Butyrylcholiesterase may be key biomarker in SIDS identification, prevention

Investigators may have found a piece of the puzzle into what causes sudden infant death syndrome.

Each year, about 3400 infants die of sudden infant death syndrome (SIDS) in the United States, according to the Centers for Disease Control and Prevention.1 SIDS is categorized as the sudden or unexpected death of a baby aged less than 1 year in which the cause cannot be determined. These deaths happen most often during an infant’s sleep or in the sleeping area. Additionally, experts don’t know which babies are at risk for SIDS or what causes it. Now, a team of Australian investigators say they’ve discovered a piece of the puzzle into its cause, and they say it lies in an enzyme called butyrylcholiesterase (BChE).2

The study, published recently in eBioMedicine, part of The Lancet Discovery Science, highlighted that autonomic dysfunction has been implicated in the pathophysiology of SIDS. BChE, they continued, is an enzyme of the cholinergic system, which is a major branch of the autonomic system and may provide a measure of autonomic (dys)function. With this in mind, a study was undertaken to measure BChE activity in infants and young children who had died from SIDS or Sudden Unexpected Death in Infancy (SUDI).

The study, which was case-controlled, measured BChE activity and total protein in the “eluate of 5μL spots punched from the dried blood spots [DBSs] taken at birth as part of the newborn screening program,” according to the investigators.

These DBSs were collected on post-natal day (PND) 2 to 4 on Whatman 903 filter paper over a 5-year period between 2016 to 2020. The samples where then stored at room temperature.

Children who were categorized as SUDI—who died less than 24 months old between July 20218 and July 2020—were identified using the databases of 3 New South Wales, Australia, forensic pathology sites.

The forensic pathologist’s death classification was used in the study in all but 5 cases. Two cases originally classified as SIDS were changed as SUDI because they were less than or equal to 3 weeks old, 1 case originally labeled SIDS was also changed to SUDI because the subject was more than 52 weeks old, and another 2 cases classified as unknown were changed to SIDS. The investigators noted that all non-SIDS cases had an identified cause of death.

For each SID or SUDI case, 10 date of birth or gender-matched samples of surviving children—who blood spot was taken on the day PND—were identified and used as study controls.

In total, they analyzed 722 DBS which included 67 DBS (58% male) from SUDI infants (26 SIDS, 41 non-SIDS), and 655 controls. The mean age at death for SIDS cases were reported as 15.7 (±8.1) weeks (4 to 36 weeks) and consisted of 54% male subjects. Of the non-SIDS cases, the mean age at death was 31.7 (±30) weeks (1-103 weeks), and was 64% male.

All DBSs were examined for BChE activity and total protein content and BChE specific activity (BChEsa) was calculated. They saw good correlation between the BChE activity of plasma QCs and corresponding DBS QCs (r .84). They noted, however, that the recovery of BChE in DBS QC compared to plasma QC was lower (23.4 ± 2%) than in previous studies. Due to several excluded samples, the study population was reduced to 30 non-SID cases (mean age of death: 23.5 [±30] weeks, range 1-103 weeks; 57% male).

Investigators normalized BChE activity to total protein content to overcome variability in punch location and hematocrit. In turn, there was good recovery of total protein in plasma QC vs its corresponding DBS QC (96.25 ± 11.8%).

Additionally, they reported: “Mean values (± Standard Deviation) for BChEsa for SIDS cases (n = 26) and their controls (n = 254) was 5·6 (±2·1) vs 7·7 (±3·6), respectively, and for non-SIDS cases (n = 30) and their controls (n=291) was 8·5 (±4·2) vs 8·5 (±3·4), respectively.”

Conditional logistic regression showed strong evidence of interaction between BChEsa and cause of death case outcome or control status (P = ·0061). In response to this finding, separate models for SIDS and non-SIDS groups were performed, concluding that the SIDS death group had strong evidence that lower BChEsa was associated with death (OR= 73 per U/mg, 95% CI .60-.89, P = .0014) and the non-SIDS death group had no evidence of a linear association between BChEsa and death (OR= 1.001 per U/mg, 95% CI .89-1.13, P = .99).

Additionally, “there was no evidence of an association between any of the predictors (BCHEsa, gender and cause of death) and age at death, in either univariable or multivariable models,” investigators wrote.

Results showed that a decrease in BChEsa was a biochemical marker distinguishing infants who succumb to SIDs from controls and infants with known causes of death. Investigators hypothesize that these findings are evidence of an altered cholinergic homeostasis and postulate that one could “plausibly produce functional alterations to an infant's autonomic and arousal responses to an exogenous stressor leaving them vulnerable to sudden death.”

Study limitations included difficulties comparing study findings of BChEsa with known BChE reference intervals and that the samples used were 2 years old and would not accurately reflect BChEsa in fresh DBSs. They tried to minimize the effect of long storage times by including 10 date of birth and gender matched, surviving controls per SIDS or non-SIDS case.

Study investigators acknowledged the need for further investigation to determine whether BChE could potentially be used as a biomarker to identify and prevent SIDS deaths.

References:

  1. About SUID and SIDS. Centers for Disease Control and Prevention. Accessed May 16, 2022. https://www.cdc.gov/sids/data.htm
  2. Harrington CT, Hafid NA, Waters KA. Butyrylcholinesterase is a potential biomarker for sudden infant death syndrome. eBioMedicine. 2022;80:104041.

This article was originally published on Contemporary Pediatrics®.