Phenylketonuria: A Summary of Existing and Prospective Treatments

Abstract

Phenylketonuria  (PKU)  is  an  autosomal  recessive  genetic  disorder  characterised  by  the  inability  to break  down  the  amino  acid  phenylalanine  (Phe),  resulting  in  toxically  elevated  levels  of  Phe  in  the body that may cause serious mental and physical disability. There are two main types of PKU, typical where  Phenylalanine  Hydroxylase  (PAH)  is  defective  and  atypical  where a  defect  is  found  in  the biosynthesis or recycling of tetrahydrobiopterin (BH₄), a cofactor for PAH.  In 1954 it was established that  the  key  to  treating  PKU  was  a  diet  low  in  Phe  starting  from  birth. Since  then  dietary  restriction and  medical  substitutes  for  foods  have  been  the  most  accessible  treatment  options. However compliance  with  this  treatment  is  suboptimal,  resulting  in  impairments  and  lower  quality  of  life.  In the  last  couple  of  years  new  therapies  have  been  developed  which  include  supplementation  with compounds  preventing  Phe  entry  into  the  brain  or  allowing  its  breakdown:  (enzyme  Phe-ammonia lyase), saproprotein, large neutral chain amino acid supplementation, genetically modified probiotics for the delivery of PAH, glycomacropeptide foods and gene therapy. The purpose of this review is to examine  prospective  PKU  treatments  and  their  necessity  in improving  the  quality  of  life  of  affected individuals.