Your disease

Short biochemical overview and consequences of enzyme deficiency

Phenylketonuria (PKU) is caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH), which converts phenylalanine to tyrosine. It is the 1st hereditary metabolic disease to be treated with a diet. As a result, it is well known and the benefits of early diet treatment are proven. This is why systematic neonatal screening has been used in France since 1975. PKU has a prevalence of about 1/16,000 births in France.

Tolerance for phenylalanine varies depending on the residual activity of the phenylalanine hydroxylase enzyme.

  • when, with a normal diet, blood phenylalanine levels remain above 20 mg/100 ml (1,200 μmol/l), the disorder is known as “classic” PKU, with zero enzyme activity and tolerance generally around 250 to 300 mg of phenylalanine daily;
  • when blood levels range from 10 to 20 mg/100 ml (600 to 1,200 μmol/l), the disorder is known as “variant” PKU, with low residual enzyme activity that is nevertheless sufficient to increase tolerance (up to 600 to 1,000 mg of phenylalanine daily);
  • when blood levels are lower than 10 mg/100 ml (600 μmol/l), the disorder is called permanent mild hyperphenylalaninemia and a special diet is not generally required. Normal protein intake is recommended.


However, this classification has several limitations because it is based on blood phenylalanine levels with a normal (i.e. phenylalanine-rich) diet.

Thus, a child who is exclusively fed breast milk can be initially managed as having mild hyperphenylalaninemia (levels < 10 mg/100 ml, as maternal milk has a lower phenylalanine content than artificial milk). Once the baby is weaned, his or her phenylalanine blood levels will rise above 10 mg/100 ml, warranting a change in classification to variant PKU.

Furthermore, the enzyme phenylalanine hydroxylase may still be immature at the time of birth, so tolerance for phenylalanine may improve over the first few years of the child’s life.


There are other forms of PKU.

In normal conditions, this enzyme requires a cofactor (see overview), BH4 tetrahydrobiopterin), to function properly.

There are also BH4-sensitive forms of PKU. In these rare cases, use of oral BH4 supplements can enhance the residual enzyme activity, opening up the possibility of drastically broadening the diet (increased tolerance for phenylalanine) and even pre-empting the need for taking the mixture of amino acids.

BH4 sensitivity is mostly seen in variant PKU and is very rare in classic PKU. The patient should therefore be tested for sensitivity to ensure a positive response and potential medicinal treatment. Cases of BH4-sensitive phenylketonuria that meet the standards for treatment will be treated with “medicines”. a commercial form of BH4 has been available in France since 2009 under the name KUVAN. It is reimbursed at 100% by Social Security and has a marketing authorisation (MA) for children over 4 years old. It is not recommended during pregnancy. There is an ongoing debate on the actual benefits of BH4 treatment in those cases where it only enables a slight broadening of the diet.

Finally, there are true BH4 synthesis deficiencies, which manifest in the form of hyperphenylalaninemia at the time of neonatal screening. In this case, it is not “true phenylketonuria” due to a deficit of phenylalanine hydroxylase, but due to a deficit of its cofactor, BH4, which is also a cofactor in other enzyme-mediated reactions. The treatment and subsequent follow-up are different and are not described here.

Imagine the case of a child who follows a hypoproteic diet based on the guiding principles outlined here, which will be explained in detail by your care team. Let us look at several questions you may have when you get back home.

Fig. 7: Simplified diagram of phenylalanine metabolism