Screening for Phenylketonuria

Newborn screening for phenylketonuria (PKU) started with Robert Guthrie (1916–1995) who developed the bacterial inhibition test for the semiquantitative analysis of phenylalanine, which was the first test suitable for high throughput analysis. In addition, he introduced the ‘Guthrie filter card’ as a transport medium for dried blood which is still used today. Realizing the potential of his approach for early diagnosis and the fact that a low-phenylalanine diet prevented the neurological sequelae of untreated PKU, Robert Guthrie became the first and utmost advocate of newborn screening for PKU. Following the first PKU newborn screening program in Buffalo, N.Y., USA, in the 1960s, additional newborn screening programs were initiated around the world in the 1960s and 1970s. Newborn screening has since been recognized as an important public health measure, and most countries have ongoing newborn screening programs for PKU and other inborn errors of metabolism. Since the first programs, it has been recognized that early diagnosis of PKU and subsequent initiation of a low phenylalanine diet results in normal neurological outcomes – in contrast to the severe mental retardation in untreated PKU. Today’s newborn screening laboratories use photometric assays or tandem mass spectrometry for analysis of phenylalanine rather than the bacterial inhibition test. This has led to an increased number of cases with hyperphenylalaninemia that often do not require dietary treatment. Any elevated phenylalanine level in a neonate needs to be followed by a second specimen for repeat analysis of phenylalanine and tyrosine. Confirmation of elevated phenylalanine levels with low to normal tyrosine levels requires analysis of urine pterines and dihydropterine reductase activity in red cells to rule out an inborn error of biopterin metabolism. In any neonate whose blood phenylalanine levels exceed 6 mg/dl, a tetrahydrobiopterin loading test should be performed and dietary therapy should be initiated. The level at which dietary therapy is started may be different between the USA, UK and continental Europe.