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Is the G985A Allelic Variant of Medium Chain Acyl-CoA Dehydrogenase (MCAD) a Risk Factor for Sudden Infant Death Syndrome (SIDS)? A Pooled Analysis. by Sophia
S. Wang*†, Ph.D., Paul M. Fernhoff‡, M.D., Affiliations: ‡Emory
University †To
whom correspondence and reprints should be addressed:
Studies examining the relationship between medium chain acyl-coA
dehydrogenase deficiency (MCADD) and sudden infant death syndrome (SIDS) have
shown conflicting results. With
greater than 90% of individuals diagnosed with MCADD possessing at least one
copy of the G985A allelic variant, it seems likely that if an association
between MCADD and SIDS existed, an association would also be seen between the
G985A and SIDS. We therefore
assessed the results from 11 studies published through 1998 that evaluated the
relationship between G985A and SIDS. Table 1 summarizes the results of the pooled analysis. Since rates for
SIDS and G985A are different between the United States (U.S.) and elsewhere
(Europe and Australia), analyses were performed stratified by the two regions.
Using published data on the rates of SIDS and G985A in different populations
and the proportion of infants with SIDS who had one or two G985A alleles, we
used Bayes’ theorem to estimate the probability of an infant with one or two
G985A alleles dying from SIDS. The
probability of SIDS among persons homozygous for the G985A allele was
estimated as 1% in the U.S. (range 0%-68%) and 3% for Europe and Australia
(range 0%-77%). This estimate is
10 times higher than the risk for SIDS in the U.S. population and 32 times
higher than the risk for SIDS in the European and Australian populations.
Using Miettinen’s formula we estimated that the proportion of SIDS in both
populations that can be attributed to homozygosity for G985A was less than
0.1%. The probability of SIDS
among infants heterozygous for the G985A allele was also estimated as less
than 0.1% for the U.S. and Europe and Australia, and produced risks 0.6 and
0.3 times the rate of SIDS in the U.S., and Europe and Australia,
respectively. TABLE
1: Pooled analysis of risk for SIDS according to G985A homozygosity and
heterozygosity.
*(a):
abstract Several issues need to be considered in interpreting these findings.
First, 7 studies are case-series and 4 studies are published as
abstracts. However, comparisons of SIDS cases to reported control groups
produced similar results, and analyses excluding abstracts do not change the
conclusions. Second, we excluded
many studies in the literature for incorrect definitions of SIDS, the sudden
and unexplained death of an infant younger than 1 year of age; however,
studies included in this analysis may suffer from potential selection bias of
their selected SIDS cohort. Third,
none of the studies possess adequate power to detect G985A homozygosity, and
their small sample sizes lead to unstable allele frequency estimates,
resulting in wide ranges of penetrance and relative risk.
Lastly, the lack of stratification by racial and ethnic groups is of
concern since heterogeneity for both G985A and SIDS exists. Despite these limitations, the data summarized are the best available
for assessing the relationship between MCADD and SIDS.
The data suggest that infants homozygous for G985A may have an
increased risk for SIDS, whereas infants heterozygous for G985A do not.
Furthermore, the G985A MCAD allelic variant accounts for a minimal
percentage of SIDS cases in the U.S. and Europe and Australia.
There is clearly a need for large population-based studies to
appropriately elucidate this relationship.
(1)
Boles R, Buck E, Blitzer M, Platt M, Cowan T, Martin S, et al.
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.
(2)
Arens R,
Gozal D, Jain K, Muscati S, Heuser E, Williams J, et al.
Prevalence of medium-chain acyl-coenzyme A dehydrogenase deficiency in
the sudden infant death syndrome. J
Pediatr 1993;122:715-18.
(3)
Ged C, El
Sebai H, de Verneuil H, Parrot-Rouleau F. Is genotyping useful for the screening of medium chain
acyl-CoA dehydrogenase deficiency in France? J Inherit Metab Dis
1995;18:253-56.
(4)
Miller M,
Brooks J, Forbes N, Inset R. Frequency
of medium-chain acyl-coA dehydrogenase deficiency G985 mutation in sudden infant
death syndrome. Pediatr Res
1992;31:305-07. Address correspondence to Dr Khoury at
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