Metabolomic changes in children with autism

Table 1 The changes observed in each amino acid metabolic pathway in individuals with autism spectrum disorder, along with relevant studies and their methods

Ref.	Study methods	Amino acid pathway	Changes in ASD
Boccuto et al[40]	Blood or CSF sample analysis	phenylalanine and glutamate	Elevated phenylalanine and glutamate levels
Ormstad et al[41]	Metabolomic profiling	phenylalanine and glutamate	Decreased glutathione and creatine levels
Almulla et al[42]	Peripheral blood analysis	Tryptophan pathway	Disrupted tryptophan metabolism
Higazi et al[56]	Genetic analysis of MAOA, HAAO and AADAT genes using real-time RT-qPCR.	tryptophan pathway	significant decrease in the expression of the selected genes within ASD children relative to children with learning disabilities and healthy controls
Naushad et al[66]	Genetic analysis	Tryptophan pathway	Lower serotonin synthesis
Naushad et al[66]	Enzyme activity measurement	Phenylalanine and tyrosine metabolism	Reduced tyrosine synthesis
Arum et al[71]	Dietary intake assessment	Phenylalanine and tyrosine metabolism	Abnormal phenylalanine-to-tyrosine ratio
Geier et al[84]	Peripheral blood analysis	Methionine and sulfur metabolism	reduced levels of serum glutathione, cysteine, methionine, cystathionine, and homocysteine in pre-pubertal children
Suh et al[85]	Genetic analysis	Methionine and sulfur metabolism	Reduced SAM levels
Guo et al[86]	Meta-analysis of metabolomic profiling	Methionine and sulfur metabolism	Impaired methylation capacity
Haghiri et al[89]	Genetic analysis	Methionine metabolism	mutations of methionine synthase in children with ASD

AADAT gene: Aminoadipate Aminotransferase gene; ASD: Autism spectrum disorder; HAAO gene: 3-Hydroxyanthranilate 3,4-dioxygenase is a monomeric cytosolic protein gene; MAOA gene: monoamine oxidase A gene; SAM: S-adenosylmethionine.

Table 2 The roles, impact, potential biomarkers, genetic associations, and therapeutic implications of both purine and pyrimidine metabolism in the context of autism spectrum disorder

Aspect	Purine metabolism	Pyrimidine metabolism
Functions	Building blocks for nucleic acid synthesis; Metabolic signals; Provide energy; Regulate cell growth; Participate in coenzymes; Contribute to sugar transport; Donate phosphate groups in phosphorylation reactions	Synthesizing DNA and RNA; Energy metabolism; Neurotransmitter signaling
Specific roles	Provide energy for membrane-active pumps like Na+/K+ ATPase; Vital for sustaining synaptic transmission; Facilitate collaboration between neurons and glial cells	Biosynthesis of polysaccharides and phospholipids; Participate in detoxification processes; Contribute to protein and lipid glycosylation
Impact on brain function	Altered purine metabolism may impact brain function and contribute to ASD symptoms; Adenosine acts as a neuromodulator, inhibiting neurotransmitter release and regulating sleep-wake cycles	Abnormalities in pyrimidine metabolism may be linked to ASD and neurodevelopmental issues; Disturbances in uracil metabolism could contribute to mitochondrial dysfunction in ASD
Potential biomarkers	Elevated adenosine levels and altered ADA activity observed in ASD; Abnormal levels of purine metabolites such as uric acid reported in ASD	Altered uracil levels and abnormal ratios of uracil to other pyrimidine bases reported in ASD; Abnormal levels of pyrimidine nucleotides observed in ASD
Genetic associations	Mutations in genes encoding enzymes involved in purine metabolism found in individuals with ASD	Genetic mutations in the gene encoding DPD identified in individuals with ASD
Therapeutic implications	Modulating adenosine signaling and targeting enzymes involved in purine metabolism could potentially improve neurochemical functioning in ASD	Supplementation with pyrimidine precursors such as uridine was explored as a possible intervention to improve mitochondrial function and neurodevelopmental outcomes in ASD

ADA: Adenosine deaminase; ASD: autism spectrum disorder; ATP: Adenosine Triphosphate; DPD: dihydro-pyrimidine dehydrogenase.

Table 3 The prevalence, causes, impact, symptoms, diagnosis, management, challenges, and ongoing research related to mitochondrial metabolic disorders in individuals with autism spectrum disorder

Aspect	Mitochondrial metabolic disorders in ASD
Overview	Mitochondria are cellular structures responsible for generating energy (ATP). High mitochondrial density in muscle and brain cells
Prevalence and causes	Increased prevalence of mitochondrial dysfunction in ASD compared to the general population. Can result from genetic mutations, environmental factors, or both
Evidence	About 80% of children with ASD show blood test indications of mitochondrial dysfunction and DNA abnormalities. Estimates of co-occurrence range from 5% to 80%
Contributing factors	Genetic mutations; Dietary deficiencies; Chemical and heavy metal exposure; Certain drugs; Bacterial and viral infections; Stressful conditions
Impact on ASD	Insufficient ATP production can affect synaptic plasticity, neuronal development, signaling, and maintenance. Oxidative stress and damage to cellular components may occur. Disruption of metabolic processes can further impact ASD development
Symptoms and diagnosis	Symptoms include delays in developmental milestones, impaired language and communication, motor difficulties, cognitive impairments, behavioral abnormalities, seizures, and gastrointestinal issues. Diagnosis involves comprehensive clinical assessments, biochemical analyses, genetic testing, and specific diagnostic criteria. Laboratory tests may include blood tests, urine tests, DNA analysis, brain imaging, and muscle biopsy
Management and treatment	Treatment strategies may include dietary interventions, nutritional supplements, antioxidants, and medications targeted at specific symptoms. A multidisciplinary approach involving healthcare professionals from various specialties is necessary for accurate diagnosis and management
Challenges and ongoing research	Diagnosis can be challenging due to overlapping symptoms and lack of specific criteria. The effectiveness of interventions in improving ASD symptoms associated with mitochondrial dysfunction is still under research

ASD: Autism spectrum disorder; ATP: Adenosine triphosphate; DNA: Deoxyribonucleic acid.

Table 4 The prevalence, contributing factors, impact, therapeutic implications, and research needs related to lipid metabolism abnormalities in individuals with autism spectrum disorder

Aspect	Lipid metabolism in ASD
Overview	Lipid metabolism involves the synthesis, breakdown, and transportation of fats, which are crucial for cell membranes and energy
Dyslipidemia in ASD	Abnormal lipid levels observed in children with ASD. Variations include elevated total cholesterol and LDL-C, reduced HDL-C, and increased triglycerides. Increased LDL-C to HDL-C ratio, a marker of cardiovascular risk
Factors contributing to abnormalities	Genetic variations in lipid metabolism-related genes. Syndromes like Smith–Melli–Opitz syndrome linked to lipid metabolism and neurodevelopmental delay. Oxidative stress and chronic inflammation are common in ASD, affecting lipid metabolism. Gut microbiota alterations and dietary factors are also implicated
Impact on ASD	Abnormal lipid metabolism can affect brain development, myelination, synaptogenesis, and neurotransmitter signaling in ASD. Disruptions may lead to oxidative stress, neuroinflammation, and neuronal damage. Potential implications for cellular energy production and utilization in the brain
Therapeutic implications	Interest in lipid-based interventions for ASD, but effectiveness needs further research. Potential therapeutic targets to address lipid disorders and associated symptoms in ASD. Complex relationship between lipid disorders and ASD, influenced by genetic, environmental, and metabolic factors
Research needs	Further research is needed to understand the mechanisms underlying lipid disorders in ASD. Investigation required into the effectiveness of lipid-based interventions on ASD symptoms and lipid profiles. Recognition that not all individuals with ASD have lipid abnormalities, and vice versa

ASD: Autism spectrum disorder; HDL-C: High-density lipoprotein cholesterol; LDL-C: low-density lipoprotein-cholesterol.