP) more extensively in patients with Charcot-Marie-Tooth type 1A (CMT1A). Therefore, we sought to determine the frequency and features of NeP in CMT1A patients and to assess the association between NeP and sociodemographic and clinical characteristics of patients with CMT1A. Our research included 51 genetically diagnosed CMT1A patients. The International Association for the Study of Pain (IASP) criteria were used for diagnosis of NeP. PainDETECT questionnaire (PD-Q) was used to assess NeP features. The Medical Research Council (MRC) Sum Score, CMT Neuropathy Score (CMTNS), Overall Neuropathy Limitation Scale (ONLS) score, and Beck Depression Inventory were also used. NeP was present in 15 (29.4%) patients with CMT1A. The average intensity of pain was 5.7 ± 2.2 out of 10. The most sensitive neuropathic symptoms were numbness, then tingling, and burning sensations, while the most specific symptom was allodynia. Patients with NeP more frequently reported pain in the back (p < 0.01) and the trunk (p < 0.05). Patients with NeP had more pronounced disability of the upper extremities and overall disability, as assessed by the ONLS score (p < 0.05). Depression was more frequent in patients with NeP compared with patients without NeP (66.7 to 13.9%, p < 0.01). NeP was present in almost one-third of the patients with CMT1A and it was moderate on average. Presence of NeP was associated with worse functional disability and depression.

Peripheral nerve imaging techniques have recently increasingly revealed their usefulness. We herein describe a man who had a subacute progression of symptom, diffuse and prominent proximal demyelination and conduction block, suggesting a diagnosis of inflammatory demyelinating polyneuropathy. Additional nerve imaging techniques revealed homogeneous and prominent nerve hypertrophy without proximal accentuation and the findings implied inherited polyneuropathies. Intravenous immunoglobulin was administered, and both the symptoms of weakness and findings of nerve conduction studies (NCS) improved. Subsequent genetic testing unveiled Charcot-Marie-Tooth 1A. To diagnose peripheral nerve disorders, a careful history, physical examination and NCS are essential diagnostic tools, but the findings of this case suggest the importance of nerve imaging techniques in clinical situations.

Nerve biopsy has been widely used to investigate patients with peripheral neuropathy, and in many centers, it is still a useful diagnostic tool in this setting. In this study, we reviewed the histopathological spectrum of the nerve biopsies performed in our center in a 30-year period and we analyzed their relevance in the clinical setting. Retrospective analysis of the retrieved data was done for cases of nerve biopsies performed in our institute between 1988 and 2018. Surgical technique and histopathological analysis were done accordingly to standard protocol. Complete clinical and pathological data were available only for 717 cases. The procedure was generally safe, with only 0.3% superimposed infection. Main pathological results were “unspecific” axonal polyneuropathy (49.8%), vasculitis neuropathy (9.3%), acquired demyelinating neuropathy (8.9%), and Charcot-Marie-Tooth (8.2%). Considering clinical-neurophysiological suspicion of vasculitis, nerve biopsy confirmed the diagnosis in 60.9% of cases. In conclusion, for inherited neuropathies, we do not recommend this invasive procedure, but we strongly suggest a genetic test. Conversely, in vasculitic neuropathies or in dysimmune neuropathies not clearly confirmed by neurophysiological examination, nerve biopsy continues to represent a useful and irreplaceable tool.

Background Charcot neuroarthropathy is a systemic disease that generates pathological changes in the musculoskeletal system, causing instability, dislocations, and deformities. Charcot neuroarthropathy of the knee, due to either diabetes mellitus or syringomyelia, is anecdotally reported with the epidemic of the diseases. However, idiopathic sensory peripheral neuropathy can inflict osteoarticular structures directly, inducing a dysfunctional Charcot neuroarthropathy. An early diagnosis and effective relief of the symptomatic deformity is essential for the treatment. Case presentation We report the case of a patient with idiopathic sensory peripheral neuropathy who presented with a swelling right knee, as well as distorted and painless gait disorder, diagnosed as Charcot neuroarthropathy of the knee. Partial weight bearing with a hinged knee brace was used to correct the abnormal alignment and gait posture, and bisphosphonates were prescribed to decrease pathological bone resorption. Although the alignment and Knee Society Score got a gradual deterioration, the combination of orthosis and pharmacy could alleviate the symptom to a certain extent. Conclusion The diagnosis of Charcot neuroarthropathy of the knee is rare that requiring early diagnosis. The presence of features, including painlessness, numbness, and deformed arthropathy following chronic-onset algesthesia loss should be taken carefully.

Diaphragm weakness in Charcot-Marie-Tooth disease 1A (CMT1A) is usually associated with severe disease manifestation. This study comprehensively investigated phrenic nerve conductivity, inspiratory and expiratory muscle function in ambulatory CMT1A patients. Nineteen adults with CMT1A (13 females, 47 ± 12 years) underwent spiromanometry, diaphragm ultrasound, and magnetic stimulation of the phrenic nerves and the lower thoracic nerve roots, with recording of diaphragm compound muscle action potentials (dCMAP, n = 15), transdiaphragmatic and gastric pressures (twPdi and twPgas, n = 12). Diaphragm motor evoked potentials (dMEP, n = 15) were recorded following cortical magnetic stimulation. Patients had not been selected for respiratory complaints. Disease severity was assessed using the CMT Neuropathy Scale version 2 (CMT-NSv2). Healthy control subjects were matched for age, sex, and body mass index. The following parameters were significantly lower in CMT1A patients than in controls (all P < .05): forced vital capacity (91 ± 16 vs 110 ± 15% predicted), maximum inspiratory pressure (68 ± 22 vs 88 ± 29 cmH2 O), maximum expiratory pressure (91 ± 23 vs 123 ± 24 cmH2 O), and peak cough flow (377 ± 135 vs 492 ± 130 L/min). In CMT1A patients, dMEP and dCMAP were delayed. Patients vs controls showed lower diaphragm excursion (5 ± 2 vs 8 ± 2 cm), diaphragm thickening ratio (DTR, 1.9 [1.6-2.2] vs 2.5 [2.1-3.1]), and twPdi (8 ± 6 vs 19 ± 7 cmH2 O; all P < .05). DTR inversely correlated with the CMT-NSv2 score (r = -.59, P = .02). There was no group difference in twPgas following abdominal muscle stimulation. Ambulatory CMT1A patients may show phrenic nerve involvement and reduced respiratory muscle strength. Respiratory muscle weakness can be attributed to diaphragm dysfunction alone. It relates to neurological impairment and likely reflects a disease continuum.

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited sensorimotor neuropathies. To clarify the genetic spectrum and clinical profiles in Chinese CMT patients, we enrolled 150 unrelated CMT patients from southeast China. We performed multiplex ligation-dependent probe amplification (MLPA) testing in all patients and next-generation sequencing (NGS) among those patients without PMP22 rearrangements. We identified PMP22 duplications in 40 patients and deletions in 12 patients. In addition, we found 19 novel variants and 36 known mutations in 57 patients. Among these 55 variants, 45 pathogenic or likely pathogenic variants were identified in 48 cases, and 10 variants with uncertain significance were identified in 9 cases. Therefore, we obtained a genetic diagnosis in 63.8% (88/138) of CMT patients and 66.7% (100/150) of all included patients. PMP22, GJB1, and MFN2 are the most common causative genes in CMT1 (demyelinated form), intermediate CMT, and CMT2 (axonal form), respectively. In this study, we identified a higher proportion of intermediate CMT, a relatively high frequency of NDRG1 mutations and clinical features of later onset age in CMT1A patients. Our results broaden the genetic and clinical spectrum of CMT patients, which can help optimize the genetic and clinical diagnosis.