section 15.3
Alternative Pathways of Glucose Metabolism and Hexose Interconversions
303
with G6PD deficiency, possibly through depletion of
NADPH.
Favism
is characterized by acute hemolysis following
ingestion of fava beans (
Viciafava
) by persons with G6PD
deficiency. The fava bean is a vegetable staple of the
Mediterranean region, an area in which G6PD deficiency
is endemic. Infants are especially susceptible to favism.
The disorder is frequently fatal unless a large amount of
blood is transfused rapidly. Not everyone with G6PD de-
ficiency reacts to fava beans, and ingestion of fava beans
does not invariably destroy 51Cr-labeled G6PD-deficient
erythrocytes
in vivo.
Thus, there may be a fundamental
difference between favism and the hemolytic response to
other agents. It has been suggested that another mutation
must also be present for the expression of favism, but the
nature of this hypothetical mutation is unknown.
Studies of the genetics of human G6PD variants have
contributed to the understanding of G6PD deficiency and
of more general aspects of human genetics. G6PD defi-
ciency is inherited as an X-linked trait, as are hemophilia
(Chapter 36) and color blindness (Chapter 38). If the
X chromosome carrying an abnormal G6PD allele is des-
ignated X*, then the three possible genotypes containing
X are
1. X*Y—hemizygous male, with full phenotypic
expression of the abnormal allele;
2. XX*—heterozygous female, with a clinically normal
phenotype in spite of the abnormal allele expressed in
about half her cells; and
3. X*X*—homozygous female, with full phenotypic
expression of the abnormal allele. Sons of affected
males are usually normal (because they receive their
X chromosome from their mothers), and daughters of
affected males are usually heterozygotes (because
they receive one X chromosome from their fathers).
The rarest genotype is that of the homozygous
female, since it requires that both parents have at least
one abnormal X chromosome.
Females heterozygous for a G6PD variant are pheno-
typic mosaics. They have two erythrocyte populations, one
containing normal G6PD, the other the variant. In fact,
in heterozygotes, every tissue has some cells expressing
the normal, and some the abnormal, G6PD gene. Random
X-chromosome inactivation early in embryonic develop-
ment causes only one of the two X chromosomes to be
active (
Lyon’s hypothesis).
Severity of the disorder in homozygotes and hem-
izygotes depends on a number of factors. G6PD vari-
ants are classified into five groups (class I being the
most severe) depending on the presence or absence of
chronic anemia and on the amount of enzyme activity
present in the erythrocytes. The most common normal
activity (class IV) allele is G6PD B. Another common
electrophoretic variant with normal activity is G6PD A.
Among North American blacks, the gene for the ab-
sence of G6PD A (G6PD A- ; class III) has an inci-
dence of about 11%. Hemizygous males have only 5-
15% of normal erythrocyte G6PD activity and exhibit
a mild hemolytic anemia following an oxidative insult,
such as primaquine administration. Hemolysis may cease
even with continued administration of the drug because
the reticulocytes, which increase in proportion follow-
ing hemolysis, have adequate G6PD activity. In persons
of Mediterranean and Middle Eastern ancestry, the most
common abnormal allele is G6PD M (G6PD Mediter-
ranean; class II) associated with severe hemolysis follow-
ing administration of an appropriate drug (Table 15-2).
The average incidence of this allele is approximately 5-
10%, but a subpopulation of Kurdish Jews is reported to
have an incidence of 50%. Enzyme activity in erythrocytes
from these patients is often less than 1 % of normal, and
transfusion is usually required following a hemolytic cri-
sis. The difference in the clinical severity of the diseases
associated with G6PD A- and G6PD M can be explained
by the characteristics of the two variants. G6PD A
has a
normal
Km
for glucose-6-phosphate (50-70 /irnol/L) and
for NADP+ (2.9-4 /xmol/L), but it exhibits an abnormal
pH activity curve. The deficiency is due to an accelerated
rate of inactivation of G6PD A- protein. Bone marrow
cells and reticulocytes have normal amounts of G6PD ac-
tivity, while activity in older red cells is very low. However,
the residual enzyme seems to be more resistant to inhibi-
tion by NADPH. In contrast, G6PD M molecules have an
intrinsically lower catalytic activity, and both reticulocytes
and older red cells have decreased amounts of G6PD activ-
ity. Consequently, when one of the drugs in Table 15-2 is
given, more cells are susceptible, and hemolysis is greater
than with G6PDA- . The low
Km
of G6PD M for G6P
and NADP
may account for the near-normal survival of
erythrocytes in the absence of oxidative stress.
A number of other enzymopathic substances (e.g., pyru-
vate kinase, Chapter 13; and pyrimidine-5'-nucleotidase,
Chapter 27), abnormal hemoglobins (Chapter 28), and ab-
normalities of the erythrocyte cytoskeleton (Chapter 10)
may cause hemolytic anemia. Because many enzymes in
the red cell are identical to those in other tissues, defects in
these enzymes may have pleiotropic effects. Thus, in addi-
tion to hemolytic anemia, triose phosphate isomerase defi-
ciency causes severe neuromuscular disease, and phospho-
fructokinase deficiency causes a muscle glycogen storage
disease (Chapter 13). Mutations that result in decreased en-
zyme stability are usually most strongly expressed in ery-
throcytes because of their inability to synthesize proteins.
