Pterins and pteridines in autism

Neopterin and Biopterin physiology

These molecules are involved with each other in their manufacture, biochemistry and use in the cell: biochemistry see Thony et al for tetrahydrobiopterin, Murr et al for neopterin and biopterin.

Neopterin and hence biopterin are a breakdown product of guanidine unlike folate, which requires to be present in the diet. Folate is needed for the formation of tetrahydrofolate and the methylation of compounds in tissues.

Most of the useful action of the group (called peridines) is unknown. They are powerful reducing agents. Tetrahydrobiopterin is a cofactor that carries electrons for REDOX reactions, as in the oxidation of phenylalanine to tyrosine. It is formed from dihydrobiopterin through the action of the enzyme dihydrofolate reductase, or from the quinonoid form of dihydrobiopterin through the action of dihydropteridine reductase.

Indications from Neopterin and Biopterin changes

They are used as indicators of inflammatory activity in that the formation of increased numbers or turnover of immune system cells in the bone marrow (e.g. neutrophils, and monocytes). This is due to the breakdown of guanidine increasing from DNA.

Suggested increase in inflammation in autism
Blood levels
Urinary levels
CSF levels
Other indications of inflammation using C-Reactive Protein in autism: none reported!
Oxidative stress changes in autism: none reported!

Treatment

The finding of low levels of tetrahydrobiopterin in CSF was treated with giving the drug orally. It was difficult to show any advantage.

Neopterin

Biopterin

Folic acid

Background

Tetrahydrobiopterin biosynthesis, regeneration and functions. Thöny B, Auerbach G, Blau N. Biochem J. 2000 Apr 1;347 Pt 1:1-16. Formed from GTP in almost all the cells of the body it acts as a co-enzyme in many pathways, and protects the nitrous oxide neuronal safety. In the nervous system, BH(4) is a self-protecting factor for NO, or a general neuroprotecting factor via the NO synthase pathway, and has neurotransmitter-releasing function. With regard to human disease, tetradrobiopterin (BH(4)) deficiency due to autosomal recessive mutations in all enzymes (except sepiapterin reductase) have been described as a cause of hyperphenylalaninaemia.

Cellular Inflammation increased

Berdowska A, Zwirska-Korczala K. Neopterin measurement in clinical diagnosis. J Clin Pharm Ther. 2001 Oct;26(5):319-29. (Neopterin is a marker associated with cell-mediated immunity. It is produced in monocytes/macrophages primarily upon stimulation with interferon-gamma. Due to its chemical structure, neopterin belongs to the class of pteridines. It is excreted in an unchanged form via the kidneys. Serum levels above 10 nmol/L are regarded as elevated.)

Neopterin and Biopterin (It is well established that increased neopterin levels are associated with activation of the cellular immune system and that reduced biopterins are essential for neurotransmitter synthesis. However, there are other methods of measuring inflammatory change and there do not appear to be many specific effects of these.

Blood levels of biopterin or neopterin

Eto I, Bandy MD, Butterworth CE Jr. Plasma and urinary levels of biopterin, neopterin, and related pterins and plasma levels of folate in infantile autism. J Autism Dev Disord. 1992 Jun;22(2):295-308. (Sixteen autistic children and 12 healthy controls were included in this study. Results indicated that the plasma and urinary levels of tetrahydrobiopterin are not statistically different between the two groups and, therefore, no simple explanation for the beneficial effects of administration of tetrahydrobiopterin on autistic children can be offered at the present time)

Sweeten TL, Posey DJ, McDougle CJ. High blood monocyte counts and neopterin levels in children with autistic disorder. Am J Psychiatry. 2003 Sep;160(9):1691-93. (They basically took the numbers of various white cells in the blood of a range of autistic patients. The interpretation is difficult. The higher plasma monocyte counts and neopterin levels reported here in autism are similar in magnitude to those seen in multiple sclerosis. Serum neopterin levels have also been found to be high in neuropsychiatric disorders in which inflammatory processes may be active, such as Alzheimer’s disease.)

Urine levels

Harrison KL, Pheasant AE. Analysis of urinary pterins in autism. Biochem Soc Trans 1995;23:603S. (increased levels found).

Messahel S, Pheasant AE, Pall H, Ahmedchoudhury J, Sungumpaliwal RS. Urinary levels of neopterin and biopterin in autism. Neurosci Lett 1998;241(1):17-20. Both urinary neopterin and biopterin were raised in the autistic children compared to controls and the siblings showed intermediate values

CSF levels

Zimmerman A, Hyonouchi H, Comi A et al. Cerebrospinal fluid and serum markers of inflammation in autism. Pediatr Neurol 2005 Sep;33(3):195-201. Neopterin and Biopterin were modified in an odd way and this was looked on as being as if an enzyme inhibition was taking place.

Decrease in 6R-5,6,7,8-tetrahydrobiopterin content in cerebrospinal fluid of autistic patients. Tani Y, Fernell E, Watanabe Y, Kanai T, Långström B. Neurosci Lett. 1994 Nov 7;181(1-2):169-72.

Treatment

Danfors T, von Knorring AL, Hartvig P, Langstrom B, Moulder R, Stromberg B, Torstenson R, Wester U, Watanabe Y, Eeg-Olofsson O. Tetrahydrobiopterin in the treatment of children with autistic disorder: a double-blind placebo-controlled crossover study. J Clin Psychopharmacol. 2005 Oct;25(5):485-9. They looked in the CSF for THBPt and in the cases with low levels they gave some in a treatment trial. Unclear effect. (Twelve children, all boys, aged 4 to 7 years, with a diagnosis of autistic disorder and low concentrations of spinal 6R-l-erythro-5,6,7,8-tetrahydrobiopterin (tetrahydrobiopterin) were selected to participate in a double-blind, randomized, placebo-controlled, crossover study. The children received a daily dose of 3 mg tetrahydrobiopterin per kilogram during 6 months alternating with placebo.)

Cerebrospinal fluid biopterin and biogenic amine metabolites during oral R-THBP therapy for infantile autism. Komori H, Matsuishi T, Yamada S, Yamashita Y, Ohtaki E, Kato H. J Autism Dev Disord. 1995 Apr;25(2):183-93. They found no difference in CSF levels between apparent responders and non-responders to tetrahydrobiopterin therapy.

Added…..

Toda Y, Mori K, Hashimoto T, Miyazaki M, Nozaki S, Watanabe Y, Kuroda Y, Kagami S. Administration of secretin for autism alters dopamine metabolism in the central nervous system. Brain Dev. 2006 Mar;28(2):99-103. (a complex study in which they gave 12 autistic children some i.v. secretin and looked for improvements in biopterin, 5HIAA, and homovanillinic acid –taken as signs of irritation, serotonin turnover and dopamine turnover- these were found in 7 but all of those with raised biopterin results initially) no patient without the elevation of the THBPt level showed improvement in the score

Folates:

Aberrations in folate metabolic pathway and altered susceptibility to autism. Mohammad NS, Jain JM, Chintakindi KP, Singh RP, Naik U, Akella RR. Psychiatr Genet. 2009 Aug;19(4):171-6. This was done as a genetic assessment by taking the sample from the child (and control) and looking for abnormalities in specific genes. Methylene tetrahydrofolate reductase 677T-allele frequency was found to be higher in autistic children compared with nonautistic children (16.3 vs. 6.5%) with 2.79-fold increased risk for autism [95% confidence interval (CI): 1.58-4.93]. They also looked for other changes in the folate chain and found no association with autism.

Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism with neurological deficits. Ramaekers VT, Blau N, Sequeira JM, Nassogne MC, Quadros EV. Neuropediatrics. 2007 Dec;38(6):276-81. Reduced folate transport to the CNS was identified in two autism spectrum disorders, i.e., Rett syndrome and infantile low-functioning autism with neurological abnormalities. In spite of normal serum folate, CSF 5MTHF was low in 23 of 25 patients. The reduced CSF folate in 19 of these 23 patients could be explained by serum FR autoantibodies blocking the folate binding site of the membrane-attached FR on the choroid epithelial cells. Oral folinic acid supplements led to normal CSF 5MTHF and partial or complete clinical recovery after 12 months.

Brief report: autistic symptoms, developmental regression, mental retardation, epilepsy, and dyskinesias in CNS folate deficiency. Moretti P, Peters SU, Del Gaudio D, Sahoo T, Hyland K, Bottiglieri T, Hopkin RJ, Peach E, Min SH, Goldman D, Roa B, Bacino CA, Scaglia F. J Autism Dev Disord. 2008 Jul;38(6):1170-7. studied seven children with CNS folate deficiency (CFD). All cases exhibited psychomotor retardation, regression, cognitive delay, and dyskinesia; six had seizures; four demonstrated neurological abnormalities in the neonatal period. Two subjects had profound neurological abnormalities that precluded formal behavioral testing No mutations were found in folate transporter or folate enzyme genes.

Cerebral folate deficiency with developmental delay, autism, and response to folinic acid. Moretti P, Sahoo T, Hyland K, Bottiglieri T, Peters S, del Gaudio D, Roa B, Curry S, Zhu H, Finnell RH, Neul JL, Ramaekers VT, Blau N, Bacino CA, Miller G, Scaglia F. Neurology. 2005 Mar 22;64(6):1088-90. A 6-year-old girl with developmental delay, psychomotor regression, seizures, mental retardation, and autistic features associated with low CSF levels of 5-methyltetrahydrofolate, the biologically active form of folates in CSF and blood. Folate and B12 levels were normal in peripheral tissues, suggesting cerebral folate deficiency. Treatment with folinic acid corrected CSF abnormalities and improved motor skills.

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