Severe Congenital Thrombocytopenia Characterized by Decreased Platelet Sialylation and Moderate Complement Activation Caused by Novel Compound Heterozygous Variants in GNE

Abstract

BackgroundHereditary thrombocytopenias constitute a genetically heterogeneous cause of increased bleeding. We report a case of a 17-year-old boy suffering from severe macrothrombocytopenia throughout his life. Whole genome sequencing revealed the presence of two compound heterozygous variants in GNE encoding the enzyme UDP-N-acetyl-glucosamine-2-epimerase/N-acetylmannosamine kinase, crucial for sialic acid biosynthesis. Sialic acid is required for normal platelet life span, and biallelic variants in GNE have previously been associated with isolated macrothrombocytopenia. Furthermore, sialic acid constitutes a key ligand for complement factor H (FH), an important inhibitor of the complement system, protecting host cells from indiscriminate attack.MethodsSialic acid expression and FH binding to platelets and leukocytes was evaluated by flow cytometry. The binding of FH to erythrocytes was assessed indirectly by measuring the rate of complement mediated hemolysis. Complement activation was determined by measuring levels of C3bBbP (alternative pathway), C4d (classical/lectin pathway) and soluble terminal complement complex assays.ResultsThe proband exhibited markedly decreased expression of sialic acid on platelets and leukocytes. Consequently, the binding of FH was strongly reduced and moderate activation of the alternative and classical/lectin complement pathways was observed, together with an increased rate of erythrocyte lysis.ConclusionWe report two previously undescribed variants in GNE causing severe congenital macrothrombocytopenia in a compound heterozygous state, as a consequence of decreased platelet sialylation. The decreased sialylation of platelets, leukocytes and erythrocytes affects the binding of FH, leading to moderate complement activation and increased hemolysis.

Hereditary thrombocytopenia with platelet sialic acid deficiency and mutations in the GNE genes

“…More recently, mutations have been identified in which the thrombocytopenia is the predominant clinical feature and there is an apparent absence of any myopathy. [16][17][18][19][20] The severity of the thrombocytopenia has also varied considerably between these patients as well as associated clinical features. Only approximately 13 cases have been described with isolated thrombocytopenia all in either Europe [16][17][19][20] or Asia, 18,21 and our case may be the first report in the US.…”

“…[16][17][18][19][20] The severity of the thrombocytopenia has also varied considerably between these patients as well as associated clinical features. Only approximately 13 cases have been described with isolated thrombocytopenia all in either Europe [16][17][19][20] or Asia, 18,21 and our case may be the first report in the US. Our case is similar to one report which showed altered platelet expression of CD42b and CD41 16 and to another report which showed a response in the platelet count in the two patients to the parenteral TPO-mimetic romiplostim.…”

Inherited Thrombocytopenia Caused by Variants in Crucial Genes for Glycosylation

“…Recently, new patients carrying biallelic variants of GNE have been published [ 45 , 46 ], however, it is still unclear why some patients present with isolated thrombocytopenia while others present with myopathy. Considering that GNE-related myopathy usually appears in the third decade of life, we cannot exclude that patients presenting with only thrombocytopenia develop myopathy later in life [ 40 ].…”

Hemostatic defects in congenital disorders of glycosylation

“…In line with these data, platelets from patients with SLC35A1-CDG were cleared very quickly (relative to control platelets) after injection into mice [ 45 ]. Similarly, another CDG related to a deficiency in GNE is reportedly associated with macrothrombocytopenia, [ [47] , [48] , [49] , [50] , [51] ] Data on this novel pathogenic variant were presented at the ISTH 2022 congress. Similar to SLC35A1-CDG, GNE-CDG might be associated with platelet hyposialylation and thus accelerated hepatic clearance—as evidenced by Noordermeer et al.…”