CHARACTERIZATION OF A SERIES OF PATIENTS WITH GNE-RELATED THROMBOCYTOPENIA: INSIGHTS INTO PATHOGENESIS, DIAGNOSIS, AND TREATMENT.

BACKGROUND: GNE-related thrombocytopenia (GNE-RT) is a very rare disorder caused by biallelic variants in GNE, encoding a key enzyme for the sialic acids biosynthesis. Patients usually present severe thrombocytopenia and excessive bleeding. Knowledge about this condition is still poor. There are no recognized tools for diagnosis. Previous study of one patient showed reduced platelet half-life as a mechanism of thrombocytopenia; however, it is still unclear if the sialylation defect also impairs platelet biogenesis. OBJECTIVES: To gain insights into clinical aspects and platelet biogenesis in GNE-RT. METHODS: We investigated 4 novel GNE-RT patients (3 families). A recently standardized flow cytometry assay was applied to characterize platelet sialylation. Patients' megakaryocytes were cultured to study megakaryopoiesis and proplatelet formation. A validated three-dimensional bone marrow model was exploited to investigate platelet production. RESULTS: We characterized 3 novel GNE variants, demonstrating the pathogenicity of 2 VUS. In all individuals, platelet flow cytometry detected an obvious increase in RCA-1 and ECL lectins binding and decreased MAL-II binding. Sialylation of serum transferrin did not show straightforward alterations. Although presenting the sialylation defect, patients' megakaryocytes showed preserved differentiation, maturation, and proplatelet formation. Megakaryocytes generated ex-vivo a normal number of normal-sized platelets. Two patients received Eltrombopag, achieving a durable clinical response (38- and 72-month follow-up). CONCLUSIONS: The profound megakaryocyte sialylation defect induced by GNE variants does not affect platelet biogenesis. Platelet flow cytometry for RCA-1 and MAL-II binding is a reliable and simple assay for diagnosis of GNE-RT. Based on literature review, 55% of GNE-RT patients responded to thrombopoietin-mimetics.