Clinical Information

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%.