Patricia C. Kane, Ph.D. Correspondence: BodyBio Centre 45 Reese Road Millville, NJ 08332
Autistic Spectrum Disorder (ASD) has led us directly towards in depth exploration seizing the complexity of this systemic presentation and addressing it fully from a cellular perspective. Previous exhaustive efforts of examining patients with ASD have revealed immune insult with an autoimmune presentation.1-23
Through the efforts of Wakefield24 at the Royal Free Hospital in London gut biopsy and ongoing clinical trials have revealed viral involvement of ASD with positive staining for measles in lymphoid follicles from measles vaccination. Wakefield has hypothesized that there may be a viral interaction between measles vaccination and exposure to chicken pox that initiates the immune derangement in ASD. Protocols for treatment of GI disturbance have been limited until Borody25 applied the work of Tvede and Rask-Madsen26 with the oral application of bacterial strains such as non-toxigenic avirulent strain of Clostridium (sixteen strains of bacteria in all were utilized) with cessation of major symptoms in five children (to date) with autism.
Renowned microbiologist Dr. Sidney Feingold27 has identified at least 12 genus of anaerobic bacterial species missing in four autistic children (hundreds of culture plates were run for this determination) in contrast to controls (forthcoming publication) after a lay facilitator, Ellen Bolte28, proposed the connection between tetanus vaccination (clostridium tetani) and autism. The hypothesis forming in regard to autism/clostridium is that neurotoxins are being formed through the immune/Gut/CNS axis creating the stereotypic behavior (actually hallucinogenic in nature) exhibited in autistic spectrum disorder. The use of potent antibiotics and therapeutic use of probiotics has not adequately addressed ASD.
Borody's approach is to sterilize the gut with potent antibiotics and re-implant the proper balance of all bacteria (including those we consider to be pathogenic). Oral application of bacteria (rather than rectal implantation) may be utilized if the gut is sterilized and meds are used to suppress acid formation (Prilosec) permitting the bacteria to pass undisturbed through the GI tract. Outcomes to date with this intervention have been surprisingly positive both to the gut and the brain.
The concept of opiate-like peptides affecting children with ASD was led by Shattock29-30, Reichelt31-32, and others33-34 through examination of urinary metabolites containing peptides from gluten and casein. The opiate antagonist naltrexone proved unsuccessful in controlled trials35-39 with dietary removal of gluten and casein yielding anecdotal positive results. Association with ASD and serotonin was scrutinized in intricate detail40-43 but not clarified until Matson44 (1996,unpublished data) isolated bufotinines, methylated serotonin compounds, in the serum of children with ASD.
Matson found that these compounds literally are created by the patient evoking hallucinogenic symptoms finding that children with ASD overmethylate. Friedman45 (stated in public forum) noted through tandem mass spec analysis in 1998 that aberrant peptides originally derived from casein/gluten as well as Clostridium created hallucinogenic effects initially linking casein ingestion to cellular surface immune response, specifically CD26, which is crucial to clearing of beta-casomorphin. Friedman continued his research (study submitted for publication) linking the effect of opiates from gluten, casein, and particular species of Clostridium upon the suppression the enzyme Dipeptidyl Peptidase-DPP4 or CD26 ultimately impacting the liver, kidney, small intestine and blood brain barrier where this enzyme predominates.
The role of CD26 is primarily one of T cell activation and the cleavage of peptides at the location of proline and alanine thereby breaking down aberrant peptides or inactivation of neuropeptides. Friedman has noted the amino acid sequencing of peptides in the urine of children containing alanine and proline in the D- rather than the L- position whereby CD26 cleavage of these isomers would be 1000 fold over peptides containing alanine and proline in the L-position. The research of Friedman and Matson link endogenous polypeptides to autistic behaviors (hallucinogenic in nature), with Matson's research oriented to serum rather than urinary metabolites, and indicating that the endogenous creation of bufotinines are related to bizarre behavior patterns.
Treatment protocols have not yet been established, but clinicians must consider that of tremendous concern in children with ASD is the very passage of peptides through the blood brain barrier, electrolyte instability, allergic manifestation, GI disturbance and intestinal permeability46 as all are indicative of a loss of cell membrane integrity. Bauman47 and Minshew48-49 have clearly identified aberrations in neurons and membrane phospholipids in ASD patients. Certainly the removal of casein and gluten may be of tremendous benefit, but the very mechanism of metabolic entropy, immune dysregulation and loss of cell membrane integrity must be addressed to sustain the health of multiple body systems.
The use of secretin for ASD has exploded into the media and parents have demanded repeated infusions without clinical trials or proper scientific investigation. Understandably the results of Secretin have been troubling as Secretin has evoked speech in some while in others the results have led to more complex immune involvement (autoimmune response after the first infusion) and seizures. The metabolic impact of Secretin is that it stimulates the arachidonic acid cascade (contraindicated in seizure disorders) and bicarbonate production, will oxidize or burn off (beta oxidize) fatty acids (including both essential fats, insulating fatty acids and very long chain fatty acids), increases the metabolism of bile acids, and theoretically may stimulate Cholecystokinin-B (CCK-B) which plays a neuromodulatory role in the regulation of GABAergic neuronal activity perhaps (theoretically) stimulating speech.
Wilson50 reports stimulation of speech at the time of administration with the use of provocative neutralization technique of Secretin thus full dose or repeated infusions may be unnecessary. Infusions of Secretin will correct the acidosis that most children with ASD present with ultimately impacting hyperammonemic (bicarbonate plus ammonia yields urea) states that may be stabilized with an increase in bicarbonate production. Perhaps one should consider oral repletion of bicarbonates as a less invasive intervention. Essentially each new aberration that is isolated in children with ASD demands that we examine the cell membrane integrity (including the blood brain barrier), membrane traffic (electrolyte stability and blood gases), the peptide-lipid membrane, nitrogen retention, and the very essence of the circuitry of the body -- -the prostaglandins. Children with ASD present with hepatic, gastrointestinal, renal, immune, endocrine and CNS disturbances reflected in striking metabolic derangement most clearly revealed in examination of red cell lipids representing four months of cellular metabolism with the accumulation of very long chain fatty acids (VLCFAs) indicative of suppressed peroxisomal beta oxidation.
Peroxisomes are organelles within cells which are pivotal in the biotransformation of endogenous compounds in lipid metabolism such as fatty acids, steroids, prostaglandins, the formation of myelin, neurotransmission, detoxification of exogenous compounds and xenobiotics.51-52 The accumulation of VLCFAs inside the cell membrane represents defects in peroxisomal beta oxidation53 which may be used to profile the deleterious effects upon the brain, endocrine, gastrointestinal and immune systems as well as hepatic cytochrome P450 derangement involving nitric oxide synthase (NOS) characteristic in autistic spectrum disorder due to autoimmune54 presentation. Therefore the toxic aspect so often described in autism may be defined clearly through examination of RBC lipids with elevation of VLCFAs a reflection of blocked detoxification mechanisms.
Presently, physicians struggle to understand when the administration of antioxidants, detoxification methods, hormonal support or the use of pro-oxidant therapies is appropriate. This dilemma can now be clarified through new understanding of cellular organelle interactions. Tremendous attention has been directed to the mitochondria (energy producing organelle) yet the most important organelle in regard to lipid metabolism and detoxification is the peroxisome. Peroxisomes, present in virtually all cells, but most prevalent in the liver and kidney, play a critical role of cellular lipid metabolism in the biosynthesis of fatty acids via beta oxidation involving physiologically important substrates for VLCFAs, dicarboxylic fatty acids, prostaglandins, thromboxanes, leukotrienes, pristanic acid, DHCA, THCA and xenobiotics.
Individuals with immune, CNS and endocrine disorders often present with complex xenobiotics involving disturbances in the cytochrome P450 superfamily which parallels disturbances in peroxisomal function. The cytochrome P450s are responsible for the biotransformation of endogenous compounds including fatty acids, steroids, prostaglandins, leukotrienes and vitamins as well as the detoxification of exogenous compounds resulting in substantial alterations of P450s as xenobiotics may turn off or greatly reduce the expression of constitutive isoenzymes.
Inappropriate use of antioxidants inhibit the beta oxidation or burning of cellular fatty acids suppressing lipid metabolism. Large dosing with Vitamin E, for example, will inhibit tumor shrinkage as beta oxidation is suppressed thus potent antioxidants are contraindicated toxic states, i.e. in the buildup of VLCFAs. The administration of DHEA, pregnenolone, or thyroid hormone stimulates the beta-oxidation of VLCFAs as would pro-oxidant nutrients and oxidative therapies. Children with ASD most often present with acidosis54, low CO2/Bicarbonate54 and low oxygen.54,55
Stimulating beta oxidation, however, concurrently stimulates the burning off of essential fatty acids (EFAs), thus it is crucial that the delicate balance of controlling redox potential, beta oxidation, and the administration of essential substrates (lipids, proteins) and catalysts (vitamins, minerals) be utilized specific to the individual child with ASD. There is now an enormous body of evidence that essential fatty acids play a vital role in the brain, cell to cell interactions, genetic expression and appear to be the focal point of man's evolution.
Understanding lipid and EFA metabolism is crucial for maintaining both physical and mental health. Newly documented research on targeted lipid manipulation has shown that dietary changes can dramatically influence the body human, and most profoundly the brain. 62 Viewing the brain of the child with ASD as a biological orchestration as it relates and interacts with membrane lipids offers a new dimension into understanding the specificity of disturbances within the brain in regard to lipids/peptide interactions on a cellular level and the intricate integration of essential fatty acids and prostaglandins.
The CNS cannot be controlled without respect to lipid substrate, yet fatty acid metabolism has been poorly delineated and often simply ignored in treatment protocols. Proper evaluation and attenuation of lipid metabolism in ASD brings a powerful therapeutic tool that integrates the complexities of multiple system involvement and the intimate link of the CNS to the immune, endocrine, hepatic, renal, gastrointestinal, pulmonary and cardiovascular systems as well as the exquisite capacity to impact the brain from a cellular perspective. Examination of over 700 red cell lipid analyses54 of children with ASD have revealed characteristic patterns as elevation of VLCFAs (erucic, lignoceric, lumequic, behenic, adrenic, pentacosanoic), depression of myelination markers as the DMA phospholipids, suppression of prostaglandin one synthesis (ASD patients respond to clonidine and pentoxifilline due to stimulus to PG156-59, elevation of the arachidonic acid cascade/prostaglandin two synthesis,60 and complex autoimmune derangement with elevation of EPA/DHA characteristic in disturbances involving the cytochrome p450 enzyme Nitric Oxide Synthase (NOS) and peroxisomal (detoxification/prostaglandin synthesis) dysfunction54.
NOS and Nitric oxide (NO) formation is augmented by supplementation of DHA (now commercially available derived from algae) and marine oils. The autoimmune presentation of ASD may initially respond negatively to marine oils, DHA or flax oil due to both the competitive inhibition of omega 3s to omega 6s (prostaglandin one series appears to be suppressed54 in children with ASD) and the stimulation of NOS/NO towards the autoimmune process. Nitric oxide as the smallest biologic product of the human cell is intimately involved in synaptic plasticity, immunity, neurotransmission, electrolytic stability, cerebral blood flow, blood pressure, neuromodulation, gastrointestinal and hepatic function. Imbalance of lipid substrate or damage to prostaglandin synthesis pathways due to immune insult may create grossly complicated Immune-CNS interactions that are riveted in disturbances within cell membrane dysfunction.
Omega 6 essential fatty acids (in this case the precursor PG1 as evening prim rose oil) must be repleted and stabilized before omega 3 supplementation commences. Consider carefully that the synthesis of prostaglandins is an oxidative process, therefore loading with antioxidants or the incorrect sequence of EFA repletion may impede progress in ASD presentation. Complex nitrogen metabolism appears to flourish in children with seizures, developmental delay and ASD involving not only Nitric Oxide but nitrogen retention as a whole (described previously as purine autism first identified by Mary Coleman61). Patients presenting with suppression of CO2 may shun nitrogen (protein) rich foods due to the formation of ammonia leading to a state of hyperammonemia.
Buffers and butyrates attenuate abnormal nitrogen metabolism however, children with ASD are unique in their presentations and as we examine nitrogen retention/NO, electrolyte stability, catalysts, lipid status to reach disturbances in metabolism requires that we act upon these aberrations in an integrative manner from a cellular perspective, not as singular interventions. Previously, we were hindered by medical literature that failed to differentiate between trans and cis isomers, neglected the importance of essential fatty acids, and sorely misinformed practitioners as to appropriate protocols for lipid manipulation. Intractable disorders such as adrenoleukodystrophy (ALD) have brought clarification to the labyrinth in the lipid pathways as separate fatty acids are studied and addressed through lipid (drug) therapy and further attenuated through systemic interventions.
Medicine has been slow to acknowledge the crucial lipid requirements (4 to 1 ratio of omega 6 to omega 3 or SR3 by Yehuda62) to address neurological degeneration, and now that the data is emerging from the medical literature it is difficult to extrapolate and utilize it towards meaningful therapeutic applications. By organizing the research data and isolating individual fatty acids in red cells we can now examine the intricate circuitry of the prostaglandins, whose substrates are fatty acids, stabilize cell membrane integrity, and for the first time lipid treatment protocols may be established due to a clear view into the brain through red cell membrane dynamics thereby opening a gateway into resolving autism and many of the neurodegenerative disorders of our time.
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