The thalassaemias

Published on 03/04/2015 by admin

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Last modified 03/04/2015

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The thalassaemias

The thalassaemias are a heterogeneous group of inherited disorders of haemoglobin synthesis. They are characterised by a reduction in the rate of synthesis of either alpha or beta chains and are classified accordingly (i.e. α-thalassaemia, β-thalassaemia). The basic haematological abnormality in the thalassaemias is a hypochromic microcytic anaemia of variable severity. Unbalanced synthesis of α- and β-globin chains can damage red cells in two ways. Firstly, failure of α and β chains to combine leads to diminished haemoglobinisation of red cells to levels incompatible with survival. Even those hypochromic cells released into the circulation transport oxygen poorly. The second mechanism for red cell damage is the aggregation of unmatched globin chains – the inclusion bodies lead to accelerated apoptosis of erythroid precursors in the bone marrow (ineffective erythropoiesis) and destruction of more mature red cells in the spleen (haemolysis). In general, the clinical severity of any case of thalassaemia is proportionate to the degree of imbalance of α- and β-globin chain synthesis.

Thalassaemias are among the most common inherited disorders. Gene carriers have some protection from falciparum malaria. Cases occur sporadically in most populations but the highest thalassaemia gene frequency is in a broad geographical region extending from the Mediterranean through the Middle East and India to South-East Asia.

Classification

The classification illustrated in Table 16.1 is based on the mode of inheritance of thalassaemia.

Table 16.1

Classification of thalassaemia

Type of thalassaemia	Heterozygote	Homozygote
α-Thalassaemia¹
α⁰ (– –/)	Thal. minor	Hydrops fetalis
α⁺ (–α/)	Thal. minor	Thal. minor
β-Thalassaemia
β⁰	Thal. minor	Thal. major
β⁺	Thal. minor	Thal. major or intermedia

¹ Compound heterozygosity (– –/–α) leads to HbH disease.

As the α-globin chain gene is duplicated on each chromosome there may be total loss of α-globin chain production (termed α⁰ or – –/haplotype) or partial loss of α-chain production resulting from loss of only one gene (termed α⁺ or –α/haplotype).

The most important clinical syndromes are haemoglobin (Hb)-Barts hydrops syndrome (– –/– –), which is incompatible with life, and Hb H disease (–α/– –). At the molecular level the α-thalassaemias result from loss of α-gene function due to gene deletion or non-deletional mutations; different types of mutations may be co-inherited.

β-Thalassaemias are autosomal recessive disorders characterised by reduced (β⁺) or absent (β⁰) production of β chains. The heterozygous (‘trait’ or ‘minor’) form of the disease is usually symptomless while homozygosity is associated with the clinical disease β-thalassaemia ‘major’. Homozygous mild (β⁺) thalassaemia may, however, lead to a less severe clinical syndrome termed ‘thalassaemia intermedia’. The β-thalassaemias are very heterogeneous at the molecular level – the large majority of mutations are single base substitutions (point mutations) and insertions or deletions of one to two bases.

Although molecular analysis may be needed, diagnosis of the major syndromes is normally possible from consideration of the clinical features and simple laboratory tests. The latter must include a blood count and blood film, and haemoglobin electrophoresis with quantification of the different types of haemoglobin (i.e. HbA, HbA₂, HbF).

Other structural Hb variants may coexist with thalassaemias giving rise to a wide range of clinical disorders. Only the more common thalassaemia syndromes are discussed here.

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