Phenylketonuria: a review of current and future treatments

Abstract

Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism caused by a deficiency in the hepatic enzyme phenylalanine hydroxylase (PAH). If left untreated, the main clinical feature is intellectual disability. Treatment, which includes a low Phe diet supplemented with amino acid formulas, commences soon after diagnosis within the first weeks of life. Although dietary treatment has been successful in preventing intellectual disability in early treated PKU patients, there are major issues with dietary compliance due to palatability of the diet. Other potential issues associated with dietary therapy include nutritional deficiencies especially vitamin D and B12. Suboptimal outcomes in cognitive and executive functioning have been reported in patients who adhere poorly to dietary therapy. There have been continuous attempts at improving the quality of medical foods including their palatability. Advances in dietary therapy such as the use of large neutral amino acids (LNAA) and glycomacropeptides (GMP; found within the whey fraction of bovine milk) have been explored. Gene therapy and enzyme replacement or substitution therapy have yielded more promising data in the recent years. In this review the current and possible future treatments for PKU are discussed.

Keywords: Phenylketonuria (PKU); dietary therapy; glycomacropeptides (GMP); large neutral amino acids (LNAA); phenylalanine ammonia lyase; phenylalanine hydroxylase (PAH); probiotic; tetrahydrobiopterin.

Figure 1

Metabolic pathway of phenylalanine (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 (adopted from Ho G 2014) (2).