CMT: Intergrated Neurology (vitamins, supplements, etc)

[Guest guest]

http://integratedneurology.net/cmt.htm

Charcot-Marie-Tooth Disease (scroll down for vitamins, supplements information)

bio on Dr. Kurn at http://integratedneurology.net/sdney_kurn_MD.htm

Described in 1886 by two French professors Jean-Martn Charcot and his

student Pierre Marie and later by Dr. Tooth of London. Also

called peroneal muscular atrophy because of early involvement of the

peroneal muscle that dorsiflexes the foot. For a time, a

classification system by Dyck and Lambert (the hereditary motor and

sensory neuropathies – HMSN) was used to classify the different

hereditary neuropathies. Identification of genetic causes for an

increasing number of neuropathies has made this system less useful.

In general, CMT1, affecting approximately 80% of CMT patients, is a

demyelinating form and CMT2 (affecting at least 20% of CMT patients)

is neuronal, involving the nerve fiber rather than the myelin

coating. Both types are autosomal dominant. CMT is fairly common

affecting 36 out of every 100,000 individuals in the United States.

CMT is now known to have multiple genetic causes. During the last

decade, 18 genes and 11 additional loci harboring candidate genes

have been associated with Charcot-Marie-Tooth disease (CMT) and

related peripheral neuropathies.

CMT 1A Autosomal dominant with duplication of a 1.5 Mb (megabase = 1

million nucleotides) region on the short arm of Chromosome 17(p11.2-

p12) containing the PMP22(peripheral myelin protein 22) gene. This

occurs in 70-90% of patients with clinical disease

Point mutation in PMP22 gene

CMT1B

CMT 1B is rare and is associated with point mutations in the myelin

protein zero(MP0 or MPZ) gene. MPZ is a major protein of compact

peripheral nervous system myelin.

Hereditary neuropathy with Deletion on chromosome 17

Liability to pressure palsy (HNPP) (same region as duplication in

CMT1A)

CMTX X linked dominant(CMTX1) and X-linked recessive(CMTX2) forms

of CMT occur due to an abnormality in the connexin 32 gene at

Xq13.1 This gene encodes a gap junction protein of peripheral myelin

protein.

CMT4B Point mutations of MTMR2 gene, encoding myotubularin-related

Protein-2

CMT 2A Gene abnormality on chromosome 1 encoding for the mitofusion

2 (MFN2) protein that controls behavior of mitochondria. Large

clusters are formed that fail to travel down the axon causing

synapses to fail.

CMT 2E Point mutations in neurofilament light (NF-L) gene

Genetic testing is available for a number of different CMT types. It

is also known that the pathologies of the different types overlap due

to the close interaction of Schwann cells (that produce myelin) and

the axons. There is evidence for abnormal communication between

Schwann cells and axons in CMT.

Clinical Features - CMT1 is associated with loss of reflexes,

hypertrophy of nerves, and slow NCV measures. CMT2 has normal

reflexes, no nerve enlargement and no or only mildly affected NCV

studies. Both may have weakness, abnormalities of gait(steppage

gait), foot deformities, loss of balance, pes cavus, hammer toes, leg

atrophy, intrinsic hand muscle atrophy, leg cramps, functional loss

of use of hands, hand tremors, stocking pin prick loss(rare) and

vibratory loss.

Medications can be used including antidepressants such as the

tricyclics such as amitryptiline, desipramine or nortriptyline or

newer antidepressants such as Remeron or Cymbalta. Anticonvulsants

can be used including Neurontin or Lyrica.

Mind – body techniques including meditation, using a mantra or

focussing on one's breath; guided imagery placing oneself in tranquil

settings and contacting " inner guides " ; deep breathing by inhaling

deeply for 4 seconds then exhaling over 4 seconds(relaxing muscles

and lowering blood pressure); progressive muscle relaxation using

tension for 5 seconds followed by relaxation starting with your fists

and moving to the rest of your muscle groups.

Acupuncture; may help pain and improve functional level. Acupuncture

increases the flow of chi, the life-force, by placing needles in

points along lines called meridians that course over the body.

Use of supplements to improve function and provide neuroprotection

Creatine - Creatine is a nitrogenous organic acid that naturally

occurs in vertebrates and helps to supply energy to muscle cells.It

keeps the ATP/ADP ratio high which ensures that the free energy of

ATP (the main energy molecule of the body) remains high and minimizes

the loss of adenosine nucleotides (components of DNA), which would

cause cellular dysfunction. Although the use of creatine in CMT has

shown " mixed results " , the most recent study revealed changes in

muscle fiber composition and improved strength in CMT patients when

combined with resistance training (1,2). Dosage is 2-5 gms/day in

three divided dosages.

Co-enzyme Q10 - Coenzyme Q10(CoQ10) is a fat soluble quinone, created

from tyrosine, occurring in the mitochondria of all cells. It is a

cofactor in the electron transport chain that generates ATP. It also

recycles vitamin E. It's level is reduced by HMG-CoA reductase

inhibitors (such as Lipitor or Pravachol) and susceptibility to

deficiency is greatest in the most metabolically active cells

including the heart, gingiva, immune system and gastric mucosa.

Inadequate nutritional intake, a genetic or acquired defect in

synthesis, increased tissue needs or advancing age can lead to

inadequate tissue levels. Several studies have shown a positive

benefit of CoQ10 in neuromuscular disorders including CMT disease

(3,4). Dosage should be at least 100mg/day (3,4).

Vitamin C - Ascorbic acid is an organic acid with antioxidant

properties. The L-enantiomer of ascorbic acid is also known as

vitamin C. The name " ascorbic " comes from its property of preventing

and curing scurvy. Ascorbate acts as an antioxidant by being itself

available for energeticaly favourable oxidation. Studies reveal that

vitamin C aids in proper myelin formation in peripheral nerves (5). A

German study in 2006 showed that ascorbic acid reduced demyelination

and premature death in a mouse model of CMT1A(6). An ongoing in

Italy is studying the effect of 1500mg of vitamin C/day in CMT

patients (7).

4. Padma - There is increasing evidence of an autoimmune component in

CMT. There appears to be increased activation of cytotoxic

lymphocytes as well as evidence for increased pro-inflammatory

metabolites of arachidonic acid (8,9,10). A 2005 German study

revealed macrophages (white blood cells who's role is to phagocytize

(engulf and then digest) cellular debris and pathogens either as

stationary or mobile cells, and to stimulate lymphocytes and other

immune cells to respond to the pathogen) attacking myelin in a mouse

model on CMT (11). This evidence suggest the use of an herbal

compound such as Padma to quiet the immune activity in CMT.

A number of countries, including Switzerland, Poland, Austria, Israel

and the United States have studied Padma 28, an herbal mixture of 25

herbal constituents combined in a specific order with strict weight

ratios. It is has been used for centuries in Tibetan medicine. Its

efficacy in various disorders is related to modulation of

immunological function. Several studies, including an Israeli study

in 1995, suggest an anti-inflammatory effect.

Padma inhibits lysozyme (a substance that breaks down tissue) release

from stimulated human neutrophils and reduces nitric oxide production

in macrophages. Nitric oxide is a small and pervasive molecule in the

body that can be involved in inflammatory processes. Two of the

constituents of Padma 28, costus root (the dried root of Saussurea

chebula) and myrobalani fructus (the dried fruit of Terminalia

chebula), by themselves inhibited nitric oxide production.

A 1999 study in the US showed that Padma 28 had a dose-dependent

effect against EAE in mice. The authors suggest that the protective

effect could best be explained by a broad protective mechanism of

action referred to as nonspecific resistance (NSR) to diverse

biological and psychological stressors. The class of herbs or

substances exhibiting these properties is called adaptogens or

bioprotectants. A Polish study in 1982 showed improved suppressor

cell function in T lymphocytes exposed to Padma 28.Suppressor cells

are a subset of lymphocytes involved in inhibiting inflammatory

reactions. The study revealed improved differentiation and maturation

of the suppressor cell subset of T lymphocytes.

Padma is safe and its properties suggest a beneficial effect in CMT.

Dose is 2-3 tablets twice/day.

5. Essential fatty acids – the activation of arachidonic acid and

the omega 6 metabolites of arachidonic acid suggest a benefit of

supplementation with the anti-inflammatory omega three fatty acids.

The most important omega three fatty acids, EPA and DHA, reduce a

number of proinflammatory substances in the body including

prostaglandin E2, and substances secreted by white blood cells

including leukotriene B4 and other proinflammatory cytokines. In

addition, EPA and DHA are precursors to the anti-inflammatory

prostaglandin 3 series. DHA may be the most critical essential fatty

acid for nerve cell membranes, including myelin, the coating around

nerves. A 1986 study supplementing CMT patients with essential fatty

acids and vitamin E revealed neurologic improvement which continued

for a year after the placebo period ended (12). The author recommends

that CMT patients supplement with heavy metal free fish oil. Dose is

approximately 500mg EPA plus DHA twice/day.

6. Phosphatidylserine – A phospholipid that is an essential

component in nerve cell membranes and myelin. It is a basic

structural component and is also involved in signal transduction.

DHA, discussed above is important as a metabolic precursor of

phosphatidyl serine. There are a number of studies showing benefit of

phosphatidylserine in cognition. Although there are no clinical

studies in CMT, its importance in myelin and in information signaling

suggests a potential benefit in CMT.

7. Vitamin E - Natural vitamin E is a fat soluble vitamin that

exists in eight different forms or isomers, four tocopherols and four

tocotrienols. It is an important anti-oxidant in the lipid or fat

soluble compartments of the body. This includes the nervous system, a

highly fatty tissue. Immune cells, such as the macrophages, decompose

their targets with a highly pro-oxidant discharge of free radicals.

As noted above, the immune system plays a role in myelin destruction

in CMT. Vitamin E would provide a natural form of protection for

myelin against free radical injury. An appropriate dosage is 400

IU/day.

8. Alpha lipoic acid - Alpha-lipoic acid is a very important

antioxidant. It is both water and fat-soluble, enters the nervous

system easily, reduces vitamins C and E from their oxidized state

(making them reusable), and increases intracellular levels of

glutathione, a critical intracellular antioxidant. Given the

potential value of vitamin C and E in CMT, the addition of alpha

lipoic acid is important in keeping C and E in their reduced or anti-

oxidant form. Dosage for alpha-lipoic acid is 300mg/day of a

sustained release formulation.

9. Vitamin B12 - The name vitamin B12 is used in two different ways.

In a broad sense it refers to a group of cobalt-containing compounds

known as cobalamins - cyanocobalamin (an artifact formed as a result

of the use of cyanide in the purification procedures),

hydroxocobalamin and the two coenzyme forms of B12, methylcobalamin

(MeB12) and 5-deoxyadenosylcobalamin (adenosylcobalamin - AdoB12). It

is know that B12 deficiency causes demyelination. The exact mechanism

of B12's role in preserving myelin is not known. Due to its complete

safety, and its role in the protection of myelin, B12 supplementation

is recommended in CMT. Suggested dosage is 1 mg/day.

10. Although there are no studies confirming the efficacy of

different herbs in CMT, their traditional usage suggest a potential

tole in CMT. The following five herbs are presented here for their

potential value in CMT:

Ginkgo - Ginkgo biloba, also called maidenhair tree, is thought to

predate the ice age, the sole remaining species of the entire

ginkophyte botanical division flourishing 250 million years ago. The

kernel has been used for several thousand years in Chinese medicine,

while the leaf is a very recent addition to herbal medicine.

Constituents include diterpenoid lactones-gingolide A,B,C;

sesquiterpene - bilobalide, flavone glycosides - kaempferol,

quercetin, isochamnetin; and tannins. There are more than 300 studies

on ginkgo, including 40 clinical trials. Ginkgo has multiple

pharmacologic effects including enhancing microcirculation,

increasing blood fluidity, increasing tissue oxygen utilization,

stabilizing blood-brain barrier and reducing cerebral edema, reducing

platelet aggregation, antioxidant effect, and increasing

dopaminergic, cholinergic and serotoninergic function. Experiments

also show improved motor nerve regeneration.

St. 's Wort - Hypericum perforatum is a perennial plant with

bright yellow flowers. Hypericum, or " over an apparition " , makes

reference to the historical use in exorcising ghosts, while

perforatum refers to the tiny translucencies in the leaves that can

be seen when holding the leaf to the sun. It's use dates back over

the centuries to ancient Greece, with topical use for wounds and

burns, and oral use for kidney and lung ailments as well as

depression. The plant contains a red pigment, hypericin, along with

essential oils, phenolic carboxylic acids, carotenoids, alkanes,

phytosterols, phloroglucin derivatives, medium-chain fatty acids,

flavonoids, xanthones and pseudohypericin. It has antimicrobial

effects against multiple viruses including herpes simplex type 1 and

2, influenza type A and B, CMV, E-B virus, hepatitus B and

retroviruses as well gram positive and negative bacteria. Originally

conjectured to have clinical MAO inhibitory activity, the actual

antidepressant mechanism is unknown. Its anti-depressant effect is

well established. It is anti-inflammatory, and considered a

vulnerary, or wound healer for the nervous system.

Ashwaghanda – an adaptogen in Ayur Vedic medicine that promotes

sleep, adaptation to stress, is anti-inflammatory and rejuvenating.

It increased strength in a clinical trial in children. It is

considered a nervine in Ayur Vedic medicine.

Bacopa – the foremost nerve tonic in Ayur Vedic medicine. Reported

to improve memory, learning and concentratrion. It improved motor

efficiency in rat studies.

Wild Oats – considered a nutritive herb for the nervous system.

Exercise – See the diagram for the rocker/balance board that can

strengthen ankles in CMT patients. Active and resistive exercises of

the dorsiflexor, plantar flexor, pronater and supinater muscles of

the feet. Use exercise puty for the intrinsic hand muscles and the

finger flexors and extensors. Adjust program to the level of

functioning and needs of the patient to maintain function and

comfort, ensure safety and protect the joints. Do exercises daily.

Can use hand splints and ADL aids. Do daily stretching of the heel

cords. Can use orthotics such as AFOs.

Surgery – Surgery can correct pes cavus, heel varus and hammer toes.

Can do triple arthrodesis of the ankle and tendon transfers in the

hands

Evaluation at a multi-modal center specializing in neuromuscular

disorders. These centers have OT, PT, physiatry and possibly

vocational rehab to assist the patient in a complete evaluation and

treatment plan.

CA et al Effects of exercise and creatine on myosin heavy

chain isoform composition in patients with Charcot-Marie-Tooth

disease. Muscle Nerve. 2006 Nov;34(5):586-94

Chetlin RD et al Resistance training exercise and creatine in

patients with Charcot-Marie-Tooth disease. Muscle Nerve. 2004 Jul;30

(1):69-76

Folkers K et al Biochemical rationale and the cardiac response of

patients with muscle disease to therapy with coenzyme Q10. Proc Natl

Acad Sci USA. 1985;82(13):4513-6

Folkers K and Simonsen R. Two successful double-nl;ind trials with

coenzyme Q10 (vitamin Q10) on muscular dystrophies and neurogenic

atrophies. Biochim Biophy Acta. 1995 May 24;1271(1):281-6

Podratz, Jl et al

Role of the extracellular matrix in myelinationb of peripheral nerve. Glia 2001,

vol 35, n1, pp. 35-40 (23ref)

Meyer zu Horate G et al

Myelin disorders:causes and perspectives of

Charcot-Marie-Tooth neuropathy. L Mol Neurosci. 2006;28(1):77-88

Pareyson D et al

A multicenter, randomized, double-blind, placebo controlled trial of long-term

ascorbic acid treatment in charcot-Marie-Tooth disease type 1A (CMT-TRIAAL): the

study protocol (EudraCT no.;2006-000032-37).

Pharmacol Res. 2006 Dec;54(6):436-41. Epub 2006 Sep 9

LL et al Acivated T cells in type I charcot-Marie-Tooth

disease: evidence for immunologic heterogeneity.

J Neuroimmnol. 1987 Nov;16(3):317-30

LL and FS Arachidonic fatty acid in red blood cell

membranes, lymphocytes, and cultured skin fibroblasts of dominant

Charcot-Maire-Tooth syndrome.

J Neurol Sci. 1993 Dec 15;120(2):195-200

LL et al Circulating cytotoxic immune components in dominant

Charcot-Marie-Tooth syndrome.

J Clin immunol. 1993 Nov;13(6):389-96

Kobsar I et al Evidence for macrophage-mediated myelin disruption in

an animal model for Charcot-Marie-Tooth neuropathy type 1A.

J Neurosci Res. 2005 Sep 15;81(6):857-64

LL et al Dietary essential fatty acids, vitamin E and Charcot-

Marie-Tooth disease. Neurology. 1986 Sep;36(9):1200-5

Dr. Sidney Kurn . 95 Montgomery Drive #126. Santa , California

95404

[Guest guest]

Earlier this week, in message #46550,I posted the link

http://integratedneurology.net/cmt.htm and information on vitamins and

supplements suggested for CMT by Dr. Sidney Kurn. I was curious, so I contacted

Dr. Kurn about his ideas and told him about my experience with vitamins and

supplements, along with info about . Below is his response. ~ Gretchen

" Good for you Gretchen - it takes work to heal - and you have done the

work. Every one has different needs and one has to keep searching since

our needs change over time. Your current formula seems very reasonable.

Like the colloidal silica...thanks for contacting me. I passed your

message on to a local CMT group " - Sidney Kurn MD

[Guest guest]

Hi Gretchen,

In your opinion, what would be the best time of the day to give each supplement

to my twelve-year-old son?

I am going to get everything from your list. I currently give him vitamin B12

after breakfast, along with Phosphatidylserire (which I buy at Whole Foods and

was prescribed to my son by a neurologist in Germany). Then during dinner, I

give him his multi-vitamin formulated for pre-teens.

What about curcummin? http://www.ajhg.org/AJHG/abstract/S0002-9297(07)61342-1

His genetics specialist in Joe DiMaggio Children's Hospital recommended it to

him.

[Guest guest]

Hi ,

I really can't say, but from my own experience, I have always taken the

Vitamins and supplements in the morning, after breakfast. That is how I

take E now. The only exception to this was in my teens when I took a

liquid potassium supplement and the doc had it prescribedd twice a day,

morning and afternoon. Perhaps your neurologist could give you better

suggestions. As for the Curcumin, there is an amazing body of written research

on it as a healer - perhaps your local health or supplement store can provide

you with suggested amount for your son's age and weight.

Gretchen

[Guest guest]

Thank you, Gretchen... Will do