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Disorders of biopterin metabolism.
J Inherit Metab Dis. 2009 Jun; 32(3):333-42.JI

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-4alpha-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.

Authors+Show Affiliations

Division of Medical Genetics, Department of Pediatrics and Pathology, University of Utah, 2C 412 SOM, 50 North Mario Capecchi Drive, Salt Lake City, UT 84132, USA. Nicola.Longo@hsc.utah.edu

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

19234759

Citation

Longo, Nicola. "Disorders of Biopterin Metabolism." Journal of Inherited Metabolic Disease, vol. 32, no. 3, 2009, pp. 333-42.
Longo N. Disorders of biopterin metabolism. J Inherit Metab Dis. 2009;32(3):333-42.
Longo, N. (2009). Disorders of biopterin metabolism. Journal of Inherited Metabolic Disease, 32(3), 333-42. https://doi.org/10.1007/s10545-009-1067-2
Longo N. Disorders of Biopterin Metabolism. J Inherit Metab Dis. 2009;32(3):333-42. PubMed PMID: 19234759.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Disorders of biopterin metabolism. A1 - Longo,Nicola, Y1 - 2009/02/09/ PY - 2008/10/03/received PY - 2008/12/12/accepted PY - 2008/12/10/revised PY - 2009/2/24/entrez PY - 2009/2/24/pubmed PY - 2009/8/20/medline SP - 333 EP - 42 JF - Journal of inherited metabolic disease JO - J Inherit Metab Dis VL - 32 IS - 3 N2 - 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-4alpha-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. SN - 1573-2665 UR - https://wwww.unboundmedicine.com/medline/citation/19234759/Disorders_of_biopterin_metabolism_ L2 - https://doi.org/10.1007/s10545-009-1067-2 DB - PRIME DP - Unbound Medicine ER -