ABC of clinical haematology: The hereditary anaemias

doi:10.1136/bmj.314.7079.492

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David J Weatherall

Introduction

Hereditary anaemias include disorders of the structure or synthesis of haemoglobin; deficiencies of enzymes that provide the red cell with energy or protect it from chemical damage; and abnormalities of the proteins of the red cell's membrane. Inherited diseases of haemoglobin, haemoglobinopathies, are by far the most important.

The structure of human haemoglobin (Hb) changes during development. By the 12th week embryonic haemoglobin is replaced by fetal haemoglobin (Hb F), which is slowly replaced after birth by the adult haemoglobins, Hb A and Hb A2. Each type of haemoglobin consists of two different pairs of peptide chains; Hb A has the structure α2β2 (namely, two α chains plus two β chains), Hb A2 has α2δ2, and Hb F has α2γ2.

Simplified representation of the genetic control of human haemoglobin. Because α chains are shared by both fetal and adult haemoglobin, mutations of the α globin genes affect haemoglobin production in both fetal and adult life; diseases that are due to defective β globin production are only manifest after birth when Hb A replaces Hb F.

The haemoglobinopathies consist of structural haemoglobin variants (the most important of which are the sickling disorders) and thalassaemias (hereditary defects of the synthesis of either the α or β globin chains).

The sickling disorders

Classification and inheritance

The common sickling disorders consist of the homozygous state for the sickle cell gene—that is, sickle cell anaemia (Hb SS)–and the compound heterozygous state for the sickle cell gene and that for either Hb C (another β chain variant) or β thalassaemia (termed Hb SC disease or sickle cell β thalassaemia). The sickle cell mutation results in a single amino acid substitution in the β globin chain; heterozygotes have one normal (β^A) and one affected β chain (β^S) gene and produce about 60% Hb A and 40% Hb S; homozygotes produce mainly …