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BH<jats:sub>4<\/jats:sub> is an essential cofactor not only for phenylalanine hydroxylase, but also for tyrosine and two tryptophan hydroxylases, three nitric oxide synthases, and glyceryl\u2010ether monooxygenase. Defective activity of tyrosine and tryptophan hydroxylases explains the neurological deterioration in patients with BH<jats:sub>4<\/jats:sub> deficiency with progressive mental and physical retardation, central hypotonia and peripheral spasticity, seizures and microcephaly. Five separate genetic conditions affect BH<jats:sub>4<\/jats:sub> synthesis or regeneration: deficiency of GTP cyclohydrolase I, 6\u2010pyruvoyl tetrahydropterin synthase, sepiapterin reductase, dihydropteridine reductase (DHPR) and pterin\u20104\u03b1\u2010carbinolamine 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 BH<jats:sub>4<\/jats:sub> 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 BH<jats:sub>4<\/jats:sub> supplements and administration of <jats:sc>l<\/jats:sc>\u2010dopa, carbidopa, 5\u2010hydroxytryptophan, and, in certain cases, a MAO\u2010B inhibitor. Patients with DHPR deficiency also require folinic acid supplements, since DHPR may help in maintaining folate in the tetrahydro form. Several patients with BH<jats:sub>4<\/jats:sub> deficiency treated since the newborn period have reached adult age with good outcome.<\/jats:p>","DOI":"10.1007\/s10545-009-1067-2","type":"journal-article","created":{"date-parts":[[2009,2,20]],"date-time":"2009-02-20T05:58:03Z","timestamp":1235109483000},"page":"333-342","source":"Crossref","is-referenced-by-count":127,"title":["Disorders of biopterin metabolism"],"prefix":"10.1002","volume":"32","author":[{"given":"Nicola","family":"Longo","sequence":"first","affiliation":[{"name":"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 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