American Association for Clinical Chemistry
Better health through laboratory medicine
November 23, 2005


In This Issue . . .

Newborn Screening Shortfalls: Are Some Disorders Being Missed?
Julie L McDowell

Earlier this year, a national advisory committee recommended to the Secretary of the U.S. Department of Health and Human Services that every state screen newborns for a uniform panel of 29 disorders. Currently, only three states—Mississippi, Iowa, and New York—are in compliance with this recommendation. However, an increasing number of state programs are using tandem mass spectrometry (MS/MS) to screen for genetic metabolic disorders by looking for elevated levels of certain amino acids. However, some metabolic disorders cause amino acid levels to decrease. This issue of Strategies examines some potential gaps in newborn screening programs based on a recent study in the New England Journal of Medicine (NEJM) that looked at congenital glutamine deficiency.

Currently, 43 out of 51 states utilize MS/MS technology to offer some variation of an “expanded” screening program, according to a November 2005 U.S. National Screening Status Report, published by the National Newborn Screening and Genetics Resource Center (NNSGRC). In these programs, screening typically looks for high levels of amino acids to indicate the potential for a metabolic disorder in a newborn. However, a recent study of congenital glutamine deficiency indicates that low levels of amino acids could signal a problem.

In the Nov. 3 issue of the NEJM, researchers conducted examinations of two newborns of Turkish descent that died due to complications associated with low levels of the amino acid glutamine, an amino acid involved in fetal energy production, cell proliferation, and cell signaling. Consequently, fetal glutamine needs are especially high, according to the researchers, who are based in Germany and France.

“Brain malformation was the principal manifestation in these two patients,” stated the researchers in the study. “This report might prompt others to consider this disorder in neonates with similar brain malformations. Obtaining serum glutamine levels in such neonates would be useful in screening for the disorder.”

Missing Low Levels

According to some experts in newborn genetic disorders, these findings highlight the drawbacks of focusing on only elevated amino acid levels. “The problem is that we may miss inborn errors of metabolism, such as the one in the study and probably in other cases where you don’t have an elevation of an amino acid,” noted Harvey L. Levy, MD, Senior Associate in Medicine at the Children’s Hospital Boston, Department of Medicine’s Division of Genetics, and Professor of Pediatrics at Harvard Medical School.

In an editorial in the same issue of NEJM, Levy wrote that it is unusual to diagnose an amino acid disorder solely on the basis of a decreased level, causing analysis to be directed toward increased levels. “Newborn screening for metabolic disorders is almost always entirely based on high levels,” he wrote. “Could amino acid disorders be missed because of this selectivity?”

There are some examples of analyzing low levels of amino acids in newborn screening, including urea cycle disorders such as OTC and CPS deficiencies, Levy explained. For these disorders, laboratorians will see a reduction in citrulline, as determined by MS/MS. But this is not the case with amino acids such as glutamine, where low levels cannot be detected by MS/MS.

“The problem is that glutamine has the same mass as another amino acid, lysine,” explained David Millington, PhD, Duke University School of Medicine, Department of Pediatrics, Division of Medical Genetics, and one of the pioneers in bringing MS/MS technology to newborn screening. “The two cannot be distinguished by the current technology that we are using, so you cannot expect to quantify either one of them with any accuracy. That is the main reason we cannot do a test for isolated glutamine at this stage, unless someone can figure out how to get a distinguishing characteristic between the two molecules in a simple way.” Millington added that he has been thinking about this problem, and believes there may be a way to chemically derivatize lysine, which would change its mass and enable glutamine to stand out, but this research is in the early stages.

Most laboratories use a reagent called butanolic HCL in screening analysis to make a derivative of amino acids to aid in detection. “When we do that, we actually degrade the glutamine, at least partially, to glutamic acid,” explained Millington. “So the very molecule you are looking for is being chemically altered by the reagents used in the derivatization, which is another problem.”

No Treatment, No Screen

Even if glutamine could be isolated, it’s unlikely it would be on any screening panel in the near future, according to both Millington and Levy. The primary motive behind newborn screening is to prevent an adverse outcome, but because glutamine deficiency impacts the brain, physicians would have no idea how to treat it. Without any potential therapy, there is little incentive for identifying patients at risk. In addition, no one knows the prevalence of glutamine deficiency—it could be so rare that there would be no justification for including it on any screening list.

“With this particular disorder, I think it’s very likely not to be on the radar screen of most specialist physicians because it’s very rare, and there’s no treatment, and there’s no incentive to screen for it,” said Millington. “For those reasons and for the fact that lysine is not distinguishable from glutamine with the current methodology, I would say there’s no incentive to screen for it at this point.”

For more information:

The National Newborn Screening and Genetics Resource Center’s National Screening Status Report can be found online at

Julie McDowell is the Editor of Strategies. She can be reached by email.