α-thalassaemia

Cornelis L Harteveld,Douglas R Higgs

doi:10.1186/1750-1172-5-13

Abstract

Alpha-thalassaemia is inherited as an autosomal recessive disorder characterised by a microcytic hypochromic anaemia, and a clinical phenotype varying from almost asymptomatic to a lethal haemolytic anaemia.It is probably the most common monogenic gene disorder in the world and is especially frequent in Mediterranean countries, South-East Asia, Africa, the Middle East and in the Indian subcontinent. During the last few decades the incidence of alpha thalassaemia in North-European countries and Northern America has increased because of demographic changes. Compound heterozygotes and some homozygotes have a moderate to severe form of alpha thalassaemia called HbH disease. Hb Bart's hydrops foetalis is a lethal form in which no alpha-globin is synthesized. Alpha thalassaemia most frequently results from deletion of one or both alpha genes from the chromosome and can be classified according to its genotype/phenotype correlation. The normal complement of four functional alpha-globin genes may be decreased by 1, 2, 3 or all 4 copies of the genes, explaining the clinical variation and increasing severity of the disease. All affected individuals have a variable degree of anaemia (low Hb), reduced mean corpuscular haemoglobin (MCH/pg), reduced mean corpuscular volume (MCV/fl) and a normal/slightly reduced level of HbA2. Molecular analysis is usually required to confirm the haematological observations (especially in silent alpha-thalassaemia and alpha-thalassaemia trait). The predominant features in HbH disease are anaemia with variable amounts of HbH (0.8-40%). The type of mutation influences the clinical severity of HbH disease. The distinguishing features of the haemoglobin Bart's hydrops foetalis syndrome are the presence of Hb Bart's and the total absence of HbF. The mode of transmission of alpha thalassaemia is autosomal recessive. Genetic counselling is offered to couples at risk for HbH disease or haemoglobin Bart's Hydrops Foetalis Syndrome. Carriers of alpha+- or alpha0-thalassaemia alleles generally do not need treatment. HbH patients may require intermittent transfusion therapy especially during intercurrent illness. Most pregnancies in which the foetus is known to have the haemoglobin Bart's hydrops foetalis syndrome are terminated due to the increased risk of both maternal and foetal morbidity.

Highlights

Why should α thalassaemia be considered in a forum dedicated to rare diseases? It is certainly not a rare genetic trait
Carriers of α thalassaemia are found at polymorphic frequencies (>1%) in all tropical and subtropical populations that have been studied and, in some areas, the carrier state has almost gone to fixation
This is because carriers of α thalassaemia are thought to be at a selective advantage in areas where falciparum malaria is or has been endemic

Summary

Introduction

Why should α thalassaemia be considered in a forum dedicated to rare diseases? It is certainly not a rare genetic trait. Some individuals who make very little or no α globin chains have a very severe form of anaemia which, if untreated, causes death in the neonatal period This condition is called the Hb Bart's hydrops foetalis syndrome [2,3,4,5]. Α0-thalassaemia due to deletions The complete or partial deletion of both α-genes in cis results in no α-chain synthesis directed by these chromosomes in vivo (Figures 6 and 7a) Homozygotes for such deletions have the Hb Bart's Hydrops Foetalis Syndrome. Diagnosis and diagnostic methods Initial laboratory testing should include a complete blood count with red cell indices, HPLC or Hb electrophoresis and eventually α/β-globin chain synthesis ratio measurement The latter procedure, is sometimes bypassed by DNA analysis as a less complicated method to diagnose α-thalassaemia.

29. Bernini L

35. Weatherall DJ

42. Vichinsky EP

69. Higgs DR

Findings

86. Bain BJ