Un nuovo studio indica che la vitamina C ferma la
progressione favorisce l’inversione
del danno nella Charcot-Marie Tooth dei topini cavia.
Griffith, M.s. Fondazione CMT
Uno studio francese pubblicato in aprile 2004 da MEDICINE NATURE indica che
l'acido ascorbico (vitamina C) ferma la progressione della malattia e
sembra invertire la Charcot-Marie- Tooth-1A (Cmt-1a) nei topi cavia.
Essendo prudentemente ottimisti, gli autori concludono che, "poiché
l'acido ascorbico è stato già approvato dalla FDA per altre indicazioni
cliniche, offre la possibilità terapeutica immediata per i pazienti con la
A Promising New Study Shows that
Vitamin C Halts the Progression-and Even Reverses-Charcot-Marie-Tooth in
JD Griffith, M.S. - CMT Foundation
A French study in the April 2004 issue of Nature Medicine shows that ascorbic
acid (Vitamin C) halts the progression of and appears to reverse
Charcot-Marie-Tooth-1A (CMT-1A) in a mouse model of CMT-1A. It also
dramatically extended 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).
So, what does this mean to the CMT patient? While we applaud these French
scientists for their excellent work, we must remember the adage "we
have cured cancer a thousand times in the mouse." Being cautiously
optimistic, the authors 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." This
is good news.
How Much Should I Take? And How
Often Should I Take It?
Before you CMT-1Aers run out to Sam's Club and load up on Vitamin C
tablets, please consider the following: The jury is still out on the safety
of large doses of ascorbic acid, so, check with your doctor before
beginning a Vitamin C blitz. Second, do your own research on the
Internet-there are lots of good health-related sites, including the Mayo
Our little furry friends were given the human dose equivalent of 4g once a
week; that computes to 4g/7day=.57g/day or 570 mg per day, not a huge
amount. The daily recommended dietary allowance (RDA) for vitamin C is 75
mg for women, 90 mg for men and 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."
When it comes to frequency, 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 two years, so
don't expect to start jogging tomorrow.
I spoke to CMT-1A friend, in Pittsburgh PA., who has been taking 2000 mg of
ascorbic acid per day for 20 years, thanks to Nobel Prizewinner Linus
Pauling's enthusiastic advocacy of Vitamin C as a cure-all. Her CMT has
slowly progressed but without a control we cannot evaluate the vitamin's
effectiveness. A case can be made for holding off on self-medication and
participating in a controlled study, when and if they become available.
Because of the variability in the progression of the disease a large
well-designed study would be required to get statistically valid results.
Another unsettling question is; because vitamin C is readily available, would
you be willing, for the benefit of the CMT community, to participate in a
double blind (neither the doctor or the patient knows who is receiving the
drug or the placebo) controlled experiment when you know you may be the
control and receiving a placebo?
An Experiment of Our Own
If you plan on incorporating Vitamin C into your health program, it would
be beneficial to you (and others) if you would document your dosage and
observations-both subjective (how you feel, your aches and pains etc.) and
objective (how long it takes to complete repeatable task, the diameter of
your calf etc.)-and report back on your progress
here. This information
will help us compile our own database of information and see for ourselves
just what impact Vitamin C has on people with CMT.
Below, please find an abstract of the
Ascorbic acid treatment corrects the
phenotype of a mouse model of Charcot-Marie-Tooth disease
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 one month and
were given large dose of ascorbic acid weekly beginning at two 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 chord, 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 antioxidant, is water-soluble; excess concentrations in
the blood in humans are rapidly secreted in the urine. The scientists 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, plus it is readily available and has
prior regulatory approval. An interesting feature of this experiment is
that the large dose was administered weekly, as opposed to daily.
A Stronger, Healthier Mouse
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 20 g mouse) corresponds to a
human dose of 57 mg/kg (26mg/lb) or 4000 mg (4 g) 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
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 cell), 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 untreated 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.
In the Future
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 result not only from its antioxidant properties, but also from
direct control of the expression of certain genes."
We hope to see more promising research and
information into this promising discovery. One of the researchers, Pauline Noack-Fraissignes,
received support from the Charcot-Marie-Tooth Association
Un nuovo trattamento promuove la rigenerazione del nervo
e la funzione sensitiva nei pazienti di CMT
Ottobre 2003, riunione dell’Associazione neurologica
americana, San Francisco - Un piccolo studio, presentato dalla
Dott.ssa Zarife Sahenk, dell'università di Stato dell'Ohio, mostra una promessa
per la malattia del Charcot-Charcot-Marie (CMT). La prova pilota di
neurotrophin-3 umano geneticamente costruito (Nt-3), un fattore di sviluppo
del nervo che preparato dalla da Regeneron Pharmaceuticals, Inc., ha
offerto statisticamente miglioramenti clinici significativi nel danno da
neuropatia e nella rigenerazione del nervo nei quattro pazienti ha trattato
con la malattia del Charcot-Marie Tooth 1A del tipo (Cmt-1a). "Nt-3 è
clinicamente il primo trattamento significativo per la malattia del Charcot-Charcot-Marie,"
hanno affermato gli sperimentatori del gruppo della Dott.ssa. Sahenk,
"e può anche avvantaggiare i pazienti con altri neuropathie
New Treatment Promotes Nerve
Regeneration and Sensory Function in Some CMT Patients
JD Griffith, M.S. CMT Foundation
October, 2003, American Neurological
Association Meeting, San Francisco -A small study, presented by Dr. Zarife Sahenk, of Ohio State
University, shows promise for Charcot-Marie-Tooth Disease (CMT). The pilot
trial of genetically engineered human neurotrophin-3 (NT-3), a nerve growth
factor being developed by Regeneron Pharmaceuticals, Inc., yielded
statistically significant clinical improvements in neuropathy impairment
and demonstrated nerve regeneration in the four patients treated with
Charcot Marie-Tooth Disease, Type 1A (CMT-1A). "NT-3 is the first
clinically significant treatment for Charcot-Marie-Tooth Disease," Dr.
Sahenk's group concluded, "and may also benefit patients with other
inherited neuropathies." In an interview with Neurology Today, Dr
Sahenk, elaborated: "Results from this pilot study need to be
substantiated with a large, multi-center clinical trial." "But,"
she added, "the take-home message for the clinical neurologist is that
hereditary neuropathies, traditionally considered a black hole without any
avenues for treatment, deserve further clinical research efforts." Dr.
Sahenk also implied that although the trial only involved patients with
CMT-1A, the treatment may be useful for other types of CMT and neuropathies
The eight patients in this pilot study tested DNA
positive for CMT-1A, the most common type of CMT.
Charcot-Marie-Tooth Disease is subdivided into CMT type-1 (defects in the
myelin sheath that surrounds the axon or nerve cell) and CMT type-2
(degeneration of the axon or nerve cell itself) (Dyke PJ, Lambert, EH, Arch
Neurol 1968 18:603-18).
Most CMT-1A is caused by an extra copy of gene on
chromosome 17, of the gene that codes for peripheral myelin protein 22
(PMP22). In nerves outside the brain and spinal chord, 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, and dramatically increases the speed
of impulse conduction. Problems with the myelin sheath, an electrical
insulator, can result in a slowing of nerve conduction velocity (the speed
the nerve impulse travels along the nerve). Nerve conduction velocity (NCV)
is one of the characteristics that differentiate demyelinating, CMT type
1(slowed NCV) from axonal, CMT type 2 (normal or near normal NVC (Dyke PJ
et al 1968). The CMT clinical symptoms of muscle atrophy (wasting) and loss
of sensation are the result of length-dependent degeneration of the nerve
cell itself, not from slow nerve conduction (Sahenk Z, 1999, Shy et al.,
Neurotrophins May Help Patients and
Neurotrophin-3 is a neurotrophin (from
the Greek trophe-nourishment), a family of short amino acids chains (small proteins),
which support neuronal development, survival and plasticity in the
developing and adult brain and peripheral nervous system. Neurotrophins are
secreted by their targets (muscles, other neurons or other structures) and
are detected by specific receptors on the membranes of nerve cells. NT-3 is
essential for the formation and viability of Schwann cells, which form the
myelin sheath surrounding neurons in the peripheral nervous system. The
first neurotrophin studied, nerve growth factor (NGF), was discovered in
the early 1950s by Rita Levi-Montalcini and Stanley Cohen, who were awarded
1986 Nobel Price in Physiology and Medicine for their work. Other members
of the neurotrophin family have since been discovered; including
brain-derived neurotrophic factor (BDNF), neurotrophin- 3 (NT-3)
neurotrophin 4 (NT-4/5) and glial cell derived neurotrophin factor (GDNF).
Neurotrophins' ability to stimulate neuron growth and support the survival
of adult nerve cells has made them a major target for drug development.
Early optimism for neurotrophins as a miracle cure for a range of disease
has waned, but the potential for therapeutic use is still exciting.
Neurotrophins are currently being investigated as potential therapies for
wide variety of conditions, including CMT, ALS (Lou Gehrig's Disease),
Alzheimer Disease, Parkinson's Disease, Huntington's Disease, Bi-polar
Disorder and neuropathic pain.
Treatment vs. Placebo
The study enrolled eight patients with CMT-1A and randomly selected four patients
to receive the NT-3, and four patients to receive the placebo. The study
was double blind; neither the investigator nor the patient knew who
received NT-3 or the placebo. The patients injected themselves with NT-3 or
the placebo three times per week for six weeks and the results were
- Using the Mayo Clinic
Neuropathic Impairment Score (NIS) (Dyke et al. 1980),
which summarizes muscle weakness and decreased sensation corrected for
age, sex and physical fitness, significant
improvements were reported in the NT-3 group in NIS and sensory tests
(pin prick, vibration and cold temperature) but not in
the placebo group.
- The pegboard test
measures a patient's ability to move their arms, hands, fingers and
finger dexterity by counting the number of pegs that can be inserted
into a board in specified time. Pegboard
performance significantly worsened in the placebo group, but was
unchanged in the NT-3 group.
- Sural nerve biopsy is an invasive procedure used frequently in
the past as a diagnostic tool and to distinguish between CMT-1 and
CMT-2. It involves the removal of a small piece of the sural nerve, a
pure sensory nerve, easily accessible behind the ankle or at the lower
part of the leg, for microscopic examination. Now, due to the
availability of genetic testing for diagnosis, such nerve biopsies are
scarce, which is probably fortunate for the patient but unfortunate
for the study of the disease. The nerve fiber regeneration was studied
by comparing sural nerve biopsies before and after six months of
treatment. The results of the study were impressive with myelinated nerve
fiber regeneration in the patients receiving NT-3 but not in the
control group. The investigators found a significant increase in
small myelinated fibers and more solitary myelinated per square
millimeter in the NT-3 group.
The investigators also measured NCV in the
patients before and after the study and found no significant change. Dr.
Sahenk said this result was not unexpected because partial nerve
regeneration would not be expected to significantly improve NCV.
We want to thank Dr. Sahenk
and the other investigators for their continued excellent research and much
appreciated interest in CMT. The study was supported by The Neuropathy
Association and Regeneron Pharmaceuticals, Inc.