Disorders of Phenylalanine and Tetrahydrobiopterin Metabolism

Hyperphenylalaninemia, a disorder of phenylalanine catabolism, is caused primarily by a deficiency of the hepatic apoenzyme phenylalanine-4-hydroxylase (PAH) or by one of the enzymes involved in its cofactor bio-synthesis (GTP cyclohydrolase I, GTPCH; and 6-pyruvoyl-tetrahydropterin synthase, PTPS) or its regeneration (dihydropteridine reductase, DHPR; and pterin carbinolamine-4a-dehydratase, PCD). Tetrahydrobiopterin (BH 4) is known to be the natural cofactor for PAH, tyrosine-3-hydroxylase, and tryptophan-5-hydroxylase. The latter two are key enzymes in the biosynth-esis of the neurotransmitters, dopamine and serotonin. Thus, any cofactor defect will result in a deficiency of biogenic amines accompanied by hyper-phenylalaninemia. Similarly, because phenylalanine is a competitive inhibi-tor of both tyrosine and tryptophan hydroxylases, depletion of catechola-mines and serotonin occurs in untreated patients with PAH deficiency. Both groups of hyperphenylalaninemias (PAH and BH 4 deficient) are heterogeneous disorders varying from severe, e.g., classical phenylketonuria (PKU), to mild, benign, and transient forms. Because of the different clinical and biochemical severities in this group of diseases, the terms ''severe " or ''mild " will be used based upon the need to treat or not treat patients. For the pterin defects, symptoms may manifest during the first weeks of life but usually are noted at about 4 months of age. Birth is generally uneventful , except for an increased incidence of prematurity and lower birth weights in severe PTPS deficiency. Two disorders of BH 4 metabolism may present without hyperphenylala-ninemia. These are Dopa-responsive dystonia (DRD; Segawa disease) and sepiapterin reductase (SR) deficiency. While DRD is caused by a mutation in the GTPCH gene and is inherited in an autosomal dominant manner, SR deficiency is an autosomal recessive trait. Both diseases evidence severe biogenic amines deficiencies. DRD usually presents with a dystonic gait and diurnal variation. At least two reports describe heteroallelic patients with DRD suggesting a wide spectrum of GTPCH variants. The simplicity and reliability of the ''Guthrie " test made it the basis for newborn screening programs around the world. Today, the Guthrie screen