Platelet proteomic profiling in sitosterolemia suggests thrombocytopenia is driven by lipid disorder and not platelet aberrations

Sitosterolemia is a rare autosomal-recessive genetic disorder in which patients develop hypercholesterolemia, and may exhibit abnormal hematologic and/or liver test results. In this disease, dysfunction of either ABCG5 or ABCG8 results in intestinal hyperabsorption of all sterols, including cholesterol and more specifically plant sterols or xenosterols, as well as in the impaired ability to excrete xenosterols into the bile. It remains unknown how and why some patients develop hematologic abnormalities. Only a few unrelated patients with hematologic abnormalities at the time of diagnosis have been reported. Here, we report on two unrelated pedigrees who were believed to have chronic immune thrombocytopenia as most prominent feature. Both consanguineous families showed recessive gene variants in ABCG5, that were associated with disease by in-silico protein structure analysis as well as clinical segregation. Hepatosplenomegaly was absent. Thrombopoietin levels and megakaryocyte numbers in bone marrow were normal. Metabolic analysis confirmed the presence of strongly elevated plasma levels of xenosterols. Potential platelet proteomic aberrations were longitudinally assessed following dietary restrictions combined with the administration of the sterol absorption inhibitor ezetimibe. No significant effects on platelet protein content before and after onset of treatment were demonstrated. Although we cannot exclude that lipotoxicity has a direct and platelet-specific impact in patients with sitosterolemia, our data suggest that the thrombocytopenia is neither caused by a lack of megakaryocytes nor driven by proteomic aberrations of the platelets themselves.