eP017: GNE gene variants associated with thrombocytopenia with or without GNE myopathy


      GNE Myopathy is a rare, degenerative skeletal muscle disease, first presenting with anterior tibialis weakness then progressing proximally, relatively sparing the quadriceps. Symptoms usually develop in early adulthood (between 20-40 years) and include bilateral foot drop and rimmed vacuoles on muscle biopsy. Most patients become wheelchair dependent within a decade after onset. Upper limbs are usually involved around a decade later than the lower limbs. GNE myopathy is caused by biallelic variants in GNE, which encodes the rate limiting bifunctional enzyme in sialic acid synthesis, UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE), leading to decreased sialic acid production. Sialic acid is a negatively charged sugar, that serves as the terminal sugar of many N- and O-linked glycoproteins; it serves many functions in cell interactions and signaling. Recently, GNE variants have been associated with thrombocytopenia, with or without manifestations of myopathy. To investigate this phenomenon, we performed a literature review and analyzed data of patients in our GNE myopathy prospective natural history (NH) study.


      Data were collected through a prospective NH study of individuals with GNE myopathy (NCT1417533). Patients are admitted to the NIH Clinical Center for investigations, including physical function tests, questionnaires, blood analysis (including a complete blood count at each visit), and cardiac and pulmonary function tests. Patient platelet data were compared to normal values. For the literature review, two authors performed a search of all reports including GNE and thrombocytopenia. Clinical manifestations as well as variants identified were compared to those of our cohort.


      We analyzed a total of 126 platelet counts obtained from 51 GNE myopathy patients (61% female), between 21 and 65 years of age at their baseline to our NH study, with at least one platelet count obtained during subsequent visits. The average platelet count for females was 251 X 109 cells/L (range 144–390) and 205 X 109 cells/L for males (range 103-300), which are within the normal range for our laboratory (173–369 and 161-347, respectively). However, these values are lower than the expected means of 271 for females (p < 0.001) or 254 for males (p < 0.0001), based upon our lab’s normal ranges. A total of 8 individuals were below the normal range at some point, but above the pathologic thrombocytopenia cutoff (100). None presented signs of thrombocytopenia.
      The literature review yielded 25 patients with thrombocytopenia (17 without myopathy and 8 with myopathy) and biallelic GNE variants. The GNE variants in the 25 patients included 7 novel variants not reported in individuals with GNE myopathy and 11 variants previously associated with GNE myopathy. The novel variants were not localized to specific functional GNE domains but were scattered across the entire GNE gene and found in Chinese, European, Pakistani, Thai, and Palestinian Arab populations. None of our 51 NH study patients had any of the 18 GNE variants associated with thrombocytopenia.


      Although there was no evident thrombocytopenia in our NH study cohort, the average platelet count was slightly lower than expected, suggesting a potential role of GNE in platelet survival. Previous studies indicate that sialic acid has a significant role in platelet function. Mice deficient in a sialyltransferase had decreased sialic acid and platelet survival times, leading to thrombocytopenia. Patients with GNE myopathy and thrombocytopenia had increased reticulated platelets, suggesting that pathogenic GNE variants may contribute to platelet surface hyposialylation, resulting in increased platelet clearance by the Ashwell-Morell receptor.
      Patients with GNE-related thrombocytopenia should be followed for developing signs of GNE myopathy, since most reported individuals were likely too young to develop signs of GNE myopathy. The addition of GNE on gene panels for platelet disorder gene panels should also be promoted. GNE myopathy patients should also have their platelets assessed and monitored. To better characterize this phenomenon, we have expanded our NH study to include other (non-muscle) GNE-related clinical conditions and younger individuals.