What is the genetic etiology of glucose-6-phosphate dehydrogenase (G6PD) deficiency?

Answer

The gene that codes for G6PD is located in the distal long arm of the X chromosome at the Xq28 locus. The G6PD gene is 18 kilobases (kb) long with 13 exons, and the G6PD enzyme has 515 amino acids. Currently, 186 mutations in the G6PD gene have been documented. Most are single-base changes that result in an amino acid substitution.^[7]

G6PD deficiency is an X-linked recessive disorder, with an inheritance pattern similar to that of hemophilia and color blindness: males usually manifest the abnormality and females are carriers. Females may be symptomatic if they are homozygous or if inactivation of their normal X chromosome occurs. The allele for G6PD has been used to establish clonality.^{[6, 7]}

Specific G6PD alleles are associated with G6PD variants with different enzyme levels and, thus, different degrees of clinical disease severity. The variation in G6PD levels accounts for differences in sensitivity to oxidants. Chronic hemolysis occurs with extremely low enzyme levels.

The G6PD A+ variant is associated with high enzyme levels and, hence, no hemolysis. G6PD A- is associated with lower enzyme levels and acute intermittent hemolysis. G6PD A- occurs in high frequency in African, Mediterranean, and Asian variants. Mediterranean G6PD A- (also called G6PD Mediterranean) is characterized by enzyme deficiencies that are more severe than in the other G6PD A- alleles. Fava bean hemolysis usually occurs in Mediterranean G6PD deficiency disorders. G6PD B is the wild type of allele (normal variant).

The World Health Organization has classified the different G6PD variants according to the degree of enzyme deficiency and severity of hemolysis, into classes I-V. Class I deficiencies are the most severe. G6PD Mediterranean deficiency usually is a class II deficiency and G6PD A- deficiency is a class III deficiency. Classes IV and V are of no clinical significance.^{[6, 7]}

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G6PD deficiency: Heinz bodies in a peripheral smear stained with a supravital stain. Heinz bodies are denatured hemoglobin, which occurs in G6PD deficiencies and in unstable hemoglobin disorders.

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Author

Srikanth Nagalla, MBBS, MS, FACP Associate Professor of Medicine, Division of Hematology and Oncology, UT Southwestern Medical Center

Srikanth Nagalla, MBBS, MS, FACP is a member of the following medical societies: American Society of Hematology, Association of Specialty Professors

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alexion; Alnylam.

Coauthor(s)

Paul Schick, MD Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital

Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Society of Hematology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, SWOG

Disclosure: Partner received none from No financial interests for none.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College

Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology

Disclosure: Received honoraria from Novartis for speaking and teaching; Received consulting fee from Novartis for speaking and teaching; Received honoraria from Celgene for speaking and teaching.

Acknowledgements

Suzanne M Carter, MS Senior Genetic Counselor, Associate, Department of Obstetrics and Gynecology, Division of Reproductive Genetics, Montefiore Medical Center, Albert Einstein College of Medicine

Suzanne M Carter, MS is a member of the following medical societies: American Bar Association

Disclosure: Nothing to disclose. Susan J Gross, MD, FRCS(C), FACOG, FACMG Codirector, Division of Reproduction Genetics, Associate Professor, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine

Susan J Gross, MD, FRCS(C), FACOG, FACMG is a member of the following medical societies: American College of Medical Genetics, American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, American Medical Association, American Society of Human Genetics, and Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

What is the genetic etiology of glucose-6-phosphate dehydrogenase (G6PD) deficiency?

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