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

Area of Science:

• Immunology
• Genetics
• Metabolic Disorders

Background:

• G6PC3 deficiency usually presents as severe congenital neutropenia with associated infections and organ abnormalities.
• Autoinflammatory syndromes are characterized by recurrent episodes of systemic inflammation.
• Primary immune deficiencies can sometimes overlap with autoinflammatory conditions.

Purpose of the Study:

• To investigate the clinical phenotype of G6PC3 deficiency in two Pakistani boys.
• To explore the metabolic and inflammatory profiles of neutrophils and monocytes in patients with G6PC3 deficiency.
• To determine the impact of G6PC3 deficiency on inflammatory cytokine production.

Main Methods:

• Clinical case description and genetic analysis (c.130 C>T mutation in G6PC3).
• Assessment of glycolytic reserve in neutrophils and monocytes.
• In vitro stimulation assays (lipopolysaccharide) to measure cytokine production (IL-1β, IL-18, IL-6, TNF).
• Evaluation of treatment response to anti-TNF therapy.

Main Results:

• Two boys with G6PC3 deficiency presented with symptoms of systemic autoinflammatory syndrome, including fever, ulcers, and arthritis.
• Patients' neutrophils and monocytes showed a reduced glycolytic reserve.
• Monocytes exhibited increased production of IL-1β and IL-18 (NLRP3 inflammasome dependent) upon LPS stimulation.
• Whole blood assays revealed enhanced IL-6 and TNF production.

Conclusions:

• G6PC3 deficiency can present with an autoinflammatory phenotype, expanding its known clinical spectrum.
• Impaired glycolysis in myeloid cells may contribute to heightened inflammatory responses in G6PC3 deficiency.
• These findings highlight the interplay between primary immune deficiencies and autoinflammatory disorders, driven by immune dysregulation.