Comprehensive Guide to Managing Autism - 7

GABA

Recent research by Ed Cook and associates at the University of Chicago established that there are one or more genes on chromosome 15 that manifest in autism. The chromosome 15 children studied so far showed regression. Between 12 and 24 months of age they lost skills. These children displayed low muscle tone. “They walked on time,” Cook says, “and they can eat OK; it’s not severe. They may have had a little trouble holding their heads up as infants, and show a history of low tone in other ways. Most kids with autism aren’t like that, so the floppy ones stand out a bit. A lot of them visually look like Fragile X, with hyper-extensibility of the joints, double-jointedness, and ears that may be a bit longer than normal, and incorrectly ‘rotated’ backward.”  

Some had speech delay, lack of social skills, and “stereotyped” or repetitive behaviors. In addition, these children had seizures and hypotonia, or low muscle tone, characteristics that are not normally associated with autism. These children all had a duplication of part of chromosome 15. 

The prospects for knowledge of chromosome 15 leading to a biomedical treatment for autism are high. This is so because the affected region on chromosome 15 contains three genes that code for the neurotransmitter gamma-amino butyric acid (GABA), This is the neurotransmitter involved in anxiety. Alcohol, anticonvulsants like Gabapentrin™ (Neurontin™) and Vigabatrin™, and anti-anxiety medications like benzodiazepine, Xanax™ and Valium™ all work by attaching to the GABA receptor. GABA is an “inhibitory” neurotransmitter; it prevents cells from firing. Some call it the brain’s “braking system.” Taking 750 mg, divided into 3 doses daily (Adult) is very effective even in acute anxiety, and may reduce nighttime urination. It is known that vitamin B₁₂ may be important for many conditions including anxiety, depression, mood swings, and memory loss, so it should be supplemented also (serum B₁₂ is not necessarily an accurate way of measuring B₁₂ status). 

This brings us to another line of converging evidence: in the cerebellum, the Purkinje cells—that Margaret Bauman has found to be diminished in the autistic brain—release GABA. 

Bolte notes that tetanus infection of the intestines leads to the formation of toxic compounds called phenols. As a corrosive substance, phenol denatures proteins and generally acts as a protoplasmic poison. Studies of autistic individuals have detected markedly elevated levels of the phenolic metabolite of tyrosine, DHPPA. [“After 5 years of research, the identity of DHPPA analog finally is established. The compound, called DHPPA analog on the organic acid test, has now been positively identified as 3-(3-hydroxyphenyl) - 3 hydroxypropionic acid (HPHPA), and after the revision of the organic acid test profile in the beginning of the year 2000, the name on the organic acid test report will be HPHPA instead of DHPPA analog”—William Shaw PhD, Great Plains Laboratory.] Several autistic children with high DHPPA (HPHPA) levels, “have shown a significant reduction in stereotyped behaviors when treated with antimicrobials effective against intestinal clostridia”—a genus of bacteria that includes tetanus. “When certain bacteria of the CLOSTIRIDUM family (genus) are present in high numbers, phenylpropionic acid or 3-hydroxytrosine may be formed in the intestinal tract. Either of these compounds may then be converted to 3-hydroxphenyl-propionic acid that is, in turn, converted to HPHPA by the enzymes in the human mitochondria that break down fatty acids”—William Shaw.  

The children treated for clostridia (usually with Flagyl™) became more sociable, spoke more, improved their eye contact, and were less hyperactive and hypersensitive. It should be noted that very high doses of L. Acidophilus may be equally effective as metronidazole (Flagyl™). Additionally, Flagyl™ has a lot of side effects, and can upset the ecological balance in the gastrointestinal tract and lead to a yeast overgrowth. Bolte adds, “Parents also noted that regression occurred very quickly” after treatment was discontinued. Given these findings, Bolte says, ”Parents, doctors, and researchers must combine efforts to determine if some people diagnosed as autistic are actually suffering from unrecognized forms of sub-acute tetanus.” This is very significant to that large block of children who do not handle phenol well (PST). The use of ORGANIC ACID TESTING can provide a valuable tool guiding therapy so that harmful microorganisms may be eliminated before treatments with amino acids like phenylalanine that might actually cause neuropsyciatric symptoms to worsen. It is most interesting to note that phenol poisoning, as suffered by the PST child, deadens the nerves endings much as does aspirin (a phenol), thereby masking pain.  

In addition, she notes, inhibitory neurons that release the neurotransmitter GABA are a preferred target for tetanus neurotoxins—and the Purkinje cells of the cerebellum, that often appear highly abnormal in autistic individuals, are inhibitory neurons that release GABA. Additionally, GABA is reported to stimulate the brain to release human growth hormone (HGH), and to stimulate the anterior pituitary function. 

Although GABA supplementation is used widely for a calming, sedative effect, there is mixed data indicating whether GABA taken orally has much clinical effect. Glutamine, a precursor of GABA, readily passes through the blood-brain barrier and is, therefore, a better supplement to take if one wants to increase brain levels of GABA, since Glutamine, once it is in the brain, converts into GABA. The question of GABA’s clinical usefulness may be a function of its dosage. That is, it appears that only mega doses of GABA have clinical effects. GABA activity is found in glands controlled by the sympathetic nervous system, namely: the pancreas and thymus. It is estimated that 30–40% of all CNS neurons utilize GABA as their primary neurotransmitter! Glutamic acid decarboxylase (GAD) the active enzyme capable of decarboxylating glutamate to GABA requires pyridoxal 5-phosphate (P5P) as cofactor. 

When there is not enough GABA a person can have a seizure because receiving neurons can be flooded with signals that say, “pass on this message.” A different type of neurotransmitter that promotes message transfer triggers the “go” messages. The charged signals they set off are positive. This time, more positively charged sodium particles (Na+) enter the neuron, which tells the receiving neurons to pass on the message. Valproic Acid (Depakote™), on the other hand, blocks GABA transaminase activity, thereby elevating GABA levels, thus alleviating seizures. Why depend on a drug that robs the body of L-carnitine and folic acid, when GABA can be increased nutritionally with glutamine, zinc, and P5P? Further, Depakote™ (Epilum) is a bad choice of anticonvulsants due to the risk of fatal hepatotoxicity, and it acts on the metabolic pathways, which could further lower the platelet levels. The hepatotoxicity is probably due to valproate-induced carnitine deficiency.  

Drug induced tremors and tics are common, and Depakote™ can cause them. To prevent, use at least 333 mg each of vitamins C, and niacinamide, and 66 mg each of vitamins B₆ and E with a good broad-based, vitamin-mineral supplement. In one ten-year study, not a single case occurred! If already suffering the devastating effects of this doctor-induced condition, use 5 to 10 times as much, and pray. I believe Ambrotose® and Phyt•Aloe®, and PLUS by Mannatech, Inc. would be mandatory. Of course, when using Depakote™, supplement Carnitine and folic acid also.  

Symptoms of carnitine deficiency are poor muscle tone and problems walking. By encouraging the oxidation of fats, carnitine will suppress glucose oxidation. This could contribute to seizures because oxidation of glucose produces more carbon dioxide than does the oxidation of fats. This is important because carbon dioxide helps get oxygen delivered to the tissue and helps protect one from seizures. So, it may be wise to test for carnitine levels before supplementing.  

This study is enlightening: Ten control subjects and 14 patients with refractory complex partial seizures were examined. Brain glutamine concentrations were above normal in three of five patients taking valproate and two of nine taking carbamazepine or phenytoin (One-third are being harmed!—WSL). Mean glutamine levels of patients taking valproate were higher than control subjects and patients taking carbamazepine or phenytoin. Brain glutamate concentrations were above normal in four of nine patients taking phenytoin or carbamazepine and two of five taking valproate. Brain GABA levels were below normal in four of nine patients taking carbamazepine or phenytoin and one of five taking valproate. Above normal glutamate or below normal GABA was present in nine of 14 patients and may contribute to their refractory epilepsy. Increased brain glutamine associated with valproate therapy may reflect mild hyperammonemia—Petroff OA, Rothman DL, Behar KL, Hyder F, Mattson RH Department of Neurology, Yale University.  

Carnitine supplementation is effective in reducing valproic-acid associated hyperammonemia. Recommended dosages for carnitine replacement are 50 mg/kg/day in children, and 1 to 3 gm per day for adults in 2 or 3 divided doses. Seizures may result from glutathione peroxidase deficiency, which could be from lack of bioavailable selenium. Selenium (seleno-methionine) supplementation in children resulted in a reduction in seizures and improvement in EEG recordings after 2 weeks. Based on the following, Epsom salts baths should be helpful to those prone to seizures. Symptoms of excess glutamate in the brain include headache, numbness, tingling, and flushing. 

This abstract is revealing of the place of vitamin B₆ and zinc in the “excess glutamate” paradox: 

From “Controlling Seizures: a Nutritional Approach”, by Dr. Ward Dean, MD. 

<<<Gamma-aminobutyric acid (GABA), the brain’s major inhibitory neurotransmitter, tends to be in lower than normal levels in seizure-prone rats and humans with epilepsy. Seizure-prone pre-eclamptic patients (hypertensive condition during late pregnancy) also have decreased brain GABA concentrations. Brain GABA levels depend on both zinc and vitamin B₆. Zinc is involved in the maintenance of pyridoxal phosphate concentrations by the activation of pyridoxal kinase. Pyridoxal kinase is important in decarboxylation, and lack of this enzyme results in lowered brain levels of GABA. Consequently, zinc deficiency may increase the risk of pre-eclamptic seizures by reducing brain GABA concentrations and lowering the seizure threshold. Unfortunately, plasma pyridoxal phosphate measurements alone do not appear to accurately reflect vitamin B₆ status or true tissue pyridoxal phosphate levels.  

Glutamate concentrations in the brain are higher in some seizure patients, and these concentrations can increase to potentially neurotoxic concentrations during seizures. These concentrations may reach levels capable of causing cell death. The importance of relative concentrations of glutamate, gamma aminobutyric acid, and pyridoxal-5-phosphate with respect to seizures is illustrated by a 33-month old male seizure patient whose cerebrospinal fluid (CSF) glutamate levels were 200 times normal! When he was given vitamin B₆ at a dose of 5mg/kg body weight per day (350 mg), his EEG normalized and his seizures stopped, but the CSF glutamate concentration was still 10 times normal. With a higher dose of B₆ (10mg/kg bw/d-700 mg), the CSF glutamic acid normalized. These results indicate that the optimal dose of B₆ for epileptics should be the dose that normalizes CSF glutamate levels, not just the control of seizures. 

Magnesium sulfate is standard therapy for pregnancy-induced hypertension (eclampsia and pre-eclampsia) to prevent seizures. Ten grams of magnesium are administered intramuscularly initially, followed by 5 gm intramuscularly every 4 hours. If administered intravenously, a 6 gm bolus over 15 minutes is given, followed by 1 to 3 gm per hour. In a comparative study, Dilantin™ was compared to magnesium in preventing seizures and reducing blood pressure. The investigators found no differences in the patient’s tolerance, adverse reactions, or outcomes between the two groups.>>> 

Nevertheless, magnesium will not suppress the immune function: Dilantin: Evidence is accumulating that this anti-seizure medication may have significant immunosuppressive effects. (Hadden 1986) National Toxicology Program studies in mice exposed to diphenylhydantoin demonstrated a selective effect on immune function resulting in depressed serum IgA levels and altered bone marrow function. Researchers are trying to correlate these findings with the IgA deficiency and increased sinuopulmonary infection that occurs in humans on long-term diphenylhydantoin treatment (NTP 1984) 

GABA“B” receptors are metabotropic receptors that are coupled to G-proteins and thereby indirectly alter membrane ion permeability and neuronal excitability. Activation of GABAB receptors in many brain regions results in an increase in K+ (potassium) channel conductance with a resultant hyperpolarization of the neuronal membrane. This increase in K+ conductance is often blocked by pretreatment with pertussis toxin (pertussis toxin uncouples Gi-protein from receptors), indicating that many postsynaptic GABAB receptors are indirectly coupled to K+ channels through an intervening G-protein. There is considerable evidence that a large proportion of GABAB receptors are coupled to G-proteins, but there is also evidence that some presynaptic GABAB receptors may be directly linked to K+ channels. The fact that GABAB receptors are coupled to G-proteins may also explain, in part, the reported effects of GABAB receptor agonists on calcium (Ca2+) conductance and secondarily neurotransmitter release.  

One mother has noted increased verbal capacity after supplementing the amino acid GABA! An adult, Polly Hattemer, says, “I tried GABA. It made me regress intellectually. I could hardly recall any nouns. GABApentin™ was helpful.” It should be noted; GABApentin™ has been associated with a worsening of hyperactivity in some cases. The types apt to respond to GABA are the clearly identified “chromosome 15” kids, and those with high phenol levels (See PST below). That encompasses about everybody! Methinks, maybe we should try glutamine with vitamin B₆ (P5P), or GABA, or even Bethanechol, before Pepcid™? Once again, strengthen the immune function by following the suggestions herein. 

Some additional thoughts on the importance of supporting the thymus: Thymus glandulars taken orally with a multiple-vitamin/mineral supplement have been proven to be modulators of the immune system, normalizing the ratio of T-helper cells to suppresser cells whether the ratio is low as in AIDS, chronic infections, and cancer; or high as in allergies, migraine headaches, and autoimmune diseases. Thymus glandulars can be dramatically effective in children suffering chronic infections. In autoimmune diseases, a high ratio of T-helper cells to suppresser cells causes a higher than normal number of antibodies to be produced which can damage body structures. A robust thymus will normalize this ratio and suppress “immune complexes”. Who needs to rebuild the thymus? Typically thymic hormone levels are very low in the elderly, in those prone to infection, in cancer and AIDS sufferers, and in those undergoing chronic stress. Specifically, those with multiple sclerosis (MS), diabetes, hepatitis, allergies, and other autoimmune diseases, the nutrient deficient (that is, those eating quantities of white sugar and refined foods), those with high cholesterol levels, and all children who never had a mother’s milk for at least four months. Did I miss anyone? Support the thymus by using a Thymus Glandular and multivitamin/mineral supplement!  

When the thymus gland dries up, no one treats that as a medical condition even though every doctor and nurse is taught that the thymus gland controls the immune system. It controls the immune system in two ways. First, it is a source of T (thymus)-cells or T-lymphocytes. It is these T-cells that fight the battle against viruses, bacteria, yeast, and other foreign invaders that attack the body’s immune system. The thymus gland seeds the bone marrow with immature T-cells that multiply and mature. Second, the thymus gland produces a variety of hormones that stimulate the maturation of T-cells and increase production of other hormones, such as interferon and the immune globulins. Several hormones have been isolated from the thymus, but the one receiving the most attention in medical studies right now is Alpha 1. Supplementation as recommended have been shown to increase Alpha 1 from 300% to 700% depending on the dosage—My Experience Treating Immune System Disorders with Glandular and Vitamin Supplements, by Dr. Carson G. Burgstiner, MD, PC. Zinc is specific to the improved function of the thymus. Except for nursing infants, 15 mg zinc daily is safe, however, when taking zinc and high amounts of vitamin C one must check copper status or run the risk of depleting copper and creating a copper anemia.