Phenylketonuria (PKU) is an autosomal recessive inherited disorder. It is monogenetic and the connected gene (PAH) is located at the chromosome 12, which encodes for the hepatic enzyme phenylalanine hydroxylase(PAH). People who suffer from this disorder have a strongly decreased activity of this enzyme and therefore suffer from the toxic effects of the accumulated phenylalanine(Phe) which leads mostly to mental retardation but also to certain other symptoms. Due to the ongoing development for treatment and adhering to dietary restrictions the patients can avoid most effects of the disease.
In 1934 this disorder was first found, but only in the concurrence of hyperphenylalaninemia (HPA) and mental retardation, by Ivar Asbjørn Følling, a Norwegian physicist. Because of this fact in Norway PKU is called Følling's disease. Dr. Følling also found that the patients not only have increased Phenylalaninelevels but their urine contains phenylpyruvic acid, which is diagnostic.
Most of the Symptoms have their cause in the competitive inhibition of the large neutral amino acid transporter (LNAAT), which is responsible for the transport of large neutral amino acids like Phenylalanine through the Blood-brain-barrier. This LNAAT is saturated by the high concentration of Phe and therefore can not transport any other essential amino acids into the brain. Those missing amino acids are crucial for the neurotransmitter and protein/hormone synthesis. As of this most of the symptoms occurring with PKU are connected with the brain development.
If the disease is recognised and treated within the first days of a newborn, before toxic amounts of phenylalanine can build, patients can avoid the symptoms of PKU. Newborn screenings generally carried out between day 2 and day 5 include a test for PKU. The most simple test is a bacterial inhibition assay (Guthrie test) that uses Bacillus subtilis, a bacteria that needs phenylalanine to grow. More reliable tests employ mass spectrometry, checking not only the level of Phe but also the tyrosine/phenylalanine ratio.
To differentiate patients with high Phe levels due to PKU from patients with BH4 deficiency, a cofactor of PAH, a 'BH4 loading test' can be performed. This also detects the subgroup of PKU patients that can be treated with BH4, since the cofactor also has some chaperone activity.
The most effective way to treat the symptoms of PKU is to avoid food rich in phenylalanine. This requires a strict diet excluding all animal protein, dairy products and many vegetable food and including medical food, especially milk powder for newborns low in Phe.
10-60 % of the patients respond to treatment with tetrahydrobiopterin (BH4), the cofactor of PAH, or a synthetic alternative. This cofactor possesses chaperone activity and apparently can restore PAH function for certain mutations.
Treatments in development are enzyme substitution therapy and gene therapy. The enzyme phenylalanine ammonia lyase (PAL) catalyses Phe to ammonia and non-toxic trans-cinnamic acid. In mice it lowered the Phe level safely and persistently and is in clinical trials for humans since 2009. Gene therapy so far has managed to temporarily restore PAH activity for up to a year. Since a viral vector containing a functional PAH-gene could be injected in the liver but was not integrated in the genome, effects vanished when the liver regenerated. Reinjection lead to an immune response to the viral vector.
PAH in external databases
The protein sequence of functional human phenylalanine hydroxylase: P00439 at Uniprot)
The gene sequence of functional human phenylalanine hydroxylase: PAH at NCBI
The protein and ligand structure: 1DMW in PDB
N. Blau, J. Hennermann, U. Langenbeck, U. Lichter-Konecki, Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies; Molecular Genetics and Metabolism 104 (2011) S2-S9