Phenylketonuria (PKU)

With an annual disease rate of 1:7000, phenylketonuria is classified as the most common autosomal recessive hereditary disorder of the amino acid metabolism in Germany. A lack of activity of the hepatic phenylalanine hydroxylase (PAH) leads to an increased concentration of phenylalanine in the blood and in the tissues. Today, phenylketonuria can be diagnosed in the first few days of life by screening newborns. Patients who have been diagnosed in time and who are consistently treated have normal mental and physical development. Patients who are not or insufficiently treated develop severe brain damage with mental and neurological disabilities in the first few years of life due to the effects of phenylalanine and its metabolites. Those patients born before the era of newborn screening (before 1968 in Germany) generally have a significant disability.

The basis of the therapy consists of a low-protein diet. This means the intake of a stringent reduced-protein diet with the additional use of reduced-protein basic foods (e.g. reduced-protein cereal products and pasta/flour products). A phenylalanine-free amino acid mixture is additionally administered as a supplement to cover the protein requirement. The amino acid mixtures administered to PKU patients are supplemented with additional vitamins and trace elements to prevent deficiency states with long-term administration of a low-protein diet. The therapy is started immediately after diagnosis and must usually be continued for life.

The intensity of the therapy depends on the phenylalanine level in the plasma, which must be checked regularly in the affected patients. In childhood, phenylalanine in plasma should be between 2-6 mg / dl (120-360 µmol / l). After the age of 12, the diet can be gradually relaxed while monitoring the phenylalanine level. According to the current research study situation, there are no consistent recommendations for phenylalanine levels in adults. In the German Metabolic Centres of Expertise, a phenylalanine level in the blood between 15-20 mg / dl (900-1,200 µmol / l) is aimed for in patients with phenylketonuria. Most patients will need to be on a reduced protein diet for life to achieve this goal. As a rule, the daily amount of the administered natural protein amounts to 10-12 g / day. Patients treated in this way must continue to take a phenylalanine-free amino acid mixture to prevent deficiency symptoms.

Neurologically healthy adult patients with a primarily adequately treated PKU that exceed the recommended target range can develop acute neurological symptoms (e.g. gait disorders, paralysis) or neuropsychological symptoms (abnormal behavior such as aggressive behavior, depression). The symptoms are usually reversible, provided they are detected in time and the patient is given a consistent diet again.

Therapy with tetrahydrobiopterin (Kuvan) has been approved in Germany several years ago. However, this cofactor of phenylalanine hydroxylase does not replace the low-protein diet. In some selected cases, it can be a therapeutic option to increase the protein tolerance. Approval is currently expected for a new enzyme therapy (Pegvaliase).

Elevated blood levels in neurologically healthy women with PKU during pregnancy (maternal PKU) can cause a malformation syndrome in the unborn child. The affected newborns of mothers with PKU often have deformities of the skull, face, heart and blood vessels as well as a mental disability (so-called maternal PKU syndrome). Maternal PKU syndrome can be avoided by strictly fine-tuning the mother’s metabolism, which should ideally be achieved 3 months prior to the start of pregnancy and should be in the range of 2-6 mg / dl (120-360 µmol / l) by birth. For the expectant mother, this means strict adherence to an extremely low-protein diet (usually 3-4 g of natural protein / day in the first months of pregnancy). In addition, a phenylalanine-free synthetic amino acid mixture is administered, which is adapted to the specific needs of the pregnant woman in terms of protein content, vitamins, trace elements and minerals. The metabolic fine-tuning is closely monitored during the whole pregnancy (2 laboratory tests / week) and the therapy is constantly adapted to the current metabolic state and the changing needs in the diet during the course of the pregnancy. If the fine-tuning of the metabolism is consistently good, the children of mothers with PKU have no increased risk of disability today.


Mahan KC, Gandhi MA, Anand S. Pegvaliase: A novel treatment option for adults with phenylketonuria. Curr Med Res Opin. 2019; 35:647-651.

The complete European guidelines on phenylketonuria: diagnosis and treatment.Orphanet J Rare Dis.2017;162: 13023-017-0685-2.

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