Is G6PD (Glucose-6-Phosphate Dehydrogenase) deficiency a genetic disorder?

G6PD Deficiency is a Genetic Disorder

Yes, G6PD (Glucose-6-Phosphate Dehydrogenase) deficiency is definitively a genetic disorder with X-linked inheritance. 1, 2

Genetic Basis of G6PD Deficiency

• G6PD deficiency is caused by mutations in the G6PD gene, which is located on the X chromosome (specifically chromosome Xq28) 2, 3
• The condition follows an X-linked inheritance pattern, meaning males (with one X chromosome) are more commonly and severely affected than females (who have two X chromosomes) 3, 4
• Over 200 different mutations in the G6PD gene have been identified, with approximately half being polymorphic (common in various populations) and half being sporadic 2
• Most mutations are missense mutations that cause amino acid replacements, resulting in decreased enzyme stability, reduced catalytic activity, or both 2, 4

Types and Geographic Distribution

• G6PD deficiency is the most common human enzyme defect, affecting approximately 400 million people worldwide 2, 3
• The geographic distribution of G6PD deficiency correlates remarkably with past and present malaria endemicity, suggesting evolutionary selection pressure 2
• Common variants include:
  • G6PD Mediterranean (Gdmed) - found predominantly in men from Mediterranean regions, India, and Southeast Asia 1, 5
  • G6PD African variant (GdA-) - found in 10-15% of Black men and women 1, 5
• The overall prevalence in India is around 8.5%, with multiple variants identified 6

Clinical Manifestations

• Most G6PD-deficient individuals (approximately 500 million people) remain asymptomatic throughout their lifetime 2
• Clinical manifestations vary based on the specific genetic variant and can include:
  • Acute hemolytic anemia triggered by oxidative stress (medications, fava beans, infections) 2, 3
  • Neonatal jaundice 3
  • Chronic non-spherocytic hemolytic anemia (in rare cases with severe mutations) 2, 4
• The severity of hemolysis varies by genetic variant:
  • Mediterranean variant typically causes more severe reactions 5
  • African variant usually results in milder, self-limited hemolysis 5

Diagnosis and Management

• Screening for G6PD deficiency is recommended before starting therapy with oxidant drugs in patients with predisposing racial or ethnic backgrounds 1, 7
• Qualitative screening is sufficient for initial assessment, but quantitative testing may be needed to determine the degree of deficiency 5, 7
• The most effective management is prevention of hemolysis by avoiding oxidative stress 3
• Medications to avoid include:
  • Dapsone 5
  • Primaquine 5, 7
  • Methylene blue 5
  • Rasburicase 2

Genetic Counseling

• Molecular characterization of G6PD variants can help identify female carriers in the maternal line of affected individuals 8
• Genetic counseling is important for families with G6PD deficiency, especially for female carriers who may pass the condition to their children 8

Clinical Pitfalls and Caveats

• Co-inheritance of other red cell disorders can modify the clinical phenotype and complicate diagnosis 6
• Negative screening tests do not completely rule out G6PD deficiency, as some variants may show normal enzyme activity between hemolytic episodes 1
• First-degree relatives of patients with G6PD deficiency should be considered for testing 7
• Immediate discontinuation of potentially hemolytic medications is essential if signs of hemolysis occur 7