PCP Autism Model
Majid Ali, M.D.
PCP AUTISM MODEL
By Majid Ali, M.D.
Early Bioenergetic-Molecular Findings Underpinning the PCP Autism* Model
In 1998, mitochondrial dysfunction and mycotoxins were reported in a four-year-old-boy with autism in an article entitled oxidative regression to primordial cellular ecology.1 He had been a colicky newborn and developed constipation with episodes of loose bowel movements and dry erythematous skin patches within months of his birth. The parents noticed that his mood was linked to his bowel movements; irritability and crying spells accompanied the constipation-diarrhea-constipation cycles. Phase-contrast microscopy of his freshly prepared unstained peripheral blood smears revealed a heavy population of organisms with morphologic features of yeast species. Some such microbial bodies had previously been identified as Candida species with immunostaining employing anti-candida IgG antibodies.2 The diagnosis of mold and food allergy was established with measurements of blood concentrations of IgE and IgG antibodies with specificity for mold and food antigens with micro-elisa essay.3,4 Mitochondrial dysfunction was established by meaurements of Krebs cycle metabolites in 24-hour urinary samples.5,6 Oxidative coagulopathy was detected with phase-contrast and darkfield microscopy.7
Brief notes concerning prior work which provided the scientific framework and underpinnings of the PCP autism model are warranted here before moving on to the account of the treatment of the four-year-old protagonist of this narrative and the challenge his single case posed to the then-prevailing psychopathology model of the autism spectrum disorder. This work included redox pathobiology,7-10 gut immunopathology,11,12 gut ecology and microbiome,13 immunostaining of fungal organisms,2 molecular biology of oxygen,14-17 and ninsulin homeostasis.18-22
In 1980, Altered States of Bowel Ecology 13 was published to introduce ecologic thinking in clinical medicine with focus on gut microbiome. Subjects covered in this monograph included: (a) basic ecologic concepts as applied to human gut; (b) essential relatedness of systemic ecosystems to ecosystems of the alimentary tract; (c) changing patterns of gut microbiome; (d) the central roles of oxygen signaling in preserving the health of the intestinal tissues as well as of the gut microbiome.8 Specifically, these subjects were addressed by raising the following questions:
*The terms autism and autism spectrum disorder are used interchangeably in this The three- part report. The entities included in the autism spectrum are different in names only, not in their underlying energetic-molecular basis of their symptom-complexes, nor do different names make any difference in treatment strategies.
- Might ecologic thinking demystify some ancient notions of health and healing? (Death begins in the colon, for instance.23)
- Might integrated studies of ecologic disruptions in various segments of the gut ecosystem provide new insights into neurodevelopmental pathways? (As roots are to roses, so the bowel to the brain.24) These simple words proved very valuable for patient education in highlighting the core importance of gut ecology and gut microbiome in nourishing and nurturing the brain in antenatal and postnatal neurodevelopment).
- Might simple words, such as of seed-feed-and weed25bring clarity to the core concept of restoring gut ecology and gut microbiome with the use of probiotics, optimal food items for microbial support , and antifingal herbs and drugs?
- Might such broad ecologic concepts advance understanding of myriad roles played by the bowel flora in inflammatory and immune responses of the alimentary tract?
- Might ecologic thinking clarify some gut-related phenomena, such as how some species of the gut genome preserve the health of some systemic organs while other species act as pathogens in those organs?
- Might ecologic perspectives developed for one segment of human lifespan cast light over those concerning other segments? Might a deeper understanding of the pathogenesis of autism deepen understanding of the pathogenesis of dementia and Alzheimer’s disease, and vice versa? (an important subject addressed later in this article?
- Might ecologic concepts provide new scientific rationale and/or basis for integrating indigenous therapies with the prevailing pharmacologic options?
In 1983, Spontaneity of Oxidation In Nature and Aging26 was published as a primer in redox pathobiology and primal mechanisms of cellular injury and repair. In 1985, some aspects of molecular biology of oxygen were presented in an article entitled The Agony and Death of a Cell.127 So began the search for the energetic-molecular basis of chronic diseases which finally led to the publication of Darwin and Dysox Triology, the 10th, 11th, an 12th volumes of the Principles and Practice of Integrative Medicine.28-30 These volumes included in-depth discussions of the subjects of (1) molecular biology of oxygen, mitochondrial dysfunction, and attenuated oxygen signaling; (2) insulin homeostasis and insulin dysregulation with accentuated insulin signaling (“dysinulin” signals); and (3) gut ecology and gut microbiome that preserves health and dominance of oxyphobic over oxyphillic gut species31,32 that set the stage for causation and perpetuation of all chronic disease. These three threats (the “mito-myco-dysinsulin trio”) forms the primal base for the initiation and perpetuation of chronic disease in general, and the autism spectrum disorder, in particular in the current context.
In Oxygen and Aging (2000),33 molecular biology of oxygen was brought within the reach of integrative clinicians. It began with the following words:”Oxygen is the organizing principle of human biology and governs the aging process.” It recognized central roles of oxygen in the health/dis-ease/healing continuum, expounded its myriad dimensions in the pathogenesis of diverse disease processes, and proposed oxygen models of diverse clinicopathologic entities,33 including autism34 and Alzheimer’s disease.35
Oxygen creates and maintains a vast network of signaling, initiated and perpetuated both by its presence and absence. It pairs with insulin to form the two primary energetic signaling systems of developmental neurobiology. These two systems are so intricately and inextricably intertwined that they may be regarded as two integral components of one “oxygen-insulin signaling matrix.21,22 Disruptions of this matrix in non-autism settings usually begin with environmental, infectious, and immune-inflammatory disorders which impede Krebs cycle and disrupt insulin homeostasis, eventually attenuating oxygen signaling14-17 and accentuating insulin signaling.18-22
In 2004, in the first column on oxygen homeostasis published in Townsend Letter, the evidence for mitochondrial dysfunction with respiratory-to-fermentative shift in ATP generation in 236 patients with chronic fatigue syndrome and fibromyalgia with immune-inflammatory disorders was published.35 In 2014, in a seminal paper, the journal Nature validated the core findings of the Townsend article.36 Prompted by the Nature report, a 2015 follow-up report in Townsend Letter published another set of mitochondrial data for 351 additional patients, which was fully concordant with data published eleven years earlier.37 The two sets of data (the old 2004 and the new 2015) were included in a communication e-published by the journal Nature38 (Table 1) and the subject was further discussed in a Townsend column.39
|Table. 1. Frequency of Increased Urinary Excretion of Krebs Cycle Metabolites* In Chronic Immune-Inflammatory Disorders.|
|Krebs Cycle Metabolites||2004 n=236 35||2015 n=31537|
- Levels of Krebs metabolites measured in mmol/mol creatinine. The mean values of 24-hour urinary succinate excretion of patients and twenty control subjects were 80.3 and 8.7 mmol/mol creatinine respectively. Laboratory reference ranges: citric acid, < 597; Succinic, < 23, Lactic acid, 19-74; Malic acid, <2.3; and Fumaric acid, <1.8).
In 2008, the column on the autism spectrum disorder in Townsend Letter40 recognized that developmental neurobiology is the voice of reason in the care of children with atypical neurodevelopmental states (ANS) while notions of autism being psychopathology are belief systems. Reason is the faculty of observing natural phenomena and integrating new observations into the existing body of information – the natural order of things – to advance knowledge and understanding. Belief systems, by contrast, perpetuate the opinions of a few individuals in control as the absolute truths. Patients, parents, and caretakers pay the price when reason is subordinated to belief. Precious resources are wasted on professional quarrels over personal devotions to naming and re-naming patterns of children’s suffering while crucial issues of toxic environment, neglected adverse food reactions, sugar-insulin roller-coasters, undetected immune-inflammatory disorders and societal neglect of their special needs remain unrecognized and un-addressed. Simple natural remedies for the all-too-common constipation-diarrhea-constipation cycles are withheld.
Those who chemicalize human habitat consider the state of neglect, or worse denial of biologic issues, by some professionals convenient. It supports their profitability goals. Regrettably, the focus shifts to “autism psychopathology” and away from disrupted bioenergetics of developmental neurobiology.
In 2016, hyperinsulinism was reported in three children on the autism spectrum disorder.41 This completed the mito-mico-dysinsulin trio of factors that impede the neuronal progenitor cell progression to structurally and functionally mature neurons, which are responsible for the full antenatal and postnatal development of the trio of speech, sociability, and stability of mood (the clinical trio of the autism spectrum). Having met the theoretical conditions for the pathogenesis of the autism spectrum disorder, this led to putting forth the progenitor cell progression model of autism (the “PCP Autism Model”)42-45 as a unifying model that integrates all antenatal and postnatal factors and processes that can be implicated in the cause of the autism spectrum disorder. It is noteworthy here that the underlying mechanism of action of all recognized maternal infectious, environmental, metabolic, and pregnancy-related risk factors of autism have in common among them the commonalities of the mito-myco-dysinsulinism trio. This, in summary, was the eighteen-year (1998-2016) journey, of inquiry, hypothesis, clinical exploration, and laboratory investigations that culminated in the formulation and publication of the PCP autism model.42-45 Some of the body of data concerning the mito-myco-disinsulinism has been presented in past publications, while newer data is presented in this three-part report.
Returning to the case of the four-year-old boy, with the diagnoses of mold and food allergy, atopic dermatitis, constipation-diarrhea-mood cycles, fungemia (with implicit dominance of oxyphobic over oxyphillic species31,32 the gut microbiome), he was treated with a robust integrated dietary, nutritional, detox, and antifungal plan employing the seed, feed, and weed approach.46, including oral Nystatin in doses of 100,000 units three times daily. Other components of the program included low carbohydrate diet with exclusion of fruit juices and desserts, sublingual immunotherapy for IgE-mediated diathesis, Nystatin as antifungal pharmacologic agent, and intramuscular injections of methylcobalamine, glutathione, taurine, magnesium, and vitamin B complex (described in the third of this three-part report). The patient responded briskly with not only positive gastrointestinal responses but also with speech-sociability-mood improvement, which was considered dramatic by the parents. Repeat phase-contrast microscopy of unstained peripheral blood samples revealed a marked reduction of yeast-like forms compared with the initial examination.
Table 2 (reproduced from the original article by kind permission of the Journal of Integrative Medicine) shows dramatic improvement in markers of mitochondrial dysfunction and a reduction in urinary excretion of mycotoxins.1
|Table 2. Pretreatment and Posttreatment 24-Hour Urinary Excretion of Krebs Cycle Metabolites and Mycotoxins of a Four-Year-Old Boy With Autism are Shown.*See Text for Comments Concerning Clinical Improvement Associated With Laboratory Changes.1|
|Kreb Metabolite Or Mycotoxins||Pretreatment||Posttreatment|
|Tartaric Acid||423||32 (0-16)|
|Furan-2.5-dicarboxylic acid||155||7 (0-50)|
|Furancarbonylglycinic acid||88||0 (0-60)|
|5-hydroxymethyl-2-furoic acid||421||42 (0-80)|
|3-hydroxy-3-methylglutaric acid||259||11 (0-36)|
|Lactic acid||98||61 (0-100)|
|Pyruvic acid||3.6||2.6 (0-50)|
|* Concentrations of Organic Acids Are Expressed in mmol/mol creatinine. Laboratory Ranges are given in Parenthesis.|
The response of autism-related symptom-complex (which included new spoken words and incomplete sentences as related by the parents) in this single case raised serious questions about the validity of the autism spectrum being considered a psychological or psychiatric disorder, as it was then generally considered. This eye-opening case study was followed by other similar case studies of autism treated with the same broad integrative approach, though none with as revealing or compelling mitochondrial dysfunction and/or mycotoxicosis. Still the die was cast. In the care of other children diagnosed previously with autism, the range of immunodiagnostic testing was expanded within a broader integrative context to include diverse aspects of redox pathobiology1,4-7 immune-inflammatory disorders,47-49 and dysfunctional oxygen metabolism (dysoxygenosis)50,51 7-49 as well as tests for thyroid function and others included in the prevailing pediatric workup. The scientific rationale and basis of specialized testing cited above were presented in a series of Townsend columns and selected other previous publications450-52
For readers interested in the subject of the essential relatedness of these aspects of such human bioenergetics to bioenegetic-molecular basis the autism spectrum disorder, I suggest Nature’s Preoccupation With Complementarity and Contrariety, the first volume of The Principles and Practice of Integrative Medicine.53