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Classification and external resources
ICD-10 E70.1 (also includes non-classic PKU)
ICD-9 270.1 (PKU)
OMIM 261600 261630

Hyperphenylalaninemia is a medical condition characterized by mildly or strongly elevated levels of the amino acid phenylalanine in the blood. Severe hyperphenylalaninemia results in phenylketonuria (PKU)[1]. Phenylalanine concentrations ([phe]) are routinely screened in newborns by the Guthrie test, which takes a few drops of blood from the heel of the infant. Standard [phe] concentrations in unaffected persons are ~60 uM: [phe] concentrations in persons with untreated phenylketonuria may be times 600 ~ 2400 uM, which indicate that the child is at risk for severe mental retardation. Phenylketonuria is classed as an autosomal recessive condition: in heterozygotes from, [phe] shows a moderate elevation, perhaps two-fold over unaffected homozygotes, which is classified as Hyperphenylalaninemia [hyper + phenylalanine + emia = high phe in blood].

Persons with the genotype for PKU are unaffected in utero because maternal circulation prevents buildup of [phe]. After birth, PKU in newborns is treated by a special diet with highly restricted phenylalanine content. Persons with genetic predisposition to PKU have normal mental development on this diet. Previously, it was thought safe to withdraw from the diet in the late teens or early twenties, after the central nervous system was fully developed; recent studies suggest some degree of relapse and a phenylalanine-restricted diet is now recommended.

PKU or Hyperphenylalaninemia may also occur in persons without the PKU genotype. If the mother has the PKU genotype but has been treated so as to be asymptomatic, high levels of [phe] in the maternal blood circulation may affect the non-PKU fetus during gestation. Mothers successfully treated for PKU are advised to return to the [phe]-restricted diet during pregnancy.

A small subset of patients with hyperphenylalaninemia shows an appropriate reduction in plasma phenylalanine levels with dietary restriction of this amino acid; however, these patients still develop progressive neurologic symptoms and seizures and usually die within the first 2 years of life ("malignant" hyperphenylalaninemia). These infants exhibit normal phenylalanine hydroxylase (PAH) activity but have a deficiency in dihydropteridine reductase (DHPR), an enzyme required for the regeneration of tetrahydrobiopterin (THB), a cofactor of PAH.

Less frequently, DHPR activity is normal but a defect in the biosyntheses of THB exists. In either case, dietary therapy corrects the hyperphenylalaninemia. However, THB is also a cofactor for two other hydroxylations required in the syntheses of neurotransmitters in the brain: the hydroxylation of tryptophan to 5-hydroxytryptophan and of tyrosine to L-dopa. It has been suggested that the resulting deficit in the CNS neurotransmitter activity is, at least in part, responsible for the neurologic manifestations and eventual death of these patients. [1]


  1. ^ "Basic Medical Biochemistry", Fourth edition