ascorbic-acid and Charcot-Marie-Tooth-Disease

CMT1A is the most common inherited peripheral neuropathy. There is currently no approved treatment. We performed a meta-analysis including four randomized, double-blind, Placebo-controlled clinical trials to assess the disease progression after one year under Placebo, Ascorbic Acid (AA) or PXT3003, a combination of three repurposed drugs. We observed a weak deterioration in patients under Placebo, well below the reported natural disease progression. Patients treated with AA were stable after one year but not significantly different from Placebo. Patients undergoing PXT3003 treatment showed an improvement in CMTNS and ONLS, statistically significant versus Placebo and potentially precursory of a meaningful change in the disease course.

Topics: Antioxidants; Ascorbic Acid; Charcot-Marie-Tooth Disease; Humans; Randomized Controlled Trials as Topic

Charcot-Marie-Tooth disease type 1A (CMT1A) is a disease for which no drug treatments are available. Passage et al. reported that ascorbic acid reduced the mRNA level of PMP22, improved motor function and increased the numbers of myelinated peripheral nerve axons in a mouse model of CMT1A. Based on these results, five clinical trials were undertaken at different centers worldwide. However, none of them demonstrated significant effectiveness. Although these outcomes were disappointing, these studies have provided many useful insights for conducting the next randomised controlled trial for CMT1A.

Topics: Animals; Ascorbic Acid; Charcot-Marie-Tooth Disease; Clinical Trials as Topic; Humans; Proteins

Charcot-Marie-Tooth disease (CMT) comprises a large group of different forms of hereditary motor and sensory neuropathy. The molecular basis of several CMT subtypes has been clarified during the last 20 years. Since slowly progressive muscle weakness and sensory disturbances are the main features of these syndromes, treatments aim to improve motor impairment and sensory disturbances to improve abilities. Pharmacological treatment trials in CMT are rare. This review was derived from a Cochrane review, Treatment for Charcot Marie Tooth disease, which will be updated via this review and a forthcoming title, Treatments other than ascorbic acid for Charcot-Marie-Tooth disease.. To assess the effects of ascorbic acid (vitamin C) treatment for CMT.. On 21 September 2015, we searched the Cochrane Neuromuscular Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and LILACS for randomised controlled trials (RCTs) of treatment for CMT. We also checked clinical trials registries for ongoing studies.. We included RCTs and quasi-RCTs of any ascorbic acid treatment for people with CMT. Where a study aimed to evaluate the treatment of general neuromuscular symptoms of people with peripheral neuropathy including CMT, we included the study if we were able to identify the effect of treatment in the CMT group. We did not include observational studies or case reports of ascorbic acid treatment in people with CMT.. Two review authors (BG and JB) independently extracted the data and assessed study quality.. Six RCTs compared the effect of oral ascorbic acid (1 to 4 grams) and placebo treatment in CMT1A. In five trials involving adults with CMT1A, a total of 622 participants received ascorbic acid or placebo. Trials were largely at low risk of bias. There is high-quality evidence that ascorbic acid does not improve the course of CMT1A in adults as measured by the CMT neuropathy score (0 to 36 scale) at 12 months (mean difference (MD) -0.37; 95% confidence intervals (CI) -0.83 to 0.09; five studies; N = 533), or at 24 months (MD -0.21; 95% CI -0.81 to 0.39; three studies; N = 388). Ascorbic acid treatment showed a positive effect on the nine-hole peg test versus placebo (MD -1.16 seconds; 95% CI -1.96 to -0.37), but the clinical significance of this result is probably small. Meta-analyses of other secondary outcome parameters showed no relevant benefit of ascorbic acid. In one trial, 80 children with CMT1A received ascorbic acid or placebo. The trial showed no clinical benefit of ascorbic acid treatment. Adverse effects did not differ in their nature or abundance between ascorbic acid and placebo.. High-quality evidence indicates that ascorbic acid does not improve the course of CMT1A in adults in terms of the outcome parameters used. According to low-quality evidence, ascorbic acid does not improve the course of CMT1A in children. However, CMT1A is slowly progressive and the outcome parameters show only small change over time. Longer study durations should be considered, and outcome parameters more sensitive to change over time should be designed and validated for future studies.

Topics: Adult; Ascorbic Acid; Charcot-Marie-Tooth Disease; Humans; Randomized Controlled Trials as Topic

Persistent feelings of fatigue (or subjective fatigue), which may be experienced in the absence of physiological factors, affect many people with peripheral neuropathy. A variety of interventions for subjective fatigue are available, but little is known about their efficacy or the likelihood of any adverse effects for people with peripheral neuropathy.. To assess the effects of drugs and physical, psychological or behavioural interventions for fatigue in adults or children with peripheral neuropathy.. On 5 November 2013, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, CINAHL Plus, LILACS and AMED. We also searched reference lists of all studies identified for inclusion and relevant reviews, and contacted the authors of included studies and known experts in the field to identify additional published or unpublished data. We also searched trials registries for ongoing studies.. We considered for inclusion randomised controlled trials (RCTs) and quasi-RCTs comparing any form of intervention for fatigue management in adults with peripheral neuropathy with placebo, no intervention or an alternative form of intervention for fatigue. Interventions considered included drugs, pacing and grading of physical activity, general or specific exercise, compensatory strategies such as orthotics, relaxation, counselling, cognitive and educational strategies.. Two review authors independently assessed risk of bias and extracted study data. We contacted study authors for additional information. We collected information on adverse events from the included trials.. The review includes three trials, which were all at low risk of bias, involving 530 people with peripheral neuropathy. The effects of amantadine from one randomised, double-blind, placebo-controlled, cross-over trial comparing amantadine with placebo for the treatment of fatigue in 80 people with Guillain-Barré syndrome (GBS) were uncertain for the proportion of people achieving a favourable outcome six weeks post-intervention (odds ratio (OR) 0.56 (95% confidence interval (CI) 0.22 to 1.35, N = 74, P = 0.16). We assessed the quality of this evidence as low. Two parallel-group randomised double-blind, placebo-controlled trials comparing the effects of two doses of ascorbic acid with placebo for reducing fatigue in adults with Charcot-Marie-Tooth disease type 1A (CMT1A) showed that the effects of ascorbic acid at either dose are probably small (standardised mean difference (SMD) -0.12 (95% CI -0.32 to 0.08, n = 404, P = 0.25)) for change in fatigue after 12 to 24 months (moderate quality evidence). Neither ascorbic acid study measured fatigue at four to 12 weeks, which was our primary outcome measure. No serious adverse events were reported with amantadine. Serious adverse events were reported in the trials of ascorbic acid. However,risk of serious adverse events was similar with ascorbic acid and placebo.. One small imprecise study in people with GBS showed uncertain effects of amantadine on fatigue. In two studies in people with CMT1A there is moderate-quality evidence that ascorbic acid has little meaningful benefit on fatigue. Information about adverse effects was limited, although both treatments appear to be well tolerated and safe in these conditions.There was no evidence available from RCTs to evaluate the effect of other drugs or other interventions for fatigue in either GBS, CMT1A or other causes of peripheral neuropathy. The cost effectiveness of different interventions should also be considered in future randomised clinical trials.

Topics: Adult; Amantadine; Ascorbic Acid; Charcot-Marie-Tooth Disease; Child; Fatigue; Guillain-Barre Syndrome; Humans; Peripheral Nervous System Diseases; Randomized Controlled Trials as Topic

Ascorbic acid and sodium-dependent vitamin C transporters (SVCT) have been shown to have important functions in the peripheral nervous system (PNS). Ascorbic acid is known to promote myelination in vitro in Schwann cell/dorsal root ganglion co-cultures by the formation of a collagen- and laminin-containing extracellular matrix.. Recently, the function of ascorbic acid and SVCT2 in the PNS has been shown in vivo as well. Several studies on ascorbic acid treatment of Charcot-Marie-Tooth neuropathy 1A (CMT1A) have been completed and showed no clinical benefit.. Possible reasons for the failure of ascorbic acid in CMT1A treatment are discussed in this review. More preclinical trials, ideally using different animal models, should be considered before the initiation of clinical trials in humans. More knowledge about ascorbic acid transport kinetics and inter-individual differences in humans is necessary for future studies.. Further research into ascorbic acid transport mechanisms in the PNS is warranted. Especially the effects of transgenic or pharmacologic SVCT2 up-regulation on PNS myelination and remyelination will be an interesting area of research in the future. Furthermore, the potential use of ascorbic acid for peripheral neuropathies other than CMT1A would be a possible future research direction.

Topics: Animals; Ascorbic Acid; Charcot-Marie-Tooth Disease; Humans; Nerve Fibers, Myelinated; Peripheral Nervous System; Randomized Controlled Trials as Topic; Sodium-Coupled Vitamin C Transporters

Charcot-Marie-Tooth disease (CMT), also called hereditary motor and sensory neuropathy (HMSN), is the most common inherited peripheral neuropathy, comprised by a group of genetically heterogeneous disorders that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, and depressed tendon reflexes. It can be categorized according to its electrophysiological or pathological features, transmission patterns, age of disease onset, and molecular pathology. CMT type 1 (CMT1; MIM 118200) is a group of autosomal dominant-inherited demyelinating neuropathies with a disease onset at or after childhood. Five different subtypes have been identified based on different causative genes. Among them, CMT1A (MIM #118220) is most common and is usually associated with a duplication of a 1.5-Mb region on chromosome 17p11.2, which includes peripheral myelin protein 22 gene (PMP22; MIM *601097). Currently, there is no cure or obviously effective disease-modifying treatment for CMT. Two potential effective therapeutic agents for CMT1A were investigated recently. One is ascorbic acid and another is neurotrophin-3 (NT-3), an important component of the Schwann cell autocrine survival loop. Early diagnosis can facilitate CMT patients to modify their life styles timely for minimizing nerve injury to delay or avoid disability. Molecular diagnosis of CMT can provide the basis for appropriate genetic counseling and further CMT research.

Topics: Animals; Ascorbic Acid; Charcot-Marie-Tooth Disease; Disease Models, Animal; Humans

Hereditary neuropathies are classified into Charcot-Marie-Tooth disease (CMT), familial amyloid polyneuropathy (FAP), hereditary motor neuropathies (HMN) and hereditary sensory (and autonomic) neuropathies (HSAN). CMTs are furthermore classified into demyelinating neuropathies (CMT1), axonal neuropathies (CMT2) and intermediate form. Duplication of PMP22 (CMT1A) accounts for about 70% of CMT1 and MFN2 mutations account for 25% of CMT2. Genes involved in phosphoinositide regulation cause CMT4; MTMR2 mutation in CMT 4B1 and MTMR13/SBF2 mutation in CMT4B2. In addition to these genes, FIG4, which is a causative gene of pale tremor mouse, is newly identified as a gene for CMT4J. MFN2 and GDAP1 cause CMT2 or CMT4. These genes regulate mitochondrial fusion and fission. Altered axonal mitochondrial transport is suggested as the pathogenesis of the CMT. In animal model with pmp22 duplication, ascorbic acid seems to be effective to prevent disease progression. Nationwide trial of ascorbic acid therapy for CMT1A is now ongoing by the intractable neuropathy study group. Curcumin treatment educes apoptosis of cells that express PMP22 point mutation and partially mitigates the severe neuropathy phenotype of Trembler-J mouse model in a dose-dependent manner. Curcumin treatment may have a potential therapeutic role in CMT with PMP22 point mutation in humans. The high throughput system of diagnosis for CMT has been developed by employing a resequencing array system.

Topics: Animals; Ascorbic Acid; Charcot-Marie-Tooth Disease; Curcumin; Humans; Mice; Myelin Proteins; Oligonucleotide Array Sequence Analysis; Point Mutation

The most frequent genetic subtype of Charcot-Marie-Tooth disease is CMT1A, linked to chromosome 17p11.2. In the majority of cases, CMT1A is a gene dosage disease associated with a 1.5 Mb large genomic duplication. Transgenic models with extra copies of the Pmp22 gene have provided formal proof that overexpression of only this candidate gene is sufficent to cause peripheral demyelination, onion bulb formation, secondary axonal loss, and progressive muscle atrophy, the pathological hallmarks of CMT1A. The transgenic CMT rat with about 1.6-fold PMP22 overexpression exhibits clinical abnormalities, such as reduced nerve conduction velocity and lower grip strength that mimick findings in CMT1A patients. Also transgenic mice, carrying yeast artifical chromosomes as Pmp22 transgenes, demonstrate the variability of disease expression as a function of increased gene dosage. Recently, the first rational experimental therapies of CMT1A were tested, using transgenic animal models. In one proof-of-principle study with the CMT rat, a synthetic antagonist of the nuclear progesterone receptor was shown to reduce PMP22 overexpression and to ameliorate the clinical severity. In another study, administration of ascorbic acid, an essential factor of in vitro myelination, prolonged the survival and restored myelination of a dysmyelinated mouse model. Application of gene expression analysis to nerve biopsies that are readily available from such CMT1A animal models might identify additional pharmacological targets.

Topics: Animals; Animals, Genetically Modified; Antioxidants; Ascorbic Acid; Charcot-Marie-Tooth Disease; Chromosomes, Human, Pair 17; Disease Models, Animal; Gene Dosage; Humans; Myelin Proteins; Neuroprotective Agents; Progesterone

The purpose of this review is to assist neurologists, neuroscientists and other interested readers in following the expanding volume of information relating to the inherited peripheral neuropathies collectively referred to as Charcot-Marie-Tooth disease. Currently, mutations in multiple different genes expressed in Schwann cells and neurons cause a variety of overlapping clinical phenotypes.. Recent articles clarify molecular pathways involved in the pathogenesis of these disorders, and for the first time provide rational treatment strategies for the most common form of Charcot-Marie-Tooth disease. The identification of many new genes associated with neuropathy demonstrate the role of axonal transport and abnormal protein trafficking in causing various forms of Charcot-Marie-Tooth. They also further define the role of axonal signaling and the molecular architecture of both Schwann cells and neurons in maintaining normal peripheral nervous system function. Finally, recent reports have shown that progesterone antagonists and ascorbic acid can successfully treat rodent models of Charcot-Marie-Tooth disease type 1A.. Taken together, results from these articles support the concept that genetic causes of Charcot-Marie-Tooth disease serve as a living microarray system to identify molecules necessary for normal peripheral nervous system function. When we can make sense of these microarrays we are likely to understand the pathogenesis and develop rational therapies for many neurodegenerative diseases including Charcot-Marie-Tooth.

Topics: Animals; Ascorbic Acid; Axonal Transport; Charcot-Marie-Tooth Disease; Glycine-tRNA Ligase; GTP Phosphohydrolases; Heat-Shock Proteins; Humans; Membrane Proteins; Mitochondrial Proteins; Myelin Proteins; Nerve Fibers, Myelinated; Nuclear Proteins; Progesterone; Protein Transport; Protein Tyrosine Phosphatases; Protein Tyrosine Phosphatases, Non-Receptor; rab GTP-Binding Proteins; rab7 GTP-Binding Proteins; Schwann Cells; Transcription Factors

Topics: Animals; Ascorbic Acid; Charcot-Marie-Tooth Disease; Connexins; Electrophysiology; Gap Junction beta-1 Protein; Gonanes; Hormone Antagonists; Humans; Mice; Myelin P0 Protein; Myelin Proteins; Peripheral Nervous System; Potassium Channels; Proteins; Rats

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.

Topics: Adolescent; Adult; Age Factors; Antioxidants; Ascorbic Acid; Charcot-Marie-Tooth Disease; Cluster Analysis; Cohort Studies; Disease Progression; Double-Blind Method; Female; Humans; Male; Middle Aged; Muscle Strength; Outcome Assessment, Health Care; Pain Measurement; Psychomotor Performance; Severity of Illness Index; Walking; Young Adult

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.. To determine whether 4-g/d AA improves the neuropathy of subjects with CMT1A.. 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.. Three referral centers with peripheral nerve clinics (Wayne State University, Johns Hopkins University, and University of Rochester).. 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.. Oral AA (4 g/d) or matching placebo.. Change from baseline to year 2 in the CMTNS, a validated composite impairment score for CMT.. 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).. 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.. clinicaltrials.gov Identifier: NCT00484510.

Topics: Adolescent; Adult; Aged; Animals; Antioxidants; Ascorbic Acid; Charcot-Marie-Tooth Disease; Disease Models, Animal; Disease Progression; Double-Blind Method; Female; Humans; Male; Medical Futility; Mice; Middle Aged; Severity of Illness Index; Time Factors; Young Adult

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.. 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).. 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.. 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.. Telethon-UILDM and AIFA (Italian Medicines Agency) for CMT-TRIAAL, and Muscular Dystrophy Campaign for CMT-TRAUK.

Topics: Adolescent; Adult; Aged; Antioxidants; Ascorbic Acid; Charcot-Marie-Tooth Disease; Double-Blind Method; Female; Humans; Male; Middle Aged; Treatment Outcome

Topics: Adolescent; Ascorbic Acid; Charcot-Marie-Tooth Disease; Child; Double-Blind Method; Female; Humans; Male; Vitamins

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited nerve disorder. CMT1A is characterised by peripheral nerve demyelination, weakness, and impaired motor function and is caused by the duplication of PMP22, the gene that encodes peripheral myelin protein 22. High-dose ascorbic acid has been shown to have remyelinating potential and to correct the phenotype of a transgenic mouse model of CMT1A by decreasing expression of PMP22. We tested the efficacy and safety of ascorbic acid supplementation in children with CMT1A.. This 12-month, randomised, double-blind, placebo-controlled trial undertaken between June, 2007, and December, 2008, assessed high-dose oral ascorbic acid (about 30 mg/kg/day) in 81 children with CMT1A (2-16 years). Randomisation was done on a 1:1 ratio by a computer-generated algorithm. All investigators and participants were blinded to treatment allocation with the exception of the trial pharmacist. The primary efficacy outcome was median nerve motor conduction velocity (m/s) at 12 months. Secondary outcomes were foot and hand strength, motor function, walking ability, and quality of life. Compliance was measured by plasma ascorbic acid concentration, pill count, and medication diary entries. Analysis was by intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, Number 12606000481572.. 81 children were randomly assigned to receive high-dose ascorbic acid (n=42) or placebo (n=39). 80 children completed 12 months of treatment. The ascorbic acid group had a small, non-significant increase in median nerve motor conduction velocity compared with the placebo group (adjusted mean difference 1.7 m/s, 95% CI -0.1 to 3.4; p=0.06). There was no measurable effect of ascorbic acid on neurophysiological, strength, function, or quality of life outcomes. Two children in the ascorbic acid group and four children in the placebo group reported gastrointestinal symptoms. There were no serious adverse events.. 12 months of treatment with high-dose ascorbic acid was safe and well tolerated but none of the expected efficacy endpoints were reached.

Topics: Administration, Oral; Adolescent; Age Factors; Antioxidants; Ascorbic Acid; Charcot-Marie-Tooth Disease; Child; Child, Preschool; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Neural Conduction; Retrospective Studies; Treatment Outcome

Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary peripheral neuropathy that affects roughly one in 5000 births. No specific therapy currently exists for this degenerative disorder, which is characterised by distal progressive muscle atrophy and sensory loss, although ascorbic acid has been shown to reduce demyelination and improve muscle function in a transgenic mouse model of CMT1A. We tested the safety and efficacy of ascorbic acid in adults with CMT1A.. This 12-month, randomised, double-blind, placebo-controlled study was undertaken between September, 2005, and October, 2008. Patients diagnosed with CMT1A according to clinical examination and confirmation by genotyping were randomly assigned in a 1:1:1 ratio to receive 1 g ascorbic acid per day, 3 g ascorbic acid per day, or placebo. Treatment allocation was based on a computer-generated list of random numbers in blocks of 12, with stratification according to study site and sex; all investigators and participants were unaware of treatment allocation. The primary outcome was the Charcot-Marie-Tooth disease neuropathy score (CMTNS) at 12 months. Analysis was by intention to treat. This study is registered with the Orphanet Database, number ORPHA60779.. The median change in CMTNS from baseline to 12 months was 0.5 points (95% CI -0.3 to 1.4) for the placebo group (n=62), 0.7 points (0.0 to 1.4) for the 1 g ascorbic acid group (n=56), and -0.4 points (-1.2 to 0.4) for the 3 g ascorbic acid group (n=61). We did not find any significant difference in these changes between the groups (p=0.14). The occurrence of adverse events did not differ between the groups (p=0.74).. Ascorbic acid at both doses was safe and well tolerated in adults with CMT1A over 12 months. However, there were no significant differences between the groups and the efficacy of ascorbic acid was not shown.

Topics: Adult; Antioxidants; Ascorbic Acid; Charcot-Marie-Tooth Disease; Double-Blind Method; Female; Hand Strength; Humans; Male; Middle Aged; Movement; Muscle Strength; Random Allocation; Sensation; Socioeconomic Factors; Treatment Outcome; Walking

High dose oral ascorbic acid substantially improved myelination and locomotor function in a Charcot-Marie-Tooth type 1A mouse model. A phase II study was warranted to investigate whether high dose ascorbic acid also has such a substantial effect on myelination in Charcot-Marie-Tooth type 1A patients and whether this treatment is safe.. Patients below age 25 years were randomly assigned to receive placebo or ascorbic acid (one gram twice daily) in a double-blind fashion during one year. The primary outcome measure was the change over time in motor nerve conduction velocity of the median nerve. Secondary outcome measures included changes in minimal F response latencies, compound muscle action potential amplitude, muscle strength, sensory function, Charcot-Marie-Tooth neuropathy score, and disability.. There were no significant differences between the six placebo-treated (median age 16 years, range 13 to 24) and the five ascorbic acid-treated (19, 14 to 24) patients in change in motor nerve conduction velocity of the median nerve (mean difference ascorbic acid as opposed to placebo treatment of 1.3 m/s, confidence interval -0.3 to 3.0 m/s, P = 0.11) or in change of any of the secondary outcome measures over time. One patient in the ascorbic acid group developed a skin rash, which led to discontinuation of the study medication.. Oral high dose ascorbic acid for one year did not improve myelination of the median nerve in young Charcot-Marie-Tooth type 1A patients. Treatment was relatively safe.. Current Controlled Trials ISRCTN56968278, ClinicalTrials.gov NCT00271635.

Topics: Administration, Oral; Adolescent; Ascorbic Acid; Charcot-Marie-Tooth Disease; Double-Blind Method; Female; Humans; Male; Median Nerve; Muscle Strength; Neural Conduction; Placebos; Sensation; Severity of Illness Index; Treatment Outcome; Vitamins; Young Adult

We assessed inter- and intra-rater reliability of outcome measures in Charcot-Marie-Tooth disease (CMT) patients. In 40 CMT patients, we assessed reliability of Overall Neuropathy Limitations Scale (ONLS), 10-m timed walk (T10MW), 9-hole-peg test (9-HPT), maximal voluntary isometric contraction (MVIC) of arm (elbow flexion, hand-grip, and three-point pinch) and leg (knee extension, foot dorsiflexion/plantar flexion). Reliability was substantial for ONLS, excellent for T10MW and 9-HPT. For MVIC, inter and intra-rater reliability was excellent for hand contractions; for leg contractions, intra-rater agreement was moderate to substantial, whereas inter-rater agreement was poor. An ad hoc device was produced to immobilize the foot and MVIC reliability was re-assessed in 26 CMT patients, resulting in excellent inter-rater and intra-rater reliability for foot dorsiflexion, and clear inter-rater improvement for foot plantar flexion. All outcome measures appear adequate for CMT assessment. Use of an immobilization device improves foot MVIC reliability, preventing biased findings in patients with greater strength.

Topics: Adolescent; Adult; Aged; Arm; Ascorbic Acid; Charcot-Marie-Tooth Disease; Disability Evaluation; Female; Humans; Leg; Male; Middle Aged; Movement; Muscle Contraction; Muscle Weakness; Muscle, Skeletal; Neurologic Examination; Observer Variation; Placebo Effect; Predictive Value of Tests; Reproducibility of Results; Restraint, Physical; Treatment Outcome

There is no treatment for Charcot-Marie-Tooth disease 1A (CMT1A), but ascorbic acid (AA) is efficacious in the transgenic mouse model. Thus, a clinical trial of AA in CMT1A is warranted. The CMT-TRIAAL is a phase III randomized, double-blind, placebo-controlled study involving 222 CMT1A adults from eight Italian centers. Eligible for the study are symptomatic adults with genetically confirmed CMT1A. Treatment consists of 2-year oral AA (1500mg/day) or placebo. The primary trial endpoint is an improvement in CMT Neuropathy Score. Secondary efficacy endpoints are changes in distal arm and leg maximum voluntary isometric contraction; 10m timed walking; 9-hole-peg test; overall neuropathy limitations scale; pain and fatigue visual analog scales; health-related quality of life (SF-36); and electrophysiology. Clinical-electrophysiological assessments are performed at baseline and every 6 months thereafter. In consenting patients from three centers, skin biopsy is performed to evaluate PMP22 expression. The study will last 34 months, starting from March 2006.

Topics: Adolescent; Adult; Aged; Antioxidants; Ascorbic Acid; Charcot-Marie-Tooth Disease; Double-Blind Method; Endpoint Determination; Female; Follow-Up Studies; Humans; Italy; Male; Middle Aged; Sample Size

Topics: Animals; Antioxidants; Ascorbic Acid; Charcot-Marie-Tooth Disease; Female; Humans; Male; Medical Futility

Topics: Ascorbic Acid; Charcot-Marie-Tooth Disease; Humans; Treatment Outcome

Ascorbic acid (vitamin C) is necessary for myelination of Schwann cell/neuron cocultures and has shown beneficial effects in the treatment of a Charcot-Marie-Tooth neuropathy 1A (CMT1A) mouse model. Although clinical studies revealed that ascorbic acid treatment had no impact on CMT1A, it is assumed to have an important function in peripheral nerve myelination and possibly in remyelination. However, the transport pathway of ascorbic acid into peripheral nerves and the mechanism of ascorbic acid function in peripheral nerves in vivo remained unclear. In this study, we used sodium-dependent vitamin C transporter 2-heterozygous (SVCT2(+/-)) mice to elucidate the functions of SVCT2 and ascorbic acid in the murine peripheral nervous system. SVCT2 and ascorbic acid levels were reduced in SVCT2(+/-) peripheral nerves. Morphometry of sciatic nerve fibers revealed a decrease in myelin thickness and an increase in G-ratios in SVCT2(+/-) mice. Nerve conduction velocities and sensorimotor performance in functional tests were reduced in SVCT2(+/-) mice. To investigate the mechanism of ascorbic acid function, we studied the expression of collagens in the extracellular matrix of peripheral nerves. Here, we show that expression of various collagen types was reduced in sciatic nerves of SVCT2(+/-) mice. We found that collagen gene transcription was reduced in SVCT2(+/-) mice but hydroxyproline levels were not, indicating that collagen formation was regulated on the transcriptional and not the posttranslational level. These results help to clarify the transport pathway and mechanism of action of ascorbic acid in the peripheral nervous system and may lead to novel therapeutic approaches to peripheral neuropathies by manipulation of SVCT2 function.

Topics: Animals; Ascorbic Acid; Cells, Cultured; Charcot-Marie-Tooth Disease; Coculture Techniques; Extracellular Matrix; Female; Male; Mice; Mice, Knockout; Nerve Fibers, Myelinated; Peripheral Nervous System; Sodium-Coupled Vitamin C Transporters

Preclinical studies have suggested that ascorbic acid (AA) treatment in a mouse model of Charcot-Marie-Tooth type 1A (CMT1A) improves motor function and prolongs lifespan.. I sought to determine the safety and tolerability of AA in adult patients with CMT1A.. An open-label cohort-controlled 2-year pilot study was used to evaluate the tolerability of 5 g of AA daily. Secondary measurements consisted of clinical and electrophysiological measurements at 0, 12, and 24 months in CMT1A patients.. Twelve CMT1A patients received AA and 10 CMT1A patients formed a cohort group followed in identical manner. Five (42%) patients tolerated this dose of AA for the entire 2-year span, with six patients (50%) developing intolerable gastrointestinal side effects. No significant differences in clinical, disability, or electrophysiological measurements occurred between baseline and final follow-up in patients receiving AA when compared with cohorts.. High dose AA was not well tolerated in all adult CMT1A patients who may be susceptible to gastrointestinal adverse effects of AA. Studies with greater powers to detect efficacy will be required to test the validity of AA as a therapy in CMT1A patients. Doses lower than 5 g of AA daily may be required for maintenance of tolerability in the CMT1A population.

Topics: Adult; Antioxidants; Ascorbic Acid; Charcot-Marie-Tooth Disease; Diarrhea; Female; Gastric Dilatation; Humans; Male; Neural Conduction; Treatment Outcome

Topics: Antioxidants; Ascorbic Acid; Charcot-Marie-Tooth Disease; Humans; Portraits as Topic

Topics: Antioxidants; Ascorbic Acid; Charcot-Marie-Tooth Disease; Child; Humans; Quality of Life; Randomized Controlled Trials as Topic

Topics: Antioxidants; Ascorbic Acid; Charcot-Marie-Tooth Disease; Child; Humans; Randomized Controlled Trials as Topic; Research Design; Sample Size; Treatment Outcome

Topics: Animals; Ascorbic Acid; Charcot-Marie-Tooth Disease; Clinical Protocols; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Netherlands; Outcome Assessment, Health Care

More than 30 genetic causes have been identified for the inherited neuropathies collectively referred to as Charcot-Marie-Tooth (CMT) disease. Previous therapies for CMT were limited to traditional approaches such as rehabilitation medicine, ambulation aids, and pain management. Identification of the genes causing CMT has led to improved genetic counseling and assistance in family planning. Identification of these genes is beginning to delineate common molecular pathways in multiple forms of CMT that can be exploited in future molecular therapies. Scientifically based clinical trials for CMT are currently being implemented. Techniques of gene therapy are advancing to the point that they may become feasible options for patients with CMT and other neurodegenerative diseases.

Topics: Animals; Antioxidants; Ascorbic Acid; Axonal Transport; Cell Membrane; Charcot-Marie-Tooth Disease; Endoplasmic Reticulum; Gene Dosage; Genetic Therapy; Humans; Intercellular Signaling Peptides and Proteins; Mitochondria; Myelin Sheath; Neurotrophin 3; Peripheral Nerves; Progesterone; Protein Folding; RNA; Schwann Cells

There has been considerable recent progress in understanding mechanisms by which gene mutations cause degeneration of motoneurons and peripheral nerves. Novel therapies inspired by these insights have begun to yield promising results in mouse models of these genetic diseases. Among these have been the use of small molecules or proteins to suppress gain-of-function mutations (eg, ascorbic acid for Charcot-Marie-Tooth disease type 1A) or to restore enzyme activities that are deficient because of loss-of-function mutations (eg, treatment of Fabry's disease with recombinant alpha-galactosidase or with low-molecular-weight alpha-galactosidase chaperones and treatment of spinal muscular atrophy with phenylbutyrate). Some of these therapies are already being tested in humans. Equally exciting is the prospect that small molecules and proteins will be identified that exert potent therapeutic effects in a broad spectrum of inherited and acquired motoneuron and peripheral nerve disorders.

Topics: alpha-Galactosidase; Animals; Antioxidants; Ascorbic Acid; Bulbar Palsy, Progressive; Charcot-Marie-Tooth Disease; Fabry Disease; Humans; Mice; Muscular Atrophy, Spinal; Neuroprotective Agents; Phenylbutyrates; Vascular Endothelial Growth Factor A

Charcot-Marie-Tooth disease (CMT) is the most common hereditary peripheral neuropathy, affecting 1 in 2,500 people. The only treatment currently available is rehabilitation or corrective surgery. The most frequent form of the disease, CMT-1A, involves abnormal myelination of the peripheral nerves. Here we used a mouse model of CMT-1A to test the ability of ascorbic acid, a known promoter of myelination, to correct the CMT-1A phenotype. Ascorbic acid treatment resulted in substantial amelioration of the CMT-1A phenotype, and reduced the expression of PMP22 to a level below what is necessary to induce the disease phenotype. As ascorbic acid has already been approved by the FDA for other clinical indications, it offers an immediate therapeutic possibility for patients with the disease.

Topics: Animals; Ascorbic Acid; Base Sequence; Charcot-Marie-Tooth Disease; DNA Primers; Female; Gene Expression Regulation; Male; Mice; Myelin Proteins; Phenotype; Sciatic Nerve

Topics: Animals; Antioxidants; Ascorbic Acid; Charcot-Marie-Tooth Disease; Chromosome Aberrations; Disease Models, Animal; Humans; Mice