Primeview - Sickle Cell Disease !

Sickle cell disease (SCD) is a group of inherited disorders caused by mutations in HBB, which encodes haemoglobin subunit β. The incidence is estimated to be between 300,000 and 400,000 neonates globally each year, the majority in sub-Saharan Africa. Haemoglobin molecules that include mutant sickle β-globin subunits can polymerize; erythrocytes that contain mostly haemoglobin polymers assume a sickled form and are prone to haemolysis. Other pathophysiological mechanisms that contribute to the SCD phenotype are vaso-occlusion and activation of the immune system. SCD is characterized by a remarkable phenotypic complexity. Common acute complications are acute pain events, acute chest syndrome and stroke; chronic complications (including chronic kidney disease) can damage all organs. Hydroxycarbamide, blood transfusions and haematopoietic stem cell transplantation can reduce the severity of the disease. Early diagnosis is crucial to improve survival, and universal newborn screening programmes have been implemented in some countries but are challenging in low-income, high-burden settings.

Sickle cell disease (SCD) is an umbrella term that defines a group of inherited diseases (including sickle cell anaemia (SCA), HbSC and HbSβ-thalassaemia) characterized by mutations in the gene encoding the haemoglobin subunit β (HBB). Haemoglobin (Hb) is a tetrameric protein composed of different combinations of globin subunits; each globin subunit is associated with the cofactor haem, which can carry a molecule of oxygen. Hb is expressed by red blood cells, both reticulocytes (immature red blood cells) and erythrocytes (mature red blood cells). Several genes encode different types of globin proteins, and their various tetrameric combinations generate multiple types of Hb, which are normally expressed at different stages of life — embryonic, fetal and adult. Hb A (HbA), the most abundant (>90%) form of adult Hb, comprises two α-globin subunits (encoded by the duplicated HBA1 and HBA2 genes) and two β-globin subunits.

A single nucleotide substitution in HBB results in the sickle Hb (HbS) allele βS; the mutant protein generated from the βS allele is the sickle β-globin subunit and has an amino acid substitution. Under conditions of deoxygenation (that is, when the Hb is not bound to oxygen), Hb tetramers that include two of these mutant sickle β-globin subunits (that is, HbS) can polymerize and cause the erythrocytes to assume a crescent or sickled shape from which the disease takes its name. Hb tetramers with one sickle β-globin subunit can also polymerize, albeit not as efficiently as HbS. Sickle erythrocytes can lead to recurrent vaso-occlusive episodes that are the hallmark of SCD. SCD is inherited as an autosomal codominant trait; individuals who are heterozygous for the βS allele carry the sickle cell trait (HbAS) but do not have SCD, whereas individuals who are homozygous for the βS allele have SCA. SCA, the most common form of SCD, is a lifelong disease characterized by chronic haemolytic anaemia, unpredictable episodes of pain and widespread organ damage.

There is a wide variability in the clinical severity of SCA, as well as in the life expectancy. Genetic and genome-wide association studies have consistently found that high levels of fetal Hb (HbF; the heterodimeric combination of two α-globin proteins and two γ-globin proteins (encoded by HBG1 and HBG2)) and the co-inheritance of α-thalassaemia (which is caused by mutations in HBA1 and HBA2) are associated, on average, with milder SCD phenotypes. However, these two biomarkers explain only a small fraction of the observed phenotypic variability. Since the 1980s, a rapidly expanding body of knowledge has promoted a better understanding of SCD, particularly in high-income countries. In the United States, research funding increased exponentially, awareness and education programmes expanded, counselling programmes were improved and universal newborn screening programmes now ensure early diagnosis and intervention. Specific research and training programmes led to a cadre of knowledgeable health professionals working in this field, improved patient management, prevention of complications and extension of life expectancy.

Download in PDF

This primeview discusses on the sickle cell disease that includes genetic conditions caused by mutations in one of the genes encoding haemoglobin. It highlights its complex pathophysiological mechanisms that stem from the polymerization of the mutant HbS variant, causing the red blood cells to acquire a characteristic crescent shape that gives the disease its name. It also focuses on SCA and aims to balance such remarkable advances with the key major challenges remaining worldwide to improve the prevention and management of this chronic disease and ultimately to discover an affordable cure.

Download Article 1»