In the category of “Interesting and Very Likely to Cause People to Overreact and Leap to Conclusions,” this new article showed an association between medications that inhibit cholesterol synthesis when used during pregnancy and a diagnosis of autism. In a database of over 6 million children along with maternal records, exposure to one of these medications was associated with a 47% increased risk of autism diagnosis, with a 33% increased risk for each additional co-prescription of another drug interfering with cholesterol synthesis.
Statins were included in this analysis, which is no surprise given they inhibit cholesterol synthesis via the enzyme HMGCR, but here is a list of additional medications affecting cholesterol synthesis that probably weren’t on your Bingo card:
-Fluoxetine
-Sertraline
-Aripiprazole
-Trazodone
-Haloperidol
-Bupropion
-Buspirone
-Metoprolol, Propranolol, Nebivolol (all 3 of these are beta blockers)
Most of these medications inhibit the enzyme 7-dehydrocholesterol reductase (DHCR7), which is the last enzymatic step in the Kandutsch-Russell pathway of cholesterol biosynthesis. If this step is inhibited, it leads to increased 7-DHCR (and its isomer sibling 8-DHCR) and decreased levels of cholesterol. (For more on the bifurcated cholesterol synthesis pathway, including the Bloch pathway, desmosterol, DHCR24, and its potential relevance to Alzheimer’s Disease, check out this podcast where I discuss this HERE).
Could there be consequences for this? Well, there is a genetic condition called Smith-Lemli-Opitz Syndrome (SLOS), which is a defect in DHCR7, and when there are that many hyphens, you know it’s serious! And these folks have high 7-DHCR and low cholesterol. Given that 7-DHCR is very susceptible to peroxidation and that 20-25% of total body cholesterol is in the brain, this can lead to a wide variety of problems.
So what happens in SLOS? Well, intellectual disability is quite common…75% of those with SLOS are also on the autism spectrum. Other birth defects are common due to defects in Sonic Hedgehog Signaling, which is a cholesterol-dependent pathway important in early development (if there’s not enough Sonic, who is a speedy hedgehog, then you might have SLO syndrome. And Sonic collects RINGS in the original video games, and cholesterol is a 4-RINGED structure). Pretty much everything in life is somehow related to 1990s video games and cholesterol!
Cholesterol is super important in bile acid synthesis and gonadal development, so digestive and genital issues are common. And the lens of the eye is a very cholesterol-rich structure, so premature cataracts can also occur!
The clinical presentation of SLOS is highly variable, but here is a little acronym that might help some of you medical students out there remember just a few of the potential anomalies:
S-Small head and stature (microcephaly and growth restriction)
L-Liver issues (typically cholestatic in nature due to bile/gall bladder dysfunction)
O–Ophthalmologic anomalies (such as cataracts)
S-Syndactyly (You’ll probably run SLO if you’ve got a webbed TOE)
And there are other potential organ systems, such as the kidneys, that can be affected as well. Curiously, those with SLOS actually have elevated vitamin D levels, since 7-DHCR is the precursor for vitamin D synthesis. It’s all connected…from the brain to the bile to the epidermis to the epididymis… it’s all about lipids!
So anyway, there is some interesting stuff here. The autism spectrum is incredibly vast and heterogeneous; the true reason or litany of reasons that two people may carry that same diagnosis is likely different; there is so much we need to learn. But maybe the spectrum of Lipid Disorders can help us better understand the Autism Spectrum…here’s to hoping!
