Newborn screening by tandem mass spectrometry (MS-MS)

Newborn screening for selected inherited metabolic disorders is a well-established public health measure in most developed countries [1/. The purpose is to identify and properly diagnose individuals in the neonatal period to enable early medical intervention to prevent or significantly reduce clinical symptoms such as mental retardation. Some of the basic criteria for determining which inherited disorders are suitable for newborn screening include: (a) the disorder has a relatively high incidence so that the cost per diagnosed individual is reasonable, (b) an effective and not overly expensive medical treatment is available, (c) a relatively tnexpensive screening test is available that is suitable for high volume testing (i.e., preferably automatable), and (d) the screening test has a very high sensitivity (i.e., a very low rate of false negatives) and high specificity (i.e., a low rate of false positives, all of which require expensive follow-up). The prototype for newborn screening based on these criteria is that for phenylketonuria (PKU), developed >30 years ago and now used for screening >10 million infants a year worldwide [2]. PKU is a relatively common inherited disorder, with a frequency of-i in 12 000. About 97% of patients with PKU have hyperphenylalaninemia due to an inherited deficiency of hepatic phenylalanine hydroxylase, which metabolizes the amino acid phenylalanine to tyrosine. Because phenylalanine is an essential amino acid derived entirely from the diet, treatment by restriction of phenylalanine intake with special formulas and diets makes it possible to lower plasma phenylalanine concentrations sufficiently to prevent mental retardation and to prevent damage to the fetus in maternal PKU [2]. The initial technique for PKU newborn screening involved obtaining blood just before discharge from the hospital by heelstick with the blood absorbed on filter paper, dried, and sent at room temperature to screening laboratories. The approximate phenylalanine concentration in discs cut from the dried blood spots was determined by the Guthrie bacterial inhibition assay, in which phenylalanine overcomes the inhibition of bacterial growth so that the diameter of the bacterial growth around the spot is proportional to the concentration of phenylalanine in the blood. This method has been replaced in many centers by a fluorometric assay for phenylalanine. Effective infrastructures have been established by each state to ensure that the screening is comprehensive and that proper follow-up of positives will both identify false positives and lead to appropriate treatment of the diagnosed PKU patients. In addition to PKU, newborn screening for …