What is phenylketonuria?

Phenylketonuria (PKU) is an inherited condition in which the body cannot properly process the amino acid phenylalanine. Phenylalanine is a building block of proteins and is present in nearly all foods that contain protein. In PKU, an enzyme called phenylalanine hydroxylase (PAH) is missing or not working properly, so phenylalanine builds up in the blood and brain. Without treatment, this buildup causes severe intellectual disability and other neurological problems.

Why newborn screening matters so much. PKU is one of the original conditions on newborn screening because the consequences of untreated PKU are severe and lifelong, but if treatment starts in the first weeks of life, normal cognitive development is the expected outcome. Most countries with newborn screening have largely prevented the severe form of PKU that was common before screening was introduced.

The traditional therapy. Lifelong low-phenylalanine diet plus a special medical formula that provides protein in a phenylalanine-free form. The diet is strict and demanding: meat, dairy, fish, eggs, nuts, beans, and standard breads and pastas all need to be avoided or carefully controlled. Specialised low-protein foods are used for daily eating.

The consequences of relaxed diet. For many years, dietary control was sometimes relaxed in adolescence and adulthood under the assumption that the brain was less vulnerable after early childhood. Modern evidence shows that adults with poorly controlled PKU often have neurocognitive consequences (attention, executive function, mood), and lifelong dietary control is now the recommended standard. Adult metabolic clinics specifically support this transition.

The medication options.

Sapropterin: an oral medicine that boosts residual PAH activity in patients whose enzyme has some residual function (BH4-responsive patients). A trial of sapropterin identifies responders. It is used together with dietary therapy and can allow some dietary liberalisation.

Pegvaliase: a different approach. It is an enzyme that breaks down phenylalanine using a different chemical pathway, given as a subcutaneous injection. Pegvaliase is approved for adults whose phenylalanine remains elevated despite other therapy. Starting pegvaliase requires careful dose escalation because it can cause severe allergic reactions in early treatment, but with appropriate management, it can substantially reduce phenylalanine levels and allow a protein-liberalised diet.

The emerging direction. AAV gene therapy delivering a working PAH gene to liver cells is reaching pivotal data. The proposition is a one-time intervention that restores enzyme function and removes the need for dietary restriction. mRNA-based protein replacement programs are in earlier-stage development.

What to expect. With early newborn screening identification, lifelong dietary control, and (where appropriate) sapropterin or pegvaliase, most people with PKU live healthy lives with normal cognitive development. The expanded medication options have particular impact for adults who have struggled with strict dietary control, and the emerging gene therapy programs may further transform the long-term picture.