Could Amino Acid Imbalance Lead to Autism Spectrum Disorder? — Conclusions from Ten Research Papers
Several research studies indicate the role of amino acid imbalance in the manifestation of ASD symptoms such as repetitive behavior, social communication difficulties, and cognitive deficits. In many cases, it may be possible to correct the amino acid imbalance with nutritional strategies. Otherwise, scientists may succeed in identifying novel therapeutic targets. The following research studies provide a deep look at the nature of the metabolic disorders and possible solutions.
[1] Low Levels of Branched-Chain Amino Acids or High Levels of Large Molecules
Mutation in the gene encoding BCKD-kinase enzyme leads to low levels of branched-chain amino acids (BCAAs) which disproportionately increases large amino acids. Scientists maintain that this may be the cause of neurological symptoms which may be fixed with protein supplements.
Callaway, in his research on the metabolic pathway (2012) identified that a certain form of autism may be related to amino acid deficiency. His experiment involved six children, whose genetic mutations were linked to amino acid depletion. Callaway maintained that the genetic mutation caused autism-related neurological problems, which could be addressed using dietary changes such as protein supplements.
The precise genetic mutation was found in genes that encode for the BCKD-kinase enzyme. The enzyme prevents the body from breaking down branched-chain amino acids such as isoleucine, leucine, and valine, which are obtained from food. The mutation leads to low levels of amino acids in the blood.
When the BCKD-gene is absent, the levels of large amino acids increase disproportionately in the brain when compared to the branched-chain amino acids. Both types of amino acids enter the brain through special transporters through the blood-brain barrier. Autism could be caused due to the low levels of branched-chain amino acids in the brain, or high levels of the larger molecules, or both. Scientists proposed that supplementing the diet with foods rich in branched-chain amino acids could resolve the condition.
[2] Reduced Utilization of Tryptophan and Large Aromatic Amino Acids (LAAs)
Mutations in genes encoding large amino acid transporters (LAT) resulted in reduced utilization of tryptophan and large aromatic amino acids (LAAs) i.e. phenylalanine, tyrosine, and tryptophan. These amino acids influence protein homeostasis, the function of serotonin, melatonin, quinolinic, and kynurenic acid, increasing the risk of ASD.
In a recent study, conducted in 2019, Cascio and colleagues found abnormalities in genes encoding large amino acid transporters (LAT), raising the risk of autism spectrum disorder (ASD). Their study indicated a reduced utilization of tryptophan as well as large aromatic amino acids (LAAs). This feature adversely affected their availability in the brain during its development and increased the risk of ASD.
Branched-chain amino acids and aromatic amino acids are collectively referred to as large neutral amino acids (LNAAs). Scientists also discovered a reduced utilization of aromatic amino acids comprising phenylalanine, tryptophan, and tyrosine. LNAAs play a major part in neurodevelopment. Genetic mutations affecting these amino acids may adversely affect protein homeostasis and their ability to act as precursors of neuroactive molecules such as serotonin and melatonin, energy transporter nicotinamide adenine dinucleotide (NAD), and neurodevelopment regulators such as quinolinic and kynurenic acid.
[3] Increased Homocysteine and Glutamate and Decreased Glutamine Levels
Increased levels of excitatory neurotransmitter glutamate and homocysteine in the brain, and decreased levels of tryptophan and glutamine, may result due to poor protein intake. Glutamate triggers neuroinflammation. Furthermore, the levels of inhibitory amino acid taurine are increased.
Autism is characterized by increased levels of homocysteine and glutamate (the major excitatory neurotransmitter in the brain) as well as decreased levels of glutamine and tryptophan. There is limited evidence on the levels of taurine and lysine. The deficiency of essential plasma amino acids may be due to poor protein intake in autism. Autistic participants were found to be deficient in valine, lysine, phenylalanine, and leucine. Glutamate plays a part in neuroinflammation in autism. The root cause of aggression in children with autism may be an abnormality in glutamate and homocysteine levels. Taurine levels are increased in autism, which is the main inhibitory amino acid. Moreover, levels of lysine and aspartic acid are increased, and tryptophan levels are decreased in autism. Glutamate passes easily through the blood-brain barrier, and the hyperglutamatergic state in autism, which is its etiology, is responsible for excitotoxicity and neurodegeneration. The excess of glutamate exacerbates inflammation in the brain. This is accompanied by a decrease in proteins that transform glutamate to GABA.
[4] Dysregulation of Glutamine, Ornithine, and Glycine Metabotypes
Scientists maintain that studying metabotypes of amino acids can lead to early diagnosis and effective interventions. They concluded this by studying metabotypes of glutamine, ornithine, and glycine to understand dysregulation in metabolism.
Smith and colleagues attempted to understand amino acid dysregulation metabotype (AADM) by comparing amino acid metabolites with BCAAs as the denominator. Their study was targeted at identifying autism biomarkers through metabolic analysis of blood samples. Autistic participants showed that a dysregulation in the levels of ornithine, glutamine, and glycine metabotypes indicated a dysregulation in amino acid / BCAA metabolism. This indicates the relevance of using metabotypes for “early diagnosis of autism and stratification for targeted therapeutic interventions”.
[5] Problems with Controlling Branched Chain Amino Acids in the Autistic Brain
Mutations in the enzymes involved in amino acid metabolism may affect neuronal function. A subset of ASD cases with abnormal levels of amino acids can be treated using nutritional interventions.
Scientists studied the role of amino acids as metabolic intermediaries and neurotransmitters involved in multiple pathways. Isoleucine, leucine, and valine are involved in the production of acetyl-CoA and succinyl-CoA for the production of ATP. Further, transamination of BCAAs to branched-chain ketoacids (BCKAs) is followed by the action of a second enzyme — branched-chain ketoacid dehydrogenase complex (BCKDC). Large neutral amino acids (LNAAs) and BCAAs, controlled by the LAT1 enzyme, including phenylalanine and tyrosine act as precursors to the production of catecholamines and serotonin. Therefore, mutations in the enzymes BCKDK and LAT1 affect neuronal circuits. BCAAs can be supplemented through an appropriate diet, and, therefore, a certain subset of ASD cases may be treatable with dietary interventions. Their study is relevant as increased levels of certain amino acids may be neurotoxic.
[6] Differences in Glutathione Metabolism as a Characteristic Feature of ASD
Glutathione (GSH) redox imbalance may explain key factors in the manifestation of ASD.
Glutathione plays a role in maintaining intercellular redox balance. In ASD glutathione (GSH) redox imbalance plays a key role in its pathogenesis. ASD is characterized by low levels of reduced glutathione (GSH), high levels of oxidized glutathione (GSSG), and abnormal expression of glutathione-related enzymes in the brain and blood. Regulation of glutamate receptors, mediated by glutathione, and glutamate as a substrate of glutathione synthesis, regulates glutamate excitotoxicity. Neuroinflammation, neuronal apoptosis, and mitochondrial dysfunction may also explain how glutathione metabolism influences ASD. Other processes affected by glutathione are epigenetics and DNA methylation. Scientists explain that an insight into glutathione redox signaling can lead to important therapeutic targets.
[7] Lowered Sulphur Amino Acids in ASD and Impaired Remethylation Pathway
Impairment in the metabolism of sulphur amino acids (SAAs) and Impaired Remethylation Pathway is Characteristic of ASD
Autism spectrum disorder (ASD) is characterized by impairment in the metabolism of sulphur amino acids. Methionine, cysteine, and S-adenosylmethionine (SAM) concentrations are lowered, implying impairment in the remethylation pathway. Further, the concentration of S-adenosylhomocysteine (SAH) is higher than healthy individuals, implicating reduced adenosylhomocysteine hydrolase activity in catabolism. The reduced SAM/SAH ratio also manifests as impaired methylation capacity. SAA metabotypes are created as a result of a combination of altered genetic makeup, altered gut microbiome, neuroinflammation, oxidative stress, and mercury exposure. Reduced SAM/SAH ratio in the brain manifests as melatonin deficiency, and hypomethylation of biomolecules such as histones, DNA, and RNA.
[8] Possible Effects of Vitamin D on Cross Pathways of Amino Acids in ASD
The transport of amino acids may be related to Vitamin D in the manifestation of ASD.
Scientists understand that blood amino acid transport, oxidative stress, and immunity are closely related to Vitamin D in ASD manifestation. A recent investigation by Wang and the team revealed that Alanine, Arginine, Glycine, Glutamine, Ornithine, and Histidine have a negative correlation with Vitamin D levels. A deficiency of Vitamin D leads to an increased risk of ASD. Age was a factor that affected ornithine and glycine, and alanine levels were affected by the BMI of participants. Scientists concluded that Vitamin D influenced cross-pathways of these amino acids in ASD.
[9] Imbalance between Excitatory and Inhibitory Amino Acid Metabolism in ASD
In an analysis of the metabolic pathways, scientists found that the ornithine/urea cycle, tryptophan metabolism, methionine cycle, and lysine metabolism had significant differences in ASD.
The ornithine or urea cycle converts toxic molecules of ammonia into non-toxic urea for excretion in urine. Amino acids involved in the ornithine (urea) cycle, namely, arginine, cysteine, and ornithine, are present in altered concentrations in individuals with ASD. Decreased concentrations of these amino acids indicate dysfunction in arginase and ornithine transcarbamylase, which may explain abnormalities in the urea cycle. This sort of perturbation in the ornithine/urea cycle leads to the accumulation of ammonia in the blood of individuals with ASD, which may decrease the activity of gamma-aminobutyric acid (GABA) transaminase, leading to accumulation of GABA. In effect, an abnormal urea cycle leads to an imbalance of inhibitory and excitatory neurotransmitter amino acids in ASD.
ASD individuals also presented an abnormal methionine cycle, impaired ability to capture free radicals, elevated levels of serotonin (tryptophan-derived inhibitory neurotransmitter), abnormal lysine metabolism leading to an imbalance of glutamate (excitatory amino acid), and lower levels of EtN which is a precursor to acetylcholine synthesis (excitatory neurotransmitter).
[10] GABA and Glutamate Imbalance in Autism Spectrum Disorder (ASD)
Increased levels of glutamate may be excitotoxic, and GABA supplementation with Vitamin D, magnesium, and calcium, may prove efficacious.
The GABAergic system is a therapeutic target in many forms of autism. Some common characteristics of autistic individuals include modified gene expression, impaired gut barrier, and blood-brain barrier. Increased glutamate levels in platelets and blood of individuals with ASD may be due to lower numbers of cerebellar GABAergic neurons, decreased levels of GABA in the brain, and less-active GABA-synthesizing enzymes. The glutamate released may be excitotoxic, triggering cascades of cellular events that may be deleterious, and lead to delayed neuronal death. This points to the probable efficacy of GABA supplementation in certain forms of ASD. Scientists recommend a strategy that involves reducing glutamate levels and maintaining functional GABA receptors, through an integrated treatment strategy comprising GABA and Vitamin D supplements, regulation of calcium and magnesium levels, and probiotics.
Therefore, abnormalities in the expression, metabolism, and transport of amino acids could explain many of the immune and neuronal symptoms in ASD. Research findings on imbalance and dysregulation of amino acids may be used to design novel therapeutic targets to help individuals diagnosed with ASD overcome behavioral, cognitive, and social communication difficulties.
