Metabolic disorder

Sudden infant death syndrome (SIDS), or the death of an infant aged <1 year that remains unexplained after a thorough investigation *, is the third most common cause of death among infants in the United States (1). Sudden, unexplained deaths also occur among children aged [greater than or equal to] 1 year; however, the number of these deaths is not well documented. Certain cases of SIDS and sudden unexplained death beyond infancy might be attributable to complications of unrecognized metabolic diseases (2-4). Tandem mass spectrometry (tandem MS) can be used to screen for several of these disorders (5). Despite the low prevalence of these diseases (6), newborn screening for these disorders has been found to compare favorably with the cost of other screening programs (7). However, the contribution of these diseases to early childhood deaths is not well understood. To determine the proportion of sudden, unexpected early childhood deaths associated with selected metabolic diseases, CDC, the Office of the Chief Medical Examiner (ME) in Virginia, and a private laboratory conducted a population-based study. This report summarizes the results of the study, which indicate that 1% of children had a positive postmortem metabolic screen using tandem MS. Of the eight children with positive screening tests, seven might have had improved outcomes had they been identified and treated during the newborn period. The use of tandem MS in newborn screening programs could offer an opportunity to prevent early childhood mortality.

The Virginia ME's records, including available autopsy reports, were reviewed for children who died before age 3 years during 1996-2001. In Virginia, the deaths of all children who die before age 18 months and whose death is attributed to SIDS, who die suddenly when in apparent good health, or who die when not under the care of a physician must be examined by the ME (8). For each child, data were recorded on demographics, the cause of death assigned by the ME, and the results of metabolic screening using tandem MS and dried postmortem blood samples [dagger], if available. Additional medical information was collected for each child who had a positive metabolic screening result. For children without a screening result (32%), an archived, dried postmortem blood spot on standard metabolic screening filter paper, if available, was sent to an independent reference laboratory (Neo Gen Screening, Inc., Bridgeville, Pennsylvania) for testing and interpretation (3). Confirmatory molecular testing, if testing was available, was performed for each child with a positive screening test. If a confirmatory test using postmortem blood was not available for an identified disease, an independent biochemical geneticist with expertise in tandem MS performed a secondary interpretation of each mass spectrum.

A total of 793 (88%) of the 904 children who died before age 3 years, whose deaths were investigated by the ME, and whose deaths occurred during 1996-2001 were included in the analysis. The remaining children were excluded because neither postmortem metabolic screening results nor stored postmortem blood were available. Among children excluded from the study, none had a cause of death listed as SIDS. Of the 793 children included in the study, eight (1%) had a positive screening result suggestive of a metabolic disease. Four children had screening results that suggested the presence of fatty acid oxidation disorders, and four had possible organic acidemias. Molecular testing for the most common genetic mutation (G985A) seen in medium-chain acyl-CoA dehydrogenase deficiency, a fatty acid oxidation disorder, confirmed the diagnosis in two children. For the remaining six children with positive tandem MS metabolic screens, no confirmatory tests using postmortem blood were available. However, their mass spectra printouts were confirmed to be indicative of the identified disorder by a second independent biochemical geneticist specializing in tandem MS who was blinded to the previous spectra interpretation.

Sex, race/ethnicity, and age group were not associated with having a positive screening result (Table). Five children had fatty livers at the time of autopsy; this finding is used occasionally to identify children for whom postmortem screening for these diseases is required. However, three children had normal liver pathology. The median age at death of the eight children with positive metabolic screens was 7.5 months (range: 2.0 days-2.7 years). Of these eight children, seven might have benefitted from identification by newborn screening. One child died at age 2 days and would not have benefitted from newborn screening because results would not have been available in time to initiate treatment. All of the children had medical histories and manners of death that were consistent with the natural history of these diseases (9).

Editorial Note: The findings in this report suggest that, during 1996-2001, undiagnosed metabolic diseases were contributing factors in 1% of unexpected deaths in young children in Virginia. Postmortem metabolic screening might have identified a cause of death for certain children who died unexpectedly. Because three of the children with positive tandem MS metabolic screens did not have fat in their livers, performing postmortem metabolic disease screening on the basis of abnormal liver pathology might not have identified all affected children. Approximately 5% of sudden infant deaths might be associated with metabolic diseases (2). The postmortem identification of affected children should prompt testing of siblings who might be affected by the same genetic disorder and might benefit from effective interventions. No population-based studies of survival have been performed for these conditions. Of the eight children with positive tandem MS metabolic screening tests, seven might have had improved outcomes if they had been identified by newborn screening and effective therapy had been initiated in time to prevent their deaths. Newborn screening programs considering including testing for metabolic diseases that can be detected by tandem MS (5) can use these results to estimate the number of children who might benefit from early identification and treatment.

The findings in this report are subject to at least three limitations. First, no test was available to confirm that six of the identified children had the disease suggested by tandem MS metabolic screening. However, the predictive value of tandem MS metabolic screening using postmortem blood is high for the fatty acid oxidation disorders identified (4). The positive predictive value of tandem MS metabolic screening for organic acidemias has not been established. Second, the contribution of metabolic diseases that can be identified by tandem MS to unexpected deaths might be underestimated. Affected persons sometimes die after age 3 years (9), and these persons were excluded from this study. In addition, children included in this study died in a manner that caused their deaths to fall under the jurisdiction of the Virginia ME; other deaths were not studied. All previously healthy children in Virginia who died suddenly or of an unknown cause should have been referred to the ME and would have been eligible for the study; however, a child with an undiagnosed metabolic disease who was under the care of a physician and whose death was attributed to another apparently clear cause (e.g., infection) might not have been referred. Finally, the sensitivity and specificity of tandem MS using postmortem blood is not known.

The data in this report illustrate one aspect of the natural history of the diseases detectable by tandem MS and could be useful to programs considering the addition of this technology to their newborn screening programs. These programs should consider several factors when deciding to add tests for metabolic diseases, including the prevalence (6) and natural history of the diseases, the availability of effective interventions, the costs and benefits of newborn screening (7), and the reliability of available screening technologies (10).

Acknowledgment

This report is based in part on contributions by P Rinaldo, MD, Mayo Clinic, Rochester, Minnesota.

* Including a scene investigation and autopsy.

([dagger]) Tandem MS can identify selected disorders of fatty acid oxidation and amino acid metabolism in dried postmortem blood samples (3).

References

(1.) CDC. Sudden infant death syndrome--United States, 1983-1994. MMWR 1996;45:859-63.

(2.) Boles R, Buck E, Blitzer M. Retrospective biochemical screening of fatty acid oxidation disorders in postmortem livers of 418 cases of sudden death in the first year of life. J Pediatr 1998;132:924-33.

(3.) Chace D, DiPerna J, Mitchell B, Sgroi, B, Hofman L, Naylor E. Electrospray tandem mass spectrometry for analysis of acylcarnitines in dried postmortem blood specimens collected at autopsy from infants with unexplained cause of death. Clin Chem 2001;47:1166-82.

(4.) Wilcox R, Nelson C, Stenzel P, Steiner R. Postmortem screening for fatty acid oxidation disorders by analysis of Guthrie cards with tandem mass spectrometry in sudden unexpected death in infancy. J Pediatr 2002;141:833-6.

(5.) CDC. Using tandem mass spectrometry for metabolic disease screening among newborns: a report of a working group. MMWR 2001; 50(No. RR-3).

(6.) Zytkovicz T, Fitzgerald E, Marsden D, Larson C. Tandem mass spectrometric analysis for amino, organic, and fatty acid disorders in newborn dried spots: a two-year summary from the New England Screening Program. Clin Chem 2001;47:1945-55.

(7.) Schoen E, Baker J, Colby C, To T. Cost-benefit analysis of universal tandem mass spectrometry for newborn screening. Pediatrics 2002;110:781-6.

(8.) CDC. Death investigation system descriptions, 2002. Available at http://www.cdc.gov/epo/dphsi/mecisp/virginia.htm.

(9.) Scriver C, Beaudet A, Sly W, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease, 8th ed. New York, New York: McGrawHill Companies, Inc., 2001.

(10.) Pourfarzam M, Morris A, Appleton M, Craft M, Bartlett K. Neonatal screening for medium-chain acyl-CoA dehydrogenase deficiency. Lancet 2001;358:1063-4.

Reported by: DH Chace, PhD, TA Kalas, MPH, Neo Gert Screening, Inc, Bridgeville, Pennsylvania. M Fierro, MD, Office of the Chief Medical Examiner, Virginia Dept of Health. H Harmon, PhD, Div of Laboratory Sciences, National Center for Environmental Health; SA Rasmussen, MD, Div of Birth Defects and Developmental Disabilities, National Center on Birth Defects and Developmental Disabilities; K Wolf, Epidemiology Program Office; J Williams, MSN, M Dott, MD, ElS officers, CDC.

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