Aetiology
Phenylketonuria (PKU) is caused by a mutation in each copy of the gene for phenylalanine hydroxylase (PAH) on chromosome 12. Both parents are carriers of a mutant gene, which in a single copy has no clinical consequences. More than 500 different mutations in the PAH locus have been described.[7]
Pathophysiology
Mutations in the gene for PAH result in either failure to produce a PAH enzyme or production of an enzyme with decreased catalytic activity. This leads to an elevation of the blood phenylalanine (phe) level and to increased transport of phe into the brain. Phe toxicity is thought to be a direct cause of neurotoxicity in PKU. Neurotransmitter deficiency and decreased protein synthesis in the brain may be other mechanisms of neurotoxicity, related to decreased tyrosine and competition at the blood brain barrier.[8] Chronic elevations of blood phe in infancy and early childhood, beyond a certain threshold, result in abnormal myelination, small brain size, seizures, and diminished IQ. The magnitude of these adverse effects is related to the extent and duration of blood phe elevation, which is a function of the severity of the enzymatic defect and the extent of metabolic control in a treated patient. Inhibition of the enzyme tyrosinase by elevated phe levels leads to decreased melanin synthesis in an untreated patient, resulting in hypo-pigmentation. An acute rise in blood phe in a treated patient with PKU later in life may result in measurable cognitive and behavioural abnormalities as well as MRI abnormalities that may be reversible with control of the blood phe level.[9] If the elevated blood phe persists for a longer duration, irreversible chronic toxicity may occur and manifest with neuropsychiatric symptoms such as anxiety, depression, phobias, and attentional disorders.[10] In particular, there is a negative impact on executive functioning which can lead to reduced educational achievement, lower socioeconomical status, and an increased risk of lower quality of life.[9]
Classification
National Institutes of Health consensus development statement[1]
Classical PKU
Non-PKU hyper-phenylalaninaemia
Informal classification in US common practice
Although there is uniform agreement on the definition of classical PKU, many terms are used in clinical practice to describe patients with lesser elevations of blood phe.
Classical PKU
Non-PKU hyper-phenylalaninaemia:
Mild-to-moderate or non-classical PKU
Benign hyper-phenylalaninaemia
Patients who have hyper-phenylalaninaemia resulting from rare defects in tetrahydrobiopterin synthesis or recycling are excluded from this classification.
European classification[2]
Classical PKU
Moderate PKU
Mild PKU
Mild hyperphenylalaninemia
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