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Biochemical ObservationsCommon features in those with autism include: raised blood or serum lactate, regional disturbances in glucose uptake in the brain, particularly in the cortex, and reduced brain levels of high-energy phosphate compounds. These observations would suggest a mitochondrial energy disorder in the brain. Mitochondrial dysfunction may result from any of the following: 1.
Impairment of mitochondrial fatty acid oxidation due to carnitine deficiency.
Carnitine pumps fatty acids into the mitochondria. With the help of vitamins B6,
C, and niacin, the body produces carnitine from the amino acids lysine and
methionine found in high quality protein. Adequate amounts are not thus formed
so some carnitine must come from muscle and organ meats in the diet for it is
not found in vegetables. Obviously, a low protein or a vegetarian diet would
likely create a deficiency of this vital nutrient, and impair the mitochondrial
function causing a loss of energy and a build up of triglycerides and fatty
acids in the blood and cells. The Cincinnati
Children’s Hospital Medical Center’s Department of Enzymology has identified
two patients with the “carbohydrate deficient glycoprotein syndrome” through
alpha-1-antitrypsin phenotyping. The carbohydrate deficient glycoprotein in the
serum of these patients produces a band on polyacrylamide gel isoelectric
focusing that moves cathodally of the Z-band. In the area of carnitine
deficiency, there is, for example, less than 5% of normal muscle carnitine
concentration. After carnitine supplementation, patients unable to talk or walk,
with hypotonic musculature and symptoms of autism, became able to walk with the
help of a walker. They could stand alone for short periods, and they acquired an
interest in their surroundings. The common findings of carnitine deficiency were
an impaired ability to walk, muscular hypotonia, reduced muscle carnitine
concentration, and an improvement in locomotion while on carnitine. Cellular energy
production itself produces free radicals that can damage cell structures,
including the mitochondria, and ultimately lead to various diseases if the
body’s natural antioxidant capacity is inadequate. Acylcarnitine and lipoic
acid are both endogenous (naturally present in the body) antioxidants that have
been shown to restore the mitochondrial function and reduce free radical damage.
(Hagen TM et al., 1998; Lyckesfeldt J et al., 1998). Together with coenzyme Q10
and NADH, they work to maintain the function of the mitochondria. It should be noted that
not only fatty acids are needed, but glucose must be able to enter the cell to
produce energy needed by the cell and by the muscles. Just as L-carnitine pumps
in fatty acids, Alpha Lipoic Acid pumps in glucose. Its supplementation tends to
overcome syndrome X, where the cells are resistant to glucose. This resistance
produces unnaturally high blood levels of insulin and sugar. Since the amino acid
L–carnitine is frequently lacking in the autistic, this could predispose to
heart problems and a lack of energy. The primary function of carnitine is to
escort fatty acids into the mitochondrial furnace where the fat is burned to
fuel ATP for energy. In this action it reduces blood levels of triglycerides and
cholesterol dramatically, and aids weight loss. It boosts energy levels for
those suffering from elevated blood sugar levels and kidney insufficiency. This
reduces fatigue. Tests by Dr. Carl Pepine at the University of Florida showed
that carnitine increases blood flow in the heart by 60%, and reduced vascular
resistance 25%. It reduces heart arrhythmias by 58% to 90% in patients with
chronic heart problems. He reported that patients were enabled to walk 80%
farther before discomfort set in. Dr. A. Feller (1988) reported in the Journal
of Nutrition that arrhythmias are usually a result of a carnitine deficiency.
The heart is enabled to pump more blood, with fewer beats, and with less
tendency toward oxygen deprivation. Vitamin E would be its ally in this for it
enables muscles to function on 40% less oxygen. This would relieve angina and
reduce risk of heart attack. A deficiency may result in chronic tiredness,
fatigue, nausea, dizziness and anemia. Lysine is converted to carnitine, and
carnitine increases Acetylcholine an important neurotransmitter. Autonomic
system abnormalities can be caused by disturbances in Acetylcholine levels,
known to be deficient in both autism and mercury poisoning. L-carnitine (500 mg
capsules twice daily on an empty stomach, or with a carbohydrate snack) reduced
ketone, triglyceride (up to 40%), and cholesterol (up to 21%) levels, and
increased HDL levels (up to 15%). The suggested use is 200 mg three times a day,
increasing after one week to 400 mg three times daily, to improve brain energy
levels. Basic L-carnitine may draw moisture and become unstable, and it is not
the most bioavailable. While the citrate, lactate, and tartrate are good forms,
the most effective form is L-carnitine fumarate. It is up to 9% more
bioavailable. Carnitine will conserve calcium, magnesium, and potassium, and may
reduce heart arrhythmias and fatigue—which will reduce risk of heart attack. Due to increased fat
burning, carnitine supplementation creates a significant need for caloric
increase. If none is supplied there will likely be weight loss. It also
generates increased free radicals that can severely damage cells unless
additional antioxidants are supplied—particularly vitamins C and E and
selenium. Additionally, lower than normal levels of certain essential fatty
acids, such as cholesterol (needed as the precursor to many hormones) and
triglycerides (a large proportion of the blood’s fatty substances) can be
exacerbated by supplemental carnitine. One Mother says, “We lost our seizure
control, and did not regain it until calories had been upped
significantly...Please, everyone, let’s consider very carefully the premise
that carnitine supplementation creates a significant need for caloric
increase.” The level of fatty acids in the autistic child is an important
factor because the endocrine system and its hormones, the brain and its
neurotransmitters, the myelin sheath, and all the immune system components are
derived from lipids (fats). However, mitochondria
cannot metabolize very long-chain, fatty acids (VLCFA) which many autistic have
accumulated; so, if carnitine pumps additional ones into the cell, they can
accumulate in the cells where they have toxic effects. Adrenoleukodystrophy (ALD) is a rare, fatal, degenerative disease caused by a build up of very
long-chain, fatty acids (c22 to c28) that destroys the myelin (protective
sheath) of the nerves. Canola oil is a very long-chain, fatty acid oil (c22).
Inability to handle VLCFAs is almost universally true in autistic children, but
is also seen in Alzheimer’s patients, chronic fatigue, and cardiovascular
disease. The accumulation of VLCFAs inside the cell membrane represents defects
in peroxisomal, beta-oxidation that is likely the result of hypothyroidism.
Therefore, the toxic aspect so often described in autism may be defined clearly
through examination of Red Blood Cell lipids with elevation of VLCFAs being a
reflection of blocked detoxification mechanisms (that is, the Phase I liver
enzymes are sluggish). These can be enhanced with milk thistle and other herbs
mentioned herein. In some cases the VLCFA DHA is reduced. In that case
supplementation of DHA has proven most helpful in relieving many symptoms of
VLCFA disease. Carnitine supplementation holds great promise, and it must be supplemented when Depakote™ is being used, but I think there are some things we must guard against. Additional carnitine will pump more fatty acids into the mitochondria to produce additional energy. It would help to know from a previous blood test that the triglycerides and cholesterol were normal or elevated. When using carnitine, to avoid creating a deficiency in fatty acids, we must supplement with Evening Primrose and cod-liver oils as outlined elsewhere in this paper, and ensure the child is getting enough calories for his size and activity. The wild card is the VLCFAs. To determine their status run the Red Blood Cell Lipid test. Symptoms of fatty acid deficiency would tend to be thirst, dry skin and hair, brittle nails, excess urination, dandruff, eczema, and rough skin. If these symptoms, or low triglyceride/cholesterol levels, or excess VLCFAs were present, I would not supplement carnitine, until these problems were being corrected. As I understand it, carnitine could lower the fatty acids and blood fats adversely, and could overload the cell with VLCFAs that it cannot burn. Look to the thyroid, do the iodine test, and if indicated, support the thyroid. 2.
A second cause of mitochondrial energy disorder is inflammation associated with
the release of excess nitric oxide. The herb Ginkgo Biloba selectively increases
the release of nitric oxide synthase, the enzyme that reacts with arginine to
produce nitric oxide. It should be avoided in this instance. Excess nitric oxide
can cause uncoupling of oxidative phosphorylation as well as inhibiting the
Krebs cycle enzyme, aconitase. This will result in organic acidemias, and low
mitochondrial energy production. Lactic acidosis and carnitine deficiency in
autistic patients suggest excessive nitric acid production in mitochondria
(Lombard, 1998, Chigani, et al, 1999), and mercury may be a participant.
Methyl mercury accumulates in the mitochondria, where it inhibits several
mitochondrial enzymes, reduces ATP production and Ca2+ (calcium) buffering
capacity, and disrupts mitochondrial respiration and oxidative phosphorylation
(Atchison & Hare, 1994; Rajanna and Hobson, 1985; Faro et al., 1998). The
behavior associated with excess NO production in the autist is maniacal
laughter. Neurological problems
are among the most common and serious of mercury poisoning, and include memory
loss, moodiness, depression, anger and sudden bursts of anger/rage,
self-effacement, suicidal thoughts, lack of strength/force to resolve doubts or
resist obsessions or compulsions. Mercury causes decreased lithium levels, which
is a factor in neurological diseases such as depression and Alzheimer’s.
Lithium protects brain cells against excess glutamate induced excitability and
calcium influx, and low levels cause abnormal brain cell balance and
neurological disturbances. Medical texts on neurology point out that chronic
mercurialism is often misdiagnosed as dementia or neurosis or functional
psychosis. Mercury at extremely
low levels interferes with formation of tubulin producing neurofibrillary
tangles in the brain similar to those observed in Alzheimer’s patients with
high levels of mercury in the brain. Mercury and the induced neurofibrillary
tangles appear to produce a functional zinc deficiency in the AD sufferers, as
well as causing reduced lithium levels. Mercury binds to hemoglobin in the red
blood cell, and will reduce the amount of oxygen that can be carried in the
blood—a major cause of Fatigue. Mercury at a level of 1 part per ten million
will actively destroy the membrane of red blood cells. Mercury binds with cell
membranes interfering with sodium and potassium enzyme functions, causing excess
membrane permeability, especially in terms of the blood-brain barrier. Less than
1 ppm mercury in the blood stream can impair the blood-brain barrier. Mercury
also blocks the immune function of magnesium and zinc. Exposure to mercury vapor
causes decreased zinc and methionine availability, depresses rates of
methylation (a bodily process of converting inorganic forms to organic forms,
part of the detox process), and increases free radicals—all factors in
increased susceptibility to chronic disease and to cancer. Mercury, especially
organic mercury, causes accumulation of calcium into the cells, therefore, one
does not want to take much calcium, and one wants to have a high ratio of
magnesium to calcium, that is, keep magnesium up and calcium down to reduce the
accumulative effects. Mercury also blocks the metabolic action of manganese,
allowing an increased production of NO and the entry of calcium ions into cell. Magnesium and manganese
are the doorkeepers regulating the proper amount of calcium entering the cell.
Mercury, if excreted in the urine, pulls out magnesium from the body, thus
increasing the manganese relative to magnesium levels. Rarely is mercury
excreted and most commonly it migrates to the brain where it can drive both
brain toxicity and increases in manganese. In either case, increases in
manganese relative to magnesium may increase measles viral mutations. Shifts in
magnesium to manganese cations in the body can significantly enhance viral
mutation rates by 6-10 fold. The significance of
this in your child’s life may be seen in the following: A group measured
mercury levels in 15 preterm and 5 term infants before and after Hep B
vaccination. According to the group, after-vaccination mercury levels in both
preterm and term infants showed a significant increase. Mercury levels in the
preterm infants were three times higher than in the term infants, and this was
statistically significant, according to the team—Dr. Gregory V. Stajich from
Mercer University, Atlanta, Georgia, A recent study
demonstrates that oral administration of N-acetylcysteine (NAC), a widely
available and largely nontoxic amino acid derivative, produces a profound
acceleration of urinary methyl mercury excretion in mice. Mice that received NAC
in the drinking water (10 mg/ml) starting at 48 hr after methyl mercury
administration excreted from 47 to 54% of the 203 Hg in urine over the
subsequent 48 hr, as compared to 4-10% excretion in control animals. When NAC
was given from the time of methyl mercury administration, it was even more
effective at enhancing urinary methyl mercury excretion, and at lowering tissue
mercury levels. In contrast, excretion of inorganic mercury was not affected by
oral NAC administration. Three other nontoxic elements that readily bond to
mercury rendering it less toxic and more easily excretable are Oxygen, Sulfur,
and Selenium. Mercury binds strongly to selenium, a trace element that is needed
for cellular health, depleting its stores. Latest research shows a conclusive
connection between reduced levels of Selenium and increased risk of cancers. A lack of selenium also affects the conversion of T4 thyroid hormone to T3. Stress reduces the conversion of T4 to the more active T3. Both cadmium and mercury inhibits the conversion of thyroxine (T4) to active T3. In a Chinese study, researchers found that selenium and vitamin E deficiency reduced blood levels of T3 by more than one-third. Vitamin E was thought to protect the T4/T3 conversion process. All myelination is controlled by T3. Free T3 regulates serotonin and melatonin metabolism. T3 controls serotonin uptake, binding to its receptors, so if there are serotonin problems, look to the thyroid. The active hormone T3 converts from T4, and to do this you need a specific ratio of zinc to copper of about 8:1. If you have had hair analysis and or fecal testing or blood tests you may know what your ratio is. If not, I would suggest finding out. Mercury (like in amalgam, and thimerosal in vaccines) will also cause hypothyroidism by interfering with selenoenzymes (Watanabe et al, 1999), and mercury competes and really messes up zinc absorption/utilization creating all kinds of effects throughout the body. 3. Defects in respiratory chain enzymes. Pyruvate Dehydrogenase or mitochondrial respiratory chain defects, that is, NAD, NADH, Coenzyme Q10, and cytochrome oxidase deficiency. Although we find a variety of autistic phenotypes to have associated mitochondrial abnormalities, the most common is nonspecific PDD, typically of a form that manifests language and cognitive regression or stagnation during the second year. Most surprising among multiplex families is that the biochemical and clinical markers of mitochondrial disease often segregate in an autosomal dominant manner (that is, genetically induced). Although no molecular lesion has yet been found in the autosomal dominant families, the biochemical findings are most consistent with abnormal mitochondrial complex I activity (that is NAD/NADH activity—WSL). Early and careful evaluation of autistic children for these more subtle mitochondrial disturbances may rescue them from more severe brain injury (Kelley, Richard, Kennedy Krieger Institute, Johns Hopkins University, Baltimore, MD). Note that the acetylaldehyde toxin given off by candida yeast inhibits the NAD/NADH exchange. 4.
Excess glutamate exposure, a common and increasing source being MSG. Generally,
autistic children show low glutamine, high glutamate readings. Plasma levels of
glutamic acid and aspartic acid are elevated even as levels of glutamine and
asparagine were low (Moreno-Fuenmayor et al, 1996). Mercury inhibits the uptake
of glutamate, with consequent elevation of glutamate levels in the extracellular
space (O’Carroll et al, 1995). Thimerosal enhances extracellular free
arachidonate and reduces glutamate uptake (Volterra et al, 1992). Excessive
glutamate is implicated in epileptiform activities (Scheyer, 1998; Chapman et
al, 1996). Cells that are without oxygen may release excessive glutamate. Low
oxygen is common in autistics. Children’s forming brains are four times more
sensitive to neuro-excitotoxins. The lower the energy production of the cell,
the more susceptible it is to excitotoxicity. Low magnesium levels (common in
“our” children) can double free radical production and magnify their
toxicity! The generation of increased levels of free radicals within the cell
can activate the p53 tumor-suppressor gene triggering apoptosis (cell suicide).
Excess glutamate can kill neurons by necrosis (by its allowing excess calcium
into the cells) as well. Magnesium is the calcium regulator. Elevated plasma
glutamate lowers cellular GSH by inhibiting cystine uptake. Additionally, high
levels of insulin inhibit an enzyme in the cell wall responsible for helping to
regulate proper intracellular calcium balance. Since the interstitial fluid
outside the cell usually contains a thousand times higher concentration of
calcium than is normally present within the cell, this excess insulin response
to our improper (high carbohydrate) diet simply opens the calcium floodgates
into the cell by inhibiting this membrane enzyme. Mercury, and especially
organic mercury, causes accumulation of calcium into the cells, therefore, one
does not want to take much calcium, at least one wants to have a high ratio of
Mg/Ca, that is, keep magnesium up and calcium down to reduce the accumulative
effects—and supplement manganese. Otherwise, excessive calcium will enter the
cells, impairing metabolism, producing cross-linkages and premature aging, and
eventually producing dangerous arterial spasms. Manganese is a natural chelating
agent when taken in the food supply or as a supplement. Manganese and magnesium
will do everything a calcium channel blocker will do, but more naturally and
effectively. There will be no excessive intracellular infiltration by calcium
transporting through the cell membrane as long as manganese and magnesium are
present. Manganese works in a similar way to magnesium’s characteristic of
displacing calcium ions. One of the keys to mercury’s effects on health may be
its ability to block the functioning of manganese, a key mineral required for
physiological reactions. New studies in humans and in the laboratory show that
PCBs and mercury interact to cause harm at lower thresholds than either
substance acting alone. Though forced to remove
MSG, baby formula today frequently utilizes caseinate that contains a high
enough level of glutamate to endanger a newborn’s brain! These excitotoxic
additives are hidden under the terms hydrolyzed vegetable protein, protein
isolate, protein extracts, caseinate, and natural flavorings! Another damaging
excitotoxin is Aspartame™
that has increased exponentially in all our foods. Some of the many aspartame
toxicity symptoms reported include seizures, headaches, memory loss, tremors,
convulsions, vision loss, nausea, dizziness, confusion, depression,
irritability, anxiety attacks, personality changes, heart palpitations, chest
pains, skin diseases, loss of blood sugar control, arthritic symptoms, weight
gain (in some cases), fluid retention, and excessive thirst or urination. The
phenylalanine in aspartame lowers the seizure threshold and depletes serotonin.
Lowered serotonin triggers manic depression, panic attacks, anxiety, rage, mood
swings, suicidal tendencies, etc. Clearly, regular exposure to a toxic substance
such as formaldehyde may worsen, or in some cases contribute to the development
of chronic diseases. Other excitotoxins include fluoride, aluminum, iron
overload, and organophosphate pesticides and herbicides. It would appear that
the pathology of autism is one of immune dysregulation, with associated food
intolerance, and opportunistic infection that triggers excessive production of
the inflammatory cytokines and nitric oxide leading eventually to neural
mitochondrial inhibition. Dr Rosemary Waring tells us that the excess cytokines
reduces available sulfates also. Nutrients that may improve the mitochondrial function include, magnesium, Coenzyme Q10, N-acetylcarnitine, N-acetylcysteine, vitamins B1, B2, niacin/niacinamide, folic acid, NAD (Nicotinamide Adenine Dinucleotide), alpha-ketoglutarate, and antioxidants such as vitamin E, C, alpha lipoic acid, manganese, and selenium. Supplementation of glutathione has improved skill with numbers and fine motor skills. Oral glutathione is expensive, and not well assimilated, though of benefit to the gut. If you use it, take it with some vitamin C that will improve its assimilation by up to 20%. Kirkman has a lotion for transdermal application that will overcome the absorption problem. Use both. Where possible, help the body produce its own supply.
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