Genetic Disorders - Phenylketonuria

Updated on May 7, 2016


Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine (Phe) metabolism resulting from deficiency of phenylalanine hydroxylase (PAH). Most forms of PKU and hyperphenylalaninaemia (HPA) are caused by mutations in the PAH gene on chromosome 12q23.2. Untreated PKU is associated with an abnormal phenotype which includes growth failure, poor skin pigmentation, microcephaly, seizures, global developmental delay and severe intellectual impairment.

Process for Diagnosis

All newborns can be screened for the disorder, with blood tests to determine their phenylalanine serum levels in their plasma, urine, and cerebrospinal fluid. If the levels are greater than 1200 μmol/L then they are diagnosed with classic PKU, and if the levels are between 600 and 1200 μmol/L then it is classified as mild.

Genes Affected and Chromosomal Locus

Most cases of PKU are due to homozygous, or compound heterozygous, mutations on the phenylalanine hydroxylase (PAH) gene which spans 90kb on chromosome 12q23.2 and contains 13 exons. A rarer form of hyperphenylalaninemia occurs when the PAH enzyme is normal, and a defect is found in the biosynthesis, or recycling, of the cofactor tetrahydrobiopterin (BH4). Mutations in the genes GCH1, PCBD1, PTS and QDPR can cause BH4 deficiency.

Metabolic Pathways Disrupted

Phenylalanine hydroxylase (PAH) is necessary to metabolize the amino acid phenylalanine to tyrosine. When PAH activity is reduced, phenylalanine accumulates and is converted into phenylpyruvate, via the minor route of phenylalanine degradation, a transaminase pathway with glutamate. Sufferers therefore have a build-up of the toxic metabolite phenylpyruvate (as well as phenylacetate and phenylethylamine), which can be detected in urine, and a tyrosine deficiency.

Inheritance Pattern and Frequency

The condition is autosomal recessive, with both parents having one copy of the mutated gene but not displaying the symptoms themselves. The frequency is thought to be 1/10000 Caucasian and 1/90000 Africans.

Affect of Mutation on RNA Product

Most PAH missense mutations impair enzyme activity by causing increased protein instability, misfolding and loss of enzymatic function.

Effect of Mutation on Cellular Function and Phenotype

Impaired cognitive development and function is the main phenotypic trait of PKU, this is due to the accumulation of phenylalanine in the brain, which becomes a major donor of amino groups in aminotransferase activity and depletes neural tissue of α-ketoglutarate and subsequently shuts down the TCA cycle. Another theory is that the reduction in brain tyrosine levels would negatively impact the synthesis of the neurotransmitters, dopamine and norepinephrine, thus causing mental retardation.


There is no cure for PKU but treatments include a diet low in phenylalanine and aspartame (as this can be broken down to phenylalanine).


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