Thalassaemias

Abstract

The thalassaemias are the commonest genetic disorders in humans, representing an imbalance in the production of the α‐ and β‐globin chains which combine to form haemoglobin. The globin chain which is present in excess may precipitate in red cell precursors, causing oxidative damage and ineffective erythropoiesis. Patients with thalassaemia are therefore anaemic despite an expansion of erythroid activity in the bone marrow. In severe cases (thalassaemia major), regular blood transfusion is needed for survival. The high prevalence of thalassaemia in tropical regions is thought to reflect the relative resistance of carriers to falciparum malaria. Although bone marrow transplantation is currently the only curative treatment, intensive study of transcriptional regulation at the loci for the globin genes has highlighted the potential for gene therapy and gene editing. However, finding approaches to treatment that are practical for the majority of affected patients who live in low income regions of the world remains a major challenge.

Key Concepts

  • Thalassaemia results from an imbalance between α‐ and β‐globin chain production.
  • Its genetic basis is very variable, with α thalassaemia usually being caused by small deletions, and β thalassaemia normally due to point mutations.
  • The high gene frequency in areas of the world affected by malaria is thought to represent the protective effect of the carrier status.
  • Clinical consequences of thalassaemia include anaemia, bone marrow expansion and iron loading.
  • Iron loading may occur as a result of increased gastrointestinal absorption and, more significantly, due to regular blood transfusion.
  • The consequences of iron overload include hepatic, cardiac and endocrine dysfunction.
  • Bone marrow transplant remains the only curative treatment at present.
  • In the investigative context, individuals have attained transfusion independence through lentiviral gene therapy.
  • Efforts to reactive foetal haemoglobin therapeutically have focused on understanding BCL11a expression.

Keywords: thalassaemia; haemoglobin; anaemia; malaria; molecular pathology

Figure 1. Human globin gene clusters on chromosomes 16 and 11. The different genes that are activated at various stages of development, together with the haemoglobins that are produced, are shown. The locus control region (LCR) and upstream elements including HS‐40 are the major ‘master’ regulatory regions for the two clusters.
Figure 2. World distribution of the thalassaemias.
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Further Reading

Steinberg MH, Forget B, Higgs DR and Weatherall DJ (2009) Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management, 2nd edn. Cambridge, MA: Cambridge University Press.

Weatherall DJ and Clegg JB (1996) Thalassaemia: a global public health problem. Nature Medicine 2: 847–849.

Weatherall DJ (2001) Phenotype–genotype relationships in monogenic disease: lessons from the thalassaemias. Nature Reviews 2: 245–255.

Weatherall DJ and Clegg JB (2001a) The Thalassaemia Syndromes, 4th edn. Oxford, UK: Blackwell Scientific Publications.

Weatherall DJ and Clegg JB (2001b) Inherited hemoglobin disorders: an increasing global health problem. Bulletin of the World Health Organization 79: 704–711.

Weatherall DJ (2010) Thalassaemia. The Biography. Oxford, UK: Oxford University Press.

Weatherall DJ, Schechter AN and Nathan DJ (eds) (2013) Hemoglobin and its Disorders. New York, NY: Cold Spring Harbor Laboratory Press.

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How to Cite close
Hay, Deborah, and Weatherall, David J(Oct 2017) Thalassaemias. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002274.pub3]