Phenylketonuria disease (PKU) occurs when a genetic mutation in the phenylalanine hydroxylase (PAH) gene drastically reduces the ability to metabolize animal proteins found in food. PKU is one of the most common inherited diseases occurring approximately one in every 12,000 live births in the US. The consequence of PAH mutation is an excess of phenylalanine (one of the essential amino acids we only get from food) and a drastic shortage of the amino acid tyrosine that is used both to make protein and necessary neurotransmitter compounds such as L-DOPA and adrenaline. It is not enough to simply reduce phenylalanine levels in the diet, although this is a strategy for treating PKU. It is also necessary to repair the defect in phenylalanine metabolism to restore tyrosine levels and support neurotransmitter production.
All children in the US are screened at birth for PKU to avoid stunted growth and impaired brain development. The most common treatment is a synthetic diet that reduces phenylalanine intake. Even with reduced dietary phenylalanine, the shortage of tyrosine increases risk for Parkinson’s disease, depression, anxiety, schizophrenia, and suicide.
Efforts to treat PKU in adults are proceeding in collaboration with the University of Pittsburgh Medical Center. Together we anticipate testing genetic medicines in humans in 2018 that may be used to treat or cure this life-threatening disease.