Thalassaemias

Secondary article
Article Contents

David Weatherall, John Radcliffe Hospital, Oxford, UK

. Introduction

The thalassaemias are the commonest genetic disorders in humans and present an
increasing public health problem in the tropical countries in which they occur at a high
frequency.

. The Different Types of Thalassaemia

. Molecular Pathology
. Clinical Features
. Reasons for Clinical Variability

Introduction

. Co-inheritance of Thalassaemia with Haemoglobin

Variants

The thalassaemias are a group of inherited disorders of

haemoglobin, rst reported independently from the United
States and Italy in 1925. The word thalassaemia, derived
from Greek roots for the sea and blood, was invented
under the mistaken belief that these disorders were
conned to the Mediterranean region. It was only later
that it was discovered that they are the commonest genetic
disorders and have a widespread distribution in many
countries of the world (Figure 1).
The thalassaemias were among the rst diseases to be
characterized at the molecular level, work that provided
some indications of the repertoire of mutations that
underlie human genetic disease. This led to a better
understanding of their clinical features and now much
can be done to prevent and treat these conditions. This is
important because, with improving socioeconomic conditions in many of the developing countries in which they are
common, these diseases will pose a major public health
problem in the new millennium.

. Distribution and Population Genetics

. Control and Treatment

and g-chain production, is defective, called db or egdb

thalassaemia respectively.
The thalassaemias are inherited in a mendelian recessive
fashion. The severe, homozygous form of the disease is
called thalassaemia major, and the carrier state, in which
only one defective globin gene is inherited, is called the
trait. The disease is very heterogeneous from the clinical
viewpoint; many patients are encountered who fall
between these extremes. These latter disorders are called
thalassaemia intermedia.

Codon 61bp
IVS 1 1 G
A
IVS 2 1 G
A
IVS 2 745 C
G
Codon 39 CAG
TAG
IVS 1 6T
C
IVS 1 110 G
A

IVS 1 5 G
C
IVS 1 1 G
T
Codons 41 42.4bp del
Codons 26 GAG
AAG (HbE)

The Different Types of Thalassaemia

The thalassaemias result from inherited defects in the
synthesis of the globin chains of haemoglobin. Humans
have dierent haemoglobins at various stages of development. Normal adults have a major haemoglobin (Hb)
called HbA, comprising about 90% of the total, and a
minor component, HbA2, which accounts for 23%. The
main haemoglobin in fetal life is HbF, traces of which are
found in normal adults. There are three embryonic
haemoglobins.
All these dierent haemoglobins are tetramers of two
pairs of unlike globin chains. Adult and fetal haemoglobins
have a chains associated with b (HbA, a2b2), d (HbA2,
a2d2), or g chains (HbF, a2g2), whereas in the embryo there
are dierent a-like chains called z chains and distinct b-like
chains called e chains. Each individual globin chain has a
haem moiety attached to it, to which oxygen is bound.
There are two common types of thalassaemia, a and b,
which result from defective synthesis of a or b chains. There
are also rarer forms in which both d and b chain, or e, g, d

29 A
G
88 C
T
Codon 24 T
PolyA T
C

IVS 2 654 G
T
Codons 41 42.4bp del
Codon 17 AAG
TAG
Codon 26 GAG
AAG (HbE)
28 A
G
29 A
G
A

IVS 1 5 G
C
619bp deletion
Codon 8/9 + G
IVS 1 1 G
T
Codons 41 42.4bp del

IVS1 5 G

Figure 1 World distribution of the b thalassaemias. Each population has a

different set of mutations. These are described either by the nucleotide base
position in introns (IVS 1 or 2) or in the particular codons in exons.
Mutations that are given the prefix are those in the 5 noncoding regions of
the b globin genes. Those marked polyA are mutations in the 3 noncoding
regions. bp, Base pair.

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Thalassaemias

Molecular Pathology

Clinical Features

Most of the thalassaemias result from mutations that

involve either the a or b globin genes.

The homozygous state for a0 thalassaemia, that is the loss

of all four a globin genes, results in the stillbirth of a
hydropic fetus, usually late in pregnancy. These infants are
anaemic and oedematous, and show all the features of
severe intrauterine hypoxia. Pregnancies carrying these
babies are complicated by a high frequency of toxaemia
and diculties in delivery, particularly because of enormously enlarged placentas. Individuals who have lost
three of their four a genes ( 2 a/ 2 2 ) have a condition
called haemoglobin H disease, which is characterized by
moderate anaemia and enlargement of the spleen. Persons
who have lost two or one of their a globin genes are not
incapacitated.
The homozyous or compound heterozygous (the inheritance of two dierent alleles) states for severe forms of
b thalassaemia are characterized by severe anaemia that is
manifest during the rst year of life when the switch from g
to b globin chain production occurs. If these children are
not given regular blood transfusions they usually die within
a few months. If they are inadequately transfused they
become growth retarded, develop a curious mongoloid
facial appearance and have gross skeletal deformities due
to overgrowth of the bone marrow, and a variety of other
complications. Children who are well transfused grow and
develop normally, but if they do not receive drugs to
remove the excess iron gained by transfusion they die from
the eects of iron overload, which involves particularly the
liver, endocrine glands and heart. Some of the milder forms
of b thalassaemia are compatible with relatively normal
development without regular blood transfusions, despite a
variable degree of anaemia.
Heterozygotes, or carriers, for b thalassaemia, usually
have very mild anaemia and are free of symptoms. The
condition can be easily identied by the haematological
changes together with an increased level of HbA2. The
carrier states for a thalassaemia vary; in some cases they
are completely silent, whereas in those that involve the loss
of two a genes there may be mild anaemia with a normal
level of HbA2. Currently, the only certain way of
identifying them is by direct analysis of the a globin genes.

a Thalassaemia
The genetics of a thalassaemia is complicated because
normal humans receive two a genes from each parent, a
genotype that is written aa/aa. There are two main classes
of a thalassaemia. First, there are the a0 thalassaemias, in
which both a genes are deleted; that is, all or part of the
gene is missing. The homozygous state is written 2 2 /
2 2 , and the heterozygous state 2 2 /aa. On the other
hand, in the a 1 thalassaemias only one of the a genes is
lost; the homozygous and heterozygous states are designated 2 a/aa and 2 a/ 2 a, respectively. Sometimes a 1
thalassaemia results from a mutation that inactivates the a
globin gene rather than deleting it. In this case the
heterozygous state is written aTa/aa.

b Thalassaemia
More than 180 dierent mutations of the b globin genes
have been found in patients with b thalassaemia. They may
aect gene function at any level between transcription,
processing of the primary messenger ribonucleic acid
transcript, translation, or post-translational stability of
the gene product. Rarely, b thalassaemia, like a thalassaemia, may result from a partial or complete deletion of the b
globin gene. Some of these mutations cause an absence of
b-chain production and the resulting disease is called b0
thalassaemia, whereas others result in a reduced output of
b chains, b 1 thalassaemia. Some of the latter forms are
extremely mild and may not be identiable in carriers; most
heterozygotes for b thalassaemia have very mild anaemia
and a raised level of HbA2.
The hallmark of all the thalassaemias is imbalanced
globin chain production. In the b thalassaemias this results
in an excess of a chains, which precipitate in the red cell
precursors, leading to their damage in the bone marrow
and shortening the survival of their progeny in the
peripheral blood. The pathology of the a thalassaemias is
dierent. In the face of defective a-chain production excess
g chains produced in fetal life form g4 molecules, while in
adults excess b chains form b4 molecules; these homotetramers are called Hbs Barts (g4) and H (b4) respectively.
They do not give up oxygen at normal physiological
tensions and are also unstable. This leads to a shortened
red cell survival and hence anaemia, and patients are
further disadvantaged because the high oxygen anity of
the homotetramers leads to reduced oxygen delivery to the
tissues.
2

Reasons for Clinical Variability

Particularly in the case of the b thalassaemia, there is
remarkable variability in the clinical severity. Several
contributing factors have been identied. First, children
with severe forms of b thalassaemia produce variable
amounts of fetal haemoglobin after the rst year of life. All
normal adults produce small amounts of fetal haemoglobin in some of their red cell precursors; in b thalassaemia
these cells come under intense selection because part of the
excess of a chains, which destroy red cell precursors, are

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Thalassaemias

bound to g chains to produce haemoglobin F. It is now

clear that one of the major factors in modifying the clinical
variability of b thalassaemia is a genetically determined
ability to produce unusually high levels of fetal haemoglobin. A second factor that has been clearly identied is that
the co-inheritance of a thalassaemia will ameliorate the b
thalassaemias. This remarkable experiment of nature
provides clearcut evidence that it is the imbalance of globin
chain production, and the excess of a chains, that is the
major reason why b thalassaemia is so severe. Patients who
are fortunate enough to inherit both types of thalassaemia
are less severely aected because the reduction of a chains
caused by the a thalassaemia gene decreases the overall
degree of globin chain imbalance and hence red cell
production in the bone marrow is more eective.
While variable function of the g and a globin genes is the
major factor that has been identied as modifying the
clinical features of b thalassaemia, this is not the whole
story. There is growing evidence that there are other
genetic modiers and it is also clear that many environmental and social factors play an important role in
determining a childs response to these diseases.

Co-inheritance of Thalassaemia with

Haemoglobin Variants
Although there are many structural haemoglobin variants,
most of them are rare and only three, haemoglobins S, C
and E, reach high frequencies. Hence it is not uncommon
for a person with b thalassaemia to co-inherit a gene for
one of these variants. The compound heterozygous state
for b thalassaemia and the sickle cell gene, sickle cell b
thalassaemia, results in a clinical picture very like sickle cell
anaemia. On the other hand, the inheritance of b
thalassaemia together with haemoglobin E, a haemoglobin
variant that is produced at a reduced rate and hence is
associated with a mild b thalassaemia phenotype, produces
a severe form of thalassaemia which is usually, but not
always, transfusion dependent. Haemoglobin E b thalassaemia is one of the commonest forms of severe
thalassaemia, and is assuming a major public health
problem in parts of India, and further east, particularly
in Thailand and Indonesia.

Distribution and Population Genetics

The thalassaemias occur at a particularly high frequency in
a band stretching from the Mediterranean region, through
the Middle East and Indian subcontinent into southeast
Asia, where they are distributed in a vertical line from
China, through the Malaysian peninsula and into the
island population of Indonesia.

Each population has its own particular varieties of a or b

thalassaemia, which suggests that they have arisen by
mutation and that the gene frequency has been increased
by a local selective process. There is good evidence that the
milder forms of a 1 thalassaemia are protective against
Plasmodium falciparum malaria. Although it has not yet
been proved formally, it seems very likely that this will also
be the case for carriers of b thalassaemia.

Control and Treatment

All the thalassaemias can be identied in the carrier state,
and most forms can be diagnosed in the fetus, and thus it is
possible to oer counselling and prenatal diagnosis for
parents who wish to terminate pregnancies carrying babies
with severe forms of the disease. This approach has
resulted in a major reduction in the birth of new cases in
some of the Mediterranean islands and in other countries.
The only denitive form of treatment for thalassaemia is
bone marrow transplantation, which is possible only when
there is a matching donor relative. Symptomatic treatment
involves regular blood transfusion and the use of ironchelating drugs to remove the excess iron that results from
transfused blood. Children with b thalassaemia who are
adequately transfused and chelated grow and develop
normally, and in some cases are now able to have children
of their own. They need expert care because they are prone
to a variety of complications, including bloodborne
infections, notably hepatitis C and human immunodeciency virus, endocrine damage leading to growth retardation and bone disease, and the side eects of chelating
agents.
Future therapeutic eorts are being aimed at trying to
stimulate the production of fetal haemoglobin production,
or developing somatic gene therapy, directed at replacing
defective a or b globin genes.

Further Reading
Cao A, Galanello R and Rosatelli MC (1998) Screening and prenatal
diagnosis of the haemoglobinopathies. Clinical Haematology 11: 215
238.
Olivieri NF, Nathan DG, MacMillan JH et al. (1994) Survival of
medically treated patients with homozygous b thalassemia. New
England Journal of Medicine 331: 574578.
Weatherall DJ (2000) The thalassemias. In: Stamatoyannopoulos G,
Perlmutter RM, Marjerus PW and Varmus H (eds) Molecular Basis of
Blood Diseases, 3rd edn. Philadelphia: WB Saunders (in press).
Weatherall DJ and Clegg JB (1996) Thalassaemia a global public
health problem. Nature Medicine 2: 847849.
Weatherall DJ and Clegg JB (2000) The Thalassaemia Syndromes, 4th
edn. Oxford: Blackwell Science (in press).
Weatherall DJ, Clegg JB, Higgs DR and Wood WG (2000) The
hemoglobinopathies. In: Scriver CR, Beaudet AL, Sly WS, Valle D,
Childs B and Vogelstein B (eds) The Metabolic and Molecular Bases of
Inherited Disease, 8th edn. New York: McGraw-Hill (in press).

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net