Glucose-6-phosphate dehydrogenase deficiency

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Contents

Introduction

The commonest human enzyme defect it is associated with multiple variations in the glucose-6-phosphate dehydrogenase gene and is X linked. The complexities of its phenotype are illustrative of the issues in understanding genetic disease affecting even one well understood metabolic step. As a X linked condition it is not recessive and is subject to X-inactivation in females (so females are more likely to have mild disease than males). About 20% with deficiency are at risk of favism, the commonest cause of haemolytic anaemia.

Classification

The WHO classification is[1]:

  1. Severe enzyme deficiency with chronic nonspherocytic haemolytic anemia
  2. Severe enzyme deficiency (less than 10% of normal)
  3. Moderate-to-mild enzyme deficiency (10%-60% of normal)
  4. Very mild or normal enzyme deficiency (60%-100% of normal)
  5. Increased enzyme activity (more than twice normal).

Historical

An example of a condition recognised since antiquity but poorly understood because of complex genetics and activating factors. The biochemistry is now well understood and shows how multiple possible mutations can be selected for minor survival advantage by an important infectious disease such as malaria[2].

  • 6th century BC Pythagoras stops followers from eating fava beans - kyamon apechehesthe -be far from the fava beans consumption[3]
  • 1894 Haemoglobinuria recognised as the main symptom of favism and that it was idiosyncratic[4]
  • 1905 Favism well described[5]
  • 1926 First reports of haemolytic anaemia with antimalarial drugs[6]
  • 1940 Possibility of genetic basis postulated[7]
  • 1956 Haemolytic anaemia due to primaquine[8] and glutathion deficiency noted in favism[9].
  • 1957 Link with glucose-6-phosphate dehydrogenase[10] and father to son inheritance of deficiency state[11]
  • 1958 Full biochemical link with favism[12].
  • 1964 Variation of glucose-6-phosphate dehydrogenase in human populations well described[13]
  • 1967 WHO standardisation [14]
  • 1969 Experimental evidence for malaria protection with G6PD deficiency [15]
  • 1979 Screening test standardisation.[16]
  • 1986 Human glucose-6-phosphate dehydrogenase gene sequence[17]
  • 1995 Isoenzyme shown to protect against malaria[18]
  • 1996 Model of human 3D structure glucose-6-phosphate dehydrogenase[19]
  • 1999 Solution structure human glucose-6-phosphate dehydrogenase[20]

Risky drugs

Lists and warnings exist from many sources but not all claimed associations in the literature may occur[21]. Definite associations exist with many sulphonamides including co-trimoxazole, some antimalarials such as primaquine and pamaquine and important antimicrobials such as dapsone, nitrofurantoin and nalidixic acid. Naththalene and TNT are well known chemicals that can cause haemolysis. Other drugs such as ascorbic acid, aspirin, chloroquine, chloramphenicol, ciprofloxacin, glibenclamide, mesalazine and warfarin have possible associations. It is possible that the complex genetics may be a reason for isolated case reports with many other drugs. With the antimalarials prior screening of G6PD enzyme levels has been shown to be useful.

Screening

Screening uses Glucose-6-phosphate dehydrogenase activity and classically deficiency was defined as activity that was 30% of normal in male volunteers as it is an X-linked condition. While this cutoff reliably identifies male hemizygotes and female homozygotes for some drugs moderate deficiency can cause haemolysis. Accordingly more reasonable cut offs from clinical trials of antimalarial drugs are suggested to be 40% in females and 70% in males as of 2019.

External links

Web Resources for Glucose-6-phosphate dehydrogenase deficiency


Genetic Databases
Relevant Clinical Literature
UK Guidance
Other Wikis

References

  1. Yoshida A, Beutler E, Motulsky AG. Human glucose-6-phosphate dehydrogenase variants. Bulletin of the World Health Organization. 1971; 45(2):243-53.
  2. Beutler E. Glucose-6-phosphate dehydrogenase deficiency: a historical perspective. Blood. 2008 Jan 1; 111(1):16-24.(Link to article – subscription may be required.)
  3. Meletis J, Konstantopoulos K. Favism - from the 'avoid fava beans' of Pythagoras to the present. Haema 2004; 7(1): 17-21
  4. Montano G. Del favismoo intossicazione fabacea. 20th Congr Med Internationale, Roma 1894, 3, 301.
  5. Fermi C. Martinetti P. Studio sul favismo. Annali di Igiene Sperimentale 1905;15:76
  6. Cordes W. Experiences with plasmochin in malaria. In: Anonymous. 15th Annual Report. Boston, MA: United Fruit Co; 1926:66-71.
  7. Meletis J, Konstantopoulos K. Favism - from the 'avoid fava beans' of Pythagoras to the present. Haema 2004; 7(1): 17-21
  8. ALVING AS, CARSON PE, FLANAGAN CL, ICKES CE. Enzymatic deficiency in primaquine-sensitive erythrocytes. Science (New York, N.Y.). 1956 Sep 14; 124(3220):484-5.
  9. SANSONE G, SEGNI G. Early determinations of serum glutathione in favism.. Bollettino della Società italiana di biologia sperimentale. 1956 Jun; 32(6):456-8.
  10. WALLER HD, LOHR GW, TABATABAI M. Hemolysis and absence of glucose-6-phosphate dehydrogenase in erythrocytes; an enzyme abnormality of erythrocytes. Klinische Wochenschrift. 1957 Oct 15; 35(20):1022-7.
  11. Browne EA. The inheritance of an intrinsic abnormality of the red blood cell predisposing to drug induced hemolytic anemia. Johns Hopkins Med J. 1957;101:115-118.
  12. SANSONE G, SEGNI G. New aspects of the biochemical alterations in the erythrocytes of patients with favism; almost complete absence of glucose-6-phosphate dehydrogenase.. Bollettino della Società italiana di biologia sperimentale. 1958 Apr 15; 34(7):327-9.
  13. PORTER IH, BOYER SH, WATSON-WILLIAMS EJ, ADAM A, SZEINBERG A, SINISCALCO M. VARIATION OF GLUCOSE-6-PHOSPHATE DEHYDROGENASE IN DIFFERENT POPULATIONS. Lancet. 1964 Apr 25; 1:895-9.
  14. Standardization of procedures for the study of glucose-6-phosphate dehydrogenase. Report of a WHO Scientific Group. World Health Organization technical report series. 1967; 366:1-53.
  15. Luzzatto L, Usanga FA, Reddy S. Glucose-6-phosphate dehydrogenase deficient red cells: resistance to infection by malarial parasites. Science (New York, N.Y.). 1969 May 16; 164(881):839-42.
  16. Beutler E, Blume KG, Kaplan JC, Löhr GW, Ramot B, Valentine WN. International Committee for Standardization in Haematology: recommended screening test for glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. British journal of haematology. 1979 Nov; 43(3):465-7.
  17. Takizawa T, Huang IY, Ikuta T, Yoshida A. Human glucose-6-phosphate dehydrogenase: primary structure and cDNA cloning. Proceedings of the National Academy of Sciences of the United States of America. 1986 Jun; 83(12):4157-61.
  18. Ruwende C, Khoo SC, Snow RW, Yates SN, Kwiatkowski D, Gupta S, Warn P, Allsopp CE, Gilbert SC, Peschu N. Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria. Nature. 1995 Jul 20; 376(6537):246-9.(Link to article – subscription may be required.)
  19. Naylor CE, Rowland P, Basak AK, Gover S, Mason PJ, Bautista JM, Vulliamy TJ, Luzzatto L, Adams MJ. Glucose 6-phosphate dehydrogenase mutations causing enzyme deficiency in a model of the tertiary structure of the human enzyme. Blood. 1996 Apr 1; 87(7):2974-82.
  20. Au SW, Naylor CE, Gover S, Vandeputte-Rutten L, Scopes DA, Mason PJ, Luzzatto L, Lam VM, Adams MJ. Solution of the structure of tetrameric human glucose 6-phosphate dehydrogenase by molecular replacement. Acta crystallographica. Section D, Biological crystallography. 1999 Apr; 55(Pt 4):826-34.
  21. Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet 2008;371:64-74