A 3-month-old infant experienced several severe seizures and was brought to the doctor for testing. The test results showed hyperphenylalaninemia and the doctor diagnosed PKU as the likely disease causing the seizures. The infant was placed on a low-phenylalanine diet but developed progressive neurological symptoms and died 6 months later. A defect in which of the following enzymes would best explain the observations and outcomes in this case

Question

Quizplus · Accepted Answer

The infant's symptoms and progression despite a low-phenylalanine diet suggest a defect in dihydropteridine reductase, which is necessary for the regeneration of tetrahydrobiopterin (BH4), a cofactor for phenylalanine hydroxylase and other hydroxylases. This leads to hyperphenylalaninemia and neurotransmitter deficiencies, causing neurological symptoms. The pathway for conversion of phenylalanine (F) to tyrosine (Y), catalyzed by phenylalanine hydroxylase (PAH), is shown in Figure 30-13. The conversion of F to Y is not only necessary for Y biogenesis but is also the first step in the catabolism of F. Classic PKU manifests with hyperphenylalaninemia, excretion of metabolites of transaminated pheylalanine (phenylpyruvate, phenylacetate, and phenyllactate), and severe mental retardation. PKU is the result of defects in PAH. However, as shown in Figure 30-13, PAH requires tetrahydrobiopterin (BH₄) as a cofactor, which is converted to dihydrobiopterin (BH₂) during the PAH reaction. Conversion of BH₄ back to BH₄ requires an additional enzyme, dihydropteridine reductase (DHPR). Defects in DHPR will result in reduced activity of any enzyme requiring BH₄ as a cofactor. Thus, defective DHPR will result in defective phenylalanine metabolism and lead to hyperphenylalaninemia with similar but distinct consequences to PKU. One distinction is that patients with DHPR defects do not respond to dietary restrictions in phenylalanine as effectively as do classic PKU patients.

A 3-Month-Old Infant Experienced Several Severe Seizures and Was Brought