Phenylketonuria: translating research into novel therapies

Abstract

Phenylketonuria (PKU) is an inborn error of metabolism of the amino acid phenylalanine. It is an autosomal recessive disorder with a rate of incidence of 1 in 10,000 in Caucasian populations. Mutations in the phenylalanine hydroxylase (PAH) gene are the major cause of PKU, due to the loss of the catalytic activity of the enzyme product PAH. Newborn screening for PKU allows early intervention, avoiding irreparable neurological damage and intellectual disability that would arise from untreated PKU. The current primary treatment of PKU is the limitation of dietary protein intake, which in the long term may be associated with poor compliance in some cases and other health problems due to malnutrition. The only alternative therapy currently approved is the supplementation of BH4, the requisite co-factor of PAH, in the orally-available form of sapropterin dihydrochloride. This treatment is not universally available, and is only effective for a proportion (estimated 30%) of PKU patients. Research into novel therapies for PKU has taken many different approaches to address the lack of PAH activity at the core of this disorder: enzyme replacement via virus-mediated gene transfer, transplantation of donor liver and recombinant PAH protein, enzyme substitution using phenylalanine ammonia lyase (PAL) to provide an alternative pathway for the metabolism of phenylalanine, and restoration of native PAH activity using chemical chaperones and nonsense read-through agents. It is hoped that continuing efforts into these studies will translate into a significant improvement in the physical outcome, as well as quality of life, for patients with PKU.

Keywords: Phenylalanine hydroxylase (PAH); diet; mutation; phenotype-genotype correlation; phenylketonuria (PKU); therapy.

Figure 1

(A) Structure of the human PAH gene. The horizontal line represents the full length of the PAH gene, spanning 79.3 kb. Each vertical bar represents an exon. The location of the start codon ATG in exon 1 is indicated (+1); (B) Schematic representation of PAH mRNA. The vertical lines mark the boundaries between exons. The three functional domain of PAH are coloured purple for the regulatory domain, light green for the catalytic domain and orange for the tetramerisation domain. UTR, untranslated regions; PAH, phenylalanine hydroxylase.

Figure 2

Metabolic pathway of l-Phe. The primary pathway (blue box) is the catalytic conversion of l-phe to l-Tyr by phenylalanine hydroxylase (PAH). In phenylketonuria (PKU), the deficiency of PAH enzyme leads to the production of phenylketones by an alternative pathway (red box). A third pathway (green box) can be found in plants and yeast involving the enzyme phenylalanine ammonia lyase (PAL).