Charcot-Marie-Tooth Disease with Myelin Protein Zero Mutation Presenting as Painful, Predominant Small-Fiber Neuropathy.

Charcot-Marie-Tooth disease (CMT) rarely presents with painful symptoms, which mainly occur in association with myelin protein zero (MPZ) gene mutations. We aimed to further characterize the features of painful neuropathic phenotypes in MPZ-related CMT. We report on a 58-year-old woman with a longstanding history of intermittent migrant pain and dysesthesias. Examination showed minimal clinical signs of neuropathy along with mild changes upon electroneurographic examination, consistent with an intermediate pattern, and small-fiber loss upon skin biopsy. Genetic testing identified the heterozygous variant p.Trp101Ter in MPZ. We identified another 20 CMT patients in the literature who presented with neuropathic pain as a main feature in association with MPZ mutations, mostly in the extracellular MPZ domain; the majority of these patients showed late onset (14/20), with motor-nerve-conduction velocities predominantly in the intermediate range (12/20). It is hypothesized that some MPZ mutations could manifest with, or predispose to, neuropathic pain. However, the mechanisms linking MPZ mutations and pain-generating nerve changes are unclear, as are the possible role of modifier factors. This peculiar CMT presentation may be diagnostically misleading, as it is suggestive of an acquired pain syndrome rather than of an inherited neuropathy.

Non-length-dependent small fiber neuropathy: Not a matter of stockings and gloves.

The clinical spectrum of small fiber neuropathy (SFN) encompasses manifestations related to the involvement of thinly myelinated A-delta and unmyelinated C fibers, including not only the classical distal phenotype, but also a non-length-dependent (NLD) presentation that can be patchy, asymmetrical, upper limb-predominant, or diffuse. This narrative review is focused on NLD-SFN. The diagnosis of NLD-SFN can be problematic, due to its varied and often atypical presentation, and diagnostic criteria developed for distal SFN are not suitable for NLD-SFN. The topographic pattern of NLD-SFN is likely related to ganglionopathy restricted to the small neurons of dorsal root ganglia. It is often associated with systemic diseases, but about half the time is idiopathic. In comparison with distal SFN, immune-mediated diseases are more common than dysmetabolic conditions. Treatment is usually based on the management of neuropathic pain. Disease-modifying therapy, including immunotherapy, may be effective in patients with identified causes. Future research on NLD-SFN is expected to further clarify the interconnected aspects of phenotypic characterization, diagnostic criteria, and pathophysiology.

Are novel outcome measures for Charcot-Marie-Tooth disease sensitive to change? The 6-minute walk test and StepWatch™ Activity Monitor in a 12-month longitudinal study.

Charcot-Marie-Tooth (CMT) is the most common inherited neuropathy, yet has no available pharmacological therapy. Past pharmacotherapy trials failed to provide positive results, possibly due to a poor choice of outcome measures. We previously performed a study in which we validated the 6-minute walk test and StepWatch™ Activity Monitor in CMT. The aim of the current study was to determine if these outcome measures are sensitive to change over a 12-month period. In this longitudinal multicenter study, 149 out of 169 initially enrolled patients were re-evaluated after 12 months using the 6-minute walk test, StepWatch™ Activity Monitor and other outcome measures commonly adopted in CMT disease. Statistical analysis showed a worsening of the CMT-Neuropathy Score (p < 0.05), strength of distal muscles measured by myometry (p < 0.05) and StepWatch™ Activity Monitor outputs (p < 0.05). The 10 meter walking test (p > 0.05), muscular strength as detected by clinical evaluation (p > 0.05), 6-minute walk test (p > 0.05), pain (p > 0.05) and quality of life (p > 0.05) showed no change. In the current study, patients showed clinical worsening over 12 months, confirmed by a reduction of activity as detected by StepWatch™ Activity Monitor. The 6-minute walk test failed to detect change.

Selected items from the Charcot-Marie-Tooth (CMT) Neuropathy Score and secondary clinical outcome measures serve as sensitive clinical markers of disease severity in CMT1A patients.

This study evaluates primary and secondary clinical outcome measures in Charcot-Marie-Tooth disease type 1A (CMT1A) with regard to their contribution towards discrimination of disease severity. The nine components of the composite Charcot-Marie-Tooth disease Neuropathy Score and six additional secondary clinical outcome measures were assessed in 479 adult patients with genetically proven CMT1A and 126 healthy controls. Using hierarchical clustering, we identified four significant clusters of patients according to clinical severity. We then tested the impact of each of the CMTNS components and of the secondary clinical parameters with regard to their power to differentiate these four clusters. The CMTNS components ulnar sensory nerve action potential (SNAP), pin sensibility, vibration and strength of arms did not increase the discriminant value of the remaining five CMTNS components (Ulnar compound motor action potential [CMAP], leg motor symptoms, arm motor symptoms, leg strength and sensory symptoms). However, three of the six additional clinical outcome measures - the 10m-timed walking test (T10MW), 9 hole-peg test (9HPT), and foot dorsal flexion dynamometry - further improved discrimination between severely and mildly affected patients. From these findings, we identified three different composite measures as score hypotheses and compared their discriminant power with that of the CMTNS. A composite of eight components CMAP, Motor symptoms legs, Motor symptoms arms, Strength of Legs, Sensory symptoms), displayed the strongest power to discriminate between the clusters. As a conclusion, five items from the CMTNS and three secondary clinical outcome measures improve the clinical assessment of patients with CMT1A significantly and are beneficial for upcoming clinical and therapeutic trials.

Painful polyneuropathy associated with restless legs syndrome. Clinical features and sensory profile.

BACKGROUND: The association of restless legs syndrome (RLS) with polyneuropathy, and its prevalence, have been evaluated differently throughout various studies. As subtypes of polyneuropathy characterized by neuropathic pain seem to be preferentially associated with RLS, we intended to investigate the prevalence and the features of RLS occurring with painful neuropathy, and to define whether there is a specific sensory phenotype. METHODS: We prospectively investigated 58 consecutive patients with distal symmetric polyneuropathy and neuropathic pain or dysesthesia, using a bedside protocol for sensory assessment. RLS was diagnosed with an interview assessing the International RLS Study Group diagnostic criteria. RESULTS: Overall, RLS was reported by 21 patients (36.2%), but it was occurring at the time of the evaluation in 12 patients (20.7%), significantly more than in controls. RLS was chronic in nine patients and remitting-intermittent in 12 patients. No difference was demonstrated between patients with or without RLS. Comparing patients with chronic RLS and remitting-intermittent RLS, the latter had more severe electrophysiological changes, whereas hyperalgesia, suggesting central sensitization, was significantly more frequent in chronic RLS patients. CONCLUSIONS: RLS is frequently associated with painful polyneuropathy, in keeping with the hypothesis that its occurrence is favored by small fiber involvement. It represents a heterogeneous entity, differentiated in chronic and remitting-intermittent subtypes, possibly conditioned by indolent or aggressive neuropathy course and phenomena of central sensitisation.

Ascorbic acid in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial.

BACKGROUND: Ascorbic acid reduced the severity of neuropathy in transgenic mice overexpressing peripheral myelin protein 22 (PMP22), a model of Charcot-Marie-Tooth disease type 1A (CMT1A) associated with the PMP22 duplication. However, in three 1-year trials, ascorbic acid had no benefit in human beings. We did a multicentre 2-year trial to test the efficacy and tolerability of ascorbic acid in patients with CMT1A. METHODS: Adult patients (aged 18-70 years) with symptomatic CMT1A were enrolled from nine centres in Italy and the UK, and were randomly assigned (1:1 ratio) to receive 1·5 g/day oral ascorbic acid or matching placebo for 24 months. The randomisation sequence was computer generated by block randomisation, stratified by centre and disease severity, and patients were allocated to treatment by telephone. The primary outcome was change in the CMT neuropathy score (CMTNS) at 24 months. Secondary outcomes were timed 10 m walk test, nine-hole peg test, overall neuropathy limitations scale, distal maximal voluntary isometric contraction, visual analogue scales for pain and fatigue, 36-item short-form questionnaire, and electrophysiological measurements. Patients, treating physicians, and physicians assessing outcome measures were masked to treatment allocation. Analysis of the primary outcome was done on all randomised patients who received at least one dose of study drug. This study is registered, numbers ISRCTN61074476 (CMT-TRAUK) and EudraCT 2006-000032-27 (CMT-TRIAAL). FINDINGS: We enrolled and randomly assigned 277 patients, of whom six (four assigned to receive ascorbic acid) withdrew consent before receiving treatment; 138 receiving ascorbic acid and 133 receiving placebo were eligible for analysis. Treatment was well tolerated: 241 of 271 patients (89% in each group) completed the study; 20 patients (nine receiving ascorbic acid) dropped out because of adverse events. Mean CMTNS at baseline with missing data imputed was 14·7 (SD 4·8) in the ascorbic acid group and 13·9 (4·2) in the placebo group. Mean worsening of CMTNS was 0·2 (SD 2·8, 95% CI -0·3 to 0·7) in the ascorbic acid group and 0·2 (2·7, -0·2 to 0·7) in the placebo group (mean difference 0·0, 95% CI -0·6 to 0·7; p=0·93). We recorded no differences between the groups for the secondary outcomes at 24 months. 21 serious adverse events occurred in 20 patients, eight in the ascorbic acid group and 13 in the placebo group. INTERPRETATION: Ascorbic acid supplementation had no significant effect on neuropathy compared with placebo after 2 years, suggesting that no evidence is available to support treatment with ascorbic acid in adults with CMT1A. FUNDING: Telethon-UILDM and AIFA (Italian Medicines Agency) for CMT-TRIAAL, and Muscular Dystrophy Campaign for CMT-TRAUK.