tetrahydropterin and Phenylketonurias

Phenylketonuria is still a brilliant example that early diagnosis, immediate onset of treatment and carefully controlled diet enable the patient to grow up normally. There are, however, other inherited disorders of amino acid metabolism in which the prognosis of the affected patients--despite some progress in the recent past--is still very poor.

Topics: Age Factors; Amino Acid Metabolism, Inborn Errors; Biopterins; Diet; Dietary Proteins; Dihydropteridine Reductase; Europe; Female; Glucosephosphate Dehydrogenase Deficiency; Humans; Infant; Infant, Newborn; Intellectual Disability; Liver; Mass Screening; Phenylalanine; Phenylalanine Hydroxylase; Phenylketonurias; Pregnancy; Pregnancy Complications; Prognosis; Pterins; Tyrosine

To report the long-term results of early initiation of treatment of 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency.. Between 1988 and 2000, 12 newborns with PTPS deficiency who underwent early treatment at our hospital were identified. All patients received tetrahydrobiopterin replacement in a daily dosage between approximately 2 and 4 mg/kg. The dosages of levodopa replacement were 10 to 15 mg/kg/d, which is considerably higher than the typically recommended dosages of less than 7 mg/kg/d for patients aged younger than 2 years and 8 to 10 mg/kg/d for patients aged 2 years or older. Replacement with 5-hydroxytryptophan varied widely among patients.. Taipei Veterans General Hospital. Patients Twelve newborns.. Treatment with tetrahydrobiopterin, levodopa, and 5-hydroxytryptophan. Main Outcome Measure IQ score.. The mean (SD) IQ score of our PTPS-deficient patients was 96.7 (9.7; range 86-119), which is considerably higher than previous reports of other populations of PTPS-deficient patients. All patients reached a normal IQ on high daily dosages of levodopa replacement, without developing apparent long-term levodopa-induced adverse effects. We also observed a correlation between long-term IQ score and genotype, birth weight, and age at initiation of treatment.. An effective newborn screening referral program and early initiation of appropriate therapy preserved the IQ scores of PTPS-deficient patients.

Topics: 5-Hydroxytryptophan; Adolescent; Adult; Asian People; Child; Child, Preschool; Female; Humans; Infant; Intelligence; Intelligence Tests; Levodopa; Longitudinal Studies; Male; Phenylketonurias; Phosphorus-Oxygen Lyases; Pterins; Retrospective Studies; Statistics, Nonparametric; Taiwan; Time Factors

Phenylketonuria (PKU) is caused by autosomal recessive variants in phenylalanine hydroxylase (PAH), leading to systemic accumulation of L-phenylalanine (L-Phe) that may reach neurotoxic levels. A homozygous Pah-R261Q mouse, with a highly prevalent misfolding variant in humans, reveals the expected hepatic PAH activity decrease, systemic L-Phe increase, L-tyrosine and L-tryptophan decrease, and tetrahydrobiopterin-responsive hyperphenylalaninemia. Pah-R261Q mice also present unexpected traits, including altered lipid metabolism, reduction of liver tetrahydrobiopterin content, and a metabolic profile indicative of oxidative stress. Pah-R261Q hepatic tissue exhibits large ubiquitin-positive, amyloid-like oligomeric aggregates of mutant PAH that colocalize with selective autophagy markers. Together, these findings reveal that PKU, customarily considered a loss-of-function disorder, can also have toxic gain-of-function contribution from protein misfolding and aggregation. The proteostasis defect and concomitant oxidative stress may explain the prevalence of comorbid conditions in adult PKU patients, placing this mouse model in an advantageous position for the discovery of mutation-specific biomarkers and therapies.

Topics: Amyloid; Animals; Autophagy; Biomarkers; Body Weight; Breeding; Female; Gene Expression Regulation; Genotype; Lipid Metabolism; Liver; Male; Metabolome; Mice; Mutant Proteins; Mutation; Neurotransmitter Agents; Oxidative Stress; Phenylalanine; Phenylalanine Hydroxylase; Phenylketonurias; Protein Aggregates; Pterins; Respiration; RNA, Messenger; Ubiquitin; Ubiquitination

Phenylketonuria (PKU) is an inborn error of metabolism caused by mutations in the phenylalanine hydroxylase (

Topics: Animals; Bombyx; Insect Proteins; Larva; Mutation; Phenylketonurias; Phosphorus-Oxygen Lyases; Pigmentation; Pterins; Sugar Acids

Queuosine is a modified pyrrolopyrimidine nucleoside found in the anticodon loop of transfer RNA acceptors for the amino acids tyrosine, asparagine, aspartic acid, and histidine. Because it is exclusively synthesized by bacteria, higher eukaryotes must salvage queuosine or its nucleobase queuine from food and the gut microflora. Previously, animals made deficient in queuine died within 18 days of withdrawing tyrosine, a nonessential amino acid, from the diet (Marks, T., and Farkas, W. R. (1997) Biochem. Biophys. Res. Commun. 230, 233-237). Here, we show that human HepG2 cells deficient in queuine and mice made deficient in queuosine-modified transfer RNA, by disruption of the tRNA guanine transglycosylase enzyme, are compromised in their ability to produce tyrosine from phenylalanine. This has similarities to the disease phenylketonuria, which arises from mutation in the enzyme phenylalanine hydroxylase or from a decrease in the supply of its cofactor tetrahydrobiopterin (BH4). Immunoblot and kinetic analysis of liver from tRNA guanine transglycosylase-deficient animals indicates normal expression and activity of phenylalanine hydroxylase. By contrast, BH4 levels are significantly decreased in the plasma, and both plasma and urine show a clear elevation in dihydrobiopterin, an oxidation product of BH4, despite normal activity of the salvage enzyme dihydrofolate reductase. Our data suggest that queuosine modification limits BH4 oxidation in vivo and thereby potentially impacts on numerous physiological processes in eukaryotes.

Topics: Animals; Hep G2 Cells; Humans; Mice; Nucleoside Q; Oxidation-Reduction; Pentosyltransferases; Phenylalanine; Phenylalanine Hydroxylase; Phenylketonurias; Pterins; RNA, Transfer; Tetrahydrofolate Dehydrogenase; Tyrosine

Topics: Biopterins; Chromatography, High Pressure Liquid; Humans; Hydro-Lyases; Infant, Newborn; Oxidation-Reduction; Oxidoreductases; Phenylalanine Hydroxylase; Phenylketonurias; Pterins; Stereoisomerism

Substantial amounts of tetrahydrobiopterin and 6-methyltetrahydropterin can be detected in CSF when these pterins are given peripherally to patients with hyperphenylalaninemia due to defective biopterin synthesis. Results of this study suggest that administration of either of these pterins in proper doses may prove to be a treatment not only for the impaired peripheral phenylalanine metabolism, but also for the neurologic disorders that are characteristic of the variant forms of hyperphenylalaninemia due to defective tetrahydrobiopterin synthesis or metabolism.

Topics: Biopterins; Brain; Child; Child, Preschool; Female; Humans; Male; Neopterin; Phenylalanine; Phenylketonurias; Pteridines; Pterins