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Research Newsletter-Spring/Summer 2006

Vitamin C for the Treatment of Charcot-Marie-Tooth Disease

Davide Pareyson, M.D.
National Neurological Institute "C. Besta", Milan, Italy

What is Charcot-Marie-Tooth Disease?

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular disorder, with an estimated prevalence of 17-41 in 100,000 people. It is genetically heterogeneous, but 60-90% of the patients affected by the demyelinating variety CMT1 (accounting for about two-thirds of all CMT cases) carry a gene duplication on a specific chromosome (CMT1A). CMT1A, therefore, is the most frequent CMT subtype, with an estimated prevalence of 1 in 5,000. The affected chromosome encompasses the gene coding for the peripheral myelin protein 22 (PMP22), which is located in the compact myelin of peripheral nerves and plays a crucial role in the formation and maintenance of myelin, and possibly in cell growth regulation and shaping. Myelin is a mostly fatty substance (80% lipids and 20% proteins) that insulates nerves. Affected patients carry multiple copies of the PMP22 gene and overexpress the protein in peripheral nerves, leading to the pathological manifestation of the disease.

Current therapy

Currently, physiotherapy and surgery for skeletal deformities and tendon tightening are the only treatments for CMT, and there is no pharmacologic therapy. However, animal models of the human disease have been developed. Transgenic rats and mice overexpressing PMP22 are good models for studying disease mechanisms and for testing possible treatments.

Why vitamin C?

Recently, Passage and colleagues reported in Nature Medicine that chronic treatment with vitamin C is a very effective treatment for mice overexpressing PMP22. The researchers performed three sets of experiments involving physical performance and balance and observed that mice treated with vitamin C had less severe neuropathy and performed much better than untreated mice. For some clinical motor tests, such as the grip test, the performance of treated mice was even better than before treatment, indicating that vitamin C not only prevents disease progression, but also partially reverses the phenotype. Histological analyses revealed that the number and percentage of myelinated nerve fibers was much greater and that the myelin was thicker in treated mice than in untreated animals. Moreover, treated mice had a normal life span compared to untreated ones, which had a decreased life span. It is well known that vitamin C in vitro promotes normal myelination. The researchers performed more experiments that showed that vitamin C decreases the amount of the PMP22 protein, possibly through a cAMPmediated mechanism. It is therefore possible that vitamin C attenuates neuropathy by decreasing PMP22 expression.

The study

The mouse study is very important because it suggests that vitamin C may be useful to treat this disease in humans. It is possible that what works in the mouse will not work as expected in humans, but since there is no effective therapy for CMT and vitamin C is very safe, a clinical trial is now appropriate. A randomized controlled trial (RCT) with vitamin C will be the first RCT for CMT. If we find that vitamin C is an effective therapy for CMT, it will be a fundamental step in the field of therapy of inherited degenerative disease.

How the trial is organized

The CMT-TRIAAL (CMT-TRial Italian with Ascorbic Acid Long term) has been recently funded by Telethon and started in March 2006. It is a randomized, double-blind, placebo-controlled trial that involves eight Italian centers and recruited over 200 patients, aged 18-70 years. These patients will be treated with either 1.5 grams per day of vitamin C or placebo and then followed for two years, which is a reasonable time period in which to observe a difference between treated and untreated patients if the effect of vitamin C is appreciable. We also considered that it is not easy to ask patients not to consume extra vitamin C. Therefore, we will check patient compliance by measuring plasma vitamin C levels. The primary outcome we will assess is the composite impairment scale CMT neuropathy score. We will also measure changes in electrophysiological parameters and in the following clinical scales: distal arm and leg strength (measured by maximum voluntary isometric contraction), 10-meter timed walking, 9-hole-peg test, Overall Neuropathy Limitations Scale, visual analogue scale for pain and fatigue, and health-related quality of life (assessed with the 36-item short-form questionnaire). Clinical-electrophysiological assessment will be performed at baseline and every six months thereafter. In a subset of patients skin biopsies will be performed to evaluate PMP22 expression at baseline and at the end of the study. We will also take plasma samples for the evaluation of antioxidant capacity if, indeed, the therapeutic activity of vitamin C in the transgenic mouse is linked to its antioxidant action. This last assay will be run by LPI affiliate investigator Dr. Francesco Visioli.

Who has organized the study?

The Principal Investigator is Dr. Davide Pareyson of the National Neurological Institute "C. Besta" in Milan, Italy, and the trial coordinator is Dr. Alessandra Solari. This trial is the first and largest of a potential collaborative network of European (and one American) institutes and hospitals. There is the potential for the evaluation of roughly 500 patients worldwide, depending on funds.

The timetable

We have recruited the patients, and the trial is under way. It will last for two years, then we will perform statistical analyses on the data. Finally, if other centers start their own trials, we might be able to merge the data to increase statistical power. Altogether, we expect a final report in approximately three years.

Last updated June, 2006