J Inherit Metab Dis. 2009 Jun;32(3):333-42. doi: 10.1007/s10545-009-1067-2. Epub 2009 Feb 9.
Disorders of biopterin metabolism.
Longo N1.
- J Inherit Metab Dis. 2009 Jun;32(3):457.
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 (SPR) 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
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.
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 (SPR) 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.
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.
- PMID:
- 19234759
- DOI:
- 10.1007/s10545-009-1067-2
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