TRPV4 neuromuscular disease registry highlights bulbar, skeletal and proximal limb manifestations.

Dominant missense mutations of the calcium-permeable cation channel TRPV4 cause Charcot-Marie-Tooth disease (CMT) type 2C and two forms of distal spinal muscular atrophy. These conditions are collectively referred to as TRPV4-related neuromuscular disease and share features of motor greater than sensory dysfunction and frequent vocal fold weakness. Pathogenic variants lead to gain of ion channel function that can be rescued by TRPV4 antagonists in cellular and animal models. As small molecule TRPV4 antagonists have proven safe in trials for other disease indications, channel inhibition is a promising therapeutic strategy for TRPV4 patients. However, the current knowledge of the clinical features and natural history of TRPV4-related neuromuscular disease is insufficient to enable rational clinical trial design. To address these issues, we developed a TRPV4 patient database and administered a TRPV4-specific patient questionnaire. Here, we report demographic and clinical information, including CMT examination scores (CMTES), from 68 patients with known pathogenic TRPV4 variants, 40 of whom also completed the TRPV4 patient questionnaire. TRPV4 patients showed a bimodal age of onset, with the largest peak occurring in the first 2 years of life. Compared to CMT1A patients, TRPV4 patients showed distinct symptoms and signs, manifesting more ambulatory difficulties and more frequent involvement of proximal arm and leg muscles. Although patients reported fewer sensory symptoms, sensory dysfunction was often detected clinically. Many patients were affected by vocal fold weakness (55%) and shortness of breath (55%), and 11% required ventilatory support. Skeletal abnormalities were common, including scoliosis (64%), arthrogryposis (33%), and foot deformities. Strikingly, patients with infantile onset of disease showed less sensory involvement and less progression of symptoms. These results highlight distinctive clinical features in TRPV4 patients, including motor-predominant disease, proximal arm and leg weakness, severe ambulatory difficulties, vocal fold weakness, respiratory dysfunction, and skeletal involvement. In addition, patients with infantile onset of disease appeared to have a distinct phenotype with less apparent disease progression based on CMTES. These collective observations indicate that clinical trial design for TRPV4-related neuromuscular disease should include outcome measures that reliably capture non-length dependent motor dysfunction, vocal fold weakness, and respiratory disease.

Genetic analysis and natural history of Charcot-Marie-Tooth disease CMTX1 due to GJB1 variants.

Charcot-Marie-Tooth disease (CMT) due to GJB1 variants (CMTX1) is the second most common form of CMT. It is an X-linked disorder characterized by progressive sensory and motor neuropathy with males affected more severely than females. Many reported GJB1 variants remain classified as variants of uncertain significance (VUS). In this large, international, multicentre study we prospectively collected demographic, clinical and genetic data on patients with CMT associated with GJB1 variants. Pathogenicity for each variant was defined using adapted American College of Medical Genetics criteria. Baseline and longitudinal analyses were conducted to study genotype-phenotype correlations, to calculate longitudinal change using the CMT Examination Score (CMTES), to compare males versus females, and pathogenic/likely pathogenic (P/LP) variants versus VUS. We present 387 patients from 295 families harbouring 154 variants in GJB1. Of these, 319 patients (82.4%) were deemed to have P/LP variants, 65 had VUS (16.8%) and three benign variants (0.8%; excluded from analysis); an increased proportion of patients with P/LP variants compared with using ClinVar's classification (74.6%). Male patients (166/319, 52.0%, P/LP only) were more severely affected at baseline. Baseline measures in patients with P/LP variants and VUS showed no significant differences, and regression analysis suggested the disease groups were near identical at baseline. Genotype-phenotype analysis suggested c.-17G>A produces the most severe phenotype of the five most common variants, and missense variants in the intracellular domain are less severe than other domains. Progression of disease was seen with increasing CMTES over time up to 8 years follow-up. Standard response mean (SRM), a measure of outcome responsiveness, peaked at 3 years with moderate responsiveness [change in CMTES (ΔCMTES) = 1.3 ± 2.6, P = 0.00016, SRM = 0.50]. Males and females progressed similarly up to 8 years, but baseline regression analysis suggested that over a longer period, females progress more slowly. Progression was most pronounced for mild phenotypes (CMTES = 0-7; 3-year ΔCMTES = 2.3 ± 2.5, P = 0.001, SRM = 0.90). Enhanced variant interpretation has yielded an increased proportion of GJB1 variants classified as P/LP and will aid future variant interpretation in this gene. Baseline and longitudinal analysis of this large cohort of CMTX1 patients describes the natural history of the disease including the rate of progression; CMTES showed moderate responsiveness for the whole group at 3 years and higher responsiveness for the mild group at 3, 4 and 5 years. These results have implications for patient selection for upcoming clinical trials.

Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study.

Mitofusin-2 (MFN2) is one of two ubiquitously expressed homologous proteins in eukaryote cells, playing a critical role in mitochondrial fusion. Mutations in MFN2 (most commonly autosomal dominant) cause Charcot-Marie-Tooth disease type 2A (CMT2A), the commonest axonal form of CMT, with significant allelic heterogeneity. Previous, moderately-sized, cross sectional genotype-phenotype studies of CMT2A have described the phenotypic spectrum of the disease, but longitudinal natural history studies are lacking. In this large multicentre prospective cohort study of 196 patients with dominant and autosomal recessive CMT2A, we present an in-depth genotype-phenotype study of the baseline characteristics of patients with CMT2A and longitudinal data (1-2 years) to describe the natural history. A childhood onset of autosomal dominant CMT2A is the most predictive marker of significant disease severity and is independent of the disease duration. When compared to adult onset autosomal dominant CMT2A, it is associated with significantly higher rates of use of ankle-foot orthoses, full-time use of wheelchair, dexterity difficulties and also has significantly higher CMT Examination Score (CMTESv2) and CMT Neuropathy Score (CMTNSv2) at initial assessment. Analysis of longitudinal data using the CMTESv2 and its Rasch-weighted counterpart, CMTESv2-R, show that over 1 year, the CMTESv2 increases significantly in autosomal dominant CMT2A (mean change 0.84 ± 2.42; two-tailed paired t-test P = 0.039). Furthermore, over 2 years both the CMTESv2 (mean change 0.97 ± 1.77; two-tailed paired t-test P = 0.003) and the CMTESv2-R (mean change 1.21 ± 2.52; two-tailed paired t-test P = 0.009) increase significantly with respective standardized response means of 0.55 and 0.48. In the paediatric CMT2A population (autosomal dominant and autosomal recessive CMT2A grouped together), the CMT Pediatric Scale increases significantly both over 1 year (mean change 2.24 ± 3.09; two-tailed paired t-test P = 0.009) and over 2 years (mean change 4.00 ± 3.79; two-tailed paired t-test P = 0.031) with respective standardized response means of 0.72 and 1.06. This cross-sectional and longitudinal study of the largest CMT2A cohort reported to date provides guidance for variant interpretation, informs prognosis and also provides natural history data that will guide clinical trial design.

Biocompatibility and feasibility of VisiPlate, a novel ultrathin, multichannel glaucoma drainage device.

BACKGROUND: Glaucoma is the leading cause of blindness worldwide. Glaucoma drainage devices and minimally invasive glaucoma surgeries (MIGS) often present with tradeoffs in safety and durability of efficacy. Using a rabbit model, we examined the biocompatibility and feasibility of VisiPlate, a novel, ultrathin, tubeless subconjunctival shunt comprised of a network of microchannels. METHODS: Six naive female New Zealand White rabbits received implants (three only in the right eye with contralateral eye untreated and three in both eyes) composed of a 400-nm-thick aluminum oxide core coated with 2 µm of parylene-C, manufactured with microelectromechanical systems (MEMS) techniques. Tonometry, slit lamp exam, clinical exam, fluorescein patency testing, and histopathology were performed. RESULTS: VisiPlate demonstrated IOP-lowering of 20-40% compared to baseline at each time point over the course of 3 months in the nine implanted eyes. All eyes developed blebs over the implant, and fluorescein testing demonstrated fluid patency at 22 days post-implantation. Slit lamp and clinical observations showed that VisiPlate was well tolerated, with low levels of conjunctival congestion, conjunctival swelling, aqueous flare, hyphema, and iris involvement from surgery that resolved over time. At sacrifice time points of 93 days and 180 days, the only notable observations were mild levels of conjunctival congestion in implanted eyes. Histopathology showed minimal tissue response and no obvious inflammation, fibrosis, or necrosis around the implant. CONCLUSIONS: The results of this in vivo study demonstrate the biocompatibility and IOP-lowering effect of a multichannel, ultrathin subconjunctival shunt in a rabbit model. The data suggest that VisiPlate may safely enhance aqueous outflow and significantly reduce intraocular pressure.

Prevalence and orthopedic management of foot and ankle deformities in Charcot-Marie-Tooth disease.

INTRODUCTION: Foot deformities are frequent complications in Charcot-Marie-Tooth disease (CMT) patients, often requiring orthopedic surgery. However, there are no prospective, randomized studies on surgical management, and there is variation in the approaches among centers both within and between countries. METHODS: In this study we assessed the frequency of foot deformities and surgery among patients recruited into the Inherited Neuropathies Consortium (INC). We also designed a survey addressed to orthopedic surgeons at INC centers to determine whether surgical approaches to orthopedic complications in CMT are variable. RESULTS: Foot deformities were reported in 71% of CMT patients; 30% of the patients had surgery. Survey questions were answered by 16 surgeons working in different specialized centers. Most of the respondents were foot and ankle surgeons. There was marked variation in surgical management. DISCUSSION: Our findings confirm that the approaches to orthopedic management of CMT are varied. We identify areas that require further research. Muscle Nerve 57: 255-259, 2018.

Anterior tibialis CMAP amplitude correlations with impairment in CMT1A.

INTRODUCTION: CMT1A is the most common form of Charcot-Marie-Tooth disease (CMT), a slowly progressive neuropathy in which impairment is length dependent. Fibular nerve conduction studies to the anterior tibialis muscle (AT) may serve as a physiological marker of disease progression in patients with CMT1A. The objective of this study is to determine whether the AT compound muscle action potential (CMAP) amplitude correlates with impairment in patients with CMT1A. METHODS: We correlated AT CMAP amplitudes and impairment measured by the CMT Neuropathy Score (CMTNS) in a cross-section of 121 patients with CMT1A and a subset of 27 patients with longitudinal data. RESULTS: AT CMAP amplitudes correlated with impairment as measured by the CMTNS in cross sectional analysis. Longitudinal changes in the AT CMAP showed a strong inverse correlation with leg strength but not other components of the CMTNS. CONCLUSIONS: AT CMAP amplitude may serve as a useful outcome measure for physiological changes in natural history studies and clinical trials for patients with CMT1A.

In vivo confocal microscopy of Meissner corpuscles as a novel sensory measure in CMT1A.

Reliable, valid, and responsive outcomes for different aspects of Charcot-Marie-Tooth (CMT) neuropathy have become increasingly important in an emerging era of therapy development. Measures of the sensory component of CMT in particular are limited. One novel approach with potential applicability to CMT is non-invasive in vivo reflectance confocal microscopy (RCM) of Meissner corpuscles (MCs). In this prospective study, we evaluated MC densities using RCM, and touch-pressure and vibration sensation thresholds in a cohort of Charcot-Marie-Tooth type 1A (CMT1A) subjects with comparison to healthy controls. MC density was lower in CMT1A subjects than in controls at the fingertip (digit V) (2.59 ± 2.73 MCs/mm(2) vs. 6.77 ± 3.68 MCs/mm(2) , p = 0.001), but not more proximally at the thenar eminence. Touch-pressure thresholds were higher in CMT1A than in controls at digit V (p = 0.002) and at the thenar eminence (p = 0.0001). Vibration thresholds in CMT1A at digit V were also higher than in controls (p = 0.0001). A lower MC density at digit V was associated with greater global CMT severity as reflected by the Charcot-Marie-Tooth neuropathy score (CMTNS) (r = -0.76, p = 0.004) and the Neuropathy impairment score (NIS) (r = -0.73, p = 0.007). Similarly, worse touch-pressure thresholds at the fingertip (digit V) were associated with more severe CMT1A on the CMTNS (r = 0.71, p = 0.009) and NIS (r = 0.70, p = 0.011). Vibration thresholds at digit V were not associated with either the CMTNS (r = 0.11, p = 0.74) or NIS (r = 0.21, p = 0.52). Non-invasive in vivo RCM of MC density at the hand and the evaluation of touch-pressure thresholds show promise as measures of sensory structure and function in CMT1A.

Shortened internodal length of dermal myelinated nerve fibres in Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease type 1A is the most common inherited neuropathy and is caused by duplication of chromosome 17p11.2 containing the peripheral myelin protein-22 gene. This disease is characterized by uniform slowing of conduction velocities and secondary axonal loss, which are in contrast with non-uniform slowing of conduction velocities in acquired demyelinating disorders, such as chronic inflammatory demyelinating polyradiculoneuropathy. Mechanisms responsible for the slowed conduction velocities and axonal loss in Charcot-Marie-Tooth disease type 1A are poorly understood, in part because of the difficulty in obtaining nerve samples from patients, due to the invasive nature of nerve biopsies. We have utilized glabrous skin biopsies, a minimally invasive procedure, to evaluate these issues systematically in patients with Charcot-Marie-Tooth disease type 1A (n = 32), chronic inflammatory demyelinating polyradiculoneuropathy (n = 4) and healthy controls (n = 12). Morphology and molecular architecture of dermal myelinated nerve fibres were examined using immunohistochemistry and electron microscopy. Internodal length was uniformly shortened in patients with Charcot-Marie-Tooth disease type 1A, compared with those in normal controls (P < 0.0001). Segmental demyelination was absent in the Charcot-Marie-Tooth disease type 1A group, but identifiable in all patients with chronic inflammatory demyelinating polyradiculoneuropathy. Axonal loss was measurable using the density of Meissner corpuscles and associated with an accumulation of intra-axonal mitochondria. Our study demonstrates that skin biopsy can reveal pathological and molecular architectural changes that distinguish inherited from acquired demyelinating neuropathies. Uniformly shortened internodal length in Charcot-Marie-Tooth disease type 1A suggests a potential developmental defect of internodal lengthening. Intra-axonal accumulation of mitochondria provides new insights into the pathogenesis of axonal degeneration in Charcot-Marie-Tooth disease type 1A.

A longitudinal study of CMT1A using Rasch analysis based CMT neuropathy and examination scores.

OBJECTIVE: To evaluate the sensitivity of Rasch analysis-based, weighted Charcot-Marie-Tooth Neuropathy and Examination Scores (CMTNS-R and CMTES-R) to clinical progression in patients with Charcot-Marie-Tooth disease type 1A (CMT1A). METHODS: Patients with CMT1A from 18 sites of the Inherited Neuropathies Consortium were evaluated between 2009 and 2018. Weighted CMTNS and CMTES modified category responses were developed with Rasch analysis of the standard scores. Change from baseline for CMTNS-R and CMTES-R was estimated with longitudinal regression models. RESULTS: Baseline CMTNS-R and CMTES-R scores were available for 517 and 1,177 participants, respectively. Mean ± SD age of participants with available CMTES-R scores was 41 ± 18 (range 4-87) years, and 56% were female. Follow-up CMTES-R assessments at 1, 2, and 3 years were available for 377, 321, and 244 patients. A mixed regression model showed significant change in CMTES-R score at years 2 through 6 compared to baseline (mean change from baseline 0.59 points at 2 years, p = 0.0004, n = 321). Compared to the original CMTES, the CMTES-R revealed a 55% improvement in the standardized response mean (mean change/SD change) at 2 years (0.17 vs 0.11). Change in CMTES-R at 2 years was greatest in mildly to moderately affected patients (1.48-point mean change, 95% confidence interval 0.99-1.97, p < 0.0001, for baseline CMTES-R score 0-9). CONCLUSION: The CMTES-R demonstrates change over time in patients with CMT1A and is more sensitive than the original CMTES. The CMTES-R was most sensitive to change in patients with mild to moderate baseline disease severity and failed to capture progression in patients with severe CMT1A. CLINICALTRIALSGOV IDENTIFIER: NCT01193075.

Diabetes mellitus exacerbates motor and sensory impairment in CMT1A.

Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a duplication of PMP22 on chromosome 17 and is the most commonly inherited demyelinating neuropathy. Diabetes frequently causes predominantly sensory neuropathy. Whether diabetes exacerbates CMT1A is unknown. We identified 10 patients with CMT1A and diabetes and compared their impairment with 48 age-matched control patients with CMT1A alone. Comparisons were made with the Charcot-Marie-Tooth disease (CMT) neuropathy score (CMTNS) and by electrophysiology. The CMTNS was significantly higher in patients with diabetes (20.25 +/- 2.35) compared with controls (15.19 +/- 0.69; p = 0.01). Values were particularly higher for motor signs and symptoms. Seven of the 10 diabetic patients had CMTNS >20 (severe CMT), while only 7 of the 48 age-matched controls had scores >20. There was a trend for CMT1A patients with diabetes to have low compound muscle action potentials and sensory nerve action potentials, although nerve conduction velocities were not slower in diabetic patients compared with controls. Diabetes was associated with more severe motor and sensory impairment in patients with CMT1A.

Cross-sectional analysis of a large cohort with X-linked Charcot-Marie-Tooth disease (CMTX1).

OBJECTIVE: To extend the phenotypic description of Charcot-Marie-Tooth disease (CMTX1) and to draw new genotype-phenotype relationships. METHODS: Mutations in GJB1 cause the main X-linked form of CMTX (CMTX1). We report cross-sectional data from 160 patients (from 120 different families, with 89 different mutations) seen at the Inherited Neuropathies Consortium centers. RESULTS: We evaluated 87 males who had a mean age of 41 years (range 10-78 years) and 73 females who had a mean age of 46 years (range 15-84 years). Sensory-motor polyneuropathy affects both sexes, more severely in males than in females, and there was a strong correlation between age and disease burden in males but not in females. Compared with females, males had more severe reduction in motor and sensory neurophysiology parameters. In contrast to females, the radial nerve sensory response in older males tended to be more severely affected compared with younger males. Median and ulnar nerve motor amplitudes were also more severely affected in older males, whereas ulnar nerve motor potentials tended to be more affected in older females. Conversely, there were no statistical differences between the sexes in other features of the disease, such as problems with balance and hand dexterity. CONCLUSIONS: In the absence of a phenotypic correlation with specific GJB1 mutations, sex-specific distinctions and clinically relevant attributes need to be incorporated into the measurements for clinical trials in people with CMTX1. CLINICALTRIALSGOV IDENTIFIER: NCT01193075.

Evaluation of a patient with suspected chronic demyelinating polyneuropathy.

Demyelinating neuropathies are typically characterized by physiological slowing of conduction velocity and pathologically by segmental loss of myelin and in some instances, evidence of remyelination. Clinically, patients with demyelinating neuropathy can be seen with inherited disorders (Charcot-Marie-Tooth disease) or acquired disorders, typically immune-mediated or inflammatory. The acquired disorders can be either acute or subacute as seen in the acute inflammatory demyelinating polyneuropathy (AIDP) form of Guillain-Barré syndrome or chronic progressive or relapsing disorders such as chronic inflammatory demyelinating polyneuropathy. It is important to develop a logical approach to diagnosing these disorders. This requires an understanding of the clinical, genetic, physiological, and pathological features of these neuropathies. Clinically, important features to consider are the temporal progression, degree of symmetry, and involvement of proximal as well as distal muscles. Genetically, recognizing the different inheritance patterns and age of onset allow for a coordinated approach to determining a specific genotype. Physiologically, besides nerve conduction slowing, other physiological hallmarks of demyelination include temporal dispersion of compound motor action potentials (CMAP) on proximal stimulation, conduction block, and distal CMAP duration prolongation with certain patterns of involvement pointing to specific disorders. This chapter focuses on these various aspects of the evaluation of patients with chronic acquired demyelinating neuropathies to develop a comprehensive and thoughtful diagnostic concept.

High-dosage ascorbic acid treatment in Charcot-Marie-Tooth disease type 1A: results of a randomized, double-masked, controlled trial.

IMPORTANCE: No current medications improve neuropathy in subjects with Charcot-Marie-Tooth disease type 1A (CMT1A). Ascorbic acid (AA) treatment improved the neuropathy of a transgenic mouse model of CMT1A and is a potential therapy. A lower dosage (1.5 g/d) did not cause improvement in humans. It is unknown whether a higher dosage would prove more effective. OBJECTIVE: To determine whether 4-g/d AA improves the neuropathy of subjects with CMT1A. DESIGN: A futility design to determine whether AA was unable to reduce worsening on the CMT Neuropathy Score (CMTNS) by at least 50% over a 2-year period relative to a natural history control group. SETTING: Three referral centers with peripheral nerve clinics (Wayne State University, Johns Hopkins University, and University of Rochester). PARTICIPANTS: One hundred seventy-four subjects with CMT1A were assessed for eligibility; 48 did not meet eligibility criteria and 16 declined to participate. The remaining 110 subjects, aged 13 to 70 years, were randomly assigned in a double-masked fashion with 4:1 allocation to oral AA (87 subjects) or matching placebo (23 subjects). Sixty-nine subjects from the treatment group and 16 from the placebo group completed the study. Two subjects from the treatment group and 1 from the placebo group withdrew because of adverse effects. INTERVENTIONS: Oral AA (4 g/d) or matching placebo. MAIN OUTCOMES AND MEASURES: Change from baseline to year 2 in the CMTNS, a validated composite impairment score for CMT. RESULTS: The mean 2-year change in the CMTNS was -0.21 for the AA group and -0.92 for the placebo group, both better than natural history (+1.33). This was well below 50% reduction of CMTNS worsening from natural history, so futility could not be declared (P > .99). CONCLUSIONS AND RELEVANCE: Both treated patients and those receiving placebo performed better than natural history. It seems unlikely that our results support undertaking a larger trial of 4-g/d AA treatment in subjects with CMT1A. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00484510.

Canaloplasty: circumferential viscodilation and tensioning of Schlemm canal using a flexible microcatheter for the treatment of open-angle glaucoma in adults: two-year interim clinical study results.

PURPOSE: To evaluate 2-year postsurgical safety and efficacy of canaloplasty (circumferential viscodilation and tensioning of the inner wall of Schlemm canal) to treat open-angle glaucoma (OAG). SETTING: Multicenter surgical sites. METHODS: This international prospective study comprised adult OAG patients having glaucoma surgery or combined glaucoma-cataract surgery. Qualifying preoperative intraocular pressure (IOP) was at least 16 mm Hg and historical IOP, at least 21 mm Hg. The full circumference of the canal was viscodilated and a trabecular tensioning suture placed with a microcatheter. Primary outcome measures included IOP and glaucoma medication use. RESULTS: At 24 months, all 127 eyes (127 patients) had a mean IOP of 16.0 mm Hg +/- 4.2 (SD) and mean glaucoma medication use of 0.5 +/- 0.8 (baseline values 23.6 +/- 4.8 mm Hg and 1.9 +/- 0.8 medications). Eyes with canaloplasty alone had a mean IOP of 16.3 +/- 3.7 mm Hg and 0.6 +/- 0.8 medications (baseline values 23.2 +/- 4.0 mm Hg and 2.0 +/- 0.8 medications). Eyes with combined glaucoma-cataract surgery had a mean IOP of 13.4 +/- 4.0 mm Hg and 0.2 +/- 0.4 medications (baseline values 23.1 +/- 5.5 mm Hg and 1.7 +/- 1.0 medications). The IOP and medication use results at all time points were statistically significant versus baseline (P <.001). The late postoperative follow-up identified 3 patients with elevated IOP. No other serious ocular or nonocular complications were reported. CONCLUSION: Canaloplasty was safe and effective in reducing IOP in adult patients with OAG.

Disorders of pulmonary function, sleep, and the upper airway in Charcot-Marie-Tooth disease.

Charcot-Marie Tooth disease (CMT) encompasses several inherited peripheral motor-sensory neuropathies and is one of the most common inherited neuromuscular diseases. Charcot-Marie-Tooth disease can be associated with several disorders that may be encountered by the pulmonary physician, including restrictive pulmonary impairment, sleep apnea, restless legs, and vocal cord dysfunction. Restrictive pulmonary impairment has been described in association with phrenic nerve dysfunction, diaphragm dysfunction, or thoracic cage abnormalities. Central sleep apnea may be associated with diaphragm dysfunction and hypercapnia, whereas obstructive sleep apnea has been reported as possibly due to a pharyngeal neuropathy. Restless legs and periodic limb movement during sleep are found in a large proportion of patients with CMT2, a type of CMT associated with prominent axonal atrophy. Vocal cord dysfunction, possibly due to laryngeal nerve involvement, is found in association with several CMT types and can often mimic asthma. There may be special therapeutic considerations for the treatment of those conditions in individuals with CMT. For instance, bi-level positive airway pressure may be more appropriate than continuous positive airway pressure (CPAP) for the treatment of sleep apnea in the individual with concomitant restrictive pulmonary impairment. The prominence of peripheral neuropathy as a cause of the restless legs syndrome in CMT may justify treatment with neuropathic medications as opposed to the more commonly recommended dopaminergic agents. The risk of progression to bilateral vocal cord dysfunction in CMT and the risk of aspiration with laryngeal neuropathy may limit the therapeutic options available for vocal cord paralysis.

Dispersion of compound muscle action potential in hereditary neuropathies and chronic inflammatory demyelinating polyneuropathy.

Distal compound muscle action potential (DCMAP) dispersion, defined as a DCMAP duration > or = 9 ms, and proximal-distal (P-D) CMAP dispersion are considered useful in the electrodiagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Distal and P-D CMAP dispersion have not been fully studied in hereditary neuropathies, and it is not known whether these measures distinguish hereditary from acquired demyelination. We compared DCMAP duration and P-D CMAP dispersion in 91 genetically characterized hereditary neuropathies and 33 subjects with CIDP. DCMAP dispersion was more frequent in nerves affected by CIDP (41.5%) than in Charcot-Marie-Tooth disease (CMT)1A (24.4%), CMT1B (7.4%), hereditary neuropathy with liability to pressure palsies (HNPP) (10.5%), or CMTX (9.8%). P-D CMAP dispersion was more frequent in CIDP (27.7% of nerves) than in hereditary neuropathies (16.3%) when applying American Academy of Neurology (AAN) criteria; however, its frequency was similar in CIDP and the hereditary neuropathies using the more restrictive criteria of the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM). Although dispersion is more common in CIDP than in the hereditary neuropathies, DCMAP and P-D dispersion occur in at least one motor nerve in a significant proportion of hereditary neuropathies, and cannot be used in isolation to distinguish acquired from hereditary demyelination.

Electrophysiologic Features of Inherited Demyelinating Neuropathies: A Reappraisal.

The observation that inherited demyelinating neuropathies tend to have uniform conduction slowing and acquired disorders (CIDP and variants) have nonuniform or multifocal slowing was made before the identification of genetic defects of specific myelin constituents that cause the different forms of Charcot-Marie-Tooth and other inherited disorders involving peripheral nerve myelin. It is becoming clear that the electrophysiologic aspects of these disorders are more complex than previously realized. We review the current information available on the electrophysiologic features of the inherited demyelinating neuropathies in hopes of clarifying the clinical electrodiagnostic features of these disorders as well as to shed light on the physiologic consequences of the different genetic mutations.

Motor unit number estimate of distal and proximal muscles in Charcot-Marie-Tooth disease.

In order to determine the utility of motor unit number estimation (MUNE) in assessing axonal loss in chronic inherited neuropathies, we determined MUNEs in 54 patients with Charcot-Marie-Tooth (CMT) disease (29 patients with CMT-1A, 13 with CMT-X, and 12 with CMT-2) by using spike-triggered averaging (STA) of the ulnar-innervated abductor digiti minimi/hypothenar muscles (ADM) and the musculo-cutaneous innervated biceps/brachialis (BB) muscles. MUNEs were analyzed in relationship to the corresponding compound muscle action potential (CMAP) amplitudes as well as to clinical strength. Proximal muscles, which appeared strong clinically, had evidence of chronic denervation/reinnervation, although to a lesser extent than weak distal hand muscles, supporting the concept that axonal loss in CMT occurs in a length-dependent fashion. The reduction in ADM-MUNE strongly correlated with clinical weakness in the hand. Both the ADM-MUNE and BB-MUNE were abnormal more often than CMAP amplitude, probably reflecting extensive motor unit reconfiguration and enlargement that maintains CMAP amplitude despite severe motor unit loss. This study suggests that MUNE can assess motor unit loss in CMT and may better reflect axonal loss than CMAP amplitude. The STA technique of MUNE may be useful in longitudinal studies of proximal and distal motor unit changes in CMT.

Phenotypic clustering in MPZ mutations.

Myelin protein zero (MPZ) is a member of the immunoglobulin gene superfamily with single extracellular, transmembrane and cytoplasmic domains. Homotypic interactions between extracellular domains of MPZ adhere adjacent myelin wraps to each other. MPZ is also necessary for myelin compaction since mice which lack MPZ develop severe dysmyelinating neuropathies in which compaction is dramatically disrupted. MPZ mutations in humans cause the inherited demyelinating neuropathy CMT1B. Some mutations cause the severe neuropathies of infancy designated as Dejerine-Sottas disease, while others cause a 'classical' Charcot-Marie-Tooth (CMT) disease Type 1B (CMT1B) phenotype with normal early milestones but development of disability during the first two decades of life. Still other mutations cause a neuropathy that presents in adults, with normal nerve conduction velocities, designated as a 'CMT2' form of CMT1B. To correlate the phenotype of patients with MPZ mutations with their genotype, we identified and evaluated 13 patients from 12 different families with eight different MPZ mutations. In addition, we re-analysed the clinical data from 64 cases of CMT1B from the literature. Contrary to our expectations, we found that most patients presented with either an early onset neuropathy with signs and symptoms prior to the onset of walking or a late onset neuropathy with signs and symptoms at around age 40 years. Only occasional patients presented with a 'classical' CMT phenotype. Correlation of specific MPZ mutations with their phenotypes demonstrated that addition of either a charged amino acid or altering a cysteine residue in the extracellular domain caused a severe early onset neuropathy. Severe neuropathy was also caused by truncation of the cytoplasmic domain or alteration of an evolutionarily conserved amino acid. Taken together, these data suggest that early onset neuropathy is caused by MPZ mutations that significantly disrupt the tertiary structure of MPZ and thus interfere with MPZ-mediated adhesion and myelin compaction. In contrast, late onset neuropathy is caused by mutations that more subtly alter myelin structure and which probably disrupt Schwann cell-axonal interactions.

Transient central nervous system white matter abnormality in X-linked Charcot-Marie-Tooth disease.

X-linked Charcot-Marie-Tooth disease (CMTX) is a hereditary demyelinating neuropathy caused by mutations in the connexin 32 (Cx32) gene. Cx32 is widely expressed in brain and peripheral nerve, yet clinical manifestations of CMTX mainly arise from peripheral neuropathy. We have evaluated two male patients with CMTX who on separate occasions developed transient ataxia, dysarthria, and weakness within 3 days of returning from ski trips at altitudes above 8,000 feet. Magnetic resonance imaging studies in both patients showed nonenhancing, confluent, and symmetrical white matter abnormalities that were more pronounced posteriorly and that resolved over several months. Magnetic transfer images in one patient demonstrated increased magnetization transfer ratios distinct from that seen in demyelination or edema. Both patients returned to their normal baseline within 2 to 3 weeks. These cases suggest that CMTX patients are at risk for developing an acute, transient, neurological syndrome when they travel to places at high altitudes and return to sea level. Cx32 mutations may cause central nervous system dysfunction by reducing the number of functioning gap junctions between oligodendrocytes and astrocytes, making both cells more susceptible to abnormalities of intercellular exchange of ions and small molecules in situations of metabolic stress.