Sudden Infant Death Syndrome

A number sign (#) is used with this entry because mutations in the mitochondrial genes MTTL1 (590050) and MTND1 (516000) may play a role in some cases of SIDS. Evidence has also been presented for a relationship between SIDS and mutations in the SCN5A (600163), KCNQ1 (607542), and CAV3 (601253) genes, which cause various forms of long QT syndrome (see LQT1, 192500). There is also evidence for associations between SIDS and mutation in the SLC6A4 gene (182138) and the GPD1L gene (611778).

Description

Sudden infant death syndrome (SIDS) is a diagnosis of exclusion which should be made only after a thorough autopsy without identification of a specific cause of death (Mage and Donner, 2004).

Weese-Mayer et al. (2007) provided a detailed review of genetic factors that have been implicated in SIDS. The authors concluded that SIDS represents more than 1 entity and has a heterogeneous etiology most likely involving several different genetically controlled metabolic pathways.

Inheritance

Kelly et al. (1982) found a higher frequency of apneic periods in newborn sibs of SIDS victims than in normal infants.

Smialek (1986) collected 9 pairs of infant twins who died suddenly and simultaneously. Two of the 9 pairs were nonidentical, and 1 family had a history of SIDS. These observations in twins appeared to support a genetic hypothesis or an interplay of genetic and environmental factors.

In a detailed analysis of infant respiratory mortality in the U.S., U.K., and Scandinavia, Mage and Donner (2004) found an approximate 50% male excess of neonatal and postnatal SIDS, which remained even when stratified for autopsied-only cases. Other causes of respiratory death that showed approximately 50% male excess included the common cold, chronic airway obstruction, bronchiolitis, bronchitis, and other diseases of the respiratory tract. The 50% male excess was consistent with an X-linked dominant allele that is protective of terminal hypoxia, with a frequency of approximately 33%. Mage and Donner (2004) suggested that SIDS may be due to an X-linked recessive allele that is only unmasked in the presence of several risk factors, including low-grade infection, apnea, anemia, prone sleep position, or neurologic prematurity.

See 107640 for a discussion of infantile central sleep apnea.

Pathogenesis

After death-scene investigations, Bass et al. (1986) emphasized that accidental asphyxiation by an object in the crib, smothering by 'overlying' while sharing a bed with a parent, hyperthermia, and violent shaking ('shaken baby syndrome') were frequent causes of sudden infant death.

Disagreement among the experts as to whether chronic abnormalities in breathing pattern run in some families predisposing to SIDS and whether SIDS is indeed a familial disorder was cited by Pinholster (1995). Studies in Europe and Australia suggested that the risk of SIDS drops by more than 50% if children sleep on their backs. Horgan (1995) quoted J. Bruce Beckwith as calling this finding the most significant he had seen since he coined the term 'SIDS' in 1969. Others suggested that the correlation between SIDS and prone position found outside the U.S. may stem from practices unique to those regions, such as the use of thick, sheepskin blankets as bedding in Australia.

Kinney et al. (1995) hypothesized that SIDS, or a subset of SIDS, is associated with deficiency in muscarinic cholinergic receptor binding in the arcuate nucleus of the ventral surface of the medulla (ventral medullary surface, VMS), which results in an impaired response to hypercarbia or asphyxia during sleep and sudden death. VMS cells are intimately associated with ventrolateral neurons of the brainstem that integrate ventilatory, pressor, and defense responses. Filiano and Kinney (1992) reported a subset of SIDS infants with a severe developmental hypoplasia of the arcuate nucleus. The hypothesis that arcuate neurons are VMS cell populations involved in the response to hypercarbia in humans is supported by functional magnetic resonance imaging (MRI) in adults exposed to hypercarbia in which CO(2) responsivity is localized to the region of the arcuate nucleus. Folgering et al. (1979) reported an infant with the congenital central hypoventilation syndrome (209880) and absence of the arcuate nucleus at autopsy. Kinney et al. (1995) used tissue receptor autoradiography to test the hypothesis that the binding of the muscarinic antagonist tritiated quinuclidinyl benzilate was decreased in the arcuate nucleus in SIDS infants. They indeed found a decrease compared to infants dying acutely of known causes. In infants with chronic oxygenation abnormalities, binding was low in other nuclei as well as in the arcuate nucleus. The authors speculated that the binding deficit in the arcuate nucleus of SIDS infants may contribute to a failure of responses to cardiopulmonary challenges during sleep.

In 17 of 17 patients who died of SIDS, Kadhim et al. (2003) detected high immunoreactivity for interleukin-1-beta (IL1B; 147720) in the arcuate and dorsal vagal nuclei in the brainstem compared to controls.

Treluyer et al. (1996) showed that the hepatic content of CYP2C proteins (see 124020) in SIDS patients was significantly enhanced; this resulted from the accumulation of RNA encoding CYP2C and was associated with a stimulation of CYP2C-dependent monooxygenase activities. Treluyer et al. (2000) studied liver samples from 6 SIDS infants, 6 controls, adults, and fetuses for CYP2C levels and arachidonic acid metabolites. In SIDS, the accumulation of CYP2C proteins was associated with a significant increase in the formation of 14,15- and 11,12-dihydroxyeicosatrienoic acid (diHETE), substances involved in the regulation of vascular tone.

Boles et al. (1998) compared findings in liver tissue (microvesicular steatosis, elevated C8-C16 fatty acids, glucose depletion, and low carnitine) in 27 cases representing 5 fatty acid oxidation disorders and in 418 cases of sudden infant death, using a retrospective, blinded analysis. All of the 34 cases of accidents or abuse tested negative; among the other cases, 25 (6%), including 9 of the 45 cases with infections, showed at least 2 abnormal findings. Fourteen of these closely matched the biochemical profiles seen in specific fatty acid oxidation disorders. Boles et al. (1998) concluded that approximately 5% of SIDS cases may be caused by fatty acid oxidation disorders.

On the basis of a large study of 34,442 infants over an 18-year period with a 1-year follow-up on 33,034 infants, Schwartz et al. (1998) concluded that prolongation of the QT interval is a risk factor in SIDS. Lucey (1999) reviewed the suggestions of Schwartz et al. (1998) that development of a simple device to be used in the physician's office to measure QT would be welcome and that some patients should receive beta-blockers. Lucey (1999) stated that 'the SIDS field of research is still bogged down by apnea monitors, which have proven of little value. Hundreds of millions of dollars have been wasted over the last 25 years. Worse still, the device continues to be used! The apnea monitoring business has become a religion. More people are living off of SIDS than dying from it.' Guntheroth and Spiers (1999) criticized the selection in the study by Schwartz et al. (1998): 2 of their cases appeared to be instances of the true long QT syndrome, which should make them ineligible for the diagnosis of SIDS. Although Schwartz et al. (1998) stated that they ruled out the long QT syndrome on the basis of family history, only 39% of all established LQTS cases have a positive family history (Garson et al., 1993). Guntheroth and Spiers (1999) pointed to the report by Moss and Robinson (1992), based on the largest registry of LQTS in the world, which found no statistically significant benefit of any treatment for the syndrome, let alone preventing SIDS. They suggested that it would be unthinkable to prescribe beta-blockers for thousands of asymptomatic infants with a statistical 'abnormality' based on a very subjective measurement with a very wide range of normal.

Hodgman and Siassi (1999) pointed to the work of Southall et al. (1986) which failed to find a difference in QT interval when surviving infants were compared with the deaths. They stated that the 'sleep apnea theory as the mechanism of SIDS, proposed over 25 years ago, although never proven has spawned an entire industry of home monitoring. Despite the fact that in the intervening years, the sleep apnea theory essentially has been discredited and monitoring has had no effect on SIDS rates, the practice is still widespread.'

Hoffman and Lister (1999) pointed to the report by Maron et al. (1976), who studied 42 sets of parents who had an infant with SIDS, and found that in 11 of the sets, at least 1 parent had prolonged QT. Furthermore, in 8 of the families with 1 parent who had prolonged QT, 9 of the 23 sibs also had prolonged QT interval, consistent with an autosomal dominant pattern of inheritance. However, the Maron report did not have measurements of QT in the SIDS victims. Hoffman and Lister (1999) suggested that the known molecular defects in the several forms of LQTS be sought in infants with apparent SIDS and in their families. They argued that the demand for extensive ECG monitoring of all infants, or even all those at risk for SIDS, should be resisted.

Lucey (1999) stated that the 'single major advance in (the SIDS) field in the last 20 years has been the introduction of the Back to Sleep Program,' with recommendation of sleeping on the back. 'The incidence of SIDS in the United States has decreased to below 1 case per 1,000 live births (1997). As compliance with the program improves, this decrease could continue. Highly specialized pathologists are finding defects in the brain and conduction system of the heart in so-called SIDS cases. Rare metabolic diseases and infanticide are also being detected more often. SIDS is a diagnosis of exclusion, so the more we know, the less likely SIDS will remain useful as a diagnosis.'

Molecular Genetics

Opdal et al. (1999) identified 3 different point mutations in the mitochondrial DNA (mtDNA) of 4 of 158 SIDS cases and in none of 97 controls. One mutation occurred in the MTTL1 gene, and the other 2 occurred in the MTND1 gene. The authors pointed to descriptions of other mutations in the MTTL1 gene that had been found in association with SIDS.

Schwartz et al. (2000) reported a clinically typical instance of 'near-SIDS' in an infant who was found to be heterozygous for a missense mutation in the SCN5A gene (600163.0015). Ackerman et al. (2001) performed postmortem mutation analysis of the SCN5A gene in 93 cases of SIDS or undetermined infant death and identified missense mutations (600163.0019-600163.0020) in 2 cases.

Schwartz et al. (2001) identified a de novo, heterozygous mutation in the KCNQ1 gene (607542.0030) in an infant who died from SIDS. They found the same mutation in affected members of a family with long QT syndrome. Schwartz et al. (2001) concluded that these findings confirmed the hypothesis that some deaths from SIDS are caused by long QT syndrome and supported implementation of neonatal electrocardiographic screening during the second or third week of life when the risk of spuriously long QT intervals (false positives) is extremely small.

Narita et al. (2001) examined the long/short promoter polymorphism of the SLC6A4 gene (182138.0001) in Japanese SIDS cases and found an excess of the L/L genotype and L allele in the SIDS group relative to controls. Weese-Mayer et al. (2003) investigated this variable tandem repeat sequence polymorphism in the promoter region in a cohort of 87 SIDS cases (43 African American and 44 Caucasian) and gender/ethnicity-matched controls. They likewise found increases in the L/L genotype and the L allele. Weese-Mayer et al. (2003) subsequently showed in the same cohort that an intron 2 polymorphism (12-repeat allele), which also differentially regulates 5-HTT expression, was associated with increased risk of SIDS in African American but not Caucasian SIDS cases.

In a review article, Opdal and Rognum (2004) stated that the genetic component of SIDS comprises 2 categories: mutations that cause genetic disorders that result in death and polymorphisms that may predispose infants to death in critical situations. A well-studied example of the former is medium-chain acyl-CoA dehydrogenase deficiency (201450), a disorder of fatty acid oxidation caused by mutation in the MCAD gene (see, e.g., 607008.0001). Another well-studied example is long QT syndrome. By contrast, evidence tended to exclude hypoglycemia and thrombosis as major causes of SIDS. The authors concluded that there is unlikely to be a single causative mutation or polymorphism in all SIDS cases; however, it is likely that there are several genes that operate to predispose infants to SIDS in combination with environmental risk factors. Opdal and Rognum (2004) emphasized the difficult position of SIDS in both the medical and legal professions.

Plant et al. (2006) identified homozygosity for the S1103Y variant of the SCN5A gene (600163.0024) in 3 African American autopsy-confirmed cases of SIDS. Among 1,056 African American controls, 120 were carriers of the heterozygous genotype, suggesting that infants with 2 copies of S1103Y have a 24-fold increased risk for SIDS. Variant Y1103 channels were found to operate normally under baseline conditions in vitro. Because risk factors for SIDS include apnea and respiratory acidosis, Y1103 and wildtype channels were subjected to lowered intracellular pH; only Y1103 channels developed abnormal function, with late reopenings suppressible by the drug mexiletine. Plant et al. (2006) suggested that the Y1103 variant confers susceptibility to acidosis-induced arrhythmia, a gene-environment interaction.

Cronk et al. (2007) analyzed the LQT9 (611818)-associated CAV3 gene in necropsy tissue from 134 unrelated cases of SIDS and identified 3 missense mutations in 3 of 50 black infants (601253.0018; 601253.0020; 601253.0021). No mutations were detected in 1 Hispanic or 83 white infants, and CAV3 mutations occurred in 2 infants who died after age 6 months versus 1 infant who died before 6 months (2 of 12 vs 1 of 124; p = 0.02). The mutations were not found in 400 reference alleles, of which 200 were ethnically matched.

Animal Model

Audero et al. (2008) investigated the consequences of altering the autoinhibitory capacity of serotonin neurons with the reversible overexpression of serotonin 1A autoreceptors (109760) in transgenic mice. Overexpressing mice exhibited sporadic bradycardia and hypothermia that occurred during a limited developmental period and frequently progressed to death. Moreover, overexpressing mice failed to activate autonomic target organs in response to environmental challenges. Audero et al. (2008) concluded that their findings showed that excessive serotonin autoinhibition is a risk factor for catastrophic autonomic dysregulation and provided a mechanism for a role of altered serotonin homeostasis in sudden infant death syndrome.

Guntheroth (2008) raised objections to a role for serotonin in SIDS, stating that studies have repeatedly shown that SIDS is not genetic, inherited, or even congenital, and that postmortem changes observed in serotonin neurons might be the result and not the cause of SIDS. The author further noted that bradycardia in SIDS cases is terminal, rather than sporadic, and that SIDS victims typically suffer from hyperthermia rather than hypothermia. In response, Gross and Audero (2008) stated that the significance of their work (Audero et al., 2008) lies in the discovery that increased autoinhibition of serotonin neurons is linked to sporadic death, and they advised caution in viewing Htr1a-overexpressing mice as a model of SIDS.

History

Steinschneider (1972) reported a family with multiple cases: a male died at 102 days of age, a female at 48 days of age, and a male at 28 months of age. The fourth- and fifth-born sibs had bouts of sleep apnea when they were monitored in the hospital. Both children died soon after they were discharged. Steinschneider (1972) concluded that 'prolonged apnea, a physiological component of sleep, is part of the final pathway resulting in sudden death. It is suggested also, that infants at risk might be identified prior to the final tragic event.' Thus, all 5 sibs in this family appeared to die of SIDS, suggesting that apnea-related SIDS runs in families. However, the family in question came to the attention of the criminal justice system and, after a lengthy investigation, the mother, one Waneta E. Hoyt, confessed to murdering her 5 babies between 1965 and 1971 (Pinholster, 1995).