Glucose-6-Phosphate Dehydrogenase Deficiency

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most commonly known enzymopathy, affecting approximately 400 million people worldwide, especially in tropical Africa, the Middle East, tropical and subtropical Asia, some areas of the Mediterranean, and Papua New Guinea. The gene frequencies are estimated to be as high as 5–25% percent in these areas.

GENETICS/BASIC DEFECTS

1. Inheritance

a. X-linked recessive in terms of clinical expression i. Not truly recessive since heterozygous females

can even develop severe hemolytic attacks ii. Coexistence in female heterozygotes of two cell

populations, G6PD( +) and G6PD(–), secondary to X-chromosome inactivation

iii. Homozygous females not rare in many popula- tions with high frequency of G6PD deficiency b. Co-dominant in terms of biochemical characteristics

of electrophoretic variants segregating in a pedigree 2. The gene mapped to Xq28 region

3. Genetic heterogeneity

a. Diverse biochemical characteristics

i. Presence of about 400 different variants

ii. Many allelic mutations in the G6PD gene caus- ing these variants

iii. Presence of several structural mutants without enzyme deficiency

b. Heterogeneous molecular characteristics

i. Some variants with different names proved to be identical

ii. Some variants thought to be homogeneous proved to be heterogeneous

c. Different mutations responsible for:

i. Chronic hemolytic anemia: less common ii. Episodic hemolysis: more frequently seen d. Diverse clinical manifestations, to a large extent,

explainable by the genetic heterogeneity 4. Pathogenesis

a. G6PD

i. A central enzyme in the pentose phosphate shunt of glucose metabolism

ii. Catalyzes glucose-6-phosphate (G6P) to 6- phosphogluconic acid (6PG)

iii. Reduce nicotinamide adenine dinucleotide phos- phate (NADP) to the reduced form of NADP (NADPH)

b. NADPH: converts glutathione disulfide (GSSG) to reduced glutathione (GSH)

c. Reduced glutathione GSH

i. Inactivates hydrogen peroxides (H

O

)

ii. Protects protein sulfhydryl groups from oxidation

iii. Neutralize agents that threaten to oxidize either hemoglobin or components of the red cell membrane

d. In the absence of G6PD

i. Red cell membrane and hemoglobin damaged by oxidant exposure

ii. Leading to rapid hemolysis

5. Hemolysis secondary to inability of G6PD-deficient red cells to withstand the oxidative damage produced, directly or indirectly, by the triggering agents:

a. Drugs b. Infections

c. Ingestion of fava beans with life-threatening manifes- tations especially favism in children

6. G6PD deficiency conferring resistance against Plasmodium falciparum malaria based on:

a. Prevalence of G6PD deficiency and the past and pres- ent endemicity of Plasmodium. falciparum malaria b. The high prevalence in malaria-endemic areas of

G6PD mutants

c. Heterozygote advantage

CLINICAL FEATURES

1. History

a. Asymptomatic in the vast majority of G6PD-deficient individuals without being aware of their genetic abnormality

b. No positive history of acute intravascular hemolytic crises without exposure to oxidant stress

c. Neonatal jaundice

d. Chronic hemolytic anemia

i. An insidious decrease in hemoglobin ii. Observed in certain variant enzymes

e. Required a careful investigation to establish the history of exposure to inciting agents

2. Common clinical manifestations

a. Neonatal jaundice: may cause permanent neurologic damage or death in some severe cases

b. Episodes of acute hemolytic anemia i. Drug-induced hemolysis ii. Infection-induced hemolysis

iii. Favism: occurrence of acute hemolysis after ingestion of broad beans (Vicia faba)

iv. Chronic nonspherocytic hemolytic anemia v. Associated with hemoglobinuria since red cell

destruction in these acute hemolytic events is largely intravascular

vi. Concomitance with a variety of clinical situa- tions, including diabetic ketoacidosis, hypo- glycemia, myocardial infarction with pericardial tamponade, and strenuous exercise

457

Glucose-6-Phosphate Dehydrogenase Deficiency

458 GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY

c. Symptoms and signs of acute hemolytic crisis i. Headache

ii. Lethargy iii. Pallor

iv. Jaundice v. Red, clear urine

3. Symptoms and signs of chronic hemolytic crisis a. Pallor

b. Jaundice

c. Severe chronic hemolysis observed in a rare subset of G6PD-deficient patients

4. Drugs responsible for hemolysis a. Antimalarials

i. Definite association (Primaquine, Pamaquine) ii. Possible association (Chloroquine)

iii. Doubtful association (Quinacrine, Quinine) b. Sulfonamides

i. Definite association (Sulfanilamide, Sulfacetamide, Sulfapyridine, Sulfamethoxazole)

ii. Possible association (Sulfadimidine, Sulfasalazine, Glyburide)

iii. Doubtful association (Sulfoxone, Sulfadiazine, Sulfisoxazole)

c. Sulfones: definite association (Dapsone)

d. Nitrofurantoin: definite association (Nitrofurantoin) e. Antipyretic/analgesic

i. Definite association (Acetanilid) ii. Possible association (Aspirin)

iii. Doubtful association (Acetaminophen, phena- cetin)

f. Other drugs

i. Definite association (Nalidixic acid, Niridazole, Methyene blue, Phenazopyridine, Sepirin) ii. Possible association (Ciprofloxacin, Chloram-

phenicol, Vitamin K analogues, Ascobic acid, p- Aminosalicylic acid)

iii. Doubtful association (PAS, Doxorbicin, Probe- necid, Dimercaprol)

g. Other chemicals

i. Definite association (Naphthalene, Trinitrotoluene) ii. Possible association (Acalypha indica)

5. Types of G6PD deficiency a. X-minus variety

i. Most common type seen in the U.S.

ii. An X-linked condition primarily affecting African-American males

iii. Females affected if homozygous for G6PD defi- ciency or if unfavorable random X chromosome inactivation resulting in a large proportion of deficient red cells

b. Mediterranean variety

i. Develops severe hemolysis when exposed to oxidant drugs

ii. Characterized by enzyme deficiency in red cells of all ages, including reticulocytes, and shows no evidence of spontaneous recovery

c. Other varieties

i. Develops chronic hemolytic anemia without external oxidant exposure

ii. Susceptible to develop cholelithiasis because of heightened bilirubin turnover

iii. Complaints of abdominal pain or fatty food intolerance

DIAGNOSTIC INVESTIGATIONS

1. Acute hemolysis a. Precipitous anemia

i. A fall in hemoglobin ii. A fall in hematocrit

iii. Subsequent rise in reticulocyte percentage b. Elevated bilirubin, particularly the indirect fraction c. Reduced haptoglobin as it binds free hemoglobin and

is removed from the circulation d. Hemoglobinemia ± hemoglobinuria

2. Definitive diagnostic test involving assay of actual enzyme activity of G6PD

a. A-minus variety

i. G6PD activity may be higher during the acute stage of hemolysis

ii. G6PD deficiency evident after hemolysis b. Other varieties: diminished G6PD activity even dur-

ing acute hemolysis

3. Direct DNA analysis (targeted mutation analysis)

GENETIC COUNSELING

1. Recurrence risk

a. Patient’s sib (if the mother is a carrier) i. 50% of male siblings affected

ii. 50% of female siblings carriers (some female heterozygotes may be affected)

b. Patient’s offspring:

i. 100% of female offspring carriers (some female heterozygotes may be affected)

ii. 50% of female offspring affected (homozygotes) if the spouse is a carrier

iii. Male offspring not affected unless the spouse is a carrier

2. Diagnostic confirmation, neonatal screening, and carrier screening available by DNA analysis and enzyme assay 3. Management

a. Remove precipitating agent b. Supportive transfusion

REFERENCES

Beutler E. The genetics of glucose-6-phosphate dehydrogenase deficiency.

Semin Hematol 27:137–164, 1990.

Beutler E. Glucose-6-phosphate dehydrogenase deficiency. N Engl J Med 324:169–174, 1991.

Beutler E: Study of glucose-6-phosphate dehydrogenase: History and molecu- lar biology. Am J Hematol 42:53, 1993.

Beutler E. G6PD deficiency. Blood 84:3613–3636, 1994.

Beutler E: G6PD: Population genetics and clinical manifestations. Blood Rev 10:45, 1996.

Beutler E, Kuhl W, Gelbart T, et al.: DNA-sequence abnormalities of human glu- cose-6-phosphate-dehydrogenase variants. J Biol Chem 266: 4145–4150, 1991.

Beutler E, Westwood B, Prchal JT, et al.: New glucose-6-phosphate dehydro-

genase mutations from various ethnic groups. Blood 80:255–256, 1992.

GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY 459

Calabro V, Mason PJ, Civitelli D, et al.: Genetic heterogeneity of glucose-6- phosphate dehydrogenase deficiency revealed by single strand conforma- tion analysis. Am J Hum Genet 52:527–536, 1993.

Carpentieri U, Moore RL, Nichols MM. Kernicterus in a newborn female with G-6-PD deficiency. J Pediatr 89:854–855, 1974.

Chang JG, Liu TC: Glucose-6-phosphate dehydrogenase deficiency. Crit Rev Oncol Hematol 20:1, 1995.

Cosgrove MS, Naylor C, Paludan S, et al.: On the mechanism of the reaction catalyzed by glucose 6-phosphate dehydrogenase. Biochemistry 37:27–59, 1998.

Davidson RG, Nitowsky HM, Childs B: Demonstration of two populations of cells in the human female heterozygous for glucose-6-phosphate dehy- drogenase variants. Proc Natl Acad Sci USA 50:481, 1963.

Gaetani GF, Ferraris AM: Recent developments on Mediterranean G6PD. Br J Haematol 68:1, 1988.

Hodge DL, Charron T, Stabile LP, et al.: Structural characterization and tissue- specific expression of the mouse glucose-6-phosphate dehydrogenase gene. DNA Cell Biol 17:283, 1998.

Kaplan M, Hammerman C. Severe neonatal hyperbilirubinemia. A potential complication of glucose-6-phosphate dehydrogenase deficiency. Clin Perinatol 25:575–590, 1998.

Kaplan M, Beutler E, Vreman HJ, et al.: Neonatal hyperbilirubinemia in glu- cose-6-phosphate dehydrogenase-deficient heterozygotes. Pediatrics 104:68–74, 1999.

Kattamis CA, Kyriazakou M, Chaidas S: Favism. Clinical and biochemical data. J Med Genet 6:34–41, 1969.

Keats B: Genetic mapping: X chromosome. Hum Genet 64:28, 1983.

Lopez R, Cooperman JM: Glucose-6-phosphate dehydrogenase deficiency and hyperbilirubinemia in the newborn. Am J Dis Child 122:66–70, 1971.

Luisada L: Favism: a singular disease affecting chiefly red blood cells.

Medicine 20:229, 1941.

Luzzatto L, Testa U: Human erythrocyte glucose 6-phosphate dehydrogenase:

structure and function in normal and mutant subjects. Curr Top Hematol 1:1, 1978.

Luzzatto L, Mehta A, Vulliamy T: Glucose 6-phosphate dehydrogenase defi- ciency. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic

& Molecular Bases of Inherited Disease. 8th ed. New York: McGraw- Hill, 2001, Chapter 179, pp 4517–4553.

Mason PJ: New insights into G6PD deficiency. Br J Haematol 94:585–591, 1996.

Martini G, Toniolo D, Vulliamy TJ, et al.: Structural analysis of the X-linked gene encoding human glucose 6-phosphate dehydrogenase. EMBO J 5:1849, 1986.

Pai GS, Sprenkle JA, Do TT, et al.: Localization of the loci for hypoxanthine phosphoribosyltransferase and glucose-6-phosphate dehydrogenase and biochemical evidence of non-random X-chromosome expression from studies of human X-autosome translocation. Proc Natl Acad Sci USA 77:2810, 1980.

Segel GB, Hirsh MG, Feig SA: Managing anemia in a pediatric office practice:

Part 2. Pediatr Rev 23:111–122, 2002.

Szabo P, Purrello M, Rocchi M, et al.: Cytological mapping of the human glucose-6-phosphate dehydrogenase gene distal to the fragile-X site sug- gests a high rate of meiotic recombination across this site. Proc Natl Acad Sci USA 81:7855, 1984.

Valaes T: Severe neonatal jaundice associated with glucose-6-phosphate dehy- drogenase deficiency: pathogenesis and global epidemiology. Acta Paediatr (Suppl 394):58–76, 1994.

Venkataram MN, Al-Suwaid AR: Glucose-6-phosphate dehydrogenase defi- ciency. Int J Dermatol 38:730, 1999.

Vulliamy TJ, Kaeda JS, Ait-Chafa D, et al.: Clinical and haematological con- sequences of recurrent G6PD mutations and a single new mutation causing chronic nonspherocytic haemolytic anaemia. Br J Haematol 101:670, 1998.

Washington EC, Ector W, Abboud M, et al.: Hemolytic jaundice due to G6PD deficiency causing kernicterus in a female newborn. South Med J 88:776–779, 1995.

WHO Working Group. Glucose-6-phosphate dehydrogenase deficiency. WHO

Bull 67:601–611, 1989.

460 GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY

Fig. 1. A 1-month-old and a 2-month-old boys with G6PD deficiency who are asymptomatic. The newborn screenings of both boys identi- fied one (hemizygous) copy of the double mutations (G202A;

A376G).

Fig. 4. Fava beans.

Fig. 2. An 8-week-old girl with G6PD deficiency who is asympto- matic. The newborn screening identified compound heterozygote con- sisting of one copy of the double mutation (G202A; A376G) and one copy of the A378G mutation. This phenotype is seen only in females since this is an X-linked disorder.

Fig. 3. A 1-month-old boy with G6PD deficiency who is asympto-

matic. The newborn screening revealed G6PD of 3.8 (10.8–16.2 U/g

Hb). Molecular analysis showed one copy of A376G mutation.