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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.

Peripheral myelin protein 22 (PMP22) related neuropathies account for over 50% of inherited peripheral neuropathies. A gene copy variation results in CMT1A (duplication) and hereditary neuropathy with liability to pressure palsies (HNPP; single deletion). Point mutations comprise both phenotypes. The underlying pathological mechanisms are incompletely understood and biallelic mutations of PMP22 are very rare. We describe a 9-year-old girl who presented before the age of 1 year with severe locomotor delay. She now requires support for standing and walking in view of her severe sensory ataxia. Strikingly, her muscle power and bulk are close to normal in all segments. Nerve conduction studies showed sensory-motor velocities below 5 m/s. Genetic analysis revealed a homozygous sequence change in the PMP22 gene causing the loss of termination codon (c.483A > G; p.[*161Trpext*10]), extending the protein by 9 amino acids. Both heterozygous parents have neurophysiological abnormalities consistent with HNPP, consistent with this being a loss-of-function mutation. PMP22-deficient human models are rare but important to decipher the physiological function of the PMP22 protein in vivo. The predominance of large fiber sensory involvement in this and other rare similar cases suggests a pivotal role played by PMP22 in the embryogenesis of dorsal root ganglia in humans.

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.

Objective To determine the rate of disease progression in a longitudinal natural history study of children with Charcot-Marie-Tooth (CMT) disease. Methods Two hundred six (103 female) participants aged 3 to 20 years enrolled in the Inherited Neuropathies Consortium were assessed at baseline and 2 years. Demographic, anthropometric, and diagnostic information were collected. Disease progression was assessed with the CMT Pediatric Scale (CMTPedS), a reliable Rasch-built linearly weighted disability scale evaluating fine and gross motor function, strength, sensation, and balance. Results On average, CMTPedS Total scores progressed at a rate of 2.4 ± 4.9 over 2 years (14% change from baseline; p

Introduction Polyneuropathy signs (Neuropathy Impairment Score, NIS), neurophysiologic tests (m+7Ionis ), disability, and health scores were assessed in baseline evaluations of 100 patients entered into an oligonucleotide familial amyloidotic polyneuropathy (FAP) trial. Methods We assessed: (1) Proficiency of grading neurologic signs and correlation with neurophysiologic tests, and (2) clinometric performance of modified NIS+7 neurophysiologic tests (mNIS+7Ionis ) and its subscores and correlation with disability and health scores. Results The mNIS+7Ionis sensitively detected, characterized, and broadly scaled diverse polyneuropathy impairments. Polyneuropathy signs (NIS and subscores) correlated with neurophysiology tests, disability, and health scores. Smart Somatotopic Quantitative Sensation Testing of heat as pain 5 provided a needed measure of small fiber involvement not adequately assessed by other tests. Conclusions Specially trained neurologists accurately assessed neuropathy signs as compared to referenced neurophysiologic tests. The score, mNIS+7Ionis , broadly detected, characterized, and scaled polyneuropathy abnormality in FAP, which correlated with disability and health scores. Muscle Nerve 56: 901-911, 2017.

Introduction The negative results in trials of vitamin C in Charcot-Marie-Tooth disease (CMT) type 1A have highlighted the lack of sensitive outcome measures. Neurofilaments are abundant neuronal cytoskeletal proteins, and their concentration in blood is likely to reflect axonal breakdown. We therefore examined plasma neurofilament heavy-chain (NfH) concentration as a potential biomarker in CMT. Methods Blood samples were collected from healthy controls and patients with CMT over a 2-year period. Disease severity was measured using the CMT Examination Score. An in-house enzyme-linked immunoabsorbent assay was used to measure plasma NfH levels. Results There was no significant difference in plasma NfH concentrations between CMT patients and controls (P = 0.449). There was also no significant difference in plasma NfH levels in the CMT group over 1 year (mean difference = -0.02, SEM = 4.44, P = 0.98). Conclusions Plasma NfH levels are not altered in patients with CMT and are not a suitable biomarker of disease activity. Muscle Nerve 53: 972-975, 2016.

Mitofusin 2 (MFN2) mutations are the most common cause of axonal Charcot-Marie-Tooth disease (CMT2). The majority are inherited in an autosomal dominant manner but recessive and semi-dominant kindreds have also been described. We previously reported a deletion of exons 7 and 8 resulting in nonsense-mediated decay, segregating with disease when present in trans with another pathogenic MFN2 mutation. Detailed clinical and electrophysiological data on a series of five affected patients from four kindreds and, when available, their parents and relatives were collected. MFN2 Sanger sequencing, multiplex ligation probe amplification, and haplotype analysis were performed. A severe early-onset CMT phenotype was seen in all cases: progressive distal weakness, wasting, and sensory loss from infancy or early childhood. Optic atrophy (four of five) and wheelchair dependency in childhood were common (four of five). All were compound heterozygous for a deletion of exons 7 and 8 in MFN2 with another previously reported pathogenic mutation (Phe216Ser, Thr362Met, and Arg707Trp). Carrier parents and relatives were unaffected (age range: 24-82 years). Haplotype analysis confirmed that the deletion had a common founder in all families.

Gait analysis of people with Charcot-Marie-Tooth (CMT) disease revealed proximal adaptive gait strategies to compensate for foot drop. We previously demonstrated that hip flexor muscle fatigue can limit walking endurance. This pilot study used a single-blinded cross over design to investigate the effect of a 16-week home-based programme of resistance training on hip flexor muscle strength. Measures of walking endurance, gait speed, exertion, fatigue, and general activity were also recorded. The exercise protocol was based on American College of Sports Medicine recommendations. A mixed effects model was used for analysis. Twenty-six people finished the study, with average reported exercise participation of 93%. No negative effects of exercise were observed. Significant increase in hip flexor muscle strength was observed on the left, but not the right. No changes were observed in walking speed and endurance measures. This pilot study of home-based resistance training showed a modest improvement in hip strength but only on one side. The lack of a more significant improvement and no improvement in walking measures suggests that this training protocol may not be optimal for people with CMT and that patients may need to stratified differently for training studies in CMT.

Introduction: Charcot-Marie-Tooth (CMT) disease type 1A is the most common form of CMT. The main clinical features are distal weakness, sensory loss, and skeletal deformities. Although pain is a frequent complaint, small fiber involvement in CMT1A has not been studied extensively. Methods: We assessed pain and small fiber involvement in 49 CMT1A patients using a variety of pain scales, pain questionnaires, and thermal thresholds. Results: Forty-three of 49 patients (88%) complained of pain. The pain was localized to the feet in 61% of patients. Only 18% of patients had neuropathic pain. Cold and warm detection thresholds were elevated in 53% and 12% of patients, respectively. Conclusions: Our findings confirm that CMT1A patients have significant pain, which is more likely to be multifactorial in origin and suggests that a proportion of patients have small fiber dysfunction affecting mainly thinly myelinated Aδ fibers. © 2014 Wiley Periodicals, Inc.

Long-term studies of Charcot-Marie-Tooth (CMT) disease across the entire lifespan require stable endpoints that measure the same underlying construct (e.g., disability). The aim of this study was to assess the relationship between the CMT Pediatric Scale (CMTPedS) and the adult CMT Neuropathy Score (CMTNSv2) in 203 children, adolescents, and young adults with CMT. There was a moderate curvilinear correlation between the CMTPedS and the CMTNSv2 (Spearman's rho ρ = 0.716, p < 0.0001), although there appears to be a floor effect of the CMTNSv2 in patients with a milder CMT phenotype. Univariate analyses indicate that the relationship between the CMTPedS and CMTNSv2 scores improves with worsening disease severity and advancing age. Although one universal scale throughout life would be ideal, our data supports the transition from the CMTPedS in childhood to the CMTNSv2 in adulthood as a continuum of measuring lifelong disability in patients with CMT.

Charcot-Marie-Tooth disease (CMT) is a common heritable peripheral neuropathy. There is no treatment for any form of CMT, although clinical trials are increasingly occurring. Patients usually develop symptoms during the first 2 decades of life, but there are no established outcome measures of disease severity or response to treatment. We identified a set of items that represent a range of impairment levels and conducted a series of validation studies to build a patient-centered multi-item rating scale of disability for children with CMT.As part of the Inherited Neuropathies Consortium, patients aged 3 to 20 years with a variety of CMT types were recruited from the USA, United Kingdom, Italy, and Australia. Initial development stages involved definition of the construct, item pool generation, peer review, and pilot testing. Based on data from 172 patients, a series of validation studies were conducted, including item and factor analysis, reliability testing, Rasch modeling, and sensitivity analysis.Seven areas for measurement were identified (strength, dexterity, sensation, gait, balance, power, endurance), and a psychometrically robust 11-item scale was constructed (CMT Pediatric Scale [CMTPedS]). Rasch analysis supported the viability of the CMTPedS as a unidimensional measure of disability in children with CMT. It showed good overall model fit, no evidence of misfitting items, and no person misfit, and it was well targeted for children with CMT.The CMTPedS is a well-tolerated outcome measure that can be completed in 25 minutes. It is a reliable, valid, and sensitive global measure of disability for children with CMT from the age of 3 years.

A few patients with mutations in the microtubule-associated protein tau gene (MAPT), affected by frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T), may clinically present with a corticobasal syndrome (CBS). We report a case of apparently sporadic CBS bearing a mutation in the MAPT gene so far associated with frontotemporal dementia (FTD) phenotype. The patient is a 41-year-old man with progressive asymmetric signs of cortical and basal ganglia involvement consistent with CBS. Magnetic resonance imaging showed asymmetric cortical atrophy and unusual corticospinal tract hyperintensity in T2-weighted images. Genetic testing revealed a heterozygous G to C mutation at the first base of codon 389 of the MAPT gene, changing glycine to arginine (G389R), in the patient and his unaffected elderly father. In conclusion, the MAPT G389R mutation shows phenotypic variability resulting in both FTD and CBS. The mutation also demonstrates incomplete penetrance. Corticospinal tract degeneration is an exceptional finding.

Background: Nuclear Factor-kB (NF-kB) is a transcription factor expressed ubiquitously, that plays an important role in immune and inflammatory responses by regulating the expression of different genes. Furthermore many studies have shown its involvement in the apoptosis of neurodegenerative disorders. Objective: The aim of the study was to evaluate the expression of this factor in inflammatory demyelinating and axonal neuropathies as well as in non-inflammatory neuropathies. Materials and Methods: We studied the expression of NF-kB by immunocytochemistry and Western Blot of nuclear extract proteins in sural nerve biopsies of 11 patients with peripheral neuropathies of different origin: 3 with CIDP, 2 with chronic axonal inflammatory neuropathy, 2 with vasculitis, 2 with CMT1 and 2 with CMT2. Three normal nerves served as controls. Immunohistochemistry for macrophages, B, CD4 and CD8 cell subsets was also performed. Results: NF-kB expression was found in some endoneurial vessel walls, many cell nuclei and in the outermost layer of myelin sheath of some nerve fibers in inflammatory axonal and demyelinating neuropathies. Few positive cells were found in hereditary neuropathies whereas no immunoreactivity was detected in normal controls. Western blot analysis confirmed such findings. Conclusion: Our findings underline the role of NF-kB in the immune response of inflammatory neuropathies. NF-kB reactivity in hereditary neuropathies may be related to the apoptotic mechanism.

Progesterone increases PMP22 expression. Transgenic rats overexpressing PMP22, a model of Charcot-Marie-Tooth type 1A (CMT1A), improve when treated with the progesterone antagonist, onapristone, and worsen with progesterone administration. CMT worsening during pregnancy (when progesterone secretion increases dramatically) has been occasionally reported. We investigated whether gender and pregnancy influence disease severity and course in CMT1A. We analyzed clinical and electrophysiological data of 94 CMT1A patients. Data in males and females were compared. We also determined disease severity in female patients in the fertile age as compared to males of the same age group. We retrospectively assessed influence of gestation on disease course in 20 CMT1A females through a comprehensive interview. There was no significant difference in disease severity in females as compared to males. Skeletal deformities, abnormalities of gait and deep tendon jerks, wasting, weakness, and sensory impairment were similar in the two genders. Nerve conduction abnormalities and decrease of sensory and motor evoked response amplitudes were comparable in the two groups. We found no difference in disease severity even when considering 15 to 50-year-old patients. Symptom worsening during pregnancy was reported by 4/20 CMT1A females. The effect of sex hormones on PMP22 does not result in a relevant difference in disease severity between the two genders. A few patients reported some worsening during pregnancy. Disease and normal controls need to be evaluated to establish whether this is a CMT1A-related phenomenon.

A 75-year-old man with HCV hepatitis developed at the age of 70 presented with rest and action tremor localized at both hands and progressive cognitive impairment with memory loss. Four years later he begun to complain of progressive fatigue, occasional falls, numbness at the extremities and orthostatic hypotension. One month after admission, he rapidly worsened with inability to walk, mainly because of autonomic failure. Neurological examination revealed gait disturbances, including a wide base of support and short stride, slurred speech, reduction of upward gaze, rest and action tremor at both hands, intrinsic hand muscle and anterior tibialis muscle wasting and weakness on both sides, absent deep tendon reflexes, loss of vibration sense at lower limbs, and bilateral pes cavus. Routine laboratory studies, autoantibodies, thyroid function, neoplastic markers and immunoelectrophoresis were normal. Cryoglobulins were absent, whereas CSF protein content was increased (142 mg/dl). Autonomic nervous system investigation detected severe orthostatic hypotension. Nerve conduction studies showed absent sensory potentials and a marked reduction of compound motor action potential amplitudes and of motor conduction velocities. A sural nerve biopsy revealed remarkable onion bulb-like changes, endoneurial and perivascular infiltrations of inflammatory cells. Psychometric tests showed mild cognitive impairment. Brain MRI was consistent with normotensive hydrocephalus. The findings indicated the presence of chronic inflammatory demyelinating polyneuropathy, autonomic nervous system involvement and normal pressure hydrocephalus. A condition of multiple system atrophy (MSA) might be taken into account, even if somatic peripheral nerve involvement may rarely occur in MSA. Moreover the normal pressure hydrocephalus could be due to the high protein content in CSF (Fukatsu R et al., 1997).