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Novel GNE gene variants associated with severe congenital thrombocytopenia and platelet sialylation defect – follow up data after hematopoietic stem cell transplantation

1Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Baden-Wurttemberg, Germany, 2Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Baden-Wurttemberg, Germany, 3Translational Glycomics Center, Versiti Blood Research Institute, Milwaukee, Wisconsin, United States, 4Versiti Blood Research Institute, Milwaukee, Wisconsin, United States, 5Clinic for Pediatric and Adolescent Medicine, SLK-Kliniken Heilbronn, Heilbronn, Baden-Wurttemberg, Germany, 6Pediatric Genetics Section, Department of Pediatrics, University of Freiburg, Freiburg, Baden-Wurttemberg, Germany, 7Department of Pediatrics, Children's University Hospital, University of Tübingen, Tübingen, Baden-Wurttemberg, Germany, 8Versiti Translational Glycomics Center, Milwaukee, Wisconsin, United States

Abstract Number: OC 64.3

Meeting: ISTH 2022 Congress

Theme: Platelet Disorders, von Willebrand Disease and Thrombotic Microangiopathies » Inherited Thrombocytopenias

Background: The GNE gene encodes an enzyme that initiates and regulates the biosynthesis of N-acetylneuraminic acid, a precursor of sialic acids. GNE mutations are classically associated with Nonaka myopathy and sialuria, following an autosomal recessive and autosomal dominant inheritance pattern. Single patients have been described with GNE variants, which only cause isolated thrombocytopenia.

Aims: To characterize the platelet defect in a young girl (6 month old) with life-threatening intracranial bleeding and severe congenital thrombocytopenia (lowest platelet count 5 G/L), who needed weekly platelet transfusions.

Methods: Bone marrow analysis and comprehensive analyses for inherited thrombocytopenia: blood smear, platelet aggregometry (LTA), platelet flow cytometry (FC) and lectin array analysis of platelet glycoproteins. Molecular analysis was performed by HTS panel and direct sequencing. Protein modelling using PyMOL.

Results: Bone marrow analysis indicated slightly increased megakaryopoiesis with mature megakaryocytes of normal morphology and hypolobulated, immature cells. LTA showed severe impaired response to Col, ADP, and Epi. FC showed moderately impaired VWF-binding after stimulation with ristocetin and severely decreased agonist-induced alpha and dense granules secretion. HTS identified two novel compound heterozygous variants in GNE (NM_005476.6:c.1250C>T and c.1259G>A.). Both alterations (p.Thr417Met and p.Arg420Gln) are located in the nucleotide-binding site of the N-acetylmannosamin kinase domain of GNE. Crystal structure of GNE kinase domain in complex with ADP shows the hydrogen-bonding interactions of T417 and R420 with ADP and in silico mutations of T417M and R420Q suggest disruption of ADP binding. Lectin array showed decreased α-2,3 sialylation on platelets, consistent with loss of sialic acid synthesis and indicative of rapid platelet clearance.

Conclusion(s): The findings led to hematopoietic stem cell transplantation (HSCT) which normalized platelet counts (follow up 15 months after HSCT: 423 G/L, no signs of myopathy). The child developed normally. To our knowledge, this was the first time that HSCT was successfully performed in a patient with GNE defect.

To cite this abstract in AMA style:

Zieger B, Boeckelmann D, Anani W, Falet H, Zhu J, Glonnegger H, Full H, Andresen F, Erlacher M, Lausch E, Fels S, Strahm B, Lang P, Hoffmeister K. Novel GNE gene variants associated with severe congenital thrombocytopenia and platelet sialylation defect – follow up data after hematopoietic stem cell transplantation [abstract]. https://abstracts.isth.org/abstract/novel-gne-gene-variants-associated-with-severe-congenital-thrombocytopenia-and-platelet-sialylation-defect-follow-up-data-after-hematopoietic-stem-cell-transplantation/. Accessed September 29, 2023.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/novel-gne-gene-variants-associated-with-severe-congenital-thrombocytopenia-and-platelet-sialylation-defect-follow-up-data-after-hematopoietic-stem-cell-transplantation/