Tetrahydrobiopterin and Autism Spectrum Disorder: A Systematic Review of a Promising Therapeutic Pathway

Abstract

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and interaction, along with restricted and repetitive patterns of behavior, interests, or activities. ASD encompasses a wide spectrum of clinical presentations and functional impairments, ranging from mild to severe. Despite its prevalence, the underlying physiopathological mechanisms of ASD remain largely unknown, resulting in a lack of effective targeted therapeutic interventions, contributing to significant financial and emotional burdens on affected families and the healthcare system. Emerging evidence suggests that dysfunction in the tetrahydrobiopterin (BH4) pathway may impair the activity of monoaminergic and nitric oxide (NO)-dependent neurons in individuals with ASD. To explore this potential mechanism, we conducted a systematic review to analyze such impairments to gather information on whether the off-label use of BH4 could represent a novel pharmacological approach for managing ASD. Following the PRISMA 2020 guidelines, we systematically reviewed the literature from four databases: PubMed, Virtual Health Library, Cochrane Library, and SciELO, from January 1967 to December 2021. The quality of the included studies was assessed using the Newcastle-Ottawa scale. The inclusion criteria for this systematic review focused on identifying articles published in English that contained the following keywords, used in various combinations: autism, ASD, autism spectrum disorder, BH4, tetrahydrobiopterin, neopterin, NO, nitric oxide. The analysis was performed between December 2020 and December 2021. The collected data demonstrated that BH4 metabolism was altered in individuals with ASD. Lower levels of BH4 were reported in biological samples from ASD-affected individuals compared to age- and sex-matched controls. Additionally, neopterin levels were elevated in plasma and urine, but decreased in cerebrospinal fluid, while nitric oxide levels were consistently reported to be higher across studies. Treatment with BH4 has shown potential in improving ASD-related symptoms. The reported increase in neopterin in biological fluids indicates inflammation, while the reduction in BH4 levels suggests a potential shift in its metabolic role. Specifically, BH4 may be diverted from its primary role in neurotransmitter synthesis to function as an antioxidant or to perpetuate inflammation through NO production. Given that BH4 is a critical cofactor in monoaminergic neurotransmission, its dysfunction highlights the molecule's therapeutic potential. BH4, already FDA-approved for other conditions, emerges as a promising off-label candidate to alleviate ASD symptomatology.

Keywords: autism; inflammation; neopterin; neurotransmitters; nitric oxide.

Figure 1

Metabolic routes involved in tetrahydrobiopterin (BH4) biosynthesis. BH4 is a mandatory cofactor for the catalytic activity of five enzymes, namely phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), all isoforms of nitric oxide synthases (NOS), and alkylglycerol monooxygenase (AGMO). These enzymes will be responsible for the production of the semi-essential amino acid tyrosine, the aminergic neurotransmitters dopamine and serotonin, nitric oxide, and neuroactive lipids, respectively. The de novo pathway will generate new molecules of BH4 by consuming energy in the form of guanosine triphosphate. The salvage pathway will also generate new BH4 molecules, but in a more economical way, and the recycling pathway will maintain the levels of BH4. The main activators of the de novo pathway are pro-inflammatory mediators, such as interferon gamma (IFN-δ); tumor necrosis factor alpha (TNF-α); interleukin 1 beta (IL-1β); IL-6 (interleukin-6); and lipopolysaccharides (LPSs). Abbreviations: GTPCH: guanosine triphosphate cyclohydrolase; PTPS: 6-Pyruvolyl tetrahydropterin synthase; SPR: sepiapterin reductase; AR: aldose reductases; CRs: carbonyl reductase; BH2: dihydrobiopterin; qBH2: dihydrobiopterin quinoid; DHFR: dihydrofolate reductase; PCD: Pterin-4-alpha-carbinolamine; DHPR: dihydropteridine reductase (DHPR). BH4 is an obligatory cofactor for the activity of the aromatic. Source: Eichwald et al. (2023), Ref. [12], with permission.

Figure 2

Flowchart for the selection of included studies. Nineteen studies were included in the review, as shown in the chart. The PubMed, BVS (Biblioteca Virtual em Saúde), Cochrane Library, and SciELO (Scientific Electronic Library Online) databases were used to identify the potential records.