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BACKGROUND AND PURPOSE: The European Academy of Neurology (EAN) was a merger from two parent societies: the European Neurological Association (ENS, founded in 1986) and the European Federation of Neurological Societies (EFNS, founded in 1987). METHODS: This article was written by nine former presidents, three of whom were also founders of the ENS, and is based on recollections and documents. It follows up on a review of the ENS history stored in the EAN archive. RESULTS: The first European society (ENS) was founded by eight individual European academic clinician-neuroscientists aiming at joining with other qualified European neuroscientists on an individual membership basis. After 1990 members were also invited from behind the former Iron Curtain. A principal goal was holding neurology meetings (700 participants in 1988 and over 3000 in 2010), promoting collaborative research projects with exchange of junior neuroscientists, and providing teaching and education independent from nationality. Health politics were not part of the agenda. The executive boards (4-year term) were staffed with academic scientists from all subspecialties of neurology. Numerous bursaries and fellowships were established for junior neurologists. The impact of ENS members on research activities of young investigators was appreciated by academia at large. After years of negotiations ENS and EFNS joint efforts resulted in forming the EAN covering all fields of neurology and neuroscience under one roof. CONCLUSION: The basic principles of the ENS were successfully integrated into the new EAN in particular documented by the number of individual members rising to over 4000 in 2024.

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BACKGROUND: To evaluate whether ongoing axonal loss can be prevented in multifocal motor neuropathy (MMN) treated with immunoglobulin G (IgG), a group of patients with a median disease duration of 15.7 years (range: 8.3-37.8), treated with titrated dosages of immunoglobulins, was studied electrophysiologically at time of diagnosis and at follow-up. RESULTS: At follow-up, the Z-score of the compound motor action potential amplitude of the median, fibular, and tibial nerves and the neurological performances were determined. In seven patients with a treatment-free period of 0.3 years (0.2-0.4), there was no progression of axonal loss (p = 0.2), whereas a trend toward further axonal loss by 1.3 Z-scores (0.9-17.0, p = 0.06) was observed in five patients with a treatment-free period of 4.0 years (0.9-9.0). The axonal loss in the group with a short treatment delay was significantly smaller than in the group with a longer treatment delay (p = 0.02). Also, there was an association between treatment delay and ongoing axonal loss (p = 0.004). The electrophysiological findings at follow-up were associated with the isokinetic strength performance, the neurological impairment score, and the disability, supporting the clinical relevance of the electrophysiological estimate of axonal loss. CONCLUSION: Swift initiation of an immediately titrated IgG dosage can prevent further axonal loss and disability in continuously treated MMN patients.

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OBJECTIVE: To evaluate the longitudinal correlations between sulfatide/lysosulfatide levels and central and peripheral nervous system function in children with metachromatic leukodystrophy (MLD) and to explore the impact of intravenous recombinant human arylsulfatase A (rhASA) treatment on myelin turnover. METHODS: A Phase 1/2 study of intravenous rhASA investigated cerebrospinal fluid (CSF) and sural nerve sulfatide levels, 88-item Gross Motor Function Measure (GMFM-88) total score, sensory and motor nerve conduction, brain N-acetylaspartate (NAA) levels, and sural nerve histology in 13 children with MLD. Myelinated and unmyelinated nerves from an untreated MLD mouse model were also analyzed. RESULTS: CSF sulfatide levels correlated with neither Z-scores for GMFM-88 nor brain NAA levels; however, CSF sulfatide levels correlated negatively with Z-scores of nerve conduction parameters, number of large (≥7 µm) myelinated fibers, and myelin/fiber diameter slope, and positively with nerve g-ratios and cortical latencies of somatosensory-evoked potentials. Quantity of endoneural litter positively correlated with sural nerve sulfatide/lysosulfatide levels. CSF sulfatide levels decreased with continuous high-dose treatment; this change correlated with improved nerve conduction. At 26 weeks after treatment, nerve g-ratio decreased by 2%, and inclusion bodies per Schwann cell unit increased by 55%. In mice, abnormal sulfatide storage was observed in non-myelinating Schwann cells in Remak bundles of sciatic nerves but not in unmyelinated urethral nerves. INTERPRETATION: Lower sulfatide levels in the CSF and peripheral nerves correlate with better peripheral nerve function in children with MLD; intravenous rhASA treatment may reduce CSF sulfatide levels and enhance sulfatide/lysosulfatide processing and remyelination in peripheral nerves.

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CANVAS including its clinical components of cerebellar ataxia, sensory neuropathy and vestibular areflexia is presented in this review. An intronic biallelic pentanucleotide expansion in RFC1 is the genetic cause of CANVAS. Several patients diagnosed with isolated "idiopathic" neurological or otological conditions might have a CANVAS spectrum disorder. The number of CANVAS patients may well increase considerably in the near future, making it important to consider the diagnostic set-up and infrastructure for counselling, treatment and follow-up in the Danish healthcare system.

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INTRODUCTION/AIMS: We hypothesized that early, pretreatment axonal loss would predict long-term disability, supported by a pilot study of selected patients with chronic inflammatory demyelinating polyneuropathy (CIDP). To further test this hypothesis, we examined a larger consecutive group of CIDP patients. METHODS: Needle electromyography and motor and sensory nerve conduction studies were carried out in 30 CIDP patients at pretreatment and follow-up 5 to 28 years later. Changes in amplitudes were expressed as axonal Z scores and changes in conduction as demyelination Z scores and correlated with findings of the Inflammatory Rasch-built Overall Disability Scale (I-RODS), the Neuropathy Impairment Score (NIS), and isokinetic dynamometry (IKS). RESULTS: At follow-up, the median I-RODS score was 73, the NIS was 23, and the IKS was 56%. The median axonal Z score was unchanged at follow-up. Conversely, the corresponding demyelination Z scores improved. The initial axonal loss was correlated with the clinical outcome and was an independent predictor of outcome by multivariate regression analysis. Axonal loss at follow-up was also correlated with the clinical outcome. Only the follow-up demyelination Z score was correlated with the clinical outcomes. Furthermore, the latency until treatment initiation was predictive of all three clinical outcome scores at follow-up, and of axonal loss and demyelination at follow-up. DISCUSSION: The present study findings indicate that pretreatment axonal loss at diagnosis in CIDP is predictive of long-term disability, neurological impairment, and strength. A delay in treatment is associated with more pronounced axonal loss and a worse clinical outcome.

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BACKGROUND AND PURPOSE: Rare diseases affect up to 29 million people in the European Union, and almost 50% of them affect the nervous system or muscles. Delays in diagnosis and treatment onset and insufficient treatment choices are common. Clinical practice guidelines (CPGs) may improve the diagnosis and treatment of patients and optimize care pathways, delivering the best scientific evidence to all clinicians treating these patients. Recommendations are set for developing and reporting high-quality CPGs on rare neurological diseases (RNDs) within the European Academy of Neurology (EAN), through a consensus procedure. METHODS: A group of 27 experts generated an initial list of items that were evaluated through a two-step Delphi consensus procedure and a face-to-face meeting. The final list of items was reviewed by an external review group of 58 members. RESULTS: The consensus procedure yielded 63 final items. Items are listed according to the domains of the AGREE instruments and concern scope and purpose, stakeholder involvement, rigour of development, and applicability. Additional items consider reporting and ethical issues. Recommendations are supported by practical examples derived from published guidelines and are presented in two tables: (1) items specific to RND CPGs, and general guideline items of special importance for RNDs, or often neglected; (2) items for guideline development within the EAN. CONCLUSIONS: This guidance aims to provide solutions to the issues specific to RNDs. This consensus document, produced by many experts in various fields, is considered to serve as a starting point for further harmonization and for increasing the quality of CPGs in the field of RNDs.

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OBJECTIVE: To assess the inter-rater reliability of MScanFit MUNE using a "Round Robin" research design. METHODS: Twelve raters from different centres examined six healthy study participants over two days. Median, ulnar and common peroneal nerves were stimulated, and compound muscle action potential (CMAP)-scans were recorded from abductor pollicis brevis (APB), abductor digiti minimi (ADM) and anterior tibial (TA) muscles respectively. From this we calculated the Motor Unit Number Estimation (MUNE) and "A50", a motor unit size parameter. As statistical analysis we used the measures Limits of Agreement (LOA) and Coefficient of Variation (COV). Study participants scored their perception of pain from the examinations on a rating scale from 0 (no pain) to 10 (unbearable pain). RESULTS: Before this study, 41.6% of the raters had performed MScanFit less than five times. The mean MUNE-values were: 99.6 (APB), 131.4 (ADM) and 126.2 (TA), with LOA: 19.5 (APB), 29.8 (ADM) and 20.7 (TA), and COV: 13.4 (APB), 6.3 (ADM) and 5.6 (TA). MUNE-values correlated to CMAP max amplitudes (R2-values were: 0.463 (APB) (p<0.001), 0.421 (ADM) (p<0.001) and 0.645 (TA) (p<0.001)). The average perception of pain was 4. DISCUSSION: MScanFit indicates a high level of inter-rater reliability, even with only limited rater experience and is overall reasonably well tolerated by patients. These results may indicate MScanFit as a reliable MUNE method with potential as a biomarker in drug trials.

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Two siblings were diagnosed with adult metachromatic leukodystrophy (MLD) and treated with hematopoietic stem cell transplantation (HSCT). While the older sibling was symptomatic at the time of diagnosis, her younger brother was diagnosed and transplanted at the presymptomatic state. We describe patients' clinical, biochemical, and genetic features, as well as neuropsychological and neurophysiological test results, and brain magnetic resonance imaging from pretransplantation and posttransplantation assessments. Both patients converted to complete donor chimerism and arylsulfatase A levels normalized 3 months posttransplantation. Twelve months posttransplantation, neurological and neuropsychological assessment for both patients showed stabilization, and they remained stable for the 38 months long observation period. To assess the effect of HSCT used as treatment for the rare, adult MLD subtype on survival and stabilization, we performed a systematic literature review and included 7 studies with a total of 26 cases. Of these 26 cases, 6 patients died of HSCT-related complications and 2 patients had graft rejection. Of the remaining 18 patients, 2 patients improved after HSCT, 13 patients stabilized, and 3 patients progressed, suggesting that HSCT potentially benefits adult MLD patients. Larger studies focusing on this subtype are needed and recommendations on criteria for HSCT in adult MLD need to be evolved.

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OBJECTIVE: To investigate early pre-treatment nerve fiber loss as a predictor of long-term clinical outcome in chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: In 14 patients, motor and sensory conduction studies of the median, fibular, and sural nerves were performed at pre-treatment and follow-up 11-28 years later. Z-scores of amplitudes were combined as biomarkers of axonal loss and Z-scores of conduction properties as demyelination scores. The axonal loss was further examined by electromyography (EMG) and motor unit number estimation. Axonal and demyelination scores were compared to clinical outcomes in the Inflammatory Rasch-built Overall Disability Scale, the Neuropathy Impairment Score, and dynamometry. RESULTS: At follow-up 12 patients walked independently, one needed support and one could not walk. The initial and follow-up axonal and demyelination scores were markedly abnormal. The initial axonal loss but not demyelination was strongly associated with both the follow-up axonal loss and the clinical measures. Moreover, delay of treatment initiation negatively influenced the axonal scores and clinical outcomes. CONCLUSION: In this hypothesis generating limited study, we found that axonal loss at early CIDP was highly predictive for long-term nerve fiber loss and disability. SIGNIFICANCE: The study indicates that prompt initiation of treatment to prevent nerve fiber loss is necessary for outcome in CIDP.

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OBJECTIVE: Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficient activity of arylsulfatase A (ASA), resulting in severe motor and cognitive dysfunction. This phase 1/2 study evaluated the safety and efficacy of intravenous (IV) recombinant human ASA (rhASA; HGT-1111, previously known as Metazym) in children with MLD. METHODS: Thirteen children with MLD (symptom onset < 4 years of age) were enrolled in an open-label, nonrandomized, dose-escalation trial and received IV rhASA at 50, 100, or 200 U/kg body weight every 14 (± 4) days for 52 weeks (NCT00418561; NCT00633139). Eleven children continued to receive rhASA at 100 or 200 U/kg during a 24-month extension period (NCT00681811). Outcome measures included safety observations, changes in motor and cognitive function, and changes in nerve conduction and morphometry. RESULTS: There were no serious adverse events considered related to IV rhASA. Motor function and developmental testing scores declined during the study in all dose groups; no significant differences were observed between groups. Nerve conduction studies and morphometric analysis indicated that peripheral nerve pathology did not worsen during the study in any dose group. INTERPRETATION: IV rhASA was generally well tolerated. There was no evidence of efficacy in preventing motor and cognitive deterioration, suggesting that IV rhASA may not cross the blood-brain barrier in therapeutic quantities. The relative stability of peripheral nerve function during the study indicates that rhASA may be beneficial if delivered to the appropriate target site and supports the development of rhASA for intrathecal administration in MLD.

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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.

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BACKGROUND: Quantitative electromyography of paraspinal muscle is a valuable diagnostic tool, but normative data are lacking. METHODS: Needle electromyography (EMG) was obtained in 65 healthy subjects (49% men, 51% women) aged 21 to 82 years at C7, Th10, and L5 segments bilaterally. The incidence of spontaneous activity; motor unit potential (MUP) amplitudes, durations, and the incidence of polyphasic potentials; and the recruitment pattern at maximal voluntary contraction (MVC) were evaluated. RESULTS: The incidence of fibrillation potentials was similar to limb muscles. The mean MUP duration and amplitude, and the amplitude at MVC increased caudally, while the incidence of polyphasic potentials was similar at all levels. EMG parameters did not correlate with sex or age. CONCLUSIONS: In contrast to limb muscles, EMG parameters did not change with age, while polyphasic potentials were more frequent in paraspinal muscle than in limb muscles. The EMG gradient suggests larger motor units at more caudal segments.

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Measurement of axonal excitability provides an in vivo indication of the properties of the nerve membrane and of the ion channels expressed on these axons. Axonal excitability techniques have been utilised to investigate the pathophysiological mechanisms underlying neurological diseases. This document presents guidelines derived for such studies, based on a consensus of international experts, and highlights the potential difficulties when interpreting abnormalities in diseased axons. The present manuscript provides a state-of-the-art review of the findings of axonal excitability studies and their interpretation, in addition to suggesting guidelines for the optimal performance of excitability studies.

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Peripheral nerve blocks (PNBs) using local anesthetic (LA) are superior to systemic analgesia for management of post-operative pain. An insufficiently short PNB duration following single-shot LA can be optimized by development of extended release formulations among which liposomes have been shown to be the least toxic. In vivo rodent models for PNB have focused primarily on assessing behavioral responses following LA. In a previous study in human volunteers, we found that it is feasible to monitor the effect of LA in vivo by combining conventional conduction studies with nerve excitability studies. Here, we aimed to develop a mouse model where the same neurophysiological techniques can be used to investigate liposomal formulations of LA in vivo. To challenge the validity of the model, we tested the motor PNB following an unilamellar liposomal formulation, filled with the intermediate-duration LA lidocaine. Experiments were carried out in adult transgenic mice with fluorescent axons and with fluorescent tagged liposomes to allow in vivo imaging by probe-based confocal laser endomicroscopy. Recovery of conduction following LA injection at the ankle was monitored by stimulation of the tibial nerve fibers at the sciatic notch and recording of the plantar compound motor action potential (CMAP). We detected a delayed recovery in CMAP amplitude following liposomal lidocaine, without detrimental systemic effects. Furthermore, CMAP threshold-tracking studies of the distal tibial nerve showed that the increased rheobase was associated with a sequence of excitability changes similar to those found following non-encapsulated lidocaine PNB in humans, further supporting the translational value of the model.

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Electrophysiology enables the objective assessment of peripheral nerve function in vivo. Traditional nerve conduction measures such as amplitude and latency detect chronic axon loss and demyelination, respectively. Axonal excitability techniques "by threshold tracking" expand upon these measures by providing information regarding the activity of ion channels, pumps and exchangers that relate to acute function and may precede degenerative events. As such, the use of axonal excitability in animal models of neurological disorders may provide a useful in vivo measure to assess novel therapeutic interventions. Here we describe an experimental setup for multiple measures of motor axonal excitability techniques in the rat ulnar nerve. The animals are anesthetized with isoflurane and carefully monitored to ensure constant and adequate depth of anesthesia. Body temperature, respiration rate, heart rate and saturation of oxygen in the blood are continuously monitored. Axonal excitability studies are performed using percutaneous stimulation of the ulnar nerve and recording from the hypothenar muscles of the forelimb paw. With correct electrode placement, a clear compound muscle action potential that increases in amplitude with increasing stimulus intensity is recorded. An automated program is then utilized to deliver a series of electrical pulses which generate 5 specific excitability measures in the following sequence: stimulus response behavior, strength duration time constant, threshold electrotonus, current-threshold relationship and the recovery cycle. Data presented here indicate that these measures are repeatable and show similarity between left and right ulnar nerves when assessed on the same day. A limitation of these techniques in this setting is the effect of dose and time under anesthesia. Careful monitoring and recording of these variables should be undertaken for consideration at the time of analysis.

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OBJECTIVE: Sensation is essential for recovery after peripheral nerve injury. However, the relationship between sensory modalities and function of regenerated fibers is uncertain. We have investigated the relationships between touch threshold, tactile gnosis, and mechanoreceptor and sensory fiber function after nerve regeneration. METHODS: Twenty-one median or ulnar nerve lesions were repaired by a collagen nerve conduit or direct suture. Quantitative sensory hand function and sensory conduction studies by near-nerve technique, including tactile stimulation of mechanoreceptors, were followed for 2 years, and results were compared to noninjured hands. RESULTS: At both repair methods, touch thresholds at the finger tips recovered to 81 ± 3% and tactile gnosis only to 20 ± 4% (p < 0.001) of control. The sensory nerve action potentials (SNAPs) remained dispersed and areas recovered to 23 ± 2% and the amplitudes only to 7 ± 1% (P < 0.001). The areas of SNAPs after tactile stimulation recovered to 61 ± 11% and remained slowed. Touch sensation correlated with SNAP areas (p < 0.005) and was negatively related to the prolongation of tactile latencies (p < 0.01); tactile gnosis was not related to electrophysiological parameters. INTERPRETATION: The recovered function of regenerated peripheral nerve fibers and reinnervated mechanoreceptors may differentially influence recovery of sensory modalities. Touch was affected by the number and function of regenerated fibers and mechanoreceptors. In contrast, tactile gnosis depends on the input and plasticity of the central nervous system (CNS), which may explain the absence of a direct relation between electrophysiological parameters and poor recovery. Dispersed maturation of sensory nerve fibers with desynchronized inputs to the CNS also contributes to the poor recovery of tactile gnosis. Ann Neurol 2017. Ann Neurol 2017;82:940-950.

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BACKGROUND: Nerve excitability testing by threshold-tracking is the only available method to study axonal ion channel function and membrane potential in the clinical setting. The measures are, however, indirect and the interpretation of neuropathic changes remains challenging. The same multiple measures of axonal excitability were adapted to further explore the pathophysiological changes in rodent disease models under pharmacologic and genetic manipulations. These studies are typically limited to the investigation of the "long nerves" such as the tail or the tibial nerves. NEW METHOD: We introduce a novel setup to explore the ulnar nerve excitability in rodents. We provide normative ulnar data in 11 adult female Long Evans rats under anaesthesia by comparison with tibial and caudal nerves. Additionally, these measures were repeated weekly on 3 occasions to determine the repeatability of these tests. RESULTS: Nerve excitability assessment of ulnar nerve proved to be a longitudinally repeatable measure of axonal function mature in rats, as were measures in tibial and caudal nerves. Comparison with existing method: Ulnar nerve motor excitability measures were different from the caudal and tibial excitability measures. Most notably, ulnar nerve showed the largest threshold changes during both depolarizing and hyperpolarizing threshold electrotonus. CONCLUSIONS: Ulnar nerves demonstrate a distinct nerve excitability profile than the caudal and tibial nerves which could have functional and pathological implications.

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Mice deficient of myelin protein P0 are established models of demyelinating Charcot-Marie-Tooth (CMT) disease. Dysmyelination in these mice is associated with an ectopic expression of the sensory neuron specific sodium channel isoform NaV1.8 on motor axons. We reported that in P0+/-, a model of CMT1B, the membrane dysfunction could be acutely improved by a novel oral NaV1.8 blocker referred to as Compound 31 (C31, Bioorg. Med. Chem. Lett. 2010, 20, 6812; AbbVie Inc.). The aim of this study was to investigate the extent to which C31 treatment could also improve the motor axon function in P0-/-, a CMT model with a much more severe neuropathy. We found that the progressive impairment of motor performance from 1 to 4 months of age in P0-/- could be acutely reversed by C31 treatment. The effect was associated with an improvement of the amplitude of the plantar CMAP evoked by tibial nerve stimulation. The corresponding motor nerve excitability studies by "threshold tracking" showed changes after C31 consistent with attenuation of a resting membrane depolarization. Our data suggest that the depolarizing motor conduction failure in P0-/- could be acutely improved by C31. This provides proof-of-concept that treatment with oral subtype-selective NaV1.8 blockers could be used to improve the motor function in severe forms of demyelinating CMT.

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Mice heterozygously deficient for the myelin protein P0 gene (P0+/-) develop a slowly progressing neuropathy modeling demyelinating Charcot-Marie-Tooth disease (CMT1B). The aim of the study was to investigate the long-term progression of motor dysfunction in P0+/- mice at 3, 7, 12 and 20months. By comparison with WT littermates, P0+/- showed a decreasing motor performance with age. This was associated with a progressive reduction in amplitude and increase in latency of the plantar compound muscle action potential (CMAP) evoked by stimulation of the tibial nerve at ankle. This progressive functional impairment was in contrast to the mild demyelinating neuropathy of the tibial nerve revealed by histology. "Threshold-tracking" studies showed impaired motor axon excitability in P0+/- from 3months. With time, there was a progressive reduction in threshold deviations during both depolarizing and hyperpolarizing threshold electrotonus associated with increasing resting I/V slope and increasing strength-duration time constant. These depolarizing features in excitability in P0+/- as well as the reduced CMAP amplitude were absent in P0+/- NaV1.8 knockouts, and could be acutely reversed by selective pharmacologic block of NaV1.8 in P0+/-. Mathematical modeling indicated an association of altered passive cable properties with a depolarizing shift in resting membrane potential and increase in the persistent Na(+) current in P0+/-. Our data suggest that ectopic NaV1.8 expression precipitates depolarizing conduction failure in CMT1B, and that motor axon dysfunction in demyelinating neuropathy is pharmacologically reversible.

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