Glucose-6-Phosphatase Catalytic Subunit 3 (G6PC3) Deficiency Associated With Autoinflammatory Complications

Abstract

G6PC3 deficiency typically causes severe congenital neutropenia, associated with susceptibility to infections, cardiac and urogenital abnormalities. However, here we describe two boys of Pakistani origin who were found to have G6PC3 deficiency due to c.130 C>T mutation, but who have clinical phenotypes that are typical for a systemic autoinflammatory syndrome. The index case presented with combination of unexplained fevers, severe mucosal ulcers, abdominal symptoms, and inflammatory arthritis. He eventually fully responded to anti-TNF therapy. In this study, we show that compared with healthy controls, neutrophils and monocytes from patients have reduced glycolytic reserve. Considering that healthy myeloid cells have been shown to switch their metabolic pathways to glycolysis in response to inflammatory cues, we studied what impact this might have on production of the inflammatory cytokines. We have demonstrated that patients’ monocytes, in response to lipopolysaccharide, show significantly increased production of IL-1β and IL-18, which is NLRP3 inflammasome dependent. Furthermore, additional whole blood assays have also shown an enhanced production of IL-6 and TNF from the patients’ cells. These cases provide further proof that autoinflammatory complications are also seen within the spectrum of primary immune deficiencies, and resulting from a wider dysregulation of the immune responses.

CDG and immune response: From bedside to bench and back

“…Concerning autoimmune and inflammatory manifestations, anticholinesterase inhibitors and steroids have had fluctuating beneficial effects on CDG patients presenting with autoimmune myasthenia gravis . Anti‐inflammatory and immunosuppressive agents have been employed to manage IBD in G6PC3‐CDG . Interestingly, in two GALNT3‐CDG patients with generalized inflammation and foamy macrophages a treatment regimen with IL‐1 antagonists resulted in decreased inflammatory markers, reduced tumor burden and improved general health in both subjects.…”

Remission of Inflammatory Bowel Disease in Glucose-6-Phosphatase 3 Deficiency by Allogeneic Haematopoietic Stem Cell Transplantation

“…23 The effects on energy generation, increased ER stress and impaired superoxide production may contribute to myeloid cell dysfunction. 14,23,27…”

“…IBD-like colitis has been described in at least 8% of patients with G6PC3 deficiency. 14,24 Patients present with Crohn’s-like inflammation, frequent stricture formation and severe oral aphthous ulceration. 12–14,24 Myeloid cells are particularly dependent on G6PC3, lacking compensatory alternative phosphatases [Supplementary Figures 1–3].…”

A Case of Adult-Onset Still’s Disease Caused by a Novel Splicing Mutation in TNFAIP3 Successfully Treated With Tocilizumab

“…Measurements were taken for 7 CAPS patients which also represent a pro-inflammatory response although not as profound as the HA20 response. ASC specs were measured as previously described ( 11 ).…”

“…Non-fluorescent microspheres (1 mm) (Cat. F13838 Thermo Fisher Scientific, UK) were used for gating and ASC specks were quantified in comparison to healthy controls (ASC speck/mL) as previously described ( 11 ). We found that patient serum contained significantly higher numbers of ASC specks compared with our healthy control range (Figure 3 I).…”