Question

If an infant is found to have hyperphenylalaninemia based on a newborn screen, but this defect doesn't respond to a low phenylalanine diet, what type of molecular defect would be suspected?

A Null mutation for phenylalanine hydroxylase
B Dominant negative mutation for phenylalanine hydroxylase
C A defect in tetrahydrobiopterin (BH4) metabolism
D A mutation in tyrosine hydroxylase
E A mutation in tryptophan hydroxylase

Answer 1

When an infant's hyperphenylalaninemia does not respond to a low phenylalanine diet, it is likely due to a defect in tetrahydrobiopterin (BH4) metabolism. BH4 is a cofactor for the phenylalanine hydroxylase enzyme, which is responsible for converting phenylalanine into tyrosine.

Step-by-step explanation:

If an infant is found to have hyperphenylalaninemia based on a newborn screen, but the defect doesn't respond to a low phenylalanine diet, a defect in tetrahydrobiopterin (BH4) metabolism would be suspected. Tetrahydrobiopterin is a cofactor necessary for the function of phenylalanine hydroxylase (PAH), the enzyme that converts phenylalanine to tyrosine. In cases of PKU where a low phenylalanine diet is ineffective, it often suggests that there is an issue beyond the PAH enzyme itself, which implicates the BH4 metabolism pathway. In contrast, a null mutation for PAH would typically lead to classic PKU, which does respond to dietary modifications, while dominant negative mutations, mutations in tyrosine hydroxylase, or tryptophan hydroxylase would not primarily result in hyperphenylalaninemia.