Laboratory Diagnosis. The diagnosis of hemoglobinopathies is made by identifying the precise amount and type of hemoglobin using hemoglobin electrophoresis, isoelectric focusing, or high-performance liquid chromatography. Every member of an at-risk population should have a precise hemoglobin phenotype performed at birth (preferably) or during early infancy. Most states perform newborn screening for sickle cell disease.
Treatment. Direct therapy of sickle cell anemia is evolving. The mainstay of care is supportive measures. The use of chronic RBC transfusions to treat patients who have had a stroke has been very successful. Chronic RBC transfusions have also been used successfully for short time periods to prevent recurrent vasoocclusive painful events, including acute chest syndrome and priapism. Hydroxyurea, which increases hemoglobin F, decreases the number and severity of vasoocclusive events and frequency of acute chest syndrome in children as early as1 year of age. Hematopoietic stem cell transplantation, using a haploidentical sibling match, has cured many children with sickle cell disease. HSCT using alternative donors for children, without a suitable sibling match, is being studied.
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Etiology. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an abnormality in the hexose monophosphate shunt pathway of glycolysis that results in the depletion of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and the inability to regenerate reduced glutathione. When a patient with G6PD is exposed to significant oxidant stress, hemoglobin is oxidized, forming precipitates of sulfhemoglobin (Heinz bodies), which are visible on specially stained preparations. The gene for G6PD deficiency is on the X chromosome.
The severity of hemolysis depends on the enzyme variant. In many G6PD variants, the enzymes become unstable with aging of the RBC and cannot be replaced because the cell is anucleated. Older cells are most susceptible to oxidant-induced hemolysis. In other variants, the enzyme is kinetically abnormal.
Epidemiology. The most common variants of G6PD deficiency have been found in areas where malaria is endemic. G6PD deficiency protects against parasitism ofthe erythrocyte. The most common variant with normalactivity is termed type B and is defined by its electrophoretic mobility. The approximate gene frequencies in AfricanAmericans are 70% type B, 20% type A, and 10% type A–. Only the A– variant, termed the African variant, is unstable. Ten percent of black males are affected. A group of variants found in Sardinians, Sicilians, Greeks, Sephardic and Oriental Jews, and Arabs is termed the Mediterranean variant and is associated with chronic hemolysis andpotentially life-threatening hemolytic disease. Because thegene for G6PD deficiency is carried on the X chromosome, clinical hemolysis is most common in males. Heterozygousfemales who have randomly inactivated a higher percentage of the normal gene may become symptomatic, as mayhomozygous females with the A– variant (0.5% to 1% offemales of African descent).