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690 Part VI: The Erythrocyte Chapter 47: Erythrocyte Enzyme Disorders 691

to be associated with anemia only under conditions of stress, such endemic countries is predicted to be 8 percent. This corresponds to 220
as the administration of oxidative drugs, infection, and the neonatal million affected males and an even greater number of females, although
period. some heterozygous females for this X-chromosome–encoded gene do
Chronic hemolysis in the absence of a stress occurs in uncommon, not have enough deficient erythrocytes to become prone to significant
9
functionally severe forms of G6PD deficiency and in patients with a hemolysis. Details on the distribution of G6PD deficiency among vari-
variety of other red cell enzyme deficiencies. Such patients suffer from ous population groups is presented elsewhere. 9–12
hereditary nonspherocytic hemolytic anemia. Although patients fitting The high frequency of G6PD-deficient genes in many populations
the description of hereditary nonspherocytic hemolytic anemia had implies that G6PD deficiency confers a selective advantage. The sug-
been documented earlier, the designation was first introduced by Crosby gestion that resistance to malaria accounts for the high frequency of
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in 1950. Dacie and colleagues subsequently reported several families G6PD deficiency paralleling the worldwide distribution of malaria is
in which affected members manifested hemolytic anemia from an early supported by the sheer diversity of variants in the G6PD gene. Many of
age and in whom the osmotic fragility of the red cells was normal. The these are found at polymorphic frequencies in genetically isolated pop-
latter finding was the main feature that distinguished this disorder from ulations, suggesting independent selection of each variant. 11–13 Impor-
hereditary spherocytosis. Thus, defined essentially by exclusion as a tant supporting evidence was obtained from studies in heterozygotes for
hereditary hemolytic anemia that is not hereditary spherocytosis (or G6PD A– that showed a higher degree of infestation of G6PD-sufficient
14
without any other major aberration of red cell morphology), it is not cells than of G6PD-deficient cells. Deficient cells infested with malaria
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at all surprising that hereditary nonspherocytic hemolytic anemia has parasites may be phagocytosed more efficiently than normal cells.
proven to be extremely heterogeneous both in etiology and in clinical Which G6PD genotypes confer protection from malarial infection is the
manifestations. Sometimes this disorder is also designated congenital subject of debate. 16–18 The majority of studies conclude that G6PD defi-
nonspherocytic hemolytic anemia, but the name hereditary hemolytic ciency in hemizygous males, and probably also homozygous females,
anemia is more accurate and is therefore preferable. Although hered- confers significant protection against malarial infection. The nature of
itary ovalocytosis, pyropoikilocytosis, and stomatocytosis (Chap. 46), protection from the mosaic state of G6PD deficiency in heterozygous
and even thalassemia major and sickle cell disease (Chaps. 48 and 49), females remains to be established. 18,19
are hereditary hemolytic anemias that are also nonspherocytic, they are It has been suggested that a higher prevalence of G6PD deficiency
not included in this category. in individuals with sickle cell disease than in the general African popu-
Although a deficiency of G6PD was found to be responsible for lation reflects a favorable effect of the enzyme deficiency on the clinical
hemolysis in a few patients with hereditary nonspherocytic hemolytic course of the sickling disorders. However, studies aimed at investi-
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anemia, in the overwhelming majority of cases the cause remained gating the effects of G6PD deficiency on the clinical manifestations of
obscure. In 1954, Selwyn and Dacie studied autohemolysis (spontane- sickle cell disease have produced conflicting results. Some studies found
6
ous lysis of red cells after sterile incubation for 24 to 48 hours at 37°C) no evidence for any such effect, 21,22 whereas others reported on lower
in four patients with hereditary nonspherocytic hemolytic anemia and hemoglobin levels in patients with both disorders, either accompanied
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found that in two of them lysis was only slightly increased and was pre- or not by signs of increased hemolysis.
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vented by glucose; these patients were designated as type 1, whereas the PK deficiency is the most common cause of hereditary nonsphero-
others, in whom glucose failed to correct autohemolysis, were classi- cytic hemolytic anemia. Based on large-scale mutation analysis, it has
fied as type 2. Autohemolysis of the erythrocytes of type 2 patients was been estimated that the population prevalence of PK deficiency among
modified by the addition of ATP. However, ATP does not penetrate the whites is approximately 50 cases per 1 million population. Estimates of
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red cell membrane and instead, its modifying influence was nonspecific frequencies of other deficiency alleles, such as those for adenylate kinase,
exerted chiefly by virtue of its effect on the osmolarity and pH of the diphosphoglycerate mutase, enolase, triosephosphate isomerase (TPI),
suspending solution. These findings suggested to DeGruchy and asso- and phosphoglycerate kinase (PGK), have been made on large num-
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ciates that patients with type 2 autohemolysis suffered from a defect in bers of cord bloods. A particularly high incidence of heterozygous TPI
ATP generation. This proposal, born of a misunderstanding of red cell deficiency (>4 percent) in Americans of African descent is supported
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biochemistry, turned out to be correct, as one of the major causes of by family studies. Because this is not reflected in a correspondingly
hereditary nonspherocytic hemolytic anemia proved to be a deficiency high birth incidence, the allele might be lethal in the homozygous state.
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of the ATP-generating enzyme pyruvate kinase (PK). PK deficiency In addition to the common G6PD mutations, there are mutations
was the first of a large number of enzyme defects that have been shown in other enzymes that are repeatedly encountered in the population. In
to account for this heterogeneous syndrome. PK, the c.1529G>A, p.(Arg510Gln) mutation is the most common muta-
tion in the United States, and in northern and central Europe ; the
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EPIDEMIOLOGY c.1456C>T, p.(Arg486Trp) mutation is prevalent in southern Europe,
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and the c.1468C>T, (p.Arg490Trp) mutation in Asia. Similarly, the
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The most common red cell enzyme abnormality is deficiency of c.315G>C, p.(Glu104Asp) mutation is recurrently encountered in TPI.
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G6PD. Its prevalence among white populations ranges from less than In phosphofructose kinase (PFK) deficiency, one-third of the reported
1 in 1000 among northern European populations to 50 percent of the patients are of Jewish origin, and in this population, an intronic splice
males among Kurdish Jews. The lowest frequencies of G6PD deficiency site mutation, c.237+1G>A, and a single base-pair deletion, c.2003delC,
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are found in both North and South America (≤1 percent), and high- are among the most frequently encountered mutations. In a number
est rates are predicted across the tropical belt of sub-Saharan Africa of these instances, the existence of each mutation in the context of the
(15 to 30 percent; Fig. 47–1). The distribution across Asia and Asia same haplotype implies that there has been a founder effect, that is,
Pacific is generally heterogeneous, ranging from virtually absent to rel- the mutation occurred only once, and all individuals now carrying it
atively high. Although many of the highest frequencies are predicted are descendants of the person who sustained the original mutation. The
9,10
from sub-Saharan African countries, the very high population densities expansion of the mutation could represent a selective advantage for het-
across Asia infers that the overall population burden is largely focused erozygotes, but also may result from random factors or from a selective
here. The overall allele frequency of G6PD deficiency across all malaria advantage provided by one or more tightly linked genes.

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