American Association for Clinical Chemistry
Better health through laboratory medicine
Tandem Mass Spectrometry Screening For Inborn Errors of Metabolism

February 7, 2006

Robert E. Grier, PhD

Newborn screening originated in the USA with testing for phenylketonuria—a genetic defect in the metabolism of phenylalanine. Testing utilized a dried blood spot from a heel stick of each infant before they left the hospital. Since that beginning almost 40 years ago, several other genetic defects have been added in the various state NBS programs. Each disorder required an individual punch from the dried blood spot for that test to be run.

Electrospray tandem mass spectrometry (MS/MS) has been pushed in its development by the pharmaceutical companies. MS/MS quickly separates and identifies compounds of close mass and structure. The technology is both sensitive and specific. It gives reasonable quantitation.

Newborn screeners recognized that MS/MS could separate and identify more than one metabolically informative compound in a single run. Early success with amino acids identification by MS/MS, led to studies of another important group of compounds, acylcarnitines. Acylcarnitines are involved with normal metabolism in the mitochondria and are found in small amounts in the plasma. Elevated levels in plasma can give indirect evidence of a mitochondrial problem (e.g., fatty acid oxidation and organic acid metabolism). Investigators found that they could identify and measure several amino acids and acylcarnitines in a single analysis using the MS/MS.

Using MS/MS, at least 35 genetic disorders of amino acid, fatty acid and organic acid metabolism can be screened from a single dried blood spot punch. This presentation will show the process of MS/MS, beginning with the justification, a cartoon of sample preparation, followed by spectra showing several genetic metabolic defects. Recognition of the genetic defect may be from the abnormal level of a single metabolite or from an abnormal pattern of several compounds.

The true frequency of genetic metabolic disorders in newborns is significant. Treatment can range from simple diet restrictions to occurrences of acute, life-threatening hospitalizations. From the group of MS/MS recognized disorders are a few with no treatment, yet parents want to know a cause of death. More importantly, they can now be counseled at to their risk as carriers of these autosomal recessive disorders. With the advent of MS/MS, the tenets of newborn screening are being modified.

Just as with all clinical testing, constant effort must be made to reduce costs, increase throughput, and reduce false positive reporting. MS/MS accomplishes these goals for newborn screening. It demonstrates itself as a platform for the future of both newborn screening and clinical testing in the hospital laboratory—just look in any recent issue of Clinical Chemistry