Hemoglobinopathy

Hemoglobinopathies are a group of inherited disorders affecting haemoglobin, the essential oxygen-carrying protein within red blood cells. These conditions are usually single-gene disorders and most commonly follow an autosomal recessive pattern of inheritance. They fall broadly into two categories: structural haemoglobin variants, which arise from mutations that alter the structure of the haemoglobin molecule, and thalassaemias, which are caused by reduced synthesis of one or more globin chains. The most prominent structural variants include HbS, HbE and HbC, while the major thalassaemia types are alpha-thalassaemia and beta-thalassaemia.
Haemoglobin plays a central physiological role by delivering oxygen from the lungs to tissues and by facilitating carbon dioxide removal. Normal haemoglobin concentrations vary with age and sex but typically range from 9.5 to 17.2 g/dL. Haemoglobin also participates in the transport of carbon dioxide as carbaminohaemoglobin and carries nitric oxide through binding to thiol groups on the globin chains, contributing to vascular regulation.

Haemoglobin Structure and Developmental Regulation

Normal human haemoglobin molecules are tetramers composed of two alpha-like and two beta-like globin chains, each associated with an iron-containing haem moiety. The synthesis of these chains is tightly coordinated to maintain balanced production throughout life. The expression of specific globin chains varies during development, with embryonic, fetal and adult haemoglobins produced at distinct stages.
Embryonic haemoglobins include:

• Hb Gower 1 (ζ₂ε₂),
• Hb Gower 2 (α₂ε₂),
• Hb Portland (ζ₂γ₂).

From around eight weeks of gestation, the predominant form shifts to fetal haemoglobin (HbF; α₂γ₂), which constitutes about 80 per cent of total haemoglobin in term neonates. Its proportion declines during early infancy, stabilising at approximately 1 per cent in childhood. By six months of age, adult haemoglobin (HbA; α₂β₂) becomes the major form, accounting for roughly 96–97 per cent of haemoglobin in healthy individuals. A minor adult haemoglobin, HbA₂ (α₂δ₂), normally comprises about 2.5–3.5 per cent of total haemoglobin.

Classification of Haemoglobinopathies

Haemoglobinopathies are categorised as qualitative defects, arising from structural abnormalities, and quantitative defects, associated with altered globin chain production.

Qualitative Defects: Structural Abnormalities

Structural haemoglobin variants involve mutations that alter the amino-acid sequence of globin chains. Many of these variants are clinically silent and are often identified incidentally or through newborn screening. Diagnostic methods include haemoglobin electrophoresis, isoelectric focusing and high-performance liquid chromatography, with confirmation by molecular genetic testing.
Key groups of structural variants include:

• Sickle cell disease: Caused by the HbS variant, which polymerises when deoxygenated. Polymer formation distorts the red cell membrane, leading to increased fragility, haemolysis and chronic anaemia.
• Unstable haemoglobin variants: These mutations predispose haemoglobin to spontaneous or oxidative precipitation. The resulting aggregates may attach to the red cell membrane, forming Heinz bodies, and lead to haemolytic anaemia.
• Oxygen-affinity variants: Altered affinity for oxygen results in clinically relevant consequences.
  • High-affinity variants (R-state stabilisation) cause erythrocytosis, as seen in Hb Chesapeake and Hb Montefiore.
  • Low-affinity variants (T-state stabilisation) such as Hb Kansas and Hb Beth Israel cause cyanosis.
• Chemical abnormalities: Methaemoglobinaemia is characterised by elevated levels of methaemoglobin, in which iron is oxidised to the ferric (Fe³⁺) state. Methaemoglobin is incapable of binding oxygen, impairing oxygen delivery. A small amount is normally produced and reduced by methaemoglobin reductase. The condition may be inherited or arise from medication exposure or recreational drug use.

Quantitative Defects: Thalassaemias

Thalassaemias result from reduced or absent synthesis of either alpha-like or beta-like globin chains, disturbing the normal ratio between them. Excess unmatched chains form unstable aggregates that precipitate, impairing erythropoiesis and reducing red cell survival.
Key forms include:

• Alpha-thalassaemia: Four genes encode the alpha globin chains, and the clinical severity depends on how many genes are affected.
  • Severe deficiency in the fetus leads to haemoglobin Barts (γ₄) formation, causing hydrops fetalis and intrauterine or early neonatal death.
  • In adults, haemoglobin H disease results from β₄ tetramers that precipitate in red cells, producing moderate to severe anaemia.
• Beta-thalassaemia: Reduced beta globin production results in excess alpha chains that precipitate in erythroid precursors, causing ineffective erythropoiesis, peripheral haemolysis and diminished haemoglobin synthesis. Clinical manifestations range from thalassaemia minor to thalassaemia major, depending on mutation severity.
• Delta-thalassaemia: A defect in delta chain production, usually asymptomatic, that primarily affects HbA₂ levels.

Combination Haemoglobinopathies

Combination haemoglobinopathies arise when two different abnormal globin genes are inherited. When two distinct mutations occur in the same globin gene, the condition is termed compound heterozygosity. Alpha-thalassaemia combinations are generally mild, whereas beta-thalassaemia combinations may produce more significant clinical effects.
Examples include:

• Beta-thalassaemia with additional variants: Conditions common in Mediterranean, African and South Asian populations may mimic the clinical severity of thalassaemia major or intermedia.
• Delta-beta thalassaemia: A rare disorder involving reduced production of both delta and beta globin chains; it is typically asymptomatic.
• Sickle haemoglobin combinations:
  • HbS/β-thalassaemia: Clinical manifestations resemble those of sickle cell disease or thalassaemia, depending on beta-thalassaemia severity.
  • HbSC disease: Occurs when one gene encodes HbS and the other encodes HbC; it shares many features with sickle cell disease.