Ascorbic Acid Treatment corrects Phenotype of a mouse model of Charcot-Marie-Tooth Disease

A French study, reported in the April 2004 issue of Nature Medicine, shows ascorbic acid (Vitamin C) halts the progression of and appears to reverse Charcot-Marie-Tooth-1A (CMT-1A) disease in a mouse model of CMT-1A, as well as dramatically extending the lives of these transgenic mice (mice with the human gene for peripheral myelin protein 22 [PMP22], the protein CMT-1A patients make too much of, incorporated into their DNA).

The French researchers, in a series of experiments, fed CMT-1A transgenic mice large doses of ascorbic acid with impressive results. The experimental mice develop symptoms of CMT by 1 month and were given large doses of ascorbic acid weekly beginning at 2 months of age. The vitamin C treatment “resulted in substantial amelioration of the CMT-1A phenotype [the observable properties of an organism, i.e. muscle weakness, poor balance etc.], and reduced the expression of PMP22 to a level below what is necessary to induce the disease phenotype.”

Most CMT-1A (the most common form of CMT) is the consequence of an extra copy of a gene on chromosome 17 that codes for the protein PMP22. In nerves outside the brain and spinal cord, the myelin sheath is formed by Schwann cell membranes, which wrap in concentric layers around the nerve cell. Because of the duplication of the PMP22 gene (3 copies of the gene instead of 2), an excess of PMP22 is produced in the Schwann cells, which disrupts the normal formation and compaction of myelin, the fatty substance that surrounds nerve cells.
In this paper the researchers show, “that treatment with ascorbic acid at least partially corrects the locomotive pathology of CMT-1A mice by promoting the remylination of the peripheral axon (nerve) fibers, probably by decreasing the expression level of PMP-22.”

Ascorbic acid, an anti oxidant, is water-soluble and excess concentrations in the blood in humans are rapidly secreted in the urine.  The scientist chose ascorbic acid as a candidate for CMT research because it is necessary for axon myelination outside the body, there is a link between ascorbic acid and femoral (thigh) neuropathies, it is also readily available and it has prior regulatory approval. An interesting feature of this experiment is that the large dose was administered weekly as opposed to daily

The mouse model of CMT-1A created by the authors contains the gene for human PMP22 and the severity of the CMT symptoms in these mice had previously been shown to be dependent on the cellular levels of PMP22. The ascorbic acid treatment was administered weekly to two- month-old mice that exhibited severe CMT symptoms. The weekly dose of ascorbic acid (1.12 mg for a 20g mouse) corresponds to a human dose of 57mg/kg (26mg/lb) or 4000 mg (4g) for a 154 lb adult human. This is close to the maximum dose suggested for human Vitamin C deficiency (scurvy). The mice were tested before treatment and then monthly for a variety of motor functions and compared to placebo-treated CMT-1A mice. The results after 3 months were dramatic.  Not only did the treated mice perform much better than the untreated mice, but in some tests their performance actually improved. The indication is that muscle strength actually increased during treatment. The treated mice also “enjoyed” a near normal average lifespan of nearly 20 months as opposed to 6 months for the placebo and untreated transgenic mice. Of interest, when the researchers doubled the dose from 1.12 mg to 2.5 mg, the motor performance was not significantly improved.

The microscopic examination of sciatic nerve fibers showed striking differences in the number of myelinated fibers and the thickness of myelin in the treated and untreated mice. The placebo-treated mice had 25% myelinated axons (nerve cells), the treated mice had 70% myelinated axons and the normal mice had 95% myelination. The myelin thickness was “abnormally thin” in the placebo, but returned to relatively normal thickness in the treated mice. The authors suggest that “ascorbic acid may reactivate the myelination process that is inhibited by the over expression of PMP22. Remylination may underlie the ascorbic acid-induced correction of the CMT-1A phenotype.”

To gain a better understanding of how ascorbic acid works, the investigators extracted RNA from the sciatic nerves of treated and untreated mice and found a tenfold greater concentration of PMP22RNA in the treated mice. What does this mean? Remember what Nobel Laureate Francis Crick, who with J. D. Watson, discovered the structure of  DNA, said, “DNA makes RNA, RNA makes protein and proteins makes us.” The DNA for human PMP22 inserted into the DNA of  these mice is making one-tenth the amount of PMP22RNA and therefore less of the offending protein. The mechanism of action is unclear, but they suggest that vitamin C may inhibit the stimulation of the expression of the gene for PMP22 by a common compound, cyclic AMP.

The authors ask two questions to be addressed in future studies. First, are the positive results of the study the result of the large single weekly dose or does the ascorbic acid remain at high levels in the nervous tissue of the mice? Second, is the action of vitamin C the result of its antioxidant properties or some other activity? The authors say, “it is likely that the effect of ascorbic acid on the organism results not only from its antioxidant properties, but also from direct control of the expression of certain genes.”

We want to thank these French scientists for their excellent work. This is a truly exciting study but transgenic mice are not men and the adage, “we have cured cancer a thousand times in the mouse” comes to mind. The authors, however, conclude that, “as ascorbic acid has already been approved by the FDA for other clinical indications, it offers immediate therapeutic possibility for patients with the disease.”

Before you CMT-1Aers run out to Sam’s Club and load up with Vitamin C tablets, please consider the following. The jury is still out on the safety of large doses of ascorbic acid.  So, first check with your doctor before downing massive amounts of vitamin C.  Second, do your own research on the internet.  There are lots of good sites including the Mayo Clinic;

Our transgenic little furry friends were given the human dose equivalent of 4g once a week; that computes to 4g/7d = .57g/day, or 570 mg per day; not a huge amount. The recommended daily dietary allowance (RDA) for vitamin C is 75mg for women and 90mg for men.  The typical daily vitamin supplement contains less than 100 mg. According to the Mayo Clinic, the “maximum daily intake (from all sources) unlikely to pose risk of side effects for adults is 2,000 mg/day. The Institute of Medicine states that there are no established benefits for consuming vitamin C in doses higher than the RDA. Other research has suggested that 200 mg/day is the optimal dose.”

The frequency of the dosage is another question, but a massive dose once a week doesn’t make sense, if only because we don’t know the equivalent of a mouse week in human terms.
Also, the average person lives 80 years: the average mouse 2 years, so don’t expect to start jogging tomorrow.

Please, it would be beneficial to yourself and others if you document your dosage and both subjective (how you feel, your aches and pains etc.) and objective (how long it takes to complete repeatable tasks, the diameter of your calf etc.) observations.

One of the researchers, Pauline Noack-Fraissignes, received support from the CMTA.

JD Griffith M.S.
CMT Foundation