Butyrylcholesterase may be a key biomarker in identifying and preventing SIDS
Every year, about 3,400 infants die from sudden infant death syndrome (SIDS) in the United States, according to the Centers for Disease Control and Prevention.1 SIDS is classified as the sudden or unexpected death of a baby under the age of one year whose cause cannot be determined. These deaths most often occur while the infant is sleeping or in the sleeping area. Also, experts don’t know which babies are at risk for SIDS or what causes it. Now a team of Australian researchers say they have discovered a piece of the puzzle in its cause, and they say it lies in an enzyme called butyrylcholiesterase (BChE).2
The study, recently published in eBioMedicine, part of The Science of Lancet Discovery, pointed out 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 can 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 died of SIDS or Sudden Unexpected Infant Death Syndrome (SUDI).
The study, which was case-control, measured BChE activity and total protein in “the eluate of 5 μL spots taken from the dried blood spots [DBSs] taken at birth as part of the newborn screening program,” according to the investigators.
These DBS were collected on postnatal day (PND) 2 to 4 on Whatman 903 filter paper over a 5-year period between 2016 and 2020. The samples were then stored at room temperature.
Children classified as SUDI – who died under the age of 24 months between July 20218 and July 2020 – were identified using databases from 3 forensic pathology sites in New South Wales, Australia.
The medical examiner’s classification of deaths was used in the study in all but 5 cases. Two cases originally classified as SIDS were changed to SUDI because they were less than or equal to 3 weeks old, 1 case initially labeled SIDS was also changed to SUDI because the subject was over 52 weeks old, and 2 other cases classified as unknown were changed to SIDS. Investigators noted that all cases other than SIDS had an identified cause of death.
For each SID or SUDI case, 10 samples of surviving children matched by date of birth or sex – whose blood spot was taken on the day of the PND – were identified and used as study controls.
In total, they analyzed 722 DBS, including 67 DBS (58% male) from SUDI infants (26 SIDS, 41 non-SIDS) and 655 controls. The mean age at death of SIDS cases was 15.7 (± 8.1) weeks (4 to 36 weeks) and included 54% male subjects. Among cases other than SIDS, the mean age at death was 31.7 (± 30) weeks (1 to 103 weeks) and 64% were male.
All DBS were examined for BChE activity and total protein content and specific BChE activity (BChEsa) was calculated. They found a good correlation between the BChE activity of plasma CQs and the corresponding DBS CQs (r 0.84). They noted, however, that the recovery of BChE in CQ DBS compared to CQ plasma was lower (23.4 ± 2%) than in previous studies. Due to several excluded samples, the study population was reduced to 30 non-AIDS cases (mean age at death: 23.5 [±30] weeks, range 1-103 weeks; 57% men).
The researchers normalized BChE activity against total protein content to overcome variability in punch location and hematocrit. In turn, there was a good recovery of total protein in plasma CQ compared to its corresponding DBS CQ (96.25 ± 11.8%).
Additionally, they reported, “Mean (± standard deviation) BChEsa values for SIDS cases (n=26) and their controls (n=254) were 5 6 (±2 1) versus 7 7 (±3 6 ), respectively, and for non-MSN cases (n = 30) and their controls (n = 291) was 8 5 (±4 2) versus 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 the 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 0.60-.89, P=0.0014) and the non-SIDS death group had no evidence of a linear association between BChEsa and death (OR=1.001 per U/mg, CI 95% 0.89-1.13, P = 0.99).
Additionally, “there was no evidence of an association between any of the predictors (BCHEsa, sex, and cause of death) and age at death, in either univariate or multivariate models,” the investigators wrote.
The 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. The investigators hypothesize that these findings are evidence of altered cholinergic homeostasis and posit that one could “plausibly produce functional alterations in an infant’s autonomic and arousal responses to an exogenous stressor.” making him vulnerable to sudden death”.
Limitations of the study included difficulties in comparing study results of BChEsa with known BChE reference ranges and the fact that the samples used were 2 years old and would not accurately reflect BChEsa in fresh DBS. They tried to minimize the effect of long storage times by including 10 surviving controls matching date of birth and sex per SIDS or non-SIDS case.
Study researchers acknowledged the need for further investigation to determine whether BChE could potentially be used as a biomarker to identify and prevent SIDS deaths.
- About SUID and SIDS. Centers for the Control and Prevention of Disasters. Accessed May 16, 2022. https://www.cdc.gov/sids/data.htm
- Harrington CT, Hafid NA, Waters KA. Butyrylcholinesterase is a potential biomarker of sudden infant death syndrome. eBioMedicine. 2022;80:104041.