Disorders of biopterin metabolism
- 9 February 2009
- journal article
- review article
- Published by Wiley in Journal of Inherited Metabolic Disease
- Vol. 32 (3), 333-342
- https://doi.org/10.1007/s10545-009-1067-2
Abstract
Defects in the metabolism or regeneration of tetrahydrobiopterin (BH4) were initially discovered in patients with hyperphenylalaninaemia who had progressive neurological deterioration despite optimal metabolic control (malignant hyperphenylalaninaemia). BH4 is an essential cofactor not only for phenylalanine hydroxylase, but also for tyrosine and two tryptophan hydroxylases, three nitric oxide synthases, and glyceryl-ether monooxygenase. Defective activity of tyrosine and tryptophan hydroxylases explains the neurological deterioration in patients with BH4 deficiency with progressive mental and physical retardation, central hypotonia and peripheral spasticity, seizures and microcephaly. Five separate genetic conditions affect BH4 synthesis or regeneration: deficiency of GTP cyclohydrolase I, 6-pyruvoyl tetrahydropterin synthase, sepiapterin reductase, dihydropteridine reductase (DHPR) and pterin-4α-carbinolamine dehydratase. Only the latter of these conditions is relatively benign and is associated with transient hyperphenylalaninaemia. All these conditions can be identified in newborns by an elevated phenylalanine, with the exception of sepiapterin reductase and the dominant form of GTP cyclohydrolase I deficiency that results in biopterin deficiency/insufficiency only in the brain. Diagnosis relies on the measurement of pterin metabolites in urine, dihydropteridine reductase in blood spots, neurotransmitters and pterins in the CSF and on the demonstration of reduced enzyme activity (red blood cells or fibroblasts) or causative mutations in the relative genes. The outcome of BH4 deficiency is no longer malignant if therapy is promptly initiated to reduce plasma phenylalanine levels and replace missing neurotransmitters. This is accomplished by a special diet and/or BH4 supplements and administration of l-dopa, carbidopa, 5-hydroxytryptophan, and, in certain cases, a MAO-B inhibitor. Patients with DHPR deficiency also require folinic acid supplements, since DHPR may help in maintaining folate in the tetrahydro form. Several patients with BH4 deficiency treated since the newborn period have reached adult age with good outcome.This publication has 44 references indexed in Scilit:
- Vascular protection by tetrahydrobiopterin: progress and therapeutic prospectsTrends in Pharmacological Sciences, 2009
- Glyceryl ether monooxygenase resembles aromatic amino acid hydroxylases in metal ion and tetrahydrobiopterin dependenceBiological Chemistry, 2008
- Serum prolactin as a tool for the follow‐up of treated DHPR‐deficient patientsJournal of Inherited Metabolic Disease, 2008
- A case of 6-pyruvoyl-tetrahydropterin synthase deficiency demonstrates a more significant correlation of l-Dopa dosage with serum prolactin levels than CSF homovanillic acid levelsBrain & Development, 2008
- Sepiapterin Reductase Deficiency: Clinical Presentation and Evaluation of Long-Term TherapyPediatric Neurology, 2006
- Mutations in the pterin-4α-carbinolamine dehydratase ( PCBD ) gene cause a benign form of hyperphenylalaninemiaHuman Genetics, 1998
- 7-Substituted pterins: Formation during phenylalanine hydroxylation in the absence of dehydrataseBiochemical and Biophysical Research Communications, 1990
- Folinic acid therapy in treatment of dihydropteridine reductase deficiencyThe Journal of Pediatrics, 1987
- Clinical role of pteridine therapy in tetrahydrobiopterin deficiencyJournal of Inherited Metabolic Disease, 1985
- Hyperphenylalaninemia Due to a Deficiency of BiopterinNew England Journal of Medicine, 1978