Haemoglobin Electrophoresis in a Family From Wayanad
A couple from a tribal settlement in Wayanad bring their 3-year-old son, who has recurrent pain crises, pallor and an enlarged spleen. His haemoglobin is 7.2 g/dL, MCV 78 fL, and the peripheral smear shows sickle cells and target cells. Haemoglobin electrophoresis at pH 8.6 shows a slow-moving band forming about 88% of his haemoglobin and no normal HbA; his mother shows HbA and HbS bands in roughly 60:40 ratio, and his father in 55:45. The mother is 10 weeks pregnant. The parents are not related and ask whether the unborn child can be affected, whether the son's percentage of HbS predicts how severe his disease will be, and why they are healthy although they carry the variant. The family lives 60 km from the district hospital, and the nearest prenatal diagnostic service is at the medical college.
1. Explain the son's electrophoresis result and the parents' results in terms of the HbS mutation.
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HbS arises from a single base change in the β-globin gene, codon 6, changing GAG to GTG and replacing glutamic acid with valine. Glutamic acid is acidic and carries a negative charge; valine is neutral. The substitution therefore reduces the negative charge of the haemoglobin molecule, so HbS migrates more slowly than HbA towards the anode at pH 8.6.
The son has only the slow band and no HbA, which is consistent with homozygosity, HbSS. The small remainder of his haemoglobin is chiefly HbF, which is why the HbS band is about 88% rather than 100%. Each parent has both HbA and HbS bands with HbA predominating, the expected pattern for heterozygotes, HbAS. The parents' health is explained by the presence of normal β-globin from one allele, so their red cells contain enough HbA to prevent sickling under ordinary conditions.
2. Calculate the probability that the unborn child will be HbSS, and explain why the son's 88% HbS value is not a reliable severity predictor.
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Both parents are HbAS. Each pregnancy has a 1 in 4 chance of HbSS, a 1 in 2 chance of HbAS and a 1 in 4 chance of normal HbAA, independent of the previous child. The risk for this fetus is therefore 25%.
The 88% figure is a laboratory proportion of haemoglobin bands, not a clinical severity score. It varies with age, transfusion history and the amount of HbF. Severity depends more on how much HbF persists, whether α-thalassaemia is co-inherited, the β-globin haplotype, hydration, infection and oxygen availability. A child with the same 88% band could have a different course from this boy. The parents should not use the percentage to predict the number of pain crises.
3. Discuss whether prenatal diagnosis should be offered and what it can and cannot tell the parents.
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Prenatal diagnosis is reasonable because the couple already has an affected child and both parents are confirmed carriers. Chorionic villus sampling at about 11–14 weeks or amniocentesis at about 15–18 weeks can provide fetal DNA for β-globin gene testing. The test can establish whether the fetus is HbAA, HbAS or HbSS with high accuracy.
It cannot measure how severe the disease will be, predict the exact number of crises, or guarantee response to treatment. Counselling should therefore be non-directive: the parents should understand the 25% risk, the range of outcomes, and the option of continuing the pregnancy with newborn follow-up. The distance to the medical college is a practical constraint that should be discussed before sampling, not after.