Background: Over the past decade laboratories that test for metabolic disorders have introduced tandem mass spectrometry (MS/MS), which is more sensitive, specific, reliable, and comprehensive than traditional assays, into their newborn-screening programs. MS/MS is rapidly replacing these one-analysis, one-metabolite, one-disease classic screening techniques with a oneanalysis, many-metabolites, many-diseases approach that also facilitates the ability to add new disorders to existing newborn-screening panels. Methods: During the past few years experts have authored many valuable articles describing various approaches to newborn metabolic screening by MS/MS. We attempted to document key developments in the introduction and validation of MS/MS screening for metabolic disorders. Our approach used the perspective of the metabolite and which diseases may be present from its detection rather than a more traditional approach of describing a disease and noting which metabolites are increased when it is present. Content: This review cites important historical developments in the introduction and validation of MS/MS screening for metabolic disorders. It also offers a basic technical understanding of MS/MS as it is applied to multianalyte metabolic screening and explains why MS/MS is well suited for analysis of amino acids and acylcarnitines in dried filter-paper blood specimens. It also describes amino acids and acylcarnitines as they are detected and measured by MS/MS and their significance to the identification of specific amino acid, fatty acid, and organic acid disorders. Conclusions: Multianalyte technologies such as MS/MS are suitable for newborn screening and other mass

This review is intended to serve as a practical guide for geneticists to current applications of tandem mass spectrometry to newborn screening. By making dried-blood spot analysis more sensitive, specific, reliable, and inclusive, tandem mass spectrometry has improved the newborn detection of inborn errors of metabolism. Its innate ability to detect and quantify multiple analytes from one prepared blood specimen in a single analysis permits broad recognition of amino acid, fatty acid, and organic acid disorders. An increasing number of newborn screening programs are either utilizing or conducting pilot studies with tandem mass spectrometry. It is therefore imperative that the genetics community be familiar with tandem mass spectrometric newborn screening.

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Investigators have reported that certain metabolic disorders (fatty acid oxidation (FAO) disorders and organic acidemias) contribute to unexpected early childhood deaths. We estimated the contribution of these metabolic disorders to a population-based sample of unexpected early childhood deaths. The study population included children less than 3 years of age who died during 1996-2001 and whose deaths were investigated by the Virginia Office of the Chief Medical Examiner (ME). Dried post-mortem blood on filter paper was sent to a reference laboratory for metabolic screening by tandem mass spectrometry. When molecular DNA analysis was available to identify known gene mutations, positive screens were confirmed. If molecular DNA analysis for a suspected disorder was not available, tandem mass spectrometry was performed on newborn blood spots when available. If DNA analysis was not available and newborn blood spots could not be obtained, an independent expert biochemical geneticist confirmed the post-mortem interpretation. We obtained screening results for 793 (88%) of 904 children examined. Eight children had a positive screen for FAO disorders or organic acidemias. One child would not have benefited from identification in the newborn period. However, seven children's outcomes might have been improved had they been identified during the newborn period and effectively treated. Post-mortem metabolic screening may identify a cause of death for about 1% of children who die unexpectedly before 3 years of age, allowing for identification and treatment of affected siblings. Identifying and treating affected children during the newborn period may offer an opportunity to reduce early childhood mortality.