Treatment and Follow-up Data for Young Patients with a Gne Defect and Congenital Thrombocytopenia

Congenital thrombocytopenia can be associated not only with a reduced production, but also with an accelerated degradation of platelets. Sialic acid binds to platelet surface glycoproteins and protects platelets from degradation via the Ashwell-Morell receptor. The GNE gene encodes an enzyme that initiates and regulates the biosynthesis of N-acetylneuraminic acid, a precursor of sialic acids. According to OMIM alterations in GNE are autosomal recessive associated with adult-onset progressive GNE myopathy (with or without thrombocytopenia) and autosomal dominant with sialuria. In recent years, biallelic GNE mutations located mainly in the N-acetylmannosamine (ManNAc) kinase domain of GNE have been described in children/young adults with otherwise unexplained thrombocytopenia.

Recently, we identified compound heterozygous GNE variants in a young girl (Pt.1) with life-threatening intracranial bleeding and severe congenital thrombocytopenia (lowest platelet count 5 x 10⁹/L), who needed weekly platelet transfusions. We showed decreased α2,3 sialic acid and increased terminal galactose and α2,6 sialic acid moieties in the girl´s platelets. She received hematopoietic stem cell transplantation (HSCT) at 2,3 years, which normalized platelet counts and function. Follow-up data showed normalized platelet function (20 months after HSCT) and counts (20, 21, and 23 months after HSCT). Following HSCT, the platelet lectin profile was markedly different from before transplantation with an increase in α2,3 sialic acid recognizing lectins WGA and MAL I compared with data before transplantation, indicating that sialic acid moieties have been normalized.

Additionally, we identified a biallelic GNE variant in two siblings (Pt.2 and Pt.3) affected by congenital thrombocytopenia. Pt.2 is a 1,8-year-old boy with thrombocytopenia since birth (lowest platelet count 6 x10⁹/L) who needed weekly platelet transfusions. His 17-year-old sister (Pt.3) presented with lifelong thrombocytopenia and suspected chronic immune thrombocytopenia; however, therapy with immunoglobulin and steroids did not elevate the platelets. The parents and two other siblings were clinically not affected. Flow cytometry performed for the affected siblings showed severely decreased thrombin-induced platelet CD62 and CD63 exposure hinting at an impaired α- and δ-granule secretion. NGS identified a homozygous GNE variant (NM_001128227.3:c.1727G>C, p.Gly576Ala) with damaging prediction to be present in both siblings. The parents and two healthy siblings are heterozygous carriers of this variant. The nucleotide change c.1726G>C leading to Gly576Arg has been described compound heterozygous in a patient with GNE myopathy. For the sister (Pt.3) lectin binding analysis showed decreased α-2,3 sialylation (MAA) and increased terminal galactose (RCA120) expression on platelets. This pattern is consistent with loss of sialic acid synthesis and indicative of rapid platelet clearance. She had received therapy with romiplostim since she was 12, resulting in stable platelet counts (> 50 x10⁹/L). At the age of 1 year, Pt.2 also started with romiplostim therapy. During the 8-month treatment, platelet counts were mainly stable above 30 x 10⁹/L. Only two transfusions were necessary when platelet counts dropped to 18 and 11 x 10⁹/L.

In conclusion, this research elucidates novel associations between GNE mutations, specifically within the ManNAc kinase domain, and congenital thrombocytopenia. These findings were derived from studying three patients carrying such mutations, underscoring this discovery's potential broad relevance. Importantly, this alteration in the GNE gene, traditionally associated with GNE myopathy, prompts us to anticipate and closely monitor the potential future development of this neuromuscular condition in these patients.

Of particular interest is the effectiveness of romiplostim in ameliorating thrombocytopenia in these cases. Both siblings in our study exhibited stable, acceptable platelet counts in response to this therapy, suggesting that romiplostim might offer a promising therapeutic strategy for managing congenital thrombocytopenia linked to GNE mutations.