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Commentary

Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD

Address correspondence to the author at: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892. e-mail venditti{at}mail.nih.gov.

Supplemental newborn screening using acylcarnitine ester profiling has greatly expanded the scope of detection of newborns with a wide range of fatty acid oxidation disorders and organic acidemias. Each metabolite, or group of metabolites, measured by tandem mass spectrometry in the newborn blood spot carries the potential to identify infants at risk for metabolic disease. Among these markers, a positive test for increased C3 species—propionylcarnitine—causes a characteristic and immediate reaction of initiating an emergency metabolic evaluation for the at-risk infant, with good reason. Increased propionylcarnitine in the blood is a biochemical hallmark of isolated methylmalonic acidemia, propionic academia, and disorders of intracellular cobalamin processing, all potentially lethal disorders of intermediary metabolism. However, experienced clinicians and newborn screening laboratories alike recognize that increased propionylcarnitine is not a perfect disease marker and in some large series, an infant with increased C3 species will more likely be categorized as a false positive vs affected with a metabolic disorder (1), an outcome far more desirable than the diagnosis of propionic or methylmalonic acidemia.

Although hereditary metabolic disorders comprise the most common true-positive subset within the group of babies with increased propionylcarnitine (1), another category includes infants born to mothers with diminished maternal vitamin B12 stores. Maternal B12 deficiency is recognized to produce a spectrum of symptoms in the infant—ranging from frank encephalopathy with severe metabolic derangements (2) to increased propionylcarnitine (1) with mild methylmalonic aciduria (3). The mother in the current case had undergone gastric bypass without subsequent vitamin B12 supplementation, and although her biochemical and hematological parameters were not documented in this report, she presumably was vitamin B12 deficient as was the proband when initially screened. Fortunately, other than mild prematurity, the baby was well and without biochemical abnormalities such as methylmalonic aciduria. In the end, a positive newborn screen enabled recognition of untreated maternal disease and demonstrates the unexpected societal benefit that can be derived from expanded newborn screening. One now wonders whether other infants in the false-positive category for increased C3 species might be instructing us to pay more attention to whether maternal pathology is present.

Acknowledgments

Author Contributions: Each author confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors’ Disclosures of Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript.

References

1. Chace DH, DiPerna JC, Kalas TA, Johnson RW, Naylor EW. Rapid diagnosis of methylmalonic and propionic acidemias: quantitative tandem mass spectrometric analysis of propionylcarnitine in filter-paper blood specimens obtained from newborns. Clin Chem 2001;47:2040-2044.[Free Full Text]
2. Higginbottom MC, Sweetman L, Nyhan WL. A syndrome of methylmalonic aciduria, homocystinuria, megaloblastic anemia and neurologic abnormalities in a vitamin B12-deficient breast-fed infant of a strict vegetarian. N Engl J Med 1978;299:317-323.[Abstract]
3. Marble M, Copeland S, Khanfar N, Rosenblatt DS. Neonatal vitamin B12 deficiency secondary to maternal subclinical pernicious anemia: identification by expanded newborn screening. J Pediatr 2008;152:731-733.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

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