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ELECTRONIC ARTICLE:
Siri H. Opdal and Torleiv O. Rognum
The Sudden Infant Death Syndrome Gene: Does It Exist?
Pediatrics 2004; 114: e506-e512 [Abstract] [Full text] [PDF]
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[Read P3R] Genetics and the Gestalt of SIDS
David T Mage, Maria Donner   (25 October 2004)
[Read P3R] SIDS and X-linked inheritance
Siri H Opdal, Torleiv Ole Rognum   (3 November 2004)

Genetics and the Gestalt of SIDS 25 October 2004
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David T Mage,
Chemical Engineer
Temple University,
Maria Donner

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Re: Genetics and the Gestalt of SIDS

david.mage{at}temple.edu David T Mage, et al.

Opdal and Rognum [1] present an excellent and thorough review of candidate genes that have been proposed to be involved in the sudden infant death syndrome (SIDS). However, the proponents of these genes seem to have “overlooked the forest for the trees.” They apparently focused on the individual SIDS cases they genotyped and not on the SIDS gestalt [the pattern of a biological phenomenon constituting a functional unit not derivable by summation of its parts] because all these genes are either autosomal or mitochondrial [2]. All alleles of autosomal genes have equal probability of being inherited by a male or a female infant because each parent transfers one copy. Mitochondrial DNA is maternally inherited so both genders receive it with equal probability. Therefore the alleles of these genes have a theoretical male to female ratio of 1:1. However, SIDS has a 50% male excess in all developed countries in periods with high standards of autopsy [3]. This includes Norway from 1986 to 2002 where there was a 5.6% male live-birth excess, and 598 male and 353 female SIDS cases [4]. This male excess of 60.4% per 1,000 live births of each gender is not significantly different from the prediction of 50% (p = 0.32) [3].

There is presently no published explanation for this consistent male excess in SIDS other than absence of a heretofore undiscovered X-linkage of a protective dominant allele with frequency of 1/3 that predicts a 50% male excess in SIDS [3] and other respiratory causes of death [5,6]. For example, infant death in the U.S. from 1979 to 2001 by accidental inhalation of food or other object, causing obstruction of the respiratory tract (9ICD 911, 912; 10ICD W79, W80) had 1,388 male and 899 female cases [7]. Given the U.S. 5.0% male excess live birth rate, this is a male excess of 47% per 1,000 live births of each gender, again not significantly different from 50% (p = 0.67). We reason that accidental inhalation of food and other objects by infants is gender independent, so we expect that an equal number of males and females per 1,000 live births must have inhaled such potentially fatal items. However, because some 50% more males than females died from this cause, the females who survived must have had a protective factor against cerebral hypoxia that the males and females who died did not have. This factor appears to have allowed emergency treatments to resuscitate them successfully. We propose that the precipitating factor in SIDS could be the absence of the same dominant X-linked allele that may be protective against cerebral hypoxia caused by accidental gender-independent respiratory obstruction [6].

In summary, if it is likely that SIDS may be polygenic, involving mitochondrial or autosomal “SIDS genes” [1], at least one additional necessary SIDS gene must be X-linked in order to explain the consistent 50% male SIDS excess.

1. Opdal SH, Rognum TO. The sudden infant death syndrome gene: does it exist? Pediatrics. 2004;114(4) e506-512.

2. Online Mendelian Inheritance in Man, OMIM (TM). McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/

3. Mage DT, Donner M. A genetic basis for the sudden infant death syndrome sex ratio. Med Hypotheses. 1997;48(2):137-42.

4. http://statbank.ssb.no//statistikkbanken/ Accessed October 8, 2004.

5. Finnström, O. A genetic reason for male excess in infant respiratory mortality? Acta Paediatr. 2004;93(9):1154-5.

6. Mage DT, Donner EM. The fifty percent male excess of infant respiratory mortality. Acta Paediatr. 2004;93(9):1210-5.

7. United States Department of Health and Human Services (US DHHS), Centers for Disease Control and Prevention (CDC), National Center for Health Statistics (NCHS), Office of Analysis, Epidemiology, and Health Promotion (OAEHP), Compressed Mortality File (CMF) compiled from CMF 1968- 1988, Series 20, No. 2A 2000, CMF 1989-1998, Series 20, No. 2E 2003 and CMF 1999-2001, Series 20, No. 2G 2004 on CDC WONDER On-line Database. Accessed October 9, 2004.

SIDS and X-linked inheritance 3 November 2004
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Siri H Opdal,
Ph.D.
Institute of Forensic Medicine, University of Oslo, Norway,
Torleiv Ole Rognum

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Re: SIDS and X-linked inheritance

s.h.opdal{at}labmed.uio.no Siri H Opdal, et al.

I thank David Mage for the response on our paper. The hypothesis of the existence of a dominant X-linked gene that protects against cerebral hypoxia, and that this same gene, or a particular allele of this gene, is absent in SIDS is an interesting thought, especially in view of the findings of elevated levels of hypoxanthine reported in vitreous humor in SIDS (1). These elevated levels may be the result of hypoxic events prior to death, as hypoxanthine is a biochemical marker of hypoxia.

Sudden infant death syndrome (SIDS) is diagnosed on the basis of exclusion of known causes of death, but there are common features in most cases, such as a typical age peak, sex distribution and risk factor profile. This have led to development of a triple-risk model for the understanding of SIDS; the fatal triangle (2, 3). This model implies that SIDS only happens if three conditions occur simultaneously: a vulnerable developmental stage; predisposing factors, including a certain genetic pattern; and trigger events. Giving the excess of male in SIDS, as in other infant deaths, it is not unlikely that one of the components in the polygenic inheritance pattern is an X-linked gene.

References 1.Rognum TO, Saugstad OD, Oyasaeter S, Olaisen B. Elevated levels of hypoxanthine in vitreous humor indicate prolonged cerebral hypoxia in victims of sudden infant death syndrome. Pediatrics 1988;82(4):615-8. 2.Rognum TO, Saugstad OD. Biochemical and immunological studies in SIDS victims. Clues to understanding the death mechanism. Acta Paediatr Suppl 1993;82 Suppl 389:82-5. 3.Guntheroth WG, Spiers PS. The triple risk hypotheses in sudden infant death syndrome. Pediatrics 2002;110(5):e64.