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Senarathne, U.D.; Indika, N.R.; Jezela-Stanek, A.; Ciara, E.; Frye, R.E.; Chen, C.; Stepien, K.M. Biochemical Investigations of Autism Spectrum Disorders. Encyclopedia. Available online: https://encyclopedia.pub/entry/43372 (accessed on 24 April 2024).
Senarathne UD, Indika NR, Jezela-Stanek A, Ciara E, Frye RE, Chen C, et al. Biochemical Investigations of Autism Spectrum Disorders. Encyclopedia. Available at: https://encyclopedia.pub/entry/43372. Accessed April 24, 2024.
Senarathne, Udara D., Neluwa-Liyanage R. Indika, Aleksandra Jezela-Stanek, Elżbieta Ciara, Richard E. Frye, Cliff Chen, Karolina M. Stepien. "Biochemical Investigations of Autism Spectrum Disorders" Encyclopedia, https://encyclopedia.pub/entry/43372 (accessed April 24, 2024).
Senarathne, U.D., Indika, N.R., Jezela-Stanek, A., Ciara, E., Frye, R.E., Chen, C., & Stepien, K.M. (2023, April 24). Biochemical Investigations of Autism Spectrum Disorders. In Encyclopedia. https://encyclopedia.pub/entry/43372
Senarathne, Udara D., et al. "Biochemical Investigations of Autism Spectrum Disorders." Encyclopedia. Web. 24 April, 2023.
Biochemical Investigations of Autism Spectrum Disorders
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The main biochemical mechanisms proposed in autism spectrum disorders (ASD) include mitochondrial dysfunction, oxidative stress, impaired methylation capacity, and altered amino acid metabolism.

autism ASD WES

1. Introduction

Autism spectrum disorders (ASD) are defined by the revised version of the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5-TR) as neuro-developmental disorders characterized by persistent deficits in reciprocal social communication and social interaction (Criterion A) and restricted and/or repetitive patterns of behaviour, interests, or activities (Criterion B), present from early childhood (Criterion C) causing clinically significant impairment in social, occupational, or other important areas of current functioning (Criterion D). The symptoms under criteria A and B are not better explained by intellectual disability or global developmental delay (Criterion E). It is known as a “spectrum” disorder because there is wide variability in the severity and pattern of symptoms, progression of the disease, and prognosis. ASD is accompanied by varying degrees of intellectual impairment and is associated with many genetic, neurodevelopmental, mental, and behavioural disorders and environmental factors [1].
The global prevalence of ASD is estimated to be 0.4–1%, with American and European countries having a higher prevalence (1%) compared to Asian (0.4%) countries [2]. The biannual estimates by ASD and the Autism and Developmental Disabilities Monitoring (ADDM) Network report a two-fold increase in ASD prevalence among 8-year-old children in the United States during the past decade, from 2008 (1.1%) to 2018 (2.3%), with boys being four times more affected than girls [3].
The etiological factors and the proposed pathogenic mechanisms in ASD are intricate and involve the interaction of genetic, epigenetic, and environmental elements [4]. The main dysregulations, including intestinal dysbiosis [5], immune dysfunction, metabolic dysfunction [6], and metal dyshomeostasis [7], have been identified using molecular biomarkers, such as gut microbiome-related metabolites, cytokine profile, autoantibodies, metabolites, and vitamin and mineral profiles [8]. These are interconnected; hence, an ASD individual can exhibit several dysfunctions. For instance, a child with gut microbial dysbiosis may exhibit core symptoms of ASD along with immune dysfunction, altered microbial metabolites, and epigenetic changes [9][10]. The gut microbiome may modulate the gut–brain axis through microbiota-derived signalling molecules, immune mediators, gastrointestinal hormones, etc. [10][11].
Although each inherited metabolic disorder (IMD) is rare in isolation, collectively, all IMDs have a combined incidence of 1:800 to 1:2500 [12][13][14]. Contributing to the heterogeneity, a number of IMD, such as 22q11.2 deletion, Angelman syndrome, Cohen syndrome, Noonan syndrome, and fragile X syndrome, are known to associate with autistic symptoms, corroborating the evidence for genetic etiologies of ASD [15][16][17][18][19][20][21]. It should also be noted that the symptoms of ASD can be present in association with many IMDs [16]. The prevalence of IMDs among ASD individuals has been estimated in different studies, ranging from 0.7% to 2.7% [22][23][24]. However, the true prevalence of IMDs among ASD patients has been speculated to be higher [25], corroborating the finding of more than 30% of ASD individuals having some form of metabolic derangement by Spilioti et al. [24]. Furthermore, more than 50% of the IMDs present with neurodevelopmental symptoms, and ASD primarily being a neurodevelopmental disorder, the rational investigation of ASD individuals for probable IMDs is appropriate, especially in communities with a high level of consanguinity [26][27][28].
To date, more than 100 autism-risk genes have been identified with a genetic cause found in 10–20% of the cases of ASD during the investigation process [22][29]. A whole-exome sequencing (WES) study identified that 52% were nuclear sequence-level variants, 46% were nuclear structural variants, and 2% were mitochondrial variants [30]. Exome sequencing is identified as a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders, including ASD, with a molecular diagnostic yield of 16% (CI: 11–24%) in ASD [31]. Additionally, chromosomal microarray (CMA) has revealed definitively pathogenic copy number variants (CNVs) in 5.4% to 14% of individuals with ASD [32]. Even though ASD-associated biallelic genetic variants are commonly reported in consanguineous families, some were observed in non-consanguineous families. Siblings from consanguineous and/or multiplex families who share identical homozygous biallelic mutation may show variable ASD phenotypes with or without intellectual disability, epilepsy, and other clinical features [33]. Moreover, it is estimated that de novo variants in protein-coding genes contribute to risk in approximately 30% of simplex families. At the same time, de novo variants in non-coding regions of the genome (particularly gene promoters) also contribute to ASD pathogenesis [34]. De novo variants in the non-coding region highlight the current need to perform ASD genetic studies using whole genome sequencing (WGS) instead of traditional exome studies [35].
Large population-based studies on the outcome of metabolic investigations in screening for IMDs among ASD individuals are lacking; hence, accurate prevalence and diagnostic yield estimates are not available. Despite the observed low yield of routine metabolic testing in ASD individuals, the positive impact on ASD management may be significantly high as it paves the path to better understanding the underlying pathophysiology, inheritance pattern, and availability of treatment [32].
With the advancement of tandem mass spectrometry, most developed countries employ expanded newborn screening (NBS) as an important public health strategy, though it is yet to become a priority in developing countries [36][37]. Therefore, children who receive an expanded NBS have the advantage of receiving the diagnosis of an IMD, if present, before they would develop any autistic symptoms, whereas, in developing countries, ASD patients may only undergo targeted/selective screening for IMDs following the establishment of the primary diagnosis of a neurological condition or ASD. Selective screening for IMDs in ASD subjects may be a cost-effective strategy to identify the patients with IMDs that remain undiagnosed in countries where mass NBS for IMDs is unavailable. If the diagnosis of an IMD was established, treatment targeted at specific metabolic abnormalities in children with ASD has potential benefits [24][38]. For instance, identifying mitochondrial dysfunction enables the implementation of targeted therapies such as vitamins, carnitine, Coenzyme Q10, etc. [39][40]. In addition, research on advancing medical treatments, such as hematopoietic stem cell transplantation, is underway, offering hope for IMDs associated with ASD [41][42].
Investigating for IMDs associated with ASD should take a multidisciplinary approach led by a clinician (psychiatrist/neurologist/paediatrician/metabolic physician) with a well-informed team, including a chemical pathologist, clinical biochemist, and clinical geneticist. The primary aim of this endeavour is to understand the underlying pathophysiology, to provide genetic counselling where appropriate, and to determine the potential therapies. The success of investigating for IMDs in ASD patients depends on the understanding of different phenotypes of known syndromes and IMDs that overlap with ASD and defining a tailored biochemical and molecular evaluation plan catering to the needs of the individual patient based on their unique clinical information [43]. The assays to be considered as a screening panel should be based on common IMDs associated with ASD, the local epidemiology of IMDs in a given country, and available resources. In addition, the coverage of the existing NBS program should be considered in determining redundant investigations.

2. Biochemical Investigations

The main biochemical mechanisms proposed in ASD include mitochondrial dysfunction [39][44], oxidative stress [45], impaired methylation capacity [46], and altered amino acid metabolism [47]. Interestingly, ASD patients had these metabolic abnormalities in the brain regions involved in speech and auditory processing, social behaviour, sensory and motor coordination, and memory, the core symptoms of ASD [48]. Corroborating the presence of mitochondrial dysfunction in ASD, a 2020 study demonstrated atypical mitochondrial morphology with mitochondrial electron transport chain abnormalities in the fibroblasts of children with ASD [49]. Furthermore, several mitochondrial functional biomarkers, such as lactate, pyruvate, carnitine, and ubiquinone, are significantly altered in ASD, while some even correlate with severity [39][44]. The impaired methylation capacity is evident by the significantly reduced S-adenosylmethionine/S-adenosylhomocysteine ratio (methylation index) in ASD, while reduced methionine levels and increased homocysteine levels indicate the impaired remethylation of homocysteine to methionine [45]. The reduced availability of the cofactors for the remethylation pathway in the brain may be attributed to reduced blood folate [45], vitamin B12 levels [45], low-activity variants of the genes (MTHFR, DHFR, FOLR1) affecting folate and cobalamin metabolism [50][51], and cerebral folate deficiency due to folate receptor α autoantibodies [52]. Deth et al. proposed a “redox/methylation hypothesis of autism” describing the pathogenesis of oxidative stress, precipitated by environmental factors in genetically vulnerable individuals, which limits the activity of methionine synthase due to its dependency on cobalamin and folate, hence impaired methylation, including dopamine-stimulated phospholipid methylation [53]. Reduced methylation capacity may also mediate epigenetic changes through modulating DNA and histone methylation in a sex-dependent manner [50]. These mechanisms are thought to induce changes in the neurotransmitter systems, such as γ-aminobutyric acid (GABA) and glutamate, serotonin, dopamine, melatonin, and acetylcholine [54], resulting in core symptoms and co-occurring behavioural and neurological symptoms.
Pathway enrichment analysis has demonstrated that microRNAs (miRNAs) differently expressed in ASD are involved in metabolic pathways, such as steroid biosynthesis, fatty acid metabolism, lysine degradation, and biotin metabolism [55]. Correspondingly ASD-associated IMDs can be mapped to disorders of the metabolism of amino acids, carbohydrates, fatty acids, sterol biosynthesis, ketone bodies, creatine, vitamins (B12, folate, and biotin), cofactors, nucleotide, mitochondrial metabolite repair, etc. Importantly, these genetic and metabolic disorders are associated with marked cognitive impairment and other clinical features, such as macrocephaly, extrapyramidal signs, motor developmental delay, dysmorphic features, failure to thrive, or hepatosplenomegaly, which are atypical for patients with ASD [17][56].
In the context of complex pathogenesis with multiple co-morbidities and the evidence of metabolic involvement and strong heritable component, although the pathophysiology is not well comprehended, the current disease trajectory is developing towards a better understanding of the metabolic component of ASD in order to advance future interventions to improve the overall quality of life for ASD individuals [57][58][59]. The future developments are mainly focused on improving early and accurate diagnostic algorithms in unravelling the metabolic and other components of ASD. The diagnostic yield of metabolic investigations in patients with isolated ASD and no clinical symptoms appears to be low [22][23].
Before the establishment of NBS, a large proportion of these individuals would have been brought to medical attention only after the development of autistic symptoms. However, with the NBS programs, especially in developed countries, many such individuals are brought to medical attention early, and necessary treatments are instigated; a good example is phenylalanine ketonuria, an IMD characterized by intellectual disability and ASD [60][61][62]. Therefore, the diagnostic approach to ASD should be equipped with a rational consideration of possible IMDs, as some are treatable [63]. A recently suggested approach to such investigation is untargeted metabolomic profiling, as many ASD patients demonstrate a wide range of metabolic abnormalities, from micronutrient deficiencies to severe metabolic derangements [64]. The basis for untargeted metabolic profiling is the emerging evidence of potential novel biomarkers of IMD associated with ASD, as found in many cohort studies conducted worldwide, further opening new avenues of treatments [24]. However, the additional healthcare costs need to be considered while expanding the investigation profile to weigh the medical benefits of further testing, and it may not be cost-effective in non-syndromic ASD [64]. Schiff et al. demonstrated that the prevalence of IMD among non-syndromic ASD individuals is not higher than the general population (<0.5%) by conducting a systematic metabolic work-up, highlighting the importance of a rational approach to metabolomics in ASD [22].

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