ABSTRACT
The existence of variant forms of hyperphenylalaninemia (HPA) resulting from abnormalities of cofactor synthesis was predicted with the discovery of biopterin and its role in the phenylalanine hydroxylase reaction. Tetrahydrobiopterin (BH4) is an essential cofactor not only for phenylalanine hydroxylase, but also for tyrosine and tryptophan hydroxylases, nitric oxide synthases, and glyceryl-ether monooxygenase. Phenylalanine hydroxylase requires BH4 for activity in the hydroxylation to tyrosine. Patients with recessively inherited defective metabolism of BH4 usually have HPA. The disorders are usually diagnosed on the basis of clinical suspicion with an excellent response to levodopa and/or an oral phenylalanine load or low levels of the neurotransmitter homovanillic acid and reduced levels of neopterin and BH4 in the cerebrospinal fluid. The outcome in BH4-deficient patients is highly variable and correlates with the patient's age at start of treatment. Pterin-4a-carbinolamine dehydratase deficiency occurs in about 4 percent of patients with defective BH4 metabolism.
