Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency)

Affected individuals exhibit a broad clinical spectrum, ranging from lifelong asymptomatic status to recurrent acute haemolytic crises precipitated by oxidative stressors such as fava bean ingestion, certain antimalarials, sulfonamides, or infection. Episodes typically present with sudden pallor, jaundice, dark urine, and exertional dyspnoea within 24–72 hours of exposure, accompanied by a fall in haemoglobin and biochemical evidence of intravascular haemolysis. Manifestations may emerge at any age once a trigger is encountered. Neonates carry an increased risk of hyperbilirubinaemia, which can escalate rapidly and result in bilirubin-induced neurologic dysfunction (BIND). Phenotypic severity varies considerably between variants, with the most clinically severe alleles producing chronic non-spherocytic haemolytic anaemia independent of trigger exposure.

The estimated median allele frequency across malaria-endemic countries is 1:12. Rates are lower in non-endemic regions.

G6PD deficiency results from germline pathogenic variants in the G6PD gene at chromosome Xq28, which encodes the rate-limiting enzyme of the pentose phosphate pathway. G6PD generates NADPH, protecting erythrocytes from oxidative damage. Loss-of-function variants reduce enzyme activity, rendering red blood cells susceptible to haemolysis upon oxidative challenge from fava beans, certain drugs, or infection. Over 1,300 G6PD variants have been functionally characterised, with the most clinically severe alleles producing chronic non-spherocytic haemolytic anaemia and milder alleles causing acute haemolytic anaemia in response to oxidative stressors.

G6PD deficiency is inherited in an X-linked recessive manner. Hemizygous males typically exhibit deficient enzyme activity, whereas female carriers show variable enzyme activity due to random X-inactivation and may experience haemolysis under sufficient oxidative challenge. Sons of carrier mothers carry a 50% risk of inheriting the variant; daughters of affected fathers are obligate carriers. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

Diagnosis rests on the demonstration of reduced G6PD enzyme activity in erythrocytes. The qualitative fluorescent spot test serves as a screening tool but may miss moderate deficiency, especially in female carriers, in whom random X-inactivation produces variable enzyme activity. Identification of pathogenic variants in G6PD through molecular genetic analysis confirms the diagnosis.

• Establishing the diagnosis: identification of the underlying pathogenic variant confirms the clinical diagnosis at the molecular level and provides a definitive aetiological basis.
• Specific and individualised clinical management: knowledge of the underlying pathogenic variant is a prerequisite for targeted medical care, supporting decisions on monitoring, supportive measures, and avoidance of triggers, taken by the treating physicians in consultation with the affected individual.
• Family member testing: once the familial pathogenic variant is known, predictive and carrier testing can be offered to at-risk relatives within genetic counselling.

• Howes RE, Piel FB, Patil AP, Nyangiri OA, Gething PW, Dewi M, et al. G6PD deficiency prevalence and estimates of affected populations in malaria endemic countries: a geostatistical model-based map. PLoS Med. 2012;9(11):e1001339. doi:10.1371/journal.pmed.1001339. PMID: . PMCID: PMC3496665.
• Lee HY, Ithnin A, Azma RZ, Othman A, Salvador A, Cheah FC. Glucose-6-phosphate dehydrogenase deficiency and neonatal hyperbilirubinemia: insights on pathophysiology, diagnosis, and gene variants in disease heterogeneity. Front Pediatr. 2022;10:875877. doi:10.3389/fped.2022.875877. PMID: . PMCID: PMC9170901.
• Geck RC, Powell NR, Dunham MJ. Functional interpretation, cataloging, and analysis of 1,341 glucose-6-phosphate dehydrogenase variants. Am J Hum Genet. 2023;110(2):228-239. doi:10.1016/j.ajhg.2023.01.003. PMID: . PMCID: PMC9943724.