Phenylketonuria

Abstract Phenylketonuria (PKU) is the most frequent disorder of amino acid metabolism. First described by Fölling in 1934, PKU is an autosomal recessive disorder involving mutations in the phenylalanine hydroxylase (PAH) gene, which inhibits the normal metabolism of phenylalanine, an amino acid found in all proteins (Scriver et al. 2001). As a result, phenylalanine cannot be converted into tyrosine and accumulates in the blood and other tissues in untreated patients on a normal diet (Huijbregts et al. 2003; Pietz et al. 1998). The degree of impairment varies significantly among patients, resulting in a broad continuum of phenotypes (NIH Consensus Development Conference Report 2001). Phenylketonuria is the most common biochemical cause of mental retardation (Scriver et al. 1995). When untreated, increased phenylalanine concentrations in blood and tissues and low to normal tyrosine concentrations result in severe mental and neurological retardation (Scriver et al. 1995). In 1953, a treatment was discovered by Horst Bickel and his colleagues in England (Bickel et al. 1953). The treatment has become a standard of care and is based on a phenylalanine-restricted diet that consists of severe restriction of natural protein supplemented with all amino acids, except phenylalanine, to compensate for the shortage of amino acids through regular protein intake (Huijbregts et al. 2003). The work of Bickel and his colleagues proved that excessive phenylalanine resulted in neurological problems and that dietary treatment was beneficial. Patients with both classical and less severe forms of PKU require dietary protein restriction to prevent neurological sequelae and to ensure normal cognitive development. The first newborn screening program began in 1961 and initial results were reported by Guthrie and Susi (1963). The Guthrie bacterial assay for the filter paper blood test made it possible to identify PKU from a drop of blood from the heel of a newborn within the first days of life. It was then possible to begin treatment and thereby prevent mental retardation. Today, laws mandating newborn screening are in place in North American and Europe.