Phenylketonuria (PKU, PAH gene): newborn screening, diet and inheritance

Protein in food is broken down into amino acids, which are then processed by enzymes. In PKU, the enzyme phenylalanine hydroxylase is missing or works poorly, so the amino acid phenylalanine builds up in the blood and brain. NHS England describes PKU as a rare but treatable inherited metabolic disorder that prevents the normal breakdown of protein, and explains that harmful levels of phenylalanine can build up in the brain and blood.

The consequences depend on whether it is treated. NHS England says untreated PKU can lead to long-term problems, including severe learning difficulties and behavioural problems, but that with newborn screening and early treatment this can be prevented. MedlinePlus Genetics adds that babies with classic PKU appear normal until a few months old, and that less severe forms such as variant PKU and non-PKU hyperphenylalaninaemia carry a smaller risk of brain damage, with very mild cases sometimes not needing treatment.

PAH holds the instructions for the enzyme. MedlinePlus Genetics explains that variants allowing the enzyme to keep some activity give milder forms, while very low or absent activity gives classic PKU, and that other genes may influence severity but little is known about them. A person has two copies of PAH, and PKU only develops when both carry a harmful variant.

Because the condition is recessive, the parents of an affected child are each carriers who typically have no signs. NHS England says that children of the same parents have a 1 in 4 chance of having the condition, and that other children in the family might be at risk even if they have never shown symptoms, so the metabolic team will discuss whether testing is necessary.

The NHS says the newborn blood spot test is recommended for all babies and normally done at 5 days old, and it checks for 10 rare conditions, PKU among them. Parents are given information in pregnancy and again after birth, and should tell their midwife or doctor early if anyone in the family has one of the conditions. Results should arrive by the time the baby is 6 weeks old, or sooner, depending on what is found.

NHS England explains what happens after a screen-positive result: a metabolic doctor, dietitian and specialist nurse see the family, blood tests confirm the diagnosis over a few days, and in the meantime the baby can continue breastfeeding or normal infant formula. If PKU is confirmed, the team starts a restricted-protein feeding plan and teaches parents how to take home blood tests that are posted to the laboratory.

NHS England describes the feeding plan for babies: a limited daily volume of breast milk or infant formula combined with a phenylalanine-free infant formula that supplies the rest of the nutrition. Phenylalanine levels are checked weekly during the first year, and the metabolic dietitian adjusts the amounts according to results and weight. The GP is asked to prescribe the phenylalanine-free formula, and the team sees the family regularly throughout childhood.

MedlinePlus Genetics, the US source used for the wider diet picture, says PKU diets avoid foods high in protein such as meat, dairy, nuts and tofu, that the safe amount of phenylalanine differs for each person, and that the artificial sweetener aspartame contains phenylalanine and should be avoided. In the UK, individual targets are set by the metabolic team.

NHS England signposts Metabolic Support UK and the National Society for Phenylketonuria (NSPKU) for information and support, and the British Inherited Metabolic Diseases Group website for a booklet about PKU.

NHS England advises that when parents of a child with PKU find out they are pregnant again, they should tell their midwife and GP about the family history of PKU and inform the metabolic team early. The team writes a birth plan, including an early screening test for the new baby between 48 and 72 hours after birth, in addition to the routine blood spot test.

For adults, MedlinePlus Genetics notes that babies born to mothers with PKU who are not following a low-phenylalanine diet have a significant risk of intellectual disability and other problems because of exposure to very high levels before birth, and that women with PKU not following the diet also have a higher risk of pregnancy loss. Women with PKU can ask their metabolic team about planning a pregnancy.