PHENYLKETONURIA (PKU)
Hyperphenylalaninemia (OMIM database No. 261600),150 an abnormal increase
in the concentration of the amino acid phenylalanine (Phe) in the blood, may be a
benign condition with little clinical significance. When the concentration of Phe is
very high (>20 mg/dL or 1210 µmol/L) and there is accumulation of
phenylketones, the condition is called classic phenylketonuria (PKU).
Incidence
Despite the fact that newborn screening has been underway for more than 40
years in the United States, data only allow estimates of the incidence and
prevalence of this disorder. This is partly because of the fact that states vary in
their definitions of hyperphenylalaninemia and PKU. For PKU, the reported
incidence ranges from 1 in 19000 to 1 in 13500 newborn infants. For non-PKU
hyperphenylalaninemia, the estimated incidence is 1 in 48000 newborn infants.
There are large variations in the incidence of PKU by ethnic and cultural groups,
with individuals of Northern European ancestry and American Indian/Alaska
Native individuals having a higher incidence than black, Hispanic, and Asian
individuals.151
Clinical Manifestations
PKU is rarely diagnosed before 6 months of age without newborn screening,
because the most common manifestation without treatment is developmental
delay followed by mental retardation. Untreated individuals may also develop
microcephaly, delayed or absent speech, seizures, eczema, and behavioral
abnormalities.
Pathophysiology
PKU results from a deficiency of activity of a liver enzyme, phenylalanine
hydroxylase (PAH), leading to increased concentrations of Phe in the blood and
other tissues. Certain mutations of the PAH gene usually result in non-PKU
hyperphenylalaninemia, and others result in classic PKU. Because siblings with
the same mutation at the PAH locus may have different clinical findings, it is likely
that other genetic and environmental factors influence the severity of the
disorder.152 In fact, a few individuals with PKU have no evidence of mental
retardation, even without dietary treatment.151 However, there is evidence that
certain genotypes are associated with higher increases of Phe concentration.153 It
is likely that Phe itself leads to the mental retardation and other findings of PKU.
In excess, Phe disturbs transport of other amino acids across the blood-brain
barrier and impairs synthesis of neurotransmitters.151 For the enzyme PAH to be
active, the cofactor tetrahydrobiopterin (BH4) is required. Impaired synthesis or
recycling of BH4 results in increased concentrations of Phe and certain other
amino acids. This condition does not respond to routine dietary management of
PKU, and hence, states have instituted additional screening programs to identify
infants with these rare disorders so that appropriate treatment can be initiated.
