Genetic disorders

of haemoglobin/
Haemoglobinopathies

Haemoglobinopathies
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D.Wamala,PhD
Haemoglobin synthesis
• Normal adult blood contains three types of haemoglobin.
• The major component is haemoglobin A with the molecular structure
α2β2.
• The minor haemoglobins contain γ (fetal Hb or HbF) or δ (Hb A 2 )
globin chains instead of β chains.
• Th e genes for the globin chains occur in two clusters: ε , γ , δ and β
on chromosome 11 and ζ and α on chromosome 16.

Haemoglobinopathies
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Globin transcription during development

Haemoglobinopathies
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The globin gene clusters on chromosomes 16 and 11. In embryonic, fetal and adult life different
genes are activated or suppressed. The different globin chains are synthesized independently and then combine
with each other to produce the different haemoglobins. The γ gene may have two sequences, which code for
either a glutamic acid or alanine residue at position 136Haemoglobinopathies
(G γ or A γ , respectively). LCR, locus control region,
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HS - 40, see text. (b) Synthesis of individual globin chains in prenatal and postnatal life.
D.Wamala,PhD
Regulation of adult β globulin expression
Haemoglobinopathies
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D.Wamala,PhD
Haemoglobin abnormalities
• These result from the following:
• 1 Synthesis of an abnormal haemoglobin.
• 2 Reduced rate of synthesis of normal α - or β - globin chains (the α -
and β - thalassaemias).

Haemoglobinopathies
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Haemoglobinopathies
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D.Wamala,PhD
Thalassaemias
• Th ese are a heterogeneous group of genetic disorders that result
from a reduced rate of synthesis of α or β chains.
• β - Th alassaemia is more common in the Mediterranean region while
α - thalassaemia is more common in the Far East.

Haemoglobinopathies
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D.Wamala,PhD
α - Thalassaemia syndromes
• These are usually caused by gene deletions and are
• As there are normally four copies of the α - globin gene, the clinical severity can
be classifi ed according to the number of genes that are missing or inactive.
Loss of all four genes completely suppresses α - chain synthesis and because the
α chain is essential in fetal as well as in adult haemoglobin this is incompatible
with life and leads to death in utero (hydrops fetalis;
• Three α gene deletions leads to a moderately severe (haemoglobin 7 – 11 g/dL)
microcytic, hypochromic anaemia with splenomegaly. This is known as Hb H
disease because haemoglobin H ( β 4 ) can be detected in red cells of these
patients by electrophoresis or in reticulocyte preparations
• In fetal life, Hb Barts ( γ 4 ) occurs

Haemoglobinopathies
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D.Wamala,PhD
α - Thalassaemia syndromes
• The α - thalassaemia traits are caused by loss of one or two genes and
are usually not associated with anaemia, although the mean
corpuscular volume (MCV) and mean corpuscular haemoglobin
(MCH) are low

Haemoglobinopathies
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D.Wamala,PhD
α - Thalassaemia: hydrops fetalis,
the result
of deletion of all four α - globin
genes (homozygous
α 0 - thalassaemia). The main
haemoglobin present is
Hb Barts ( γ 4 ). The condition is
incompatible with life
beyond the fetal stage. (Courtesy of
Professor D.
Todd)

Haemoglobinopathies
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D.Wamala,PhD
α - Thalassaemia: haemoglobin H disease (three α - globin gene deletion). The blood fi lm shows
marked hypochromic microcytic cells with target cells and poikilocytosis. (b) α - Thalassaemia: haemoglobin H
disease. Supravital staining with brilliant cresyl blue reveals multiple fi ne, deeply stained deposits ( ‘ golf ball ’
cells) caused by precipitation of aggregates of β - globin chains. Hb H can also be detected as a fast - moving
band on haemoglobin electrophoresis (Fig. 7.12 ).

Haemoglobinopathies
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D.Wamala,PhD
β - Thalassaemia syndromes
• Either no β chain ( β 0 ) or small amounts ( β + ) are synthesized. Excess α chains precipitate in erythroblasts
and in mature red cells causing the severe ineff ective erythropoiesis and haemolysis that are typical of this
disease

Haemoglobinopathies
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D.Wamala,PhD
Haemoglobinopathies
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D.Wamala,PhD
β - Thalassaemia syndromes
• Thalassaemia major is often a result of inheritance of two diff erent mutations, each aff ecting β - globin
synthesis (compound heterozygotes).

Haemoglobinopathies
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D.Wamala,PhD
• Clinical features
• 1 Severe anaemia becomes apparent at 3 – 6 months after birth when
the switch from γ - to β – chain.
• 2 Enlargement of the liver and spleen occurs as a result of excessive
red cell destruction, extramedullary haemopoiesis and later because
of iron overload.
• 3 Expansion of bones caused by intense marrow hyperplasia leads to
a thalassaemic facies

Haemoglobinopathies
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D.Wamala,PhD
The facial appearance of a child
with
β - thalassaemia major. The skull
is bossed with
prominent frontal and parietal
bones; the maxilla is
enlarged.

Haemoglobinopathies
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D.Wamala,PhD
Figure 7.10 The skull X - ray in β -
thalassaemia major.
There is a ‘ hair - on - end ’
appearance as a result of
expansion of the bone marrow into
cortical bone.

Haemoglobinopathies
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D.Wamala,PhD
Blood film in
β - thalassaemia major post -
splenectomy. There are
hypochromic
cells, target cells and many
nucleated red cells
(normoblasts).
Howell – Jolly bodies are seen
in
same red cells

Haemoglobinopathies
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D.Wamala,PhD
Thalassaemia intermedia
• Th is is a clinical syndrome which may be caused by a variety of
genetic defects: homozygous β - thalassaemia with production of
more Hb F thanusual, e.g. from mutations of the BCL11A gene orwith
mild defects in β - chain synthesis, by β -thalassaemia trait alone of
unusual severity ( ‘ dominant’ β - thalassaemia) or β - thalassaemia
trait inassociation with mild globin abnormalities such asHb Lepore

Haemoglobinopathies
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Haemoglobinopathies
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β - Thalassaemia t rait ( minor)
• Th is is a common, usually symptomless, abnormality characterized
like α - thalassaemia trait by a hypochromic microcytic blood picture
(MCV and ineff ective erythropoiesis.
• Conversely, patients withβ - thalassaemia trait who also have excess
(fi ve or six)α genes tend to be more anaemic than usual. Th epatient
with thalassaemia intermedia may showbone deformity, enlarged
liver and spleen, extramedullaryerythropoiesis (

Haemoglobinopathies
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D.Wamala,PhD