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Protecting children from the burden of inherited diseases is the aim of newborn screening. Selection of candidate disorders depends upon the following prerequisites: 1) feasible means of disease detection in a presymptomatic/early stage of the disease; 2) treatability of the disease; 3) ability to start of treatment in the presymptomatic/early stage.

Screening of neonates for signs of disease or distress has several components, with the perinatal clinical evaluation being of first and foremost importance. The clinical approach to screening is limited to the detection of symptoms, which in many disorders have been proven to be irreversible if not treated. For example, classic phenylketonuria (PKU) due to phenylalanine (Phe) hydroxylase deficiency is characterized by the insidious development of irreversible neurological damage unless treatment is initiated within the first few weeks of life. Newborn screening was first developed for the identification of this inborn error of amino acid metabolism, which was typically not diagnosed before 6 months of life and mostly even much later when developmental delay or other nonspecific neurologic symptoms become apparent. Treatment based on a Phe-restricted diet was developed by Horst Bickel in the 1950s, but it was quickly realized that therapy only improved the patient’s symptoms but was inadequate to reverse neurologic damage.1 Furthermore, it was recognized that a limited intake of the essential amino acid Phe requires the regular monitoring of its concentration in blood. A simple method for Phe determination was developed by Robert Guthrie, a scientist initially working in cancer research and the father of a child with mental retardation.2 This test was a bacterial inhibition assay (BIA) performed on serum dried on filter paper. Guthrie then began to apply his BIA to the analysis of Phe in small blood samples also dried on filter paper with the aim of allowing the presymptomatic identification of PKU in patients and facilitating the timely initiation of dietary intervention.3 Once the efficacy of this assay was established, newborn screening began 50 years ago in several regions of the United States and Germany and rapidly spread around the world using the Guthrie test.4,5 Over the ensuing 30 years, a few additional disorders such as congenital hypothyroidism, galactosemia, and sickle cell disease were gradually added to many newborn screening programs, usually one new assay for each additional disorder.

The BIA was initially modified to detect other disease markers and eventually more sophisticated technologies were applied, such as fluorometric, colorimetric, and immunoassays to determine either disease-related metabolites or specific enzyme activities. Over the last two decades, the introduction of tandem mass spectrometry (MS/MS) into newborn screening laboratories has dramatically expanded the number of disorders that can be detected in a single blood spot. More than 30 additional conditions can be detected by simultaneous acylcarnitine and amino acid analyses, including inborn errors of amino acid, organic acid, and fatty acid metabolism.



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