Clinical Information

Newborn screening as a public health measure was initiated in the early 1960s to identify infants affected with phenylketonuria (PKU). Since then, additional genetic and nongenetic conditions have been 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 typically 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 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. The simultaneous MS/MS analysis of amino acids, acylcarnitines, and succinylacetone in dried blood spots can be performed in less than 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 one separate test for each disorder. In Mayo Clinic's experience, the combined incidence of the disorders identifiable by MS/MS in a single blood spot analysis is approximately 1 in 1700 newborns.

Supplemental newborn screening by MS/MS as described here does not replace current state screening programs because MS/MS does not provide primary screening for galactosemia, congenital hypothyroidism, congenital adrenal hyperplasia, cystic fibrosis, biotinidase, sickle cell disease, mucopolysaccharidosis type I, adrenoleukodystrophy, Pompe disease, severe combined immune deficiency, spinal muscular atrophy, critical congenital heart disease, and congenital hearing loss.

The Health and Human Services Secretary's Advisory Committee on Heritable Disorders in Newborns and Children recommends all programs screen for 34 core disorders.

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.

*This test does not screen for critical congenital heart disease and congenital hearing loss, both of which are tested in the nursery using methods other than blood spots (audiometry, pulse oximetry).

Screening tests do not conclusively determine disease status but measure analytes that, in most cases, are not specific for a particular disease. This is the reason why the Health and Human Services Secretary also recognizes more than 25 additional conditions as secondary targets that do not meet all inclusion criteria but are identified nevertheless because most are components of the differential diagnosis of screening results observed in core conditions. Even for the secondary conditions, the possibility of making a diagnosis early in life not only helps avoid unnecessary diagnostic testing but is also beneficial to patients' families, as genetic counseling and prenatal diagnosis can be offered.

Guanidinoacetate methyltransferase (GAMT), a disorder of creatine synthesis recently added to the recommended uniform screening panel, is a condition included in the Mayo Clinic Laboratories' supplemental newborn screen. When untreated, this disorder results in a depletion of cerebral creatine, leading to global developmental delays, intellectual disability, severe speech delays, and seizures. Patients with GAMT deficiency exhibit behavioral problems and features of autism. Treatment consists of lifelong supplementation with creatine monohydrate, ornithine, and dietary protein restriction to decrease cerebral guanidinoacetic acid levels. Individuals with GAMT who are treated before the appearance of symptoms may exhibit normal neurodevelopmental outcomes.