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

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          Summary

          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-TRI AAL ).

          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-TRI AAL, and Muscular Dystrophy Campaign for CMT-TRAUK.

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          Most cited references 25

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          The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection.

          A 36-item short-form (SF-36) was constructed to survey health status in the Medical Outcomes Study. The SF-36 was designed for use in clinical practice and research, health policy evaluations, and general population surveys. The SF-36 includes one multi-item scale that assesses eight health concepts: 1) limitations in physical activities because of health problems; 2) limitations in social activities because of physical or emotional problems; 3) limitations in usual role activities because of physical health problems; 4) bodily pain; 5) general mental health (psychological distress and well-being); 6) limitations in usual role activities because of emotional problems; 7) vitality (energy and fatigue); and 8) general health perceptions. The survey was constructed for self-administration by persons 14 years of age and older, and for administration by a trained interviewer in person or by telephone. The history of the development of the SF-36, the origin of specific items, and the logic underlying their selection are summarized. The content and features of the SF-36 are compared with the 20-item Medical Outcomes Study short-form.
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            • Article: not found

            The Italian SF-36 Health Survey: translation, validation and norming.

             G Apolone,  P. Mosconi (1998)
            This article reports on the development and validation of the Italian SF-36 Health Survey using data from seven studies in which an Italian version of the SF-36 was administered to more than 7000 subjects between 1991 and 1995. Empirical findings from a wide array of studies and diseases indicate that the performance of the questionnaire improved as the Italian translation was revised and that it met the standards suggested by the literature in terms of feasibility, psychometric tests, and interpretability. This generally satisfactory picture strengthens the idea that the Italian SF-36 is as valid and reliable as the original instrument and applicable and valid across age, gender, and disease. Empirical evidence from a cross-sectional survey carried out to norm the final version in a representative sample of 2031 individuals confirms the questionnaire's characteristics in terms of hypothesized constructs and psychometric behavior and gives a better picture of its external validity (i.e., robustness and generalizability) when administered in settings that are very close to real world.
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              Diagnosis, natural history, and management of Charcot-Marie-Tooth disease.

              Charcot-Marie-Tooth disease is the most common inherited neuromuscular disorder. There have been substantial advances in elucidating the molecular bases of this genetically heterogeneous neuropathy and, in most cases, molecular diagnosis is now possible. The diagnostic approach requires careful assessment of clinical presentation and mode of inheritance, nerve-conduction studies, and DNA testing, and current research is focused on assessing natural history and finding effective treatments. Disease course is variable because of genotypic and phenotypic heterogeneity. At present, there is no drug therapy for Charcot-Marie-Tooth disease, and rehabilitation therapy and surgical procedures for skeletal deformities are the only available treatments, although best practice has not been defined. Animal models are proving useful for the identification of therapeutic targets and approaches. Progesterone antagonists, neurotrophic factors, ascorbic acid, and curcumin have shown promising results in experimental models, and ascorbic acid is being studied in large randomised controlled trials.
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                Author and article information

                Journal
                Lancet Neurol
                Lancet Neurol
                Lancet Neurology
                Lancet Pub. Group
                1474-4422
                1474-4465
                April 2011
                April 2011
                : 10
                : 4
                : 320-328
                Affiliations
                [a ]Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation, Carlo Besta Neurological Institute, Milan, Italy
                [b ]Medical Research Council Centre for Neuromuscular Diseases, University College London Institute of Neurology, London, UK
                [c ]Department of Neurology, Ophthalmology, and Genetics, University of Genoa, Genoa, Italy
                [d ]Department of Neurological, Neuropsychological, Morphological, and Motor Sciences, University of Verona, Verona, Italy
                [e ]Department of Neurological Sciences, Federico II University of Naples, Naples, Italy
                [f ]Department of Neurosciences, Psychiatry, and Anaesthesiology, University of Messina, Messina, Italy
                [g ]Department of Medical Sciences, Institute of Neurology, University Magna Graecia, Catanzaro, Italy
                [h ]Neuroimaging Research Unit, National Research Council, Catanzaro, Italy
                [i ]Department of Neuroscience, Institute of Neurology, Catholic University, Rome, Italy
                [j ]Don Gnocchi Foundation, Milan, Italy
                [k ]Department of Neurosciences, University of Parma, Parma, Italy
                [l ]Department of Pharmacological Sciences, University of Milan, Milan, Italy
                [m ]Madrid Institute for Advanced Studies on Food (IMDEA Food), Madrid, Spain
                [n ]Department of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
                Author notes
                [* ]Correspondence to: Dr Davide Pareyson, Clinic of Central and Peripheral Degenerative Neuropathies Unit, Department of Clinical Neurosciences, IRCCS Foundation, Carlo Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy davide.pareyson@ 123456istituto-besta.it
                [‡]

                Members listed at end of paper

                Article
                LANEUR70025
                10.1016/S1474-4422(11)70025-4
                3154498
                21393063
                © 2011 Elsevier Ltd. All rights reserved.

                This document may be redistributed and reused, subject to certain conditions.

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