| Hemoglobinopathies and their effect on parasite growth |
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| Taylor SM,
Cerami C, Fairhurst RM. Hemoglobinopathies: slicing the Gordian knot of
Plasmodium falciparum malaria pathogenesis. PLoS Pathog.
2013;9(5):e1003327.� PMID: 23696730 |
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| Hemoglobinopathy� |
Epidemiology� |
Genotype� |
Molecular Pathology� |
Clinical Phenotype |
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Parasite Invasion |
Parasite Development |
| a-thalassemias |
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| a+-thal trait |
Global |
Loss of one a-globin gene (aa/a-) |
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Asymptomatic;
normal RBC size, quantity, and peripheral blood smear |
Normal |
Norma/lreduced |
| a0-thal trait |
Global |
Loss of two a-globin genes (aa/-) |
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Mild anemia |
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Normal/reduced |
Normal/reduced |
| Hemoglobin
H (HbH) disease |
Global |
Loss of three a-globin genes (a-/--) |
Accumulation of unpaired b-chains that form HbH
and precipitate in RBCs |
Chronic hemolytic
anemia with hepatic, splenic, skeletal, and metabolic sequelae; transfusion
support required in 2nd to 3rd decade of life |
Reduced |
Reduced |
| Hydrops fetalis/Hb Barts |
Global |
Loss of all four a-globin genes (--/--) |
Accumulation of unpaired g-chains in utero, forming
Hb Bart�s, which is unable to release oxygen |
Incompatible with extra-uterine life |
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| b-thalassemias |
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| Minor trait/heterozygosity |
Global |
Reduced expression of one b-globin gene |
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Typically
asymptomatic; normal hematocrit, low mean corpuscular volume hematocrit, low
mean corpuscular |
Normal |
Normal/reduced |
| Major |
Global |
Reduced expression of both b-globin genes |
Accumulation of unpaired a-chains, leading to
oxidant damage to RBCs and erythroid precursors |
Profound anemia
leading to transfusion dependence, complicated by iron overload |
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| Hemoglobin S |
Central, East, and West
Africa; Arabian peninsula; South Asia |
Glu→Val at position 6
of b-globin |
Aggregation of deoxygenated
HbS into polymers, leading to RBC deformation, hemolysis, and
microcirculatory obstruction |
Sickle-cell
disease with frequent pain crises, transfusions, and acute chest syndrome
when inherited as HbSS; asymptomatic when inherited as HbAS |
HbSS Increased HbSA normal |
Reduced Normal/reduced |
| Hemoglobin C |
West Africa, centered on
western Burkina Faso and northern Ghana |
Glu→Lys at position 6
of b-globin |
Formation of hexagonal HbC crystals |
Mild hemolysis
and anemia when inherited as HbCC; asymptomatic when inherited as HbAC |
HbCC Normal HbAC normal |
Reduced Normal |
| Hemoglobin E |
Southeast Asia, centered on
border of Thailand, Laos, and Cambodia |
Glu→Lys at position
26 of b-globin |
Mildly reduced expression
of b-globin due to
insertion of splice site and resulting mRNA degradation |
Mild anemia, microcytosis, and hypochromia |
HbEE reduced HbAE normal |
Normal/reduced
Normal/reduced |
| Hemoglobin F |
>50% of hemoglobin at
birth, largely absent by 6 months of age |
Normal |
Tetramer consisting of two a-chains and two g-chains |
Greater oxygen
affinity within RBCs than adult hemoglobin A due to attenuated interactions
with 2,3-bisphosphoglycerate |
Increased/normal |
Reduced |
| b-thalassemia/HbE |
Global |
co-inheritance of
β-thalassemia and the structural variant HbE, a G→A substitution
in codon #26 of the β-globin gene |
globin chain imbalance,
ineffective erythropoiesis, apoptosis, oxidative damage, and shortened red
cell survival |
Marked clinical
variability, ranging from a mild and asymptomatic anaemia to a
life-threatening disorder requiring transfusions from infancy |
Normal/reduced |
Reduced |
| The human genome normally contains four copies of a-globin genes (in paired
copies on chromosome 16: genotype aa aa) and two copies of b-globin genes (on
chromosome 11). Normal adult hemoglobin (HbAA) is a tetramer of two a-globin and two b-globin proteins. |
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