Sickle Cell Disease Explained: Inheritance, Haemoglobin S and Why Cells Sickle

Sickle cell disease is a group of hereditary haemolytic anaemias caused by abnormalities in haemoglobin S. It results from a single gene point mutation: a substitution of valine for glutamic acid at the sixth position of the beta globin chain. Every clinical manifestation of sickle cell disease, from acute pain crises to long-term organ damage, is ultimately caused by the properties of this one abnormal haemoglobin.

How the Disease Is Inherited

Sickle cell disease follows an autosomal recessive pattern of inheritance. When two carrier parents, each with one sickle gene, have a child, there is a 25% chance the child inherits both copies and develops the disease, a 25% chance the child is completely unaffected, and a 50% chance the child inherits only one copy and becomes a carrier, like the parents. Sickle cell trait itself is not a disease. Carriers have roughly 40% haemoglobin S, a completely normal lifespan, and few medical issues beyond an increased risk of certain problems at high altitude, such as splenic infarction, and a higher risk of renal medullary carcinoma compared with patients who have sickle cell anaemia itself. Disease severity is also affected by which other haemoglobin variants coexist with the sickle gene: combinations with HbC disease, thalassaemia, HbO Arab or HbD Punjab, or a concurrent alpha gene deletion, can all change how severely the sickling complications present.

Why the Red Cells Sicken the Body

Haemoglobin S polymerises under conditions the body frequently encounters: oxygen desaturation, acidosis, dehydration, infection and fever all trigger it. Polymerisation increases red cell breakdown (causing jaundice from hyperbilirubinaemia), makes red cells stickier and less able to flow smoothly through vessels, and makes them adhere to the vessel endothelium while reducing nitric oxide availability, which causes vasoconstriction. Together these changes starve tissue of oxygen in repeated cycles of ischaemia and reperfusion, which is the mechanism behind the pain crises and the organ damage, in the chest, brain, lungs, eyes and skin, that define the disease. The normal red blood cell survives 90 to 120 days; a sickled red cell survives only 15 to 20 days, and it is not just this shortened lifespan and increased destruction that causes problems, but the abnormal shape and stickiness of the cell itself.

Where Sickle Cell Disease Occurs

Sickle cell disease occurs worldwide, with the highest incidence and prevalence in sub-Saharan Africa and the Caribbean, and further pockets in Latin America, the Mediterranean, the Middle East and the Indian subcontinent. Analysis of DNA polymorphisms shows four distinct sickle haplotypes prevalent across Africa depending on geography, the Senegal, Benin, Bantu and Cameroon haplotypes, while the Arab-Indian haplotype found in Indian and Arabian populations tends to produce milder disease, since patients with this haplotype carry higher levels of fetal haemoglobin.

This article is based on a Jivo Masterclass session conducted by Dr. Divya Doval, Senior Consultant, Bone Marrow Transplant & Haemato-Oncology, BLK-Max Super Speciality Hospital, New Delhi. The article has been summarised with the assistance of an AI tool from the original masterclass recording. Watch the full Masterclass recording