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Newborn screening as a public health measure was initiated in the early 1960s for the identification of infants affected with phenylketonuria (PKU). Since then, additional genetic and nongenetic conditions were included in state screening programs. The goal of newborn screening is to detect diagnostic markers of the selected disorders in blood spots collected from presymptomatic newborns. Inherited disorders of amino acid, fatty acid, and organic acid metabolism typically manifest during the first 2 years of life as acute metabolic crises and usually result in severe neurologic impairment or death. These metabolic decompensations are usually triggered by intermittent febrile illness, such as common viral infections leading to prolonged fasting and increased energy demands. Early identification of affected newborns allows for early initiation of treatment to avoid mortality, morbidity, and disabilities due to these disorders.
Tandem mass spectrometry (MS/MS) is a powerful multianalyte screening method, which is ideally suited for population-wide testing. Since the early 1990s, MS/MS has made screening possible for more than 30 genetic disorders affecting the metabolism of amino acids, fatty acids, and organic acids based on the profiling of amino acids and acylcarnitines in blood spots. In Mayo's experience, the combined incidence of the disorders identifiable by MS/MS in a single blood spot analysis is approximately 1 in 1,700 newborns.
The Secretary's Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) recommends all programs screen for 32 core disorders (available at http://www.hrsa.gov/advisorycommittees/mchbadvisory/heritabledisorders/recommendedpanel/). These conditions are considered to fulfill 3 basic principles:
-Condition is identifiable at a period of time (24-48 hours after birth) at which it would not ordinarily be clinically detected.
-Test with appropriate sensitivity and specificity is available.
-Demonstrated benefits of early detection, timely intervention, and efficacious treatment.
In acknowledgement of the fact that screening tests do not primarily determine disease status, but measure analytes which in most cases are not specific for a particular disease, the American College of Medical Genetics and Genomics report includes 26 secondary conditions that did not meet all 3 selection criteria but are identified nevertheless because most of them are included in the differential diagnosis of screening results observed in core conditions (see Informative Markers for Supplemental Newborn Screening at Mayo Clinic in Special Instructions). Although these conditions do not meet all 3 selection criteria, the possibility of making the diagnosis early in life not only helps avoid unnecessary diagnostic testing, but is also beneficial to the patient's families because genetic counseling and prenatal diagnosis can be offered for subsequent pregnancies.
Supplemental newborn screening by MS/MS as described here does not replace current state screening programs, because MS/MS does not allow primary screening for galactosemia, congenital hypothyroidism, congenital adrenal hyperplasia (CAH), cystic fibrosis, biotinidase, sickle cell disease, Pompe disease, severe combined immune deficiency (SCID), critical congenital heart disease, and congenital hearing loss.
The simultaneous MS/MS analysis of amino acids, acylcarnitines, and succinylacetone in dried blood spots can be performed in <3 minutes per specimen, generating metabolite profiles that allow for the biochemical diagnosis of multiple disorders. This is in contrast to conventional screening techniques traditionally based on the principle of 1 separate test for each disorder. The performance of Mayo's supplemental newborn screening program is characterized by a very low false-positive rate of 0.024% and a high positive predictive value of 69%.
Presymptomatic identification of disorders to allow for early initiation of treatment and consequent improvement in the long-term prognosis of affected patients
The quantitative measurements of the various amino acids, acylcarnitines, and succinylacetone support the interpretation of the complete profile but for the most part are not diagnostic by themselves. The interpretation is by pattern recognition. Abnormal results are not sufficient to conclusively establish a diagnosis of a particular disease. To verify a preliminary diagnosis, independent biochemical (ie, in vitro enzyme assay) or molecular genetic analyses are required, many of which are offered within Mayo Clinic's Division of Laboratory Genetics.
The reports are in text form only, values for the more than 60 analytes and analyte ratios are not provided. A report for a normal screening result is reported as: "In this blood spot sample, the amino acid and acylcarnitine profiles by tandem mass spectrometry showed no biochemical evidence indicative of an underlying metabolic disorder."
A report for an abnormal screening result includes a quantitative result of the abnormal metabolites, a detailed interpretation of the results, including an overview of the results significance, possible differential diagnoses, recommendations for additional biochemical testing and confirmatory studies (enzyme assay, molecular analysis), and a phone number for a contact at Mayo Clinic if the referring physician has additional questions.
Testing is only appropriate for patients <1 week of age as part of prospective newborn screening.
This test is supplemental and not intended to replace state mandated newborn screening.
Test is not appropriate for metabolic screening of symptomatic patients.
In a few instances, falsely abnormal results may occur in the analysis of amino acid and acylcarnitine profiles. To keep the number of false-positive and false-negative results to a minimum, results are interpreted based on the metabolite profiles, the information provided on the newborn screening card, and second-tier tests for several nonspecific analytes. Using this approach our false-positive rate is only 0.024%.
Newborns discharged on the first day of life will need to be retested during the first week of life, eg, at the first well-child examination, as is customary for state-mandated newborn screening programs. This is necessary to avoid false-negative amino acid results due to limited protein intake on the first day of life.
Carrier status (heterozygosity) for inborn errors of metabolism cannot be reliably detected by amino acid and acylcarnitine profiling.
1. Watson MS, Mann MY, Lloyd-Puryear MA, et al: Newborn Screening: toward a uniform screening panel and system. Genet Med 2006;8(5):1S-11S
2. Rinaldo P, Zafari S, Tortorelli S, Matern D: Making the case for objective performing metrics in newborn screening by tandem mass spectrometry. MRDD Res Rev 2006;12:255-261
3. Matern D, Tortorelli S, Oglesbee D, et al: Reduction of the false-positive rate in newborn screening by implementation of MS/MS-based second-tier tests: The Mayo Clinic experience (2004-2007). J Inherit Metab Dis 2007;30(4):585-592
4, McHugh D, Cameron CA, Abdenur JE, et al: Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project. Genet Med 2011;13:230-254
5. Marquardt G, Currier R, McHugh DM, et al: Enhanced interpretation of newborn screening results without analyte cutoff values. Genet Med 2012;14:648-655