Advances and challenges in phenylketonuria

Phenylketonuria (PKU; OMIM 262600), one of the most common inborn errors of metabolism, is caused by recessively inherited deficiency of the enzyme phenylalanine hydroxylase (PAH; EC 1.14.16.1) (Blau et al. 2010). PAH catalyses the irreversible hydroxylation of phenylalanine (Phe) to tyrosine. PAH is expressed primarily in the liver but also in the kidney and pancreas, and its activity requires the unconjugated pterin co-factor, tetrahydrobiopterin (BH4). PAH deficiency causes hyperphenylalaninaemia, but hyperphenylalaninaemia can also be caused by inherited deficiency of enzymes involved in BH4 synthesis or recycling (Blau et al. 2010). Chronic, untreated, severe hyperphenylalaninaemia in infants and children leads to seizures and mental retardation. Newborn screening and early initiation of PKU therapy has eliminated the major manifestations of the disease, but shortcomings in our current therapeutic approach remain. Contemporary therapy for PKU is centered upon tight restriction of dietary Phe intake and requires supplementation with special medical foods that supply sufficient essential amino acids and energy from fat and carbohydrate. Institution and maintenance of the PKU diet are difficult, and the required medical foods are often unpalatable. Dietary therapy is recommended for life (Anon 2001), but non-compliance with the dietary prescription is commonplace, particularly during adolescence and adulthood. Hyperphenylalaninaemia in adults is often associated with attention problems, mood instability and poor job performance. Chronically elevated Phe may cause a progressive neurodegenerative disorder affecting white matter that leads to seizures and gait disturbance. Finally, untreated maternal hyperphenylalaninaemia during pregnancy is the only teratogen guaranteed to cause birth defects, which include microcephaly, mental retardation and congenital heart disease (Levy et al. 2003), the so-called maternal PKU syndrome. For all these reasons, novel alternative therapies for PKU are being sought. Phe itself, accumulating to extremely high levels, is primarily responsible for the phenotype associated with untreated PKU. Accumulation of Phe in blood (normally less than 150 μM but often over 2,000 μM in untreated patients) severely interferes with growth and maturation of the developing brain, although the exact molecular mechanism by which this occurs has yet to be elucidated. Over 50 years of experience with PKU treatment based upon the restriction of dietary Phe intake have firmly demonstrated the link between clinical outcome and blood Phe levels (Azen et al. 1996). So, any treatment approach that results in decreased blood Phe levels will ameliorate the PKU phenotype. BH4 supplementation is a novel therapeutic approach that is effective in a subset of individuals with PKU (Blau 2010; Harding 2010). In addition to PAH, BH4 is a cofactor Presented in part at the 1st European Phenylketonuria Group Symposium, January, 2009 in Barcelona, Spain (supported by Serono Symposia International Foundation).