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Almost always, PKU is due to deficiency of phenylalanine hydroxylase.
Rarely, it can also be due to deficiency of tetrahydrobiopterin (THB). This type is called malignant PKU.
| Deficiency of phenylalanine hydroxylase = classic phenylketonuria
Deficiency of tetrahydrobiopterin = malignant phenylketonuria |
Notice that THB is a cofactor for both phenylalanine hydroxylase and tyrosine hydroxylase. In PKU, whether classic or malignant, the treatment is ↓ phenylalanine and ↑ tyrosine in diet.
The difference is that in malignant PKU, once tyrosine is given as Tx, it cannot be converted efficiently to L-Dopa (and further to dopamine).
Therefore:
| In malignant PKU, galactorrhea (hyperprolactinemia) can result from ↓ dopamine secondary to ↓ L-Dopa. In classic PKU, there is no hyperprolactinemia because tyrosine can still be converted to L-Dopa. |
In both forms of PKU, there is mental impairment if phenylalanine is not removed from the diet. Aspartame, an artificial sweetener found in many diet beverages, contains phenylalanine and must be avoided in PKU patients.
| Eczema, fair skin and “musty” or “mousy” body odor are common USMLE findings. |
One other important point about PKU is its relation to pregnancy. Let’s say the fetus does not have PKU, but the mom does. If the mom does not strictly watch her diet while pregnant, small elevations in blood phenylalanine can cause mental impairment and signs of PKU in the fetus. This is because lack of maternal enzyme can lead to increased phenylalanine crossing the placenta to the fetus. This is called maternal PKU.
In contrast, let’s say the fetus actually does have PKU but the mom is a mere carrier (i.e., does not have PKU). A normal maternal diet (i.e., no restriction of phenylalanine) will not lead to symptoms of PKU in the fetus because the mother still has sufficient enzyme to metabolize the phenylalanine.
| PKU is screened for in newborns via a heel-prick test because it is a preventable cause of mental retardation. This PKU screening test (and screening tests in general) must be very sensitive because a false (-) result could have devastating consequences. |
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