Clinical Information

Phenylketonuria (PKU) is the most frequent inherited disorder of amino acid metabolism (occurring in about 1:10,000-1:15,000 births) and was the first successfully treated inborn error of metabolism. It is inherited in an autosomal recessive manner and is caused by a defect in the enzyme phenylalanine hydroxylase (PAH), which converts the essential amino acid phenylalanine to tyrosine. Deficiency of PAH results in decreased levels of tyrosine and an accumulation of phenylalanine in blood and tissues. Untreated PKU leads to severe brain damage with intellectual impairment, behavior abnormalities, seizures, and spasticity. The level of enzyme activity differentiates classic PKU (PAH activity <1%) from other milder forms; however, all are characterized by increased levels of phenylalanine (hyperphenylalaninemia). Treatment includes the early introduction of a diet low in phenylalanine. Some patients may also benefit from adjuvant tetrahydrobiopterin (BH4) supplementation (a cofactor for PAH) or enzyme substitution therapy.

BH4 is a cofactor of not only PAH but also of the tyrosine and tryptophan hydroxylases. Approximately 2% of patients with hyperphenylalaninemia have a deficiency of BH4, which causes a secondary deficit of the neurotransmitters dopamine and serotonin. There are 4 autosomal-recessive disorders associated with BH4 deficiency plus hyperphenylalaninemia; guanosine triphosphate cyclohydrolase deficiency, 6-pyruvoyl tetrahydropterin synthase deficiency, dihydropteridine reductase deficiency, and pterin-4 alpha carbinolamine dehydratase (PCD) deficiency. This group of disorders, except for PCD, is characterized by progressive dystonia, truncal hypotonia, extremity hypertonia, seizures, and intellectual disability though milder presentations exist. PCD has no symptoms other than transient alterations in tone. Treatment may include administration of BH4, L-dopa (and carbidopa) 5-hydroxytryptophan supplements, and a low phenylalanine diet.

Tyrosine is a nonessential amino acid that is derived from dietary sources, the hydroxylation of phenylalanine, or protein breakdown. Primary (PKU) and secondary (defects of BH4 metabolism) hyperphenylalaninemia can cause abnormally low levels of tyrosine. Measurement of the phenylalanine:tyrosine ratio is helpful in monitoring appropriate dietary intake.