**Background:** Reactive oxygen species (ROS) are highly reactive oxygen-containing compounds formed by incomplete reduction of oxygen. At physiological levels, ROS serve important signaling and immune functions, but when their production overwhelms the cell's anti-oxidative capacity, oxidative stress occurs, damaging biomolecules and contributing to diseases such as cancer, stroke, and neurodegeneration. This review focuses on monogenic disorders caused by germline pathogenic variants in genes directly responsible for endogenous ROS production or the primary anti-oxidative defense machinery—specifically, the initial encounters with ROS, including production, scavenging, and recycling of scavengers. It excludes repair mechanisms and secondary oxidative stress effects seen in other genetic diseases.
**Methods:** The authors conducted a narrative review of the literature, summarizing known monogenic disorders linked to genes involved in ROS production (mitochondrial respiratory chain, hemoglobin, NADPH oxidases, myeloperoxidase, xanthine oxidoreductase, nitric oxide synthases) and primary anti-oxidative defense (superoxide dismutases, catalase, glutathione peroxidases, peroxiredoxins, glutathione, thioredoxins, and their reductases, as well as NADPH-producing enzymes). For each gene, they describe the associated disorder, inheritance pattern, and key clinical features, drawing on published case reports, cohort studies, and animal models.
**Key Results:** The review catalogs numerous monogenic disorders. For ROS production: sickle cell disease (HBB, AR), methemoglobinemia (HBB, AD), chronic granulomatous disease (CYBB, CYBA, NCF1, NCF2, NCF4; XLR or AR), myeloperoxidase deficiency (MPO, AR), and xanthinuria type I (XDH, AR). For anti-oxidative enzymes: amyotrophic lateral sclerosis 1 (SOD1, AD/AR), progressive spastic tetraplegia with axial hypotonia (SOD1, AR), acatalasemia (CAT, AR), hemolytic anemia due to GPX1 deficiency (GPX1, AR), Sedaghatian type spondylometaphyseal dysplasia (GPX4, AR), spinocerebellar ataxia-32 (PRDX3, AR), and punctiform and polychromatic pre-Descemet corneal dystrophy (PRDX3, AD). For thiols and recycling: hemolytic anemia due to GCLC deficiency (GCLC, AR), glutathione synthetase deficiency (GSS, AR), combined oxidative phosphorylation deficiency 29 (TXN2, AR), and hemolytic anemia due to GSR deficiency (GSR, AR). For NADPH production: G6PD deficiency (G6PD, XL), 6-phosphogluconate dehydrogenase deficiency (PGD, AD), hyperinsulinism-hyperammonemia syndrome (GLUD1, AD), D-2-hydroxyglutaric aciduria 2 (IDH2, AD), combined immunodeficiency and megaloblastic anemia (MTHFD1, AR), and a proposed neuro-ichthyotic syndrome (ALDH1L2, AR). The review notes that for many ultra-rare disorders, only a handful of patients have been described, and some genotype-phenotype associations remain tentative.
**Clinical Implications:** Understanding these monogenic disorders provides insight into the fundamental role of redox balance in human health. Many conditions, such as G6PD deficiency, are common and have well-known triggers (e.g., fava beans, drugs) that precipitate hemolytic crises. Others, like acatalasemia, predispose to age-related oxidative stress diseases (e.g., type II diabetes, Parkinson's disease). The identification of new disorders, such as PRDX3-related spinocerebellar ataxia and TXN2-related combined oxidative phosphorylation deficiency, highlights the potential for targeted antioxidant therapies. The authors emphasize that comprehensive re-analysis of diagnostic databases may uncover additional patients, strengthening genotype-phenotype links and improving diagnostics for rare redox-related diseases.