Low Butyrylcholinesterase: A Possible Biomarker of SIDS Risk?

Reduced levels of the cholinergic-system enzyme butyrylcholinesterase (BChE) may provide another piece of the puzzle for sudden infant death syndrome (SIDS), preliminary data from Australian researchers suggested.

A small case-control study led by Carmel T. Harrington, PhD, a sleep medicine expert and honorary research fellow at the Children"s Hospital at Westmead (Australia), found that measurements in 722 dried blood spots taken during neonatal screening 2 or 3 days after birth were lower in babies who subsequently died of SIDS, compared with those of matched surviving controls and other babies who died of non-SIDS causes.

In groups in which cases were reported as SIDS death (n = 26) there was strong evidence that lower BChE-specific activity was associated with death (odds ratio, 0.73 per U/mg; 95% confidence interval, 0.60-0.89, P = .0014). In groups with a non-SIDS death (n = 41), there was no evidence of a linear association between BChE activity and death (OR, 1.001 per U/mg; 95% CI, 0.89-1.13, P = .99). A cohort of 655 age- and sex-matched controls served as a reference group.

Writing online in eBioMedicine, the researchers concluded that a previously unidentified cholinergic deficit, identifiable by abnormal BChE-specific activity, is present at birth in SIDS babies and represents a measurable, specific vulnerability prior to their death. "The finding presents the possibility of identifying infants at future risk for SIDS and it provides a specific avenue for future research into interventions prior to death."

They hypothesized that the association is evidence of an altered cholinergic homeostasis and claim theirs is the first study to identify a measurable biochemical marker in babies who succumbed to SIDS. The marker "could plausibly produce functional alterations to an infant"s autonomic and arousal responses to an exogenous stressor leaving them vulnerable to sudden death."

Commenting in a press release, Harrington said that "babies have a very powerful mechanism to let us know when they are not happy. Usually, if a baby is confronted with a life-threatening situation, such as difficulty breathing during sleep because they are on their tummies, they will arouse and cry out. What this research shows is that some babies don"t have this same robust arousal response." Despite the sparse data, she believes that BChE is likely involved.

Providing a U.S. perspective on the study but not involved in it, Fern R. Hauck, MD, MS, a professor of family medicine and public health at the University of Virginia, Charlottesville, said that "the media coverage presenting this as the "cause of SIDS," for which we may find a cure within 5 years, is very disturbing and very misleading. The data are very preliminary and results are based on only 26 SIDS cases." In addition, the blood samples were more than 2 years old.

This research needs to be repeated in other labs in larger and diverse SIDS populations, she added. "Furthermore, we are not provided any racial-ethnic information about the SIDS cases in this study. In the U.S., the infants who are at greatest risk of dying from SIDS are most commonly African American and Native American/Alaska Native, and thus, these studies would need to be repeated in U.S. populations."

Hauck added that, while the differences in blood levels of this enzyme were statistically different, even if this is confirmed by larger studies, there was enough overlap in the blood levels between cases and controls that it could not be used as a blood test at this point with any reasonable predictive value.

As the authors pointed out, she said, the leading theory of SIDS causation is that multiple factors interact. "While everyone would be happy to find one single explanation, it is not so simple. This research does, however, bring into focus the issues of arousal in SIDS and work on biomarkers. The arousal issue is one researchers have been working on for a long time."

The SIDS research community has long been interested in biomarkers, Hauck continued. "Hannah Kinney"s first autoradiography study reported decreased muscarinic cholinergic receptor binding in the arcuate nucleus in SIDS, which the butyrylcholinesterase work further elaborates. More recently, Kinney reported abnormal cholinergic binding in the mesopontine reticular formation that is related to arousal and REM."

Moreover, Robin Haynes and colleagues reported in 2017 that differences in serotonin can similarly be found in newborns on a newborn blood test, she said. "Like the butyrylcholinesterase research, there is a lot of work to do before understanding how specifically it can identify risk. The problem with using it prematurely is that it will unnecessarily alarm parents that their baby will die, and, to make it worse, be inaccurate in our warning."

She also expressed concern that with the focus on a biomarker, parents will forget that SIDS and other sleep-related infant deaths have come down considerably in the United States thanks to greater emphasis on promoting safe infant sleep behaviors.

The research was supported by a crowdfunding campaign and by NSW Health Pathology. The authors disclosed no conflicts of interest. Hauck disclosed no conflicts of interest.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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Cite this: Low Butyrylcholinesterase: A Possible Biomarker of SIDS Risk? - Medscape - May 16, 2022.