Insights into neutrophil dysfunction in inherited metabolic disorders

BACKGROUND: Inherited metabolic disorders (IMDs) often manifest with defects in neutrophil development, function, or survival, resulting in recurrent severe infections and elevated morbidity. Although neutropenia and immunodeficiency are frequently underrecognized, they are central to the clinical course of several IMDs. SUMMARY: Advances in human genetics and immunometabolism have elucidated the multifaceted mechanisms linking metabolic abnormalities to impaired innate immunity. This review provides a comprehensive analysis of current understanding regarding the pathophysiology, clinical presentation, and management of IMDs with prominent neutrophil involvement, including glycogen storage disease type Ib (GSD-Ib), glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency, glucose-6-phosphate dehydrogenase (G6PD) deficiency, glucose transporter-1 (GLUT1) deficiency syndrome (GLUT1DS1), propionic acidemia (PA), methylmalonic acidemias (MMA), and Barth syndrome (BTHS). We discuss how impaired glucose metabolism, redox imbalance, and disrupted mitochondrial metabolism undermine neutrophil homeostasis and effector function, resulting in increased susceptibility to infections, failure to thrive, and, in some cases, life-threatening inflammatory complications. Emerging therapies, ranging from dietary metabolic or pharmacological interventions to experimental gene therapies, are reshaping clinical management of IMDs. KEY MESSAGE: Rare IMDs involving neutrophil dysfunction reveal essential links between metabolism, intracellular trafficking, and innate immunity. Molecular diagnosis is crucial for guiding targeted treatments, preventing infectious complications, and improve outcomes. Defining the precise immunometabolic disturbance in these diseases not only advances clinical care but also deepens our understanding of neutrophil biology in broader infectious and inflammatory contexts.