Atypical phenylketonuria due to tetrahydrobiopterin deficiency. Diagnosis and treatment with tetrahydrobiopterin, dihydrobiopterin and sepiapterin

Curtius, Hans−Christoph; Niederwieser, A.; Viscontini, M.; Otten, A.; Schaub, J.; Scheibenreiter, S; Schmidt, H

doi:10.1016/0009-8981(79)90097-4

Cited by 114 publications

(46 citation statements)

References 25 publications

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“…Sepiapterin and 7,8BH 2 were proven to be the intermediate precursors of BH 4 in a vertebrate system using bull frog (23). Actually, patients of BH 4 -deficiency were reported to have been relieved from abnormal urinary excretion of high phenylalanine and low serotonin by a single administration of sepiapterin (9,10). In the early 1980s, on the other hand, it was feared that since this pathway included dihydrofolate reductase as an immediate to BH 4 production, an MTX supplement might possibly deplete tissues of BH 4 (32).…”

Section: Discussionmentioning

confidence: 99%

Tetrahydrobiopterin Uptake in Supplemental Administration: Elevation of Tissue Tetrahydrobiopterin in Mice Following Uptake of the Exogenously Oxidized Product 7,8-Dihydrobiopterin and Subsequent Reduction by an Anti-folate-Sensitive Process

2004

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Abstract. In order to increase the tissue level of tetrahydrobiopterin (BH 4 ), supplementation with 6R-tetrahydrobiopterin (6RBH 4 ) has been widely employed. In this work, the effectiveness of 6RBH 4 was compared with 7,8-dihydrobiopterin (7,8BH 2 ) and sepiapterin by administration to mice. Administration of 6RBH 4 was the least effective in elevating tissue BH 4 levels in mice while sepiapterin was the best. In all three cases, a dihydrobiopterin surge appeared in the blood. The appearance of the dihydrobiopterin surge after BH 4 treatment suggested that systemic oxidation of the administered BH 4 had occurred before accumulation of BH 4 in the tissues. This idea was supported by the following evidences: 1) An increase in tissue BH 4 was effectively inhibited by methotrexate, an inhibitor of dihydrofolate reductase which reduces 7,8BH 2 to BH 4 . 2) When the unnatural diastereomer 6SBH 4 was administered to mice, a large proportion of the recovered BH 4 was in the form of the 6R-diastereomer, suggesting that this BH 4 was the product of a dihydrofolate reductase process by which 7,8BH 2 converts to 6RBH 4 . These results indicated that the exogenous BH 4 was oxidized and the resultant 7,8BH 2 circulated through the tissues, and then it was incorporated by various other tissues and organs through a pathway shared by the exogenous sepiapterin and 7,8BH 2 in their uptake. It was demonstrated that maintaining endogenous tetrahydrobiopterin in tissues under ordinary conditions was also largely dependent on an methotrexate-sensitive process, suggesting that cellular tetrahydrobiopterin was maintained both by de novo synthesis and by salvage of extracellular dihydrobiopterin.

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Section: Discussionmentioning

confidence: 99%

Tetrahydrobiopterin Uptake in Supplemental Administration: Elevation of Tissue Tetrahydrobiopterin in Mice Following Uptake of the Exogenously Oxidized Product 7,8-Dihydrobiopterin and Subsequent Reduction by an Anti-folate-Sensitive Process

2004

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“…The BH4 loading test was initially used to discriminate between patients with elevated phenylalanine levels due to PAH deficiency and patients with elevated Phe levels due to BH4 deficiency (enzyme defects in the biosynthesis or regeneration of the cofactor BH4) [11,12]. Thus, the loading test is an additional useful tool for the early detection of BH4 deficiencies and it was used in Europe for almost 30 years.…”

Section: Bh4 Loading Testmentioning

confidence: 99%

Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies

Blau

Hennermann

Langenbeck

et al. 2011

Molecular Genetics and Metabolism

206

168

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This article summarizes the present knowledge, recent developments, and common pitfalls in the diagnosis, classification, and genetics of hyperphenylalaninemia, including tetrahydrobiopterin (BH4) deficiency. It is a product of the recent workshop organized by the European Phenylketonuria Group in March 2011 in Lisbon, Portugal. Results of the workshop demonstrate that following newborn screening for phenylketonuria (PKU), using tandem mass-spectrometry, every newborn with even slightly elevated blood phenylalanine (Phe) levels needs to be screened for BH4 deficiency. Dried blood spots are the best sample for the simultaneous measurement of amino acids (phenylalanine and tyrosine), pterins (neopterin and biopterin), and dihydropteridine reductase activity from a single specimen. Following diagnosis, the patient's phenotype and individually tailored treatment should be established as soon as possible. Not only blood Phe levels, but also daily tolerance for dietary Phe and potential responsiveness to BH4 are part of the investigations. Efficiency testing with synthetic BH4 (sapropterin dihydrochloride) over several weeks should follow the initial 24-48-hour screening test with 20mg/kg/day BH4. The specific genotype, i.e. the combination of both PAH alleles of the patient, helps or facilitates to determine both the biochemical phenotype (severity of PKU) and the responsiveness to BH4. The rate of Phe metabolic disposal after Phe challenge may be an additional useful tool in the interpretation of phenotype-genotype correlation. This article summarizes the present knowledge, recent developments, and common pitfalls in the diagnosis, classification, and genetics of hyperphenylalaninemia, including tetrahydrobiopterin (BH4) deficiency. It is a product of the recent workshop organized by the European Phenylketonuria Group in March 2011 in Lisbon, Portugal. Results of the workshop demonstrate that following newborn screening for phenylketonuria (PKU), using tandem mass-spectrometry, every newborn with even slightly elevated blood phenylalanine (Phe) levels needs to be screened for BH4 deficiency. Dried blood spots are the best sample for the simultaneous measurement of amino acids (phenylalanine and tyrosine), pterins (neopterin and biopterin), and dihydropteridine reductase activity from a single specimen. Following diagnosis, the patient's phenotype and individually tailored treatment should be established as soon as possible. Not only blood Phe levels, but also daily tolerance for dietary Phe and potential responsiveness to BH4 are part of the investigations. Efficiency testing with synthetic BH4 (sapropterin dihydrochloride) over several weeks should follow the initial 24-48-hour screening test with 20 mg/kg/day BH4. The specific genotype, i.e. the combination of both PAH alleles of the patient, helps or facilitates to determine both the biochemical phenotype (severity of PKU) and the responsiveness to BH4. The rate of Phe metabolic disposal after Phe challenge may be an additional useful tool in the interp...

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“…The ultraviolet spectrum of BH2 in 0.1 M phosphate buffer, pH 6.8 has three broad peaks centered at 230 nm (E, 'It has been reported that these patients excrete dihydroxanthopterin which could be derived from PHz [21,[25][26][27][28][29]. (Fig.1A).…”

Section: Identiji:cation Of Ph2 and Bh2mentioning

confidence: 99%

The auto‐oxidation of tetrahydrobiopterin

Davis

Kaufman

Milstien

1988

European Journal of Biochemistry

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The product of the aerobic oxidation of tetrahydrobiopterin, quinonoid dihydrobiopterin, is unstable and rapidly rearranges to form a 7,s-dihydropteridine. Kaufman [Kaufman, S. (1967) J. Biol. Chem. 242,3934-39431 identified the stable product produced in 0.1 M phosphate pH 6.8, as 7,s-dihydrobiopterin. However, Armarego et al. [Armarego, W. L. F., Randles, D. and Taguchi, H. (1983) Eur. J. Biochem. 135 393-4031 questioned this assignment because they found that the dihydroxypropyl group on C-6 was eliminated and 7,s-dihydropterin was the predominant product when the aerobic oxidation was performed in 0.1 M Tris pH 7.6. In the present study we demonstrate that the rearrangement of the unstable quinonoid dihydrobiopterin results in a mixture of these two 7,8-dihydropteridines at neutral pH, 25 "C. Furthermore, we find that the loss or retention of the alkyl sidechain is not solely dependent on the pH of the reaction mixture, as was previously assumed by Armarego et al., but rather is strongly influenced by the temperature and the type of buffer. In addition, we describe a new method for quantifying the relative amounts of these two 7,8-dihydropteridines in mixtures of unknown concentrations. This method relies on multicomponent analysis of second derivative spectra and results in values which agree with the concentrations determined directly by HPLC.A reduced pteridine cofactor is necessary for phenylalanine hydroxylase to catalyze the conversion of phenylalanine to tyrosine [l]. The natural cofactor for this enzyme (as well as for tyrosine hydroxylase [2-51 and tryptophan hydroxylase [6, 71 is tetrahydrobiopterin, (BH,) [S]. During the hydroxylation reaction at neutral pH, there is a stoichiometric oxidation of BH4 to quinonoid dihydrobiopterin (qBH2) [9, 101. This latter species can then be reduced back to BH4 by the NADH-dependent enzyme, dihydropteridine reductase [ l l -151. qBH2 is unstable and, in the absence of the reductase, rapidly rearranges to a 7,s-dihydropteridine [9]. It was concluded that 7,s-dihydrobiopterin (BH,) was the product of the tautomerization of qBH2 [16,17] because when the auto-oxidation of BH4 was performed in 0.1 M phosphate pH 6.8 at ambient temperature, the ultraviolet spectrum of the product was identical to that of authentic BH2 [16]. This conclusion was also strongly supported by the finding that one of the products of the aerobic oxidation of BH4 in phosphate buffer was a substrate for sepiapterin reductase, an enzyme that catalyzes the NADP-dependent oxidation of the 2'-hydroxyl group on the side-chain of BH2 [16].However, it has become apparent that the unstable qBH2 does not always isomerize to BH,. Whereas the oxidation of Correspondence to

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Atypical phenylketonuria due to tetrahydrobiopterin deficiency. Diagnosis and treatment with tetrahydrobiopterin, dihydrobiopterin and sepiapterin

Cited by 114 publications

References 25 publications

Tetrahydrobiopterin Uptake in Supplemental Administration: Elevation of Tissue Tetrahydrobiopterin in Mice Following Uptake of the Exogenously Oxidized Product 7,8-Dihydrobiopterin and Subsequent Reduction by an Anti-folate-Sensitive Process

Tetrahydrobiopterin Uptake in Supplemental Administration: Elevation of Tissue Tetrahydrobiopterin in Mice Following Uptake of the Exogenously Oxidized Product 7,8-Dihydrobiopterin and Subsequent Reduction by an Anti-folate-Sensitive Process

Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies

The auto‐oxidation of tetrahydrobiopterin

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