ABSTRACT
Sickle cell disease (SCD) is more common than any other major human genetic condition yet described. The most common form of SCD results from the inheritance of two copies of the βs-allele, a single-point mutation (rs334 A>T) in the β-globin gene (HBB), commonly known as sickle cell anaemia (SCA). However, SCD can also result from the heterozygous inheritance of the βs-allele in combination with various other structural or functional mutations in HBB that mean that the predominant form of haemoglobin in circulation is haemoglobin S (HbS). SCD is the textbook example of balancing selection: heterozygosity for the rs334 A>G mutation (sickle cell trait; HbAS) has come under strong positive selection historically, because of the survival advantage it confers against malaria at the expense of reduced fertility and premature death in subjects with SCD. The current distribution of SCA globally results from multiple factors including the time-depth and intensity of malaria in specific populations and more recent migration from malaria-endemic to non-endemic regions. Today, more than 300,000 children are born with SCA worldwide every year, approximately three-quarters in Africa, one-fifth in India and the Middle East, and one-tenth in Europe and North America. Until very recently, most children born with SCA in Africa have been dying, usually undiagnosed, in early life. While the causes are not completely understood, severe anaemia, often precipitated by malaria, and invasive bacterial infections are probably the most important. However, with increasing demographic and epidemiological transition, the introduction of vaccines against Streptococcus pneumoniae and Haemophilus influenzae, and wider access to diagnosis and treatment, a larger proportion of children with SCA are now surviving until later life. Going forward, it is important that such children are provided with suitable medical support, including early diagnosis and the provision of specialist medical care, access to adequate and safe supplies of blood for transfusion, and programmes aimed at the prevention of strokes and silent cerebral infarcts.
