Phenylketonuria (PKU) is an autosomal recessive disorder caused by deficiency of phenylalanine hydroxylase (PAH). Demonstration of mutations in the PAH gene establishes PAH deficiency as the cause of hyperphenylalaninaemia in the newborn and provides a basis for predicting the metabolic phenotype and anticipating the dietary requirements of the patient. Mutations in the PAH gene are well archived in the PAH Locus Knowledgebase. Loss of PAH protein is a consequence of misfolding, aggregation and accelerated degradation of the enzyme. BH₄ rescues the activity of mutant PAH enzymes by functioning as a chaperone to stabilise enzyme structure or by overcoming defects that alter the K_m for BH₄. Defects in BH₄ metabolism can be divided into those associated with hyperphenylalaninaemia and those presenting without hyperphenylalaninaemia. The diagnosis of BH₄ deficiencies has to be considered for all conditions with hyperphenylalaninaemia. The measurement of pteridines in urine discriminates BH₄ synthesis deficiency from PKU children. Therapy is aimed at normalising Phe levels and brain neurotransmitters (Matalon et al., 2006). Treatment includes a special diet and/or BH₄ supplements.

Key Concepts:

• Deficiency of phenylalanine hydroxylase (PAH; E.C. 1.14.16.1.) is caused by mutations in the PAH gene.
  
• PAH is inherited in an autosomal recessive pattern (MIM #).
  
• PAH deficiency is a highly heterogeneous disorder that has been divided into four arbitrary phenotype categories: classic, moderate and mild PKU, and mild hyperphenylalninaemia (MHP).
  
• More than 450 mutated versions of PAH have been reported worldwide, each producing a protein with partial or total loss of enzyme activity.
  
• A clear correlation between genotype and phenylalanine tolerance has been documented and genotype/phenotype correlations are established on the basis of patient data.