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, which encodes a key enzyme in sialic acid biosynthesis. Patients usually present with severe thrombocytopenia and excessive bleeding. Knowledge of this condition remains limited. There are no recognized diagnostic tests for the diagnosis of GNE-RT. A previous study showed reduced platelet half-life as a mechanism of thrombocytopenia; however, it remains unclear whether the sialylation defect also impairs platelet biogenesis. OBJECTIVES: To gain insights into the clinical aspects and platelet biogenesis of GNE-RT. METHODS: We investigated 4 new GNE-RT patients (3 families). A recently standardized flow cytometry assay was used to characterize platelet sialylation. Patients' megakaryocytes were cultured to study megakaryopoiesis and proplatelet formation. A validated 3-dimensional bone marrow model was used to investigate platelet production. RESULTS: We characterized 3 novel GNE variants and demonstrated the pathogenicity of 2 variants of uncertain significance. In all individuals, platelet flow cytometry showed increased RCA-1 and ECL lectin binding and decreased MAL-II binding. Sialylation of serum transferrin showed no clear alterations. Despite the sialylation defect, patients' megakaryocytes showed preserved differentiation, maturation, and proplatelet formation. Ex vivo, megakaryocytes produced a normal number of normal-sized platelets. Two patients received eltrombopag and achieved a durable clinical response (38- and 72-month follow-up). CONCLUSION: The profound megakaryocyte sialylation defect induced by GNE variants does not affect platelet biogenesis. Platelet flow cytometry assessing RCA-1 and MAL-II binding is a reliable, simple assay for diagnosing GNE-RT. Based on a literature review, 55% of GNE-RT patients respond to thrombopoietin mimetics.