Table of Contents<\/b><\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_single_image image=”5963″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Figure 1. (1) 5,6,7,8-tetrahydrofolate (THF); (2) 5,6,7,8-tetrahydrobiopterin (BH<\/b>4<\/sub>).<\/b> Natural pteridines contain a 2-amino,4-oxopteridine <\/b>(or \u2018pterin\u2019<\/b>) ring<\/b>. Folic acid<\/b> and biopterin<\/b> contain a fully oxidized pterin ring (five double bonds<\/b>) but in vivo<\/i> the number and disposition of double bonds and protons are in the dihydro-<\/b> or tetrahydro- form<\/b> (as shown above), enabling pteridines to act as proton donors<\/b> and acceptors<\/b>. Various substituent groups may be attached at position 6, biopterins having a dihydroxypropyl<\/b>, and folate a methylene\/<\/b>p<\/i><\/b>-aminobenzoate\/glutamate group<\/b>. Folates may carry additional methyl (CH3<\/sub><\/b>), formyl (CHO<\/b>), or formimino (CHNH<\/b>) groups at N5, CHO<\/b> at N10 or methenyl (CH<\/b>) or methylene (CH2<\/sub><\/b>) groups linking N5 and N10, reflecting the role of folate in 1-carbon <\/b>(1-C<\/b>) transfer<\/b>. Amethopterin<\/i><\/b> (<\/i>methotrexate<\/i><\/b>)<\/i> is a synthetic pteridine <\/i><\/b>which differs from folic acid in having an amino-group instead of an oxo-group at position 4 and a methyl group at position 10.<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”introduction” el_class=”u-orange”][vc_column][vc_custom_heading text=”Introduction”][vc_column_text single_style=””]<\/p>\n Phenylketonuria<\/b> (PKU<\/b>) is a rare but potentially serious inherited disorder<\/b>. Our bodies break down the protein in foods, such as meat and fish, into amino acids, which are the \u2018building blocks<\/b>\u2019 of protein<\/b>. These amino acids are then utilized to make our own new proteins. Any amino acids that are not required are broken down further and excreted from the body. Individuals with PKU cannot break down the amino acid phenylalanine<\/b> (PA<\/b>), which in turn builds up in their blood and brain. This can lead to brain damage<\/u>.<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point”][vc_column][vc_custom_heading text=”The Biopterin System, Coenzyme of Aromatic Amino Acid Hydroxylases”][vc_single_image image=”5958″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Figure 2. (1) 7,8-dihydrobiopterin (BH2<\/sub>) and (2) 5,6,7,8-tetrahydobiopterin (BH4<\/sub>).<\/b> L-erythro-5,6,7,8-tetrahydrobiopterin (<\/i>BH<\/i><\/b>4<\/sub><\/b>) is a common natural cofactor for hydroxylases of phenylalanine, tyrosine, and tryptophan, and is thought to play an important role in the regulation of monoamine neurotransmitter biosynthesis.<\/i><\/span> In fact, it is well known that in \u2018atypical phenylketonuria<\/b>,\u2019 BH4<\/sub> deficiency results in severe neurological problems as result of decreased biosynthesis of brain catecholamines and 5-hydroxytrptamine (5-HT<\/b>). Furthermore, it has been reported that the content of BH<\/i>4<\/sub> is reduced in the brain and\/or cerebrospinal fluid (CSF) of several neuropsychiatric diseases<\/i><\/span>, such as Parkinson\u2019s disease, Alzheimer\u2019s disease, depression, and dystonia; and most importantly, in autism spectrum disorders (ASD<\/b>). Administration of BH4<\/sub> improve clinical signs and symptoms of these diseases; and therapeutic efficacy are mainly due to enhancement of neurotransmitter release.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n PKU is a metabolic disorder that is inherited in an autosomal recessive fashion<\/b> and is caused by a defect in the hepatic PA hydroxylating system<\/b> [1]. This system consists of two enzymes, viz.:<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n as well as a coenzyme, tetrahydrobiopterin (BH<\/b>4<\/sub>) (see Figure 1 and 2<\/b>), which acts not only on PAH but also on, for instance:<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n The former on the \u2018dopamine and norepinephrine synthesis pathway;\u2019 and the later on the \u2018serotonin synthesis pathway\u2019 (see Figure 3<\/b>). (cf. previous blogs entitled as: (i)<\/b> \u2018The Neurotypical Brain versus the Autistic Brain: Neurotypical Brain Chemistry,\u2019<\/i><\/u> (ii)<\/b> \u2018The Neurotypical Brain versus the Autistic Brain: Brain Chemistry in ASD.\u2019<\/i><\/u>).<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n During hydroxylation cycle of these three enzymes (PAH, TH, TPH<\/b>), BH4<\/sub> is oxidized to quinonoid dihydrobiopterin (q-BH2<\/sub>), the latter being transformed partly into L-erthro-7,8-dihydrobiopterin (7,8-BH2<\/sub>). They are further reduced to BH4 by dihydropteridine reductase (DHPR<\/b>) and by dihydrofolate reductase (DHFR<\/b>), respectively (see Figure 3<\/b>) [2].<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n The classic form of PKU is caused by a lack of PAH activity, which normally transforms PA into tyrosine. This defect produces hyperphenylalaninemia<\/b> (HPA<\/b>) which, if left untreated, results in severe mental disability (cf. previous blog entitled as: \u2018Developmental Delays in Infancy and Early Childhood: Phenylalanine and Tyrosine Metabolism Disorders.\u2019<\/i><\/u>). [\/vc_column_text][vc_single_image image=”5956″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Figure 3. The biopterin system, coenzymes of aromatic amino acid hydroxylase. (1) <\/b>Guanosine triphosphate cyclohydrolase; (2) <\/b>dihydrobiopterin synthetase; (3)<\/b> phenylalanine 4-hydroyxlase, tyrosine 3-hydroxylase, tryptophan 5-hydroxylase; (4)<\/b> dihydropteridine reductase; and (5) <\/b>dihydrofolate reductase. [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-1″][vc_column][vc_custom_heading text=”Epidemiology”][vc_column_text single_style=””]<\/p>\n PKU is one of the most frequent inherited disorders in Europeans; and the reported incidence of PKU from newborn screening programs ranges from 1 in 13,500 to 19,000 newborns<\/b> in the United States. Some 1.5% – 2% of PKU cases<\/b> are not due to a defect in PAH but are due to a defect in BH4<\/sub> synthesis or in the regeneration of BH4<\/sub> (DHPR deficiency<\/b>; see Figure 4<\/b>).<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_class=”u-orange” el_id=”blog-scroll-point-2″][vc_column][vc_custom_heading text=”Clinical Features of HPA”][vc_column_text single_style=””]<\/p>\n In either case, the result is the development of \u2018malignant HPA<\/b>,\u2019 that is PKU which does not respond to a good dietary control of blood-PA levels and leads to an irreversible neurologic deterioration that becomes apparent between 3 to 5 months of age. This is characterized by the following clinical features, for example:<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n This deterioration which occurs in spite of satisfactory blood-PA levels is due to biogenic amine deficiency, viz., serotonin, dopamine, and norepinephrine. Death typically occurs by age 5 \u2013 7 years<\/u>.<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-3″][vc_column][vc_custom_heading text=”Diagnosing HPA”][vc_column_text single_style=””]<\/p>\n Of paramount importance is early recognition of these cases<\/b>. \u2018DHPR and biopterin assay<\/i><\/span> \u2019 on dried blood spots and biopterin assay on filter paper spots of urine should be carried out in every infant with a positive neonatal screening for HPA.<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-4″][vc_column][vc_custom_heading text=”Treating HPA”][vc_column_text single_style=””]<\/p>\n Positive results require dietary control of blood-PA levels, a supplementation with neurotransmitter precursor, such as L-dopa<\/b> and 5-hydroxy tryptophan <\/b>(5-HT<\/b>) (with a peripheral inhibitor of aromatic amino acid decarboxylase, carbidopa<\/b>). As well as in cases of BH4<\/sub> synthesis deficiency, a replacement therapy with BH<\/b>4<\/sub>.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Nevertheless, it has recently become evident that the treatment of DHPR deficiency is not fully satisfactory if <\/i>folinic acid<\/i><\/b> (<\/i>5-formyl-tetrahydorfolate<\/i><\/b>, [<\/i>THF<\/i><\/b>]) supplementation is not started early<\/i><\/span>. DHPR-deficient patients has led us to a better understanding of \u2018the relationship between folate and biopterin metabolism<\/b>.\u2019 In such patients, folic acid deficiency in blood and brain seems usual, with development of basal ganglia calcifications, as in cases of inherited defect of folate transfer into brain<\/u> [3].<\/p>\n [\/vc_column_text][vc_column_text single_style=”” el_class=”u-orange”]<\/p>\n In addition, some cases of DHPR deficiency with good dietary control of blood-PA levels, sufficient neurotransmitters precursor supplementation, and normal neurologic status; have developed at age 2 \u2013 3 years, an unexpected neurologic deterioration with signs and symptoms similar to early manifestations of untreated cases and associated with decreased levels of CSF amine metabolites. This late neurologic deterioration is secondary to <\/i>brain and CSF 5-methyl-THF deficiency;<\/i><\/b> and has been cured by 5-formyl-THF (folinic acid) in occasional patients<\/i><\/u>.<\/p>\n [\/vc_column_text][vc_single_image image=”5957″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Figure 4. Salvage Pathways in Dihydropteridine Reductase (DHPR) Deficiency and Potential Secondary Effects on Folate Metabolism.<\/b> [q-BH2, quinonoid dihydrobiopterin; BH4<\/sub>, tetrahydrobiopterin; 7,8-BH2<\/sub>, L-erythro<\/i>-7,8-dihydrobiopterin; DHF, dihydrofolate; THF, tetrahydrofolate; 5,10-CH2<\/sub>-THF, 5,10-methylene-tetrahydrofolate; 5-CH3<\/sub>-THF, 5-methyl-tetrahydrofolate; MTHFR, 5,10-methylene-tetrahydrofolate reductase; DHPR, dihydropteridine reductase; DHFR, dihydrofolate reductase; MS, methionine synthase; CH3<\/sub>-B12<\/sub>, methylcobalamin]<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-5″ el_class=”u-orange”][vc_column][vc_custom_heading text=”The Relationship Between Biopterin and Folate Metabolism”][vc_column_text single_style=”” el_class=”u-orange”]<\/p>\n DHPR is well represented in brain<\/b>, even in the area without tyrosine or tryptophan hydroxylase activity. DHPR has been shown to catalyze the reduction of quinonoid dihydrofolate to THF (see Figure 4<\/b>). DHPR deficiency results in low brain and CSF folate concentrations<\/u>. DHFR, well represented in liver but not in brain can reduce 7,8-BH2<\/sub> to BH4<\/sub> (see Figure 4<\/b>) [4].<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n In DHPR-deficient patients, a competition between 7,8-BH2<\/sub> (derived from q-BH2<\/sub> accumulated above the metabolic block) and dihydrofolate could lead to THF deficiency peripherally and secondarily in brain CSF. 5, 10-methylene-THF reductase (MTHFR), which normally catalyzes the reduction of 5,10-methylene THF to 5-methyl-THF (the essential folate derivative), present in liver and brain, could, in DHPR-deficient patients, help to reduce q-BH2<\/sub> to BH4<\/sub>. A competition between q-BH2 and 5,10-methylene-THF, could decrease the production of 5-methyl-THF (see Figure 4<\/b>).<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Patients with MTHFR deficiency, who also have a severe deficiency in brain CSF 5-methyl-THF, have low levels of amine metabolites in CSF. It has been shown in a DHPR-deficient patient that some salvage of BH<\/b>4<\/sub> exist, likely by means of MTHFR and DHFR<\/b>.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n In DHFR-deficient patients, the decreased level of reduced folate in brain seems to impede the control of biogenic amine release rather than the amine synthesis. It has been demonstrated on homogenized fresh rat brain that the addition of 5-methyl-THF<\/b>, hydroxocobalamin<\/b>, and ascorbate<\/b> increased the in vitro<\/i> synthesis of biopterin<\/b>.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Folinic acid (5-formyl-THF) supplementation, by providing increased amounts of reduced folate for MTHFR, peripherally and in the brain, can correct 5-methyl-THF deficiency<\/u>, and thus prevent basal ganglia calcifications and delayed neurologic deterioration in DHPR-deficient patients. [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-6″ el_class=”u-orange”][vc_column][vc_custom_heading text=”Tetrahydrobiopterin (BH4<\/sub>) Deficiency in ASD”][vc_column_text single_style=””]<\/p>\n ASD is a disorder that describes individuals who have persistent deficits in: (i)<\/b> social communication and social interaction;<\/b> with (ii) restricted, repetitive patterns of behavior, interest, or activity<\/b>. ASD represents a large spectrum of classifications and presentations, from mild to severe impairment<\/b> [5].<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n ASD\u2019s pathophysiology is not very well understood; however, evidence from the literature indicates that a specific modulation of the BH4 <\/sub> pathway affecting the activity of the monoaminergic neurons that might be downregulated in the disease<\/u>. In fact, reduced levels of BH4<\/sub> have been demonstrated in the blood, urine, and CSF of ASD-affected children.<\/u><\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Furthermore, several reports have demonstrated that a therapeutic effect of BH4<\/sub> supplementation in children with ASD. BH<\/i><\/b>4 <\/i><\/b><\/sub>daily doses of 1 to 3 mg\/kg for 4 to up to 105 weeks<\/i><\/b> elicited noticeable improvements in social responsiveness<\/b>, communication<\/b>, and cognitive abilities<\/b> in over 300 mildly to severely affected ASD children. These improvements were marked in children with higher intelligence <\/i><\/span>and younger than 5 years old<\/i><\/span>. Remarkably, BH4<\/sub> daily supplementation with 20 mg\/kg induced similar effects than lower doses [6-7].<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_class=”blog-text-35795″ el_id=”blog-scroll-point-7″][vc_column][vc_custom_heading text=”Take Home Messages” el_class=”blog-text-35795″][vc_column_text single_style=””]<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_class=”blog-text-35795″ el_id=”conclusion”][vc_column][vc_custom_heading text=”Summary and Conclusions” el_class=”blog-text-35795″][vc_column_text single_style=””]<\/p>\n Here we have provided an overview of the relationship between biopterin and folate metabolism and the accompanying consequences of tetrahydrobiopterin (BH4<\/sub>) deficiency pertaining to neuropsychiatric\/neurodevelopmental conditions. As well as therapeutic benefits of BH4<\/sub> replacement along with folinic acid (5-formyl-THF) to ameliorate these neurological conditions.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Most importantly, the main objective of this blog is to highlight the fact that, the significance of BH4<\/sub> in ASD and other neurodevelopmental conditions should not be understated or ignored. Low CNS BH4<\/sub> levels can result in devastating neurodevelopmental consequences. Because BH4<\/sub> is an enhancer of synaptic release of a wide range of neurotransmitters, such as biogenic amines (serotonin, dopamine, and norepinephrine), acetylcholine, glutamate, and gamma-aminobutyric acid (GABA). Therefore, BH4<\/sub> is involved in several metabolic and neurotransmitter pathways critical from CNS function and development.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Low BH4<\/sub> during development could have detrimental consequences to the CNS, leading to or potentiating the neuropathology underlying ASD. The central role of BH4<\/sub> in a wide range of CNS and non-CNS metabolic pathways, which are known to be dysfunctional in ASD, and one that may have a therapeutic role.<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_column_text single_style=”” el_class=”blog-banner-section”]<\/p>\n Folate (vitamin B9) is very important for your child\u2019s brain development!<\/p>\n During pregnancy, it helps prevent neural tube defects and plays a big role in forming a normal and healthy baby\u2019s brain and spinal cord. Folate also helps cells divide and assists in both DNA and RNA synthesis.<\/p>\n Emerging research suggests that the presence of FRAAs negatively impacts folate transport into the brain.<\/p>\n Yes, there is a test – The Folate Receptor Antibody Test (FRAT\u00ae<\/sup>) has emerged as a diagnostic tool for detecting the presence of FRAAs.<\/p>\n It is important to screen at an early age or as soon as possible as there may be corrective measures available. Please consult your physician for further information.<\/p>\n To request a test kit, click on the button below.<\/p>\n Request Now<\/a><\/p>\n<\/div>\n<\/div>\n [\/vc_column_text][vc_column_text single_style=”” el_class=”text-gray-23″]For information on autism monitoring, screening and testing please read our blog<\/a>.[\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-references” el_class=”blog-text-35795″][vc_column][vc_custom_heading text=”References” use_theme_fonts=”yes”][vc_column_text single_style=”” el_id=”blog-ref-3564″]<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row]<\/p>\n","protected":false},"excerpt":{"rendered":" Uncover the link between biopterin and folate metabolism in developmental delays. Explore BH4<\/sub> deficiency, its impact on neurotransmitters, and potential treatments for ASD and other conditions.<\/p>\n","protected":false},"author":3,"featured_media":5959,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[73,64],"tags":[],"yoast_head":"\n\n
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\nMoreover, hyperphenylalaninemia impedes the transfer of L-tryptophan and L-tyrosine at the blood-brain barrier (BBB)<\/strong> level. This results in a decreased synthesis of \u2018biogenic amines.\u2019 Additionally, increased levels of PA in brain seems to directly inhibit TH and TPH activities. The correction of HPA with a low-PA diet leads to a normal biogenic amine synthesis<\/u>. Neonatal screening for HPA and early low-PA diet allow a normal development in children with PKU<\/u><\/span>.<\/p>\n
\n[L-erythro<\/i>-7,8-dihydrobiopterin \u2013 a 7,8-dihydrobiopterin in which the 1,2-dihydroxypropyl group has (1<\/b>R<\/i><\/b>,2<\/b>S<\/i><\/b>)-configuration, and a naturally occurring form \u2013 It is an enantiomer of a D-erythro-7,8-dihydrobiopterin; D-erythro<\/i>-7,8-dihydrobiopterin in which the 1,2-dihydroxypropyl group has (1<\/b>S<\/i><\/b>,2<\/b>R<\/i><\/b>)-configuration; 6R-<\/i>L-erythro<\/i>-5,6,7,8-tetrahydrobiopterin \u2013 5,6,7,8-tetrahydrobiopterin in which the 1,2-dihydroxypropyl side-chain has L-erythro<\/i>-configuration.]<\/p>\n\n
\n5-methyl-THF seems too unstable to be used as a therapeutic agent. Not only folic acid (FA) is ineffective, but by competitive inhibition with 5-methyl-THF at the BBB level, can aggravate the neurologic status of such children.<\/p>\n\n
Did You Know? Folate Receptor Autoantibodies (FRAAs) may impede proper folate transport.<\/h4>\n
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Is there a test for identifying Folate Receptor Autoantibodies (FRAAs)?<\/h4>\n
![\"FRAT](\"https:\/\/autism.fratnow.com\/blog\/wp-content\/uploads\/2023\/12\/frat-mascot-image.webp\")
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\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/388868\/<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/3540926\/<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/32744952\/<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/21310276\/<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/37237903\/<\/a><\/li>\n
\nhttps:\/\/www.najms.com\/index.php\/najms\/article\/viewFile\/148\/140<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/20643376\/<\/a><\/li>\n<\/ol>\n<\/div>\n