One of the many, many worries that hover around the minds of new parents is the possibility of “crib death”, Sudden Infant Death Syndrome. SIDS has been an unexplained problem for a very long time, long enough to where it was probably the improvements in public and natal health during the 20th century that made it possible to recognize. Gradually other common causes of infant death receded to leave a residue of unexplained cases: apparently normal babies who would take naps and die, for no reasons that anyone could pinpoint.
You can see how this might add to the general uncertainties of being a new parent! I well recall that era in our own household, now well over twenty years back. The advice on what position your infant should sleep in (back? stomach? side?) actually changed in between our first child and our second, which wasn’t so helpful, and I’m pretty sure it changed again after that. We fortunately lost track after our children aged out of the risk demographic, but when the risk demographic is just “any babies that fall asleep”, what is anyone to do? The theories and suggested actions multiplied beyond counting over the decades, but nothing ever seemed to do any good. At the back of every parents’ mind was the worry that there must be something you could do to protect your infant, but no one could tell you what it might be. If something happened, if the worst happened, then would it be your fault for not having taken enough care? Welcome to parenthood.
One of the really interesting possibilities about SIDS is that it might be a problem with the autonomic nervous system – brainstem stuff to do with heartrate, breathing, waking from sleep, and so on. There’s been some accumulating evidence there, and now a new paper has a very strong correlation (and a potential diagnostic) to add to it. A team from Australia studied the newborn blood spot samples of infants who had later died of SIDS versus matched controls of surviving infants and those who died of other causes. They were looking for butyrylcholinesterase activity, BChE, and the SIDS samples showed strong and very significantly lower BchE activity compared to the controls. It’s really quite a dramatic effect, especially considering the amount of effort that’s been put in over the years to distinguish SIDS cases from other infants.
it’s worth a bit of detail about why they would have picked that enzyme. Despite that name, butyrylcholinesterase does not hydrolyze butyrylcholine esters in the body – we don’t actually have butyrylcholine esters, although we have a number of others, chiefly acetylcholine (ACh). That is a famous neurotransmitter, secreted and recycled in nerve terminals across the body and the brain, where it is picked up on the other side of the synapse by muscarinic and nicotinic receptors. Acetylcholinesterase is the equally famous enzyme that hydrolyzes Ach, and it’s really an enzyme’s idea of an enzyme. It’s amazingly efficient and active, and the chemical inhibitors of it are known to the world as insecticides and nerve gases (you really do not want anything messing with all that AchE activity). But what about “butyrylcholinesterase“, then?
That’s a different-but-similar enzyme with somewhat broader specificity for choline esters. Also known as “pseudocholinesterase”, it’s found in blood serum and in the liver, among other places, and elevated levels of it are in fact a sign of liver damage leaking it into the circulation. You can tell the difference between it and acetylcholinesterase by giving them both some synthetic butyrylcholine to work on: acetylcholinesterase won’t hydrolyze it, but pseudocholinesterase will. It will also hydrolyze the ester linkages in cocaine, while acetylcholinesterase won’t – if you engineer mice to have higher levels of butyrylcholinesterase (or a more catalytically active form of it), you prevent them from become addicted on cocaine exposure, since it gets cleared so much more rapidly. Injected butyrylcholinesterase is also a remedy for nerve gas exposure, soaking up the dangerous agents in the bloodstream before they can do further harm. The traditional view of BChE is that it’s just some sort of general detoxifying enzyme, a nonspecific esterase.
It’s been speculated for many years, though, that butyrylcholinesterase may have functions in the autonomic nervous system that different from acetylcholinesterase. There are populations of neurons that have more BChE than others, but no one is quite sure why. It’s been suggested as a target in Alzheimer’s disease (its levels and activity do change with increasing levels of dementia), but the etiology there (as with all Alzheimer’s ideas) is not clear, and as a marker for inflammation or malnutrition. Adults with dysfunctional BChE mutations appear normal, though. But this study is going to make people re-evaluate that, and rather quickly. If its hypothesis is correct, low BChE in infants is a strong marker of dysfunctional neurotransmission, with fatal consequences. It could be that the adults with low BChE activity are the ones with some sort of compensatory mechanism that gave them a higher survival chance?
The weight of the evidence is getting stronger that SIDS infants die because of some sort of neurotransmission problem, and this new work suggests that the problem is innate, present from birth, and can potentially be screened for. What to do about it is another question! Perhaps high-risk infants could be given supplemental BChE intravenously? It has a fairly long half-life, I believe – that might even be practical. But one immediate effect of this work is (or should be) to reassure parents: SIDS is not happening because of something you did, or failed to do. It is not your fault. It is a subtle birth defect, and now it’s up to us to address it and learn the details.
