genetics of g6pd

1. GLUCOSE 6 PHOSPHATE
DEHYDROGENASE DEFICENCY
SAURABH WANI
GARWARE COLLEGE
10

2. G6PD DISCOVERY
• In 1931: German biochemists Warburg and Christian discovered G6PD.
• ◊ They isolated G6PD enzyme from Brewer’s yeast.
• ◊ Origin name of G6PD was Zwischenferment:
• Zwischen: between
• Ferment: fermentation

3. GLUCOSE 6 PHOSPHATE DEHYDROGENASE
DEFICENCY
• G6PD deficiency is the most common disease producing enzyme abnormalities
in humans, affecting more than 200 million individuals worldwide.
• The highest prevalence in the Middle East, tropical Africa & Asia.
• G6PD Deficiency is caused by 400 different mutations in gene coding for G6PD,
only few of them causes the clinical symptoms of the disease.

4. MODE OF INHERITENCE OF G6PD DEFICENCY
It is X- linked recessive genetic disorder (gene is carried on X-chromosome).
The gene is present on the X chromosome
The inheritance follows specific pattern:
Males have one X chromosome
So, they will be diseased if they have the affected gene (xY)
Females have 2 X chromosomes
may be homozygous or heterozygous

5. Homozygous: are diseased (xx)
Heterozygous: are not diseased
BUT: carriers (Xx) can transfer the disease to their sons

7. G6PD is an metabolic enzyme is involved in pentose phosphate
pathway, especially important in red blood cell metabolism
It also protects red blood cells from the effects of potentially harmful
molecules called REACTIVE OXYGEN SPECIES

8. WHAT IS FAVISM ?
• Favism is formally defined as hemolytic response to the consumption of
broad beans
• Favism is disorder characterized by hemolytic reaction to the consumption
of broad beans
• All individual with favism show G6PD deficiency
• However not all individuals with G6PD deficiency
Show favism

9. DECREASED AMOUNTS OF REDUCED
GLUTATHIONE
DUE TO DECREASED PRODUCTION OF NADPH
• Reduction of amounts of NADPH in RBCs in G6PD deficiency causes decrease
in reduction of oxidized glutathione to reduced glutathione.
• Role of reduced glutathione in RBCs:
•
•
1- Reduced glutathione gets rid of Reactive oxygen species including
hydrogen peroxide.
2- Reduced Glutathione helps to keep sulfhydryl groups of haemoglobin
protein in the reduced state.

10. Reduction of production of reduced glutathione results in:
1- A decrease in detoxication of peroxides. This causes damage to RBCs
membrane and hemolysis (ending in hemolytic anemia).
2- Hemoglobin protein is denatured forming insoluble masses (Heinz
bodies). Heinz bodies attach to red cell membranes.
Membrane proteins are also oxidized.
Accordingly, red cells become rigid and removed from the circulation
by macrophages in the spleen and liver ending in anemia

12. Deficiency of G6PD occurs in all cells of affected individual.
It is severe in RBCs because the only pathway to form NADPH in RBCs is
pentose phosphate pathway (using G6PD).
Individuals who have inherited one of the many G6PD mutations do not show
clinical manifestation.
Some of patients with G6PD develop hemolytic anemia if they are exposed or
ingest any of the followings oxidizing agents:
Oxidant drugs:
Antibiotics : e.g. sulfamethoxazole
Antimalarial : e.g. primaquine
Antipyretics : e.g. acetanilide

13. G6PD VARIANTS
• Most G6PD variants are caused by point mutations in the G6PD gene.
• Some of these point mutations do not disturb the structure of the enzyme's
active site and hence, do not affect enzyme activity.
• Other point mutations may lead to production of mutant enzymes with one or
more of the following:
•
•
•
altered catalytic activity,
decrease stability
an alteration of binding affinity for NADP+ or Glucose 6-phosphate.
• The severity of diseases usually correlates with the amount of residual enzyme
activity in the patient’s red cells.

14. G6PD Variants can be classified into :
Class III (G6PD Group A-) :
A moderate form of the disease
RBCs contain unstable G6PD enzyme, but normal activity in younger RBCs and
reticulocytes.
Accordingly, only older RBCs are hemolysed in a hemolytic episode.
Class II mutations (G6PD Mediterranean):
More severe
G6PD enzyme shows normal stability but, very low activity in all RBCs.
Class I mutations:
It is often associated with chronic non spherocytic anemia
(occurs even in absence of oxidative stress).

15. Both G6PD Mediterranean and G6PD A- represent mutant enzymes that differ
from the normal variants by a single amino acid. This change is due to DNA
changes in the form of point mutations or missense mutations.
Frame shift mutations or large deletions have not been identified indicating that
the complete absence of G6PD is lethal.

16. DIAGNOSIS OF G6PD DEFICIENCY
HEMOLYTIC ANEMIA
• The diagnosis of G6PD deficiency is made by a quantitative
spectrophotometric analysis
• Fluorescent spot test detecting the generation of NADPH from NADP. The
test is positive if the blood spot fails to fluoresce under ultraviolet light.
• Tests based on polymerase chain reaction detect specific mutations and
are used for population screening, family studies, or prenatal diagnosis.
• In patients with acute hemolysis, testing for G6PD deficiency may be falsely
negative because older erythrocytes with a higher enzyme deficiency have
been hemolyzed.
• Female heterozygotes may be hard to diagnose because of Xchromosome mosaicism leading to a partial deficiency that will not be
detected reliably with screening tests.

17. FREQUENCY OF G6PD
• Prevalence of G6PD deficiency in the Indian community was first reported from
the Parsi population of Mumbai The prevalence rate of G6PD deficiency varies
between 0-28% in different caste, tribe and ethnic groups. The highest
frequency (27.94%) has been reported from Vataliya Prajapati from Surat,
Gujarat.
• A few relatively recent studies reporting the prevalence of G6PD among the
Indians and in populations of Indian origin A great variation can be observed
among the different populations of India.
• The variation can be explained in terms of the evolutionary history of the
population and their endogamous nature. High prevalence in tribes can be
explained in terms of the geographical spread of malaria. Only few studies
report the prevalence of specific variants and fewer still have reported the
prevalence of different G6PD variants at the DNA level.

18. CURE FOR G6PD
• The most important measure is prevention – avoidance of the drugs and foods
that cause hemolysis. Vaccination against some common pathogens (e.g.
hepatitis A and hepatitis B) may prevent infection-induced attacks.
• In the acute phase of hemolysis, blood transfusions might be necessary, or even
dialysis in acute renal failure. Blood transfusion is an important symptomatic
measure, as the transfused red cells are generally not G6PD deficient and will
live a normal lifespan in the recipient's circulation.
• Some patients may benefit from removal of the spleen (splenectomy) as this is
an important site of red cell destruction. Folic acid should be used in any
disorder featuring a high red cell turnover. Although vitamin E and selenium
have antioxidant properties, their use does not decrease the severity of G6PD
deficiency.

19. THANKYOU