Tetrahydrobiopterin is an essential cofactor for critical metabolic pathways, including those involved in the production of monoamine neurotransmitters and nitric oxide. Cerebrospinal fluid studies suggest that tetrahydrobiopterin concentrations in the central nervous system (CNS) may be lower in children with autism spectrum disorder (ASD) as compared to typically developing children. Clinical trials, including double-blind placebo controlled studies, suggest that oral tetrahydrobiopterin supplementation is therapeutic in children with ASD. Despite these previous studies, no clinical description of children with ASD and CNS tetrahydrobiopterin deficiency has been published. A series of six patients with ASD who were found to have CNS tetrahydrobiopterin deficiency is described. Most (83%) had global developmental delay while two (33%) had slow regression into an autism phenotype and only one (17%) had epilepsy. The pattern of metabolic abnormalities was not consistent with a primary disorder of pterin production. Overall, this case series suggests that children with ASD can have a CNS deficiency in tetrahydrobiopterin and that this deficiency is probably not a primary disorder of tetrahydrobiopterin production, but rather most likely secondary to reduced precursor availability, reduced recycling and/or increased utilization due to other multifactorial abnormalities associated with ASD such as abnormalities in CNS folate and/or oxidative stress
