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Disrupted homeostasis in phytosterolemia: a hypothesis inspired by David Mymin, MD

Pediatric Research volume 98, pages 341–342 (2025)Cite this article

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Much of the etiology and pathogenesis of Phytosterolemia has now been elucidated, some 50 years since its recognition. Furthermore, we now have, in the Niemann-Pick C1-like 1 (NPC1L1) inhibitor, ezetimibe, a reasonably effective and well-tolerated treatment.1 Nevertheless, the disorder remains perplexing. We know that Phytosterolemia is caused by a bi-allelic mutation affecting either one of the components of the ABCG5-G8 heterodimer, which encode for the proteins Sterolin 1 and Sterolin 2, either of which is thereby rendered defunct. Both sterolins need to be intact for normal reverse transport of cholesterol and sterols to occur at the enterocyte and hepatocyte levels, failing which, abnormally high levels of cholesterol and sterols in blood and tissues ensue, leading often to pathological consequences. Loss of G5/G8 additionally leads to shellfish sterol accumulation,2 prompting Salen and colleagues to suggest that the disease should be referred to as xenosterolemia.3 In addition, total sterols are increased in cells but these are esterified pools- the free sterols seem about the same and that even when plasma is examined, the total sterols are not elevated, though cholesterol is reduced and replaced by xenosterols. However, this simple sterolin deficit model leaves us well short of a full understanding of the disorder.

Herein concerns are discussed: there is an obvious paradox in that cholesterol levels are often normal or moderately elevated in Phytosterolemia whereas the phenotype of defunct sterolin activity would lead one to expect the norm to be very high cholesterol levels.4 Indeed, in Bhattacharyya and Connor’s original report of the condition, their two patients had normal cholesterol levels of 193 and 206 mg/dL, respectively.5

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Acknowledgements

This manuscript is dedicated to the memory of our friend and colleague Dr. David Mymin, MD, former Associate Professor of Internal Medicine and Director of the Lipid Clinic at the University of Manitoba. Supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) (RGPIN-05368-2019).

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Authors and Affiliations

  1. Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada

    Patrick C. Choy

  2. Department of Pharmacology & Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada

    Grant M. Hatch

  3. Childrens Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada

    Grant M. Hatch

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  1. Patrick C. Choy
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  2. Grant M. Hatch
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G.M.H. wrote the manuscript and was responsible for conceptual development. G.M.H. and P.C.C. edited the manuscript.

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Correspondence to Grant M. Hatch.

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Choy, P.C., Hatch, G.M. Disrupted homeostasis in phytosterolemia: a hypothesis inspired by David Mymin, MD. Pediatr Res 98, 341–342 (2025). https://doi.org/10.1038/s41390-025-03849-w

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