An overview of traditional and novel therapeutic options for the management of phenylketonuria

Phenylketonuria (PKU) is an autosomal recessive disorder caused by the deficiency of phenylalanine hydroxylase enzyme that catalyzes the conversion of L-phenylalanine to L-tyrosine using tetrahydrobiopterin (BH4) as a cofactor. Among aminoacidopathies, PKU is one of the most prevalent disorders in different populations. It may be caused by deficiency of BH4 or mutations in PAH. About 98% of PKU patients have mutations in the PAH, while the remaining have BH4 deficiency. If PKU is diagnosed earlier in life using advance analytical techniques (e.g., high performance liquid chromatography, mass spectrometry, and polymerase chain reaction), then it is potentially treatable by special diets (L-phenylalanine-free medical formula). However, some complications such as vitamin B ₁₂ deficiency, cardiovascular problems, and neurodevelopmental problems have been reported in PKU patients when they ate special diets for a long period. Hence, special diet alone is not a good option for proper treatment. Next generation therapies require structure-function based development. For therapies which target PAH gene (e.g., gene therapy, RNAi, gene editing), a lot of research has yet to be done. Treatment with BH4 therapy is safe and effective but only in BH4-responsive PKU patients. Therefore, research efforts should be focused on the development of more targeted pharmacological and genetic therapies especially PAH gene therapy, which can reduce the burden or deleterious effects of this disease in affected patients.