Phenylketonuria

Phenylketonuria (PKU), also known as phenylalanine hydroxylase deficiency, is the most common inborn error of amino acid metabolism and the first specific cause of mental retardation to be discovered.

PKU is caused by pathogenic variants in the PAH gene, which encodes phenylalanine hydroxylase. This enzyme catalyzes the transformation of the amino acid phenylalanine into tyrosine. The clinical manifestations of the pathology are the result of the toxic accumulation of phenylalanine in the blood and brain.

The prevalence of PKU is 1 case in 10,000 live births in Europe, with a higher rate in countries such as Ireland and Italy. The prevalence is particularly high in Turkey, where 1 in 4,000 births have PKU. The disorder is usually diagnosed through neonatal screening programs.

If not detected and treated immediately, symptoms usually appear during the first months of life, and can range from very mild to severe. These include gradual developmental and growth retardation, microcephaly, seizures, tremors, eczema and vomiting. Untreated patients develop intellectual disability, behavioral disorders (hyperactivity) and motor disorders.

The basis of the treatment, which has been used for about 60 years, is a lifelong diet in which phenylalanine is restricted. In this diet, natural sources of protein are replaced by medical foods, free of phenylalanine, which provide a mixture of amino acids. However, although this treatment is well established, the results are still suboptimal and some patients find it difficult to follow.

On the other hand, there are pharmacological treatments, such as tetrahydrobiopterin (BH4), which is effective in only a few patients (especially those with mild PKU), and pegylated phenylalanine ammonia lyase, which requires daily injections and can cause adverse immune reactions.