Dr. Debra E. Weese-Mayer, professor of pediatrics and director of Pediatric Respiratory Medicine at Rush and colleagues from the University of Pittsburgh conducted a case-control study in which they compared genetic material from 92 SIDS babies and 92 control subjects (who survived the first year of life and had no family history for autonomic diseases).
Her study found 11 different protein-changing rare mutations in 14 of the 92 SIDS cases but only one such mutation in two of the 92 control cases. Of the 15.2 percent of the SIDS babies who had one of these mutations, 71 percent were African American babies, an observation that may explain in part the ethnic disparity in SIDS, Weese-Mayer said.
SIDS is frequently described as a parent's worst nightmare because it strikes without warning, usually in seemingly healthy babies. As the name implies, SIDS is the sudden and unexplained death of an infant who is younger than 1 year old. Most SIDS deaths are associated with sleep (hence the common reference to "crib death"), and infants who die of SIDS show no signs of suffering.
While most conditions or diseases usually are diagnosed by the presence of specific symptoms, SIDS is a diagnosis of exclusion, given only after all other possible causes of death have been ruled out through an autopsy, an examination of the death scene, and a complete review of the infant's medical history. These procedures help distinguish true SIDS deaths from those resulting from accidents, abuse, and previously undiagnosed conditions, such as cardiac or metabolic disorders.
"Tragically, infants of all ethnic groups continue to succumb to SIDS despite many parents demonstrating full compliance with known modifiable risk factors," she said.
The realization that even with the Back to Sleep campaigns, nearly 2,300 babies were still dying each year from SIDS in the U.S., many of whom had no identifiable risk factors or behavioral compliance issues, spurred researchers like Weese-Mayer to pursue non-traditional explanations for SIDS. In 2000, Boston researchers identified decreased serotonergic receptor binding in the brainstems of SIDS victims. Then in 2001, Japanese researchers studied the serotonin transporter gene promoter region and discovered an association between the long allele and SIDS in Japanese babies.
In 2003 Weese-Mayer and colleagues confirmed this association in white and African American SIDS cases relative to controls. Later in the same year, Weese-Mayer and colleagues reported an association between SIDS and a serotonin transporter gene intron 2 polymorphism, also known to regulate serotonin transporter expression. The association was significant in black SIDS cases vs. controls, with the SIDS-associated genotype leading to more effective transporter production. Further, the SIDS-related polymorphisms in the promoter and intron 2, when paired, were significantly associated with SIDS in the black subgroup. Taken together, these results provide strong evidence for a relationship between SIDS risk and serotonin transporter gene activity and represent an important step in the study of a genetic basis for SIDS.
The serotonin connection provided the logical segue to the current study by Weese-Mayer and colleagues. Specifically, serotonin influences a broad range of physiological systems and is involved in ANS regulation. Dysfunction in the ANS has been reported among infants who have succumbed to SIDS. Accordingly, to further elucidate the genetic profile that might increase an infant ™s vulnerability to SIDS, Dr. Weese-Mayer and colleagues focused on genes pertinent to the embryologic origin of the ANS. This approach has been successful in clarifying the genetic basis of idiopathic congenital central hypoventilation syndrome (CCHS), also known to have associated ANS dysregulation and thought to be related to SIDS.
Children with CCHS have been recently identified as heterozygous for the polyalanine expansion mutation in the PHOX2b gene in up to 97% of cases. Just as in the early investigation of CCHS, Dr. Weese-Mayer and colleagues hypothesized that a subset of SIDS cases might have unique mutations or polymorphisms in genes identified embryologically or through knock-out models to be involved in ANS regulation. The specific genes reported in this new publication include MASH1, BMP2, PHOX2a, PHOX2b, RET, ECE1, EDN1, TLX3 and EN1.
"These data represent further refinement of the genetic profile that might place an infant at increased risk for SIDS," Weese-Mayer concluded.
These results represent the first report describing analysis of homeobox and signal transduction genes important in specifying cell fate in ANS differentiation in SIDS cases. The observation that none of the SIDS cases demonstrated the PHOX2b mutation previously identified in CCHS indicates less specific overlap between the two diseases than previously considered (children with CCHS have generalized ANS dysregulation and typically present in the newborn period requiring artificial ventilatory support; infants who succumb to SIDS are seemingly normal yet have ANS dysregulation). However, as families of CCHS probands have a higher incidence of SIDS history in a family member, it may still be appropriate to evaluate SIDS cases for the PHOX2b mutation to ascertain that CCHS was not the cause of death.
The mutations identified in this study may be benign polymorphisms or may be mutations specifically related to the SIDS phenotype. The greatest number of rare mutations was identified in the RET gene. This is of particular interest because of the relationship of RET to Hirschsprung disease and to CCHS, and because of the RET knockout model with a depressed ventilatory response to inhaled carbon dioxide with decreased frequency and tidal volume. The knock out models for ECE1 and TLX3 also include impaired breathing and/or early death in the mouse phenotype, with suggestion of a central respiratory deficit. Further research is necessary to better understand the role of these and other genes in the SIDS phenotype and in explaining the ethnic disparity in SIDS. Once the genetic profile is complete, then intervention strategies can be considered and ideally implemented.
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