Mitochondrial dysfunction and metabolic abnormalities are well established findings in a significant subset of those with autism. In their 2011 study of mitochondrial dysfunction, Frye and Rossignol state the following symptoms may be associated;
loss of skills
Abnormalities in: endocrine, growth, gastrointestinal system, lactate, pyruvate and alanine.
Multiple metabolic abnormalities have been discovered in those with autism, including; redox function, oxidative stress, glutathione metabolism, melatonin production, methylation and folate pathways, and cholesterol metabolism.
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Metabolic and Mitochondrial
"This is the first systematic investigation of the effects of BT on mitochondrial function in LCLs as well as the first study to demonstrate the effect of BT on mitochondria in tissues from individuals with ASD. In this study, we examined the effect of BT on mitochondrial function in transformed B-cells (i.e., LCLs) derived from children with ASD with and without a unique type of mitochondrial dysfunction as well as LCLs from typically developing age-matched boys...There are many lines of evidence that BT may be helpful in normalizing the behavior and physiological abnormalities in ASD. In animal models of ASD, BT positively modulates neurotransmitter gene expression67, and rescues the ASD-type behavior66 and brain pathology66,68 induced by prenatal valproic acid exposure66. Additionally, BT has been found to modulate the ASD-related genes in cell line models33. BT has interesting effects on behavior and gene expression in the brain of the BTBR mouse model of ASD. BT decreased the excitatory and increased the inhibitory neurotransmitter genes in the prefrontal cortex and had a positive effect on behavior by increasing social behavior and decreasing repetitive behavior through modulating the excitatory–inhibitory balance of the brain67."
Translational Psychiatry (2018)8:42
"The prevalence of mitochondrial disease in the ASD population is estimated to be about 5.0%, 500 times higher than that found in the general population (≈0.01%). The prevalence of abnormal metabolic biomarkers is even higher, suggesting that as many as 30% of children with ASD may experience metabolic abnormalities: almost one-third of autistic children have documented elevations in plasma lactate and/or the lactate-to-pyruvate ratio, and the levels of many other mitochondrial biomarkers (pyruvate, carnitine, and ubiquinone) are significantly different between ASD and controls (Rossignol and Frye, 2012)...At present, there is strong evidence that mitochondrial and metabolic dysfunction may underlie the complex pathophysiology of ASD."
Cheng, Ning, Jong M. Rho, and Susan A. Masino. “Metabolic Dysfunction Underlying Autism Spectrum Disorder and Potential Treatment Approaches.” Frontiers in Molecular Neuroscience 10 (2017): 34. PMC.
"Such supplements include L-carnitine, coenzyme Q10, ubiquinol, B vitamin-containing multivitamins, ascorbic acid, α-tocopherol, and N-acetyl-L-cysteine [117, 119]. Treatment with L-carnitine, an essential nutrient important for the fatty acid transport across the mitochondrial membrane, was shown to improve core and associated ASD symptoms in a number of controlled trials [119–121]. In one of these investigations, serum carnitine levels were found to correlate with cognitive and behavioral scores .
In other work, supplementation with antioxidants such as N-acetyl-L-cysteine (a precursor to glutathione), coenzyme Q10, ubiquinol, ascorbic acid, α-tocopherol, methylcobalamin, and carnosine also improved behavioral symptoms associated with autism [122–129]. In a randomized double-blind placebo controlled trial, a formulation of multivitamins combined with mineral supplements (containing multiple mitochondrial cofactors, vitamins, and antioxidants) improved plasma or erythrocyte levels of methylation, glutathione, oxidative stress, sulfation, ATP, nicotinamide adenine dinucleotide (NADH), and nicotinamide adenine dinucleotide phosphate (NADPH) and improved overall behavior, hyperactivity, tantrums, and receptive language in children and adults with ASD [126, 127]..Folic acid is important for redox metabolism, methylation, and mitochondrial homeostasis [132, 133]. Disruption of folate receptor αactivity occurs in autism due to autoantibodies and mitochondrial dysfunction and results in CNS folate deficiency . Severe reductions in cerebral folate levels can lead to neurodevelopmental regression and the autism phenotype . Importantly, targeted treatment with folinic acid has been shown to partially or completely improve communication, social interaction, attention, and stereotypical ASD behavior in patients with autoantibodies to folate receptor α[135–137]."
Griffiths, Keren K., and Richard J. Levy. “Evidence of Mitochondrial Dysfunction in Autism: Biochemical Links, Genetic-Based Associations, and Non-Energy-Related Mechanisms.” Oxidative Medicine and Cellular Longevity 2017 (2017): 4314025. PMC.
"This study found an improvement in an important core ASD symptom, verbal communication, in non-syndromic ASD children receiving high-dose folinic acid vs placebo, particularly in those participants who were positive for FRAAs. Improvement in a number of secondary outcomes was observed as well, with no significant adverse events. The effect of folinic acid is consistent with the
This study suggests that FRAAs predict response to high-dose folinic acid treatment. This is consistent with the notion that children with ASD and FRAAs may represent a distinct subgroup.61 Other factors such as genetic polymorphisms in folate-related genes or mitochondrial dysfunction may be important in determining treatment response but were not examined in this study. When methylcobalamin was combined with folinic acid, improvement in communication as well as glutathione redox status was found."
Frye, R, et al. "Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial" Molecular Psychiatry advance online publication 18 October 2016; doi: 10.1038/mp.2016.168
This is the first study to demonstrate evidence for mitochondrial dysfunction in vivo in the brains of individuals with ASD. Our study yielded an overall prevalence estimate of 13% for ASD with concomitant mitochondrial dysfunction, but it was considerably higher (20%) for adults with ASD...A key finding from this study is the higher rate of elevated brain lactate in ASD adults...Second, the age-specific findings could represent a worsening of mitochondrial function with aging.27...Determining the underlying cause of impaired mitochondrial function in ASD will require further investigation of children and adults and consideration of both primary causes of mitochondrial dysfunction (e.g., mutations in mitochondrial or nuclear genes that play a role in mitochondrial metabolism) and secondary causes (e.g., inflammation, neurodegeneration, and excess oxidative stress).
Our study not only demonstrated elevated brain lactate in ASD, but it also allowed us to map the distribution of lactate in the brain."
Goh, Suzanne et al. “Brain Imaging Evidence That Mitochondrial Dysfunction Is a Neurobiological Subtype of Autism Spectrum Disorder.” JAMA psychiatry 71.6 (2014): 665–671. PMC.
"Higher oxidative stress in cells of children with autism was evidenced by higher rates of mitochondrial reactive oxygen species production (1.6-fold), higher mitochondrial DNA copy number per cell (1.5-fold), and increased deletions. Mitochondrial dysfunction in children with autism was accompanied by a lower (26% of TD children) oxidative burst by PMA-stimulated reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase and by a lower gene expression (45% of TD children's mean values) of the nuclear factor erythroid 2–related factor 2 transcription factor involved in the antioxidant response. Given that the majority of granulocytes of children with autism exhibited defects in oxidative phosphorylation, immune response, and antioxidant defense, our results support the concept that immunity and response to oxidative stress may be regulated by basic mitochondrial functions as part of an integrated metabolic network."
Napoli, Eleonora et al. “Deficits in Bioenergetics and Impaired Immune Response in Granulocytes From Children With Autism.” Pediatrics 133.5 (2014): e1405–e1410. PMC.
"This manuscript examines the evidence linking oxidative stress, mitochondrial dysfunction and immune dysregulation/inflammation in the brain of ASD individuals, suggesting that ASD has a clear biological basis with features of known medical disorders. This understanding may lead to new testing and treatment strategies in individuals with ASD...A recent systematic review of 112 individuals with ASD and concomitant mitochondrial disease found that only about 21% had a genetic abnormality that could account for the reported mitochondrial problem (Rossignol and Frye, 2012a). Mitochondrial dysfunction found in some individuals with autism could be related to inflammation or immune dysregulation. For example, TNF-alpha is known to inhibit mitochondrial function (Suematsu et al., 2003; Vempati et al., 2007; Samavati et al., 2008) and elevations in TNF-alpha, from individuals with ASD compared to controls, have been reported in lymphocytes (Malik et al., 2011a), amniotic fluid (Abdallah et al., 2013), CSF (Chez et al., 2007) and brain samples (Li et al., 2009). GSH protects mitochondria against the adverse effects of TNF-alpha (Fernandez-Checa et al., 1997) and GSH deficiency can lead to impaired mitochondrial function (Vali et al., 2007). Interestingly, TNF-alpha (also known as cachexin) is known to decrease mitochondrial enzymatic function, including cytochrome c oxidase (complex IV) activity (Remels et al., 2010)."
Rossignol, Daniel A., and Richard E. Frye. “Evidence Linking Oxidative Stress, Mitochondrial Dysfunction, and Inflammation in the Brain of Individuals with Autism.” Frontiers in Physiology 5 (2014): 150.
"A group of ASD has been linked to mitochondrial dysfunction with subsequent deficiency in energy production. Patients with ASD and mitochondrial disease often show signs and symptoms uncommon to idiopathic ASD such as cardiac, pancreatic or liver dysfunction, cardiac, growth retardation, fatigability, but in some cases semiology is different. We show two clinical cases of ASD associated to a deficiency of the mitochondrial respiratory chain (complex I+III and IV) with different clinical presentations. In one case, signs and symptoms of mitochondrial disorder were mild and the second diagnosis was attained many years after that of ASD. These findings support the recent growing body of evidence that ASD can be associated with mitochondrial disorder. Children with ASD and abnormal neurologic or systemic findings should be evaluated for mitochondrial disorder.
Guevara-Campos, J., González-Guevara, L., Puig-Alcaraz, C. et al. "Autism spectrum disorders associated to a deficiency of the enzymes of the mitochondrial respiratory chain" Metab Brain Dis (2013) 28: 605. https://doi.org/10.1007/s11011-013-9419-x
"Overall, our findings suggest that ASD/MD children with a more chronic oxidized microenvironment have better development. We interpret this finding in light of the fact that more active mitochondrial can create a greater oxidized microenvironment especially when dysfunctional. Thus, compensatory upregulation of mitochondria which are dysfunctional may both increase activity and function at the expense of a more oxidized microenvironment...These results suggest that children with ASD/MD are true a subgroup of ASD children with distinct clinical, developmental and metabolic characteristics...Several reports have documented that inflammatory processes, especially involving fever, that are triggered by illnesses or vaccines, can result in neurodevelopmental regression, including regression into ASD, in children with underlying MD,73 even if MD was not diagnosed before the illness.74 Inflammation and inflammatory mediators can inhibit mitochondrial function30, 31, 32 and increased oxidative stress associated with inflammation may cause further mitochondrial dysfunction,33, 34 potentially leading to long-term mitochondrial damage."
Frye, R E et al. “Redox Metabolism Abnormalities in Autistic Children Associated with Mitochondrial Disease.” Translational Psychiatry 3.6 (2013): e273–. PMC.
"Overall, 17% of individuals with ASD demonstrated consistently abnormal acyl-carnitine panels. Next, it was determined if specific acyl-carnitine species were consistently elevated across the individuals with consistently abnormal acyl-carnitine panels. Significant elevations in short-chain and long-chain, but not medium-chain, acyl-carnitines were found in the ASD individuals with consistently abnormal acyl-carnitine panels-a pattern consistent with the PPA rodent ASD model. Examination of electron transport chain function in muscle and fibroblast culture, histological and electron microscopy examination of muscle and other biomarkers of mitochondrial metabolism revealed a pattern consistent with the notion that PPA could be interfering with mitochondrial metabolism at the level of the tricarboxylic-acid cycle (TCAC). The function of the fatty-acid oxidation pathway in fibroblast cultures and biomarkers for abnormalities in non-mitochondrial fatty-acid metabolism were not consistently abnormal across the subgroup of ASD children, consistent with the notion that the abnormalities in fatty-acid metabolism found in this subgroup of children with ASD were secondary to TCAC abnormalities. Glutathione metabolism was abnormal in the subset of ASD individuals with consistent acyl-carnitine panel abnormalities in a pattern similar to glutathione abnormalities found in the PPA rodent model of ASD. These data suggest that there are similar pathological processes between a subset of ASD children and an animal model of ASD with acquired mitochondrial dysfunction."
Frye, R E, S Melnyk, and D F MacFabe. “Unique Acyl-Carnitine Profiles Are Potential Biomarkers for Acquired Mitochondrial Disease in Autism Spectrum Disorder.” Translational Psychiatry 3.1 (2013): e220–. PMC.
"This systematic review and meta-analysis found that abnormal biochemical markers of mitochondrial function are relatively common in the general population of children with ASD and that a relatively high percentage of children with ASD (∼5%) have MD...Several metabolic abnormalities and/or exposures to environmental toxicants could result in secondary mitochondrial dysfunction in children with ASD, or these factors could worsen mild mitochondrial dysfunction in some children, transforming mild dysfunction into more severe dysfunction. Some children demonstrated regression into ASD and MD following fever, suggesting children who develop MD may be vulnerable to external factors causing regression into ASD in children who may already have existing, but unidentified, MD. This suggests that it is important for children with MD to be identified early in life."
Rossignol, D A, and R E Frye. “Mitochondrial Dysfunction in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis.” Molecular Psychiatry 17.3 (2012): 290–314. PMC.
"Individuals with ASD have been shown, as a group, to be under higher oxidative stress and have reduced levels of antioxidants as compared to controls (63–65). It is likely that mitochondrial dysfunction could be the cause of abnormally high levels of oxidative stress found in ASD individuals...The depletion of reduced glutathione in mitochondria has been associated with impaired mitochondrial function (66) and additional ROS production (67). This may initiate a vicious cycle as increased ROS can further impair mitochondrial function (67, 68)..Mitochondrial dysfunction is the most common metabolic abnormality associated with ASD (5, 78)...Mitochondrial dysfunction can unify the seemingly disparate clinical findings and physiological abnormalities associated with ASD...Estimates of the prevalence of mitochondrial dysfunction in ASD vary widely. While a large population-based study estimated the prevalence of mitochondrial disease in ASD as 7.2% (11), a more recent controlled study in the Journal of the American Medical Association suggested that mitochondrial dysfunction may be present in up to 80% of children with ASD (12). In addition, while some investigators have proposed a “mitochondrial autism” subgroup (13). In a systematic review and meta-analysis, we recently demonstrated that there is significant evidence for both mitochondrial disease and dysfunction in children with ASD (5)."
Frye, Richard E., and Daniel A. Rossignol. “Mitochondrial Dysfunction Can Connect the Diverse Medical Symptoms Associated with Autism Spectrum Disorders.” Pediatric research 69.5 Pt 2 (2011): 41R–47R. PMC.
"Certain biomarkers may be useful for evaluating possible MtD in autistic individuals. Some researchers suggest pyruvate levels should be measured during routine evaluation of ASD children. However, measuring a pyruvate level is not always practical because typically it is only available in teaching or specialty hospitals. The plasma alanine to lysine ratio (normal range is 1.5-2.5) is a surrogate marker for pyruvate; a ratio above 2.5 is consistent with an elevation in pyruvate. A lactate level is “a simple, non-invasive, low-cost means for the initial diagnostic approach” of mitochondrial problems. Mitochondrial problems can also be screened for by examining urinary organic acids. Assessing carnitine and ammonia levels and oxidative stress markers may also be useful. Screening for any of these blood and urine tests may be helpful in identifying MtD in ASD...Treatment of oxidative stress with antioxidants and other nutritional supplements may ameliorate MtD in some individuals with autism."
Daniel A. Rossignol, J. Jeffrey Bradstreet "Evidence of Mitochondrial Dysfunction in Autism and Implications for Treatment"
American Journal of Biochemistry and Biotechnology 4 (2): 208-217, 2008
"If such dysfunction is present at the time of infections and immunizations in young children, the added oxidative stresses from immune activation on cellular energy metabolism are likely to be especially critical for the central nervous system, which is highly dependent on mitochondrial function. Young children who have dysfunctional cellular energy metabolism therefore might be more prone to undergo autistic regression between 18 and 30 months of age if they also have infections or immunizations at the same time. Although patterns of regression can be genetically and prenatally determined,9 it is possible that underlying mitochondrial dysfunction can either exacerbate or affect the severity of regression. Abnormalities of oxidative phosphorylation can be developmental and age related and can normalize with time.10
Our findings of mildly increased aspartate aminotransferase and serum creatine kinase level in children with autism might reflect abnormal mitochondrial function in skeletal muscle since alanine transaminase and other liver enzymes were normal."
Poling, Jon S. et al. “Developmental Regression and Mitochondrial Dysfunction in a Child With Autism.” Journal of child neurology 21.2 (2006): 170–172. PMC.
"A minority of cases of autism has been associated with several different organic conditions, including bioenergetic metabolism deficiency. In a population-based study, we screened associated medical conditions in a group of 120 children with autism (current age range 11y 5mo to 14y 4mo, mean age 12y 11mo [SD 9.6mo], male:female ratio 2.9:1). Children were diagnosed using Diagnostic and Statistical Manual of Mental Disorders criteria, the Autism Diagnostic Interview--Revised, and the Childhood Autism Rating Scale; 76% were diagnosed with typical autism and 24% with atypical autism. Cognitive functional level was assessed with the Griffiths scale and the Wechsler Intelligence Scale for Children and was in the normal range in 17%. Epilepsy was present in 19 patients. Plasma lactate levels were measured in 69 patients, and in 14 we found hyperlactacidemia. Five of 11 patients studied were classified with definite mitochondrial respiratory chain disorder, suggesting that this might be one of the most common disorders associated with autism (5 of 69; 7.2%) and warranting further investigation."
Oliveira G, et al. "Mitochondrial dysfunction in autism spectrum disorders: a population-based study." Dev Med Child Neurol. 2005 Mar;47(3):185-9.
Metabolic abnormalities and emerging biomarkers
"The aim of the SAT‐1 trial was to test the safety, pharmacokinetics, and pharmacodynamics of low‐dose suramin in children with ASD. A self‐limited rash was seen, but no serious adverse events occurred. Pharmacometabolomic analysis showed that the pathways changed by suramin treatment in ASD were previously known mediators of the cell danger response (CDR)8 and that purine metabolism was changed most. Seventy‐five percent of the pathways changed by suramin in children with ASD were also changed by suramin in mouse models.12, 13, 14... Metabolomic studies confirmed the importance of the cell danger response (CDR)8 and purinergic signaling.12, 13, 14 A single intravenous dose of suramin was associated with improved scores for language, social interaction, and decreased restricted or repetitive behaviors measured by ADOS, ABC, ATEC, and CGI scores. None of these improvements occurred in the five children who received placebo."
Naviaux, Robert K. et al. “Low‐dose Suramin in Autism Spectrum Disorder: A Small, Phase I/II, Randomized Clinical Trial.” Annals of Clinical and Translational Neurology 4.7 (2017): 491–505. PMC.
"Our findings confirm previous studies indicating abnormal mitochondrial and related biomarkers in children with ASD including pyruvate, creatine kinase, Complex 1, Glutathione S-Transferase, glutathione and Caspase 7. As a novel finding, we report that lactate dehydrogenase is abnormal in children with ASD. We also identified that only the most severe children demonstrated abnormalities in Complex 1 activity and Glutathione S-Transferase. Additionally, we find that several biomarkers could be candidates for differentiating children with ASD and typically developing children, including Caspase 7, gluthatione and Glutathione S-Transferase by themselves and lactate dehydrogenase and Complex I when added to other biomarkers in combination. Caspase 7 was the most discriminating biomarker between ASD patients and healthy controls suggesting its potential use as diagnostic marker for the early recognition of ASD pathophysiology. This study confirms that several mitochondrial biomarkers are abnormal in children with ASD and suggest that certain mitochondrial biomarkers can differentiate between ASD and typically developing children, making them possibly useful as a tool to diagnosis ASD and identify ASD subgroups."
Asma M. Khemakhem, et. al: Novel biomarkers of metabolic dysfunction is autism spectrum disorder: potential for biological diagnostic markers; Metab Brain Dis. 2017 Aug 22. doi: 10.1007/s11011-017-0085-2
"Here, we applied redox proteomics approaches to analyze the carbonylated proteins in the plasma of autistic patients. The results revealed that the carbonyl levels of two proteins (i.e., C8A and IGKC) were significantly increased in autistic subjects compared with age-matched controls. C8A is involved in complement and coagulation cascades and IGKC involved in immune response. Interestingly, complement active and immune dysfunction has been related to the pathogenesis of autism [32, 33]. The complement system comprises a group of proteins which, when activated, provide one of the first lines of defense by promoting lysis and removal of invading microbes . The complement system may also be involved in cellular apoptosis in brain and peripheral differences of immune molecules that could impact indirectly on the developing brain in autism . Comparison with healthy controls, several up-regulated complement proteins have been reported in the serum of ASD , including complement factor H related protein (FHR1), complement C1q and complement factor I (CFI). Increases in three peptides that correspond to C3 complement protein fragments were identified in the plasma of children with ASD . Here, C8A showing significantly increased carbonyl levels in the plasma from autistic children compared with controls, demonstrating and supporting the option that complement system may be involved in the pathophysiology of autism [32, 33]."
Feng, Chengyun et al. “Redox Proteomic Identification of Carbonylated Proteins in Autism Plasma: Insight into Oxidative Stress and Its Related Biomarkers in Autism.” Clinical Proteomics 14 (2017): 2. PMC
"As a novel finding, we report that lactate dehydrogenase is abnormal in children with ASD. We also identified that only the most severe children demonstrated abnormalities in Complex 1 activity and Glutathione S-Transferase. Additionally, we find that several biomarkers could be candidates for differentiating children with ASD and typically developing children, including Caspase 7, gluthatione and Glutathione S-Transferase by themselves and lactate dehydrogenase and Complex I when added to other biomarkers in combination. Caspase 7 was the most discriminating biomarker between ASD patients and healthy controls suggesting its potential use as diagnostic marker for the early recognition of ASD pathophysiology. This study confirms that several mitochondrial biomarkers are abnormal in children with ASD and suggest that certain mitochondrial biomarkers can differentiate between ASD and typically developing children, making them possibly useful as a tool to diagnosis ASD and identify ASD subgroups."
Khemakhem, A.M., Frye, R.E., El-Ansary, A. et al. "Novel biomarkers of metabolic dysfunction is autism spectrum disorder: potential for biological diagnostic markers" Metab Brain Dis (2017). https://doi.org/10.1007/s11011-017-0085-2
"This hypothesis paper highlights the need for future studies to investigate the levels of multiple steroid hormones in individuals with ASD – especially cholesterol and VitD...We would suggest that in new studies in the field of neurodevelopmental disorders and possible links with sterol abnormalities, all of the following (and possibly more) should be included in the “work‐up kit” in all individuals recruited for study: serum levels of cholesterol, 7‐ and 8 dehydrocholesterol, 25‐OH vitamin D, testosterone, estrogen, cortisol (although diurnal variation may be a particular aspect to consider here) and 7‐dehydrocholesterol reductase. In collaboration with chemists and geneticists a variety of enzyme and gene tests may then be added to the protocol depending on specific research questions in any particular study."
Gillberg, Christopher et al. “The Role of Cholesterol Metabolism and Various Steroid Abnormalities in Autism Spectrum Disorders: A Hypothesis Paper.” Autism Research 10.6 (2017): 1022–1044. PMC.
"Autism spectrum disorder (ASD) is a complex, life-long neurodevelopmental disorder currently affecting an estimated 1 out of 68 among children aged 8 y in the United States. ASD has complex genetic and epigenetic features that lead to the phenotype and there is no single genetic marker for the diagnosis. Therefore, the diagnosis for ASD is phenotype- based with no validated or credible laboratory tests available. Evidence-based treatments for ASD are limited. There is no FDA approved medical therapy that addresses either core ASD symptoms or pathophysiological processes associated with ASD. We outline herein, several ASD-associated basic physiological pathways that can be regulated by the small molecule phytochemical sulforaphane, as an example of a druggable small molecule target for which much in vitro, pre-clinical, and clinical evidence already exists: (1) redox metabolism/oxidative stress, (2) mitochondrial dysfunction, (3) immune dysregulation/neuroinflammation, (4) febrile illness and the heat shock response, and (5) synaptic dysfunction. Furthermore, we identify the biomarkers that can be used to assess the functioning of these pathways as well as suggesting how these biomarkers could guide novel treatment strategies to correct these biochemical abnormalities in order to improve core and associated symptoms of ASD."
Hua Liu, Paul Talalay, Jed W. Fahey. "Biomarker-Guided Strategy for Treatment of Autism Spectrum Disorder (ASD)"
CNS Neurol Disord Drug Targets. 2016;15(5):602-13
"This excess of urinary purinergic metabolites has been interpreted as part of a “cell danger metabolic response” involving mitochondrial dysfunction, adenosine triphosphate (ATP), and adenosine diphosphate (ADP) release, activation of a variety of purinergic receptors yielding microglial activation, innate, and adaptive immunity responses and leukocyte chemotactics . Inborn errors of purine metabolism are associated with behavioral abnormalities including autistic features . Strikingly, inhibition of purine metabolism by suramin, a competitive antagonist at P2X and P2Y purinergic receptors, reverses behavioral, neurochemical, transcriptional, and metabolomics abnormalities both in the Fmr1 knock-out mouse and in MIA mice exposed to poly(I:C) during pregnancy [35–37]. Conceivably, this metabolic abnormality, shared between human ASD and genetic/immunological rodent models could thus represent a valuable biomarker to help guide therapeutic interventions....Targeting young autistic children and tightly matched controls, using the sensitive approach HILIC UHPLC-MS, and applying metabolic pathway analysis, we identified several urinary metabolic pathways significantly altered in ASD: tryptophan, purine, and vitamin B6 metabolisms; phenylalanine, and tyrosine biosynthesis; and to a lesser extent, pantothenate and CoA, riboflavin, and pyrimidine metabolisms. Several of these same pathways, especially tryptophan, purine, and gut microbiome metabolisms, are also abnormal in animal models of ASD and provide very interesting leads toward possible pathophysiological explanations for specific symptoms present in many autistic children, such as seizures and sleep disorders."
Gevi, Federica et al. “Urinary Metabolomics of Young Italian Autistic Children Supports Abnormal Tryptophan and Purine Metabolism.” Molecular Autism 7 (2016): 47. PMC.
"Some biomarkers of the metabolic pathways discussed have been consistently found to be abnormal across studies, such as low GSH and SAM, while other biomarkers have been inconsistently found to be abnormal...Given the heterogeneity of autism, it is highly likely that different metabolic phenotypes will be associated with different subgroups of children...It is becoming clear that the etiology of most ASD cases involves complicated interactions between genetic predisposition with environmental exposures or triggers. The metabolic pathways discussed within this article demonstrate how multiple genes and environmental factors could come together to disrupt metabolism...Biomarkers discussed within this article should be particularly useful in understanding the connection between genetic predisposition and environmental triggers since biomarkers can re ect genetic polymorphisms that disrupt metabolic path- ways as well as environmental exposures that interfere with normal metabolic redux. Most importantly, bio- markers are potentially useful for identifying those individuals who are most vulnerable to environmental triggers so they can be protected from developing pathology associated with autism."
Autism spectrum disorder is associated with metabolic disturbances
• Many children with autism spectrum disorder have disruptions in several physiological systems, including redox, folate, methylation (epigenetics) and mitochondrial metabolism, despite not having any de ned genetic defect to account for these abnormalities.
Redox metabolism is important for maintaining cell health
Redox metabolism balances reactive oxygen and nitrogen species to maintain a healthy redox potential in the cell.
Abnormally high levels of reactive oxygen and nitrogen species can overwhelm the antioxidant mechanisms of the cell, resulting in oxidative stress, which can cause damage to the cellular molecules.
Glutathione metabolism is important for protecting the cell
Glutathione metabolism is important for maintaining redox homeostasis and control of the levels of reactive oxygen and nitrogen species in the cell, and is important for detoxification and elimination of environmental toxins from the cell.
Glutathione metabolism abnormalities are associated with autism spectrum disorder
Several studies have verified abnormalities in glutathione metabolism in plasma, immune cells and brains of children with autism spectrum disorder.
Glutathione metabolism is associated with abnormalities in other metabolic pathways in autism spectrum disorder
Glutathione metabolism is associated with folate and methylation metabolism, both of which have
abnormalities associated with autism spectrum disorder.
The combination of glutathione metabolism abnormalities associated with abnormalities in folate and
methylation pathways may represent a distinct endophenotype of autism.
Metabolic abnormalities may be amendable to treatment
Studies have demonstrated that treatments that address metabolic abnormalities in the glutathione, methylation and folate pathways may improve both metabolic biomarkers and core symptoms of autism spectrum disorder.
"The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis. The resulting metabolic mismatch between available resources and functional capacity produces a cascade of changes in cellular electron flow, oxygen consumption, redox, membrane fluidity, lipid dynamics, bioenergetics, carbon and sulfur resource allocation, protein folding and aggregation, vitamin availability, metal homeostasis, indole, pterin, 1-carbon and polyamine metabolism, and polymer formation.
The first wave of danger signals consists of the release of metabolic intermediates like ATP and ADP, Krebs cycle intermediates, oxygen, and reactive oxygen species (ROS), and is sustained by purinergic signaling. After the danger has been eliminated or neutralized, a choreographed sequence of anti-inflammatory and regenerative pathways is activated to reverse the CDR and to heal. When the CDR persists abnormally, whole body metabolism and the gut microbiome are disturbed, the collective performance of multiple organ systems is impaired, behavior is changed, and chronic disease results. Metabolic memory of past stress encounters is stored in the form of altered mitochondrial and cellular macromolecule content, resulting in an increase in functional reserve capacity through a process known as mitocellular hormesis. The systemic form of the CDR, and its magnified form, the purinergic life-threat response (PLTR), are under direct control by ancient pathways in the brain that are ultimately coordinated by centers in the brainstem. Chemosensory integration of whole body metabolism occurs in the brainstem and is a prerequisite for normal brain, motor, vestibular, sensory, social, and speech development. An understanding of the CDR permits us to reframe old concepts of pathogenesis for a broad array of chronic, developmental, autoimmune, and degenerative disorders. These disorders include autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), asthma, atopy, gluten and many other food and chemical sensitivity syndromes, emphysema, Tourette's syndrome, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), chronic traumatic encephalopathy (CTE), traumatic brain injury (TBI), epilepsy, suicidal ideation, organ transplant biology, diabetes, kidney, liver, and heart disease, cancer, Alzheimer and Parkinson disease, and autoimmune disorders like lupus, rheumatoid arthritis, multiple sclerosis, and primary sclerosing cholangitis."
"In this open-label dose-escalation study of supplemental melatonin, we found that (1) The majority of children responded to a 1 mg or 3 mg dose given 30 minutes before bedtime with an improvement in sleep latency; (2) This improvement was seen within the first week of dosing at the effective dose; (3) The medication was tolerated well with minimal adverse effects and no changes in laboratory values; (4) Actigraphy data was collectable over 17 weeks; and (5) Actigraphy, as well as parent-completed surveys focusing on sleep and behavior, showed change with the intervention...In summary, our findings provide unique information on dosing, tolerance/safety, and outcome measures for the use of melatonin in pre-pubertal children with ASD."
Malow, Beth A. et al. “Melatonin for Sleep in Children with Autism: A Controlled Trial Examining Dose, Tolerability, and Outcomes.” Journal of Autism and Developmental Disorders 42.8 (2012): 1729–1737. PMC.
"The glutathione redox ratio (GSH/GSSG) and the percentage oxidized glutathione equivalents are dynamic indicators of cytosolic and mitochondrial redox status as well as the severity of oxidative stress. The present findings provide the first evidence that intracellular redox status is compromised in LCLs derived from autistic children and that the redox status of isolated mitochondria is similarly compromised. In isolated mitochondria from the autism LCLs, a significant decrease in GSH and the GSH/GSSG redox ratio was associated with a significant increase in the oxidized GSSG disulfide form of glutathione. Further, the percentage oxidized glutathione equivalents, which take into account alterations in the absolute values of GSH and GSSG, was significantly increased (P<0.001). These data support and extend previous findings in extracellular fluids indicating that biomarkers of oxidative stress may be elevated in a subset of autistic children. Because mitochondria are both the major source and primary target of ROSs, the decrease in mitochondrial glutathione redox potential in LCLs from autistic individuals implies that mitochondrial antioxidant defense mechanisms are insufficient to maintain redox homeostasis."
James, S. Jill et al. “Cellular and Mitochondrial Glutathione Redox Imbalance in Lymphoblastoid Cells Derived from Children with Autism.” The FASEB Journal 23.8 (2009): 2374–2383. PMC.
"This study investigated 1) the incidence of biochemically diagnosed SLOS in blood samples from a cohort of subjects with ASD from families in which more than one individual had ASD and 2) the type and incidence of other sterol disorders in the same group. Using gas chromatography/mass spectrometry, cholesterol and its precursor sterols were quantified in one hundred samples from subjects with ASD obtained from the Autism Genetic Resource Exchange (AGRE) specimen repository. Although no sample had sterol levels consistent with SLOS, 19 samples had total cholesterol levels lower than 100 mg/dL, which is below the 5th centile for children over age 2 years. These findings suggest that, in addition to SLOS, there may be other disorders of sterol metabolism or homeostasis associated with ASD...The detection of a high incidence of hypocholesterolemia in our patient population is a finding of potential clinical significance regarding the possible role of non-SLOS cholesterol disorders in the etiology of ASD...profile in SLOS, SLOS is a rare cause of ASD, accounting for no more than 1% of ASD. However, the unexpected finding that up to 20% of children from a sample of mostly multiplex ASD sibships have substantial hypocholesterolemia warrants further research, since the study of hypocholesterolemia and its predicted effects on neurosteroid metabolism may offer important insights into the cause and treatment of ASD."
Tierney, Elaine et al. “Abnormalities of Cholesterol Metabolism in Autism Spectrum Disorders.” American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 141B.6 (2006): 666–668. PMC.
Metabolic Disorders associated with Autism
Creatine deficiency and disorders of creatine transport
Disorders of purine metabolism
Cerebral folate deficiency
Carbamoyl phosphate synthetase deficiency
Ornithine transcarbamlylase deficiency
Smith Lemli-Opitz Syndrome