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Tetrahydrobiopterin Deficiency in Autism Spectrum Disorder

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Tetrahydrobiopterin Deficiency in Autism Spectrum Disorder North American Journal of Medicine and Science Jul 2014 Vol 7 No.3 93 Original Research Tetrahydrobiopterin Deficiency in Autism Spectrum Disorder Richard E. Frye, MD, PhD* Arkansas Children’s Hospital Research Institute, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 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. [N A J Med Sci. 2014;7(3):93-96. DOI: 10.7156/najms.2014.0703093] Key Words: Tetrahydrobiopterin, autism spectrum disorder, mitochondrial disease, folate receptor alpha autoantibodies INTRODUCTION Autism spectrum disorder (ASD) is a neurodevelopmental disorder behaviorally characterized by impairments in communication and social interaction along with restrictive and repetitive behaviors.1 An estimated 1 out of 68 individuals in the United States are currently affected with ASD with the prevalence continuing to rise. Although several genetic syndromes, such as Fragile X and Rett syndromes, have been associated with ASD, empirical studies have estimated that genetic syndromes only account for a minority of ASD cases.2 Thus, the majority of ASD cases cannot be linked to a single gene or chromosomal disorder. Many studies have now suggested that cellular abnormalities not necessarily with the central nervous system (CNS) are associated within ASD,3-6 suggesting that systemic abnormalities may play a role in some children with ASD. Over the last decade, publications have started to implicate physiological systems that transcend specific organ Figure 1. The pterin production pathway. Several enzymes are required to dysfunction, such as immune dysregulation and abnormalities produce tetrahydrobipterin (BH4). Guanosine-5′-triphosphate (GTP) in various metabolic systems.7 cyclohydrolase I converts GTP, which is derived from the folate cycle, into 7,8-dihydroneopterin triphosphate which is either used to produce neopterin, an inflammatory mediator, or 7,8-dihydroneopterin triphosphate using 6- __________________________________________________________________________________________________ pyruvoyl tetrahydropterin synthase. Tetrahydrobipterin (BH4) can be produced by sepiapterin reductase from 7,8-dihydroneopterin triphosphate. Received: 06/05/2014; Revised: 07/10/2014; Accepted: 07/15/2014 Tetrahydrobipterin (BH4) is easily oxidized to 7,8-dihydrobiopterin (BH2) *Corresponding Author: Arkansas Children's Hospital Research Institute, and, in fact, can act as an antioxidant. 7,8-dihydrobiopterin (BH2) is recycled Slot 512-41B, 13 Children's Way, Little Rock, AR 72202. Tel: 501-364- back to tetrahydrobipterin (BH4) using the folate-dependent enzyme 4662, Fax: 501-364-1648. (Email: [email protected]) dihydrofolate reductase. 94 Jul 2014 Vol 7 No.3 North American Journal of Medicine and Science Abnormalities in pterin metabolism have been associated Despite the evidence for abnormalities in BH4 metabolism in with ASD, although still little is known about the biological ASD, there is only limited knowledge as to whether such basis of this association. The pterin pathway is responsible abnormalities are associated with a specific ASD phenotype. for the production of the two better-known pterins: In fact, no clinical description of children with ASD and CNS tetrahydrobiopterin (BH4) and neopterin (Figure 1). BH4 deficiency has been published. Here the results from a Neopterin is associated with immune activation. Several series of children with ASD and CSF examinations were immune modulators, such as TNF-alpha and IFN-gamma, reviewed to determine the characteristics of patients with increase activity of the first enzyme in the pterin production CNS BH4 deficiency. pathway, guanosine-5'-triphosphate (GTP) cyclohydrolase I, resulting in an increase in 7,8-dihydroneopterin triphosphate, METHODS the precursor to neopterin and tetrahydrobiopterin. Evidence As part of a medically based autism clinic, patients with for changes in neopterin in ASD is mixed with some studies neurodevelopmental disorders, particularly ASD, underwent reporting elevated neopterin levels in urine8 and blood9 and a CSF examination when indicated. Here the results to 40 other studies reporting reduced neopterin levels in urine,10 children with ASD and CSF examinations were reviewed to 10 11 plasma and cerebrospinal fluid (CSF). determine the patients that demonstrated BH4 deficiency as determined by the age-dependent laboratory normative Perhaps BH4 is the more important pterin in relation to ASD values. The laboratory only provides the normal range of because of its role as an essential cofactor for several critical values, so percentiles of normative values were not available. metabolic pathways, particularly those responsible for the All children met the Diagnostic and Statistical Manual of breakdown of phenylalanine and the production of Mental Disorders – Fourth Edition – Text Revision1 criteria monoamine neurotransmitters and nitric oxide.12 Abnormal for ASD and had previously been diagnosed with ASD by a BH4 metabolism is associated with neurometabolic disease. developmental pediatrician, pediatric neurologist or clinical A deficiency in BH4 synthesis or recycling can result in psychologist. Review of each child’s medical record was neurological disorders including phenylketonuria type IV13 obtained through an Institutional Review Board approved and dopamine-responsive dystonia,13 all of which protocol. The CSF findings of three of the cases reported demonstrate accompanying changes in CSF monoamine herein were published in a study focused on peripheral 16 neurotransmitter metabolites in addition to changes in CSF biomarkers of CSF BH4 concentration. The previous study BH4 concentrations. CNS BH4 deficiency with associated did not concentrate on the clinical history of individuals with abnormalities in CSF monoamine neurotransmitter CNS BH4 deficiency as is done here. metabolites has also been reported as a secondary consequence of cerebral folate deficiency syndrome.14 Some RESULTS abnormalities in BH4 metabolism may be somewhat specific Six of 40 (15%) cases of children with ASD demonstrated to ASD as reduced CSF BH4 concentrations without changes below normal CSF BH4 concentrations. These cases are listed in CSF monoamine neurotransmitter metabolites have been in Table 1 along with important clinical information and reported in children with ASD15,16 and several clinical trials laboratory values. All cases demonstrated normal serum have shown that children with ASD have a favorable phenylalanine levels thereby ruling out phenylketonuria type 17-19 response to BH4 supplementation. IV and all cases demonstrated normal CSF neurotransmitter levels. Only one child (case 6) demonstrated a frankly low The reason for reduced BH4 CSF concentrations in children neopterin level, while three other children demonstrated very with ASD is not known, but it has been suggested that BH4 low normal neopterin levels (cases 2, 3 and 5) and the other overuse and poor recycling could contribute to the two cases demonstrated low normal neopterin levels (cases 1 16 deficiency. Indeed, BH4 can act as an excellent antioxidant, and 4). This suggests that the low BH4 concentrations in but requires recycling through a folate-dependent salvage general were not due to a primary defect in the pterin pathway once it is oxidized.12 The mechanism behind the production pathway (Figure 1) but could be due to other therapeutic response to treatment with BH4 in ASD is unclear factors that indirectly affect CNS pterin concentrations. as only three studies have measured CSF BH4 concentrations prior to treatment19-21 and only two studies have examined The majority of the cases reported (5/6; 83%; cases 1-5) the relationship between CSF BH4 concentrations and manifested global developmental delay. Two (2/6; 33%; treatment response.19,21 One study found a borderline cases 2 and 6) manifested a slow regressive phenotype with significant correlation between CSF BH4 concentration one child (case 2) having this regression after global before treatment and improvement in social interactions with developmental delay was well established. Epilepsy was only 21 BH4
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