Thalassaemia
Confirmatory testing by DNA
What is it?
Thalassaemia is a group of inherited disorders that affect
the amount of haemoglobin a person produces.
Haemoglobin refers to a family of compounds all made up of
haem (an iron-containing complex), and various globins
(protein chains that surround the haem complex).
Haemoglobin (Hb) molecules are found in all red blood cells,
and are the reason for their red colour. They bind oxygen in the
lungs, carry it through the bloodstream, and release it to the
body’s tissues.
Normal adult haemoglobins include:
• Haemoglobin A (about 95% - 98%). HbA contains two
alpha (α) chains and two beta (ß) chains.
• HbA2 (about 2% - 3.5%), has two alpha (α) and two delta
(δ) chains
• HbF (up to 2%). This is the primary haemoglobin
produced by the fetus during gestation. Its production
usually falls to a low level within a year after birth. HbF
has two alpha (α) and two gamma (γ) chains.
Mutations in the genes coding for the globin chains can cause
disorders in haemoglobin production. There are 4 genes coding
for alpha globin chains and 2 genes coding for the beta globin
chains.
Inherited disorders of haemoglobin production fall into two
categories:
• Thalassaemia: decreased production of normal
haemoglobins
• Haemoglobinopathy: production of an abnormal
haemoglobin molecule
Thalassaemias are a group of disorders in which mutations in
one or more of the alpha or beta globin genes cause a
reduction in the amount of the HbA produced. This leads to a
reduction in HbA, the relative increase in the amount of minor
haemoglobins HbA2 and HbF, and perhaps detection of unusual
haemoglobin types.
The thalassaemias are usually classified by the type of globin
chain whose synthesis is reduced.
Thalassaemia Classifications
Alpha thalassaemia
is due to a deletion or mutation in one or more of the 4 alpha
globin gene copies. The more genes affected, the less alpha
globin produced. The four different types of alpha thalassaemia
include:
• Silent Carrier State (1 affected gene). The silent carrier
will have normal haemoglobin levels red cell indices which are
normal or show a slightly decreased MCH (hypochromia).
Carriers can pass on the affected gene to their offspring. Often
these individuals are identified only after having a child with
HbH disease or alpha thalassaemia trait.
• Alpha Thalassaemia Trait (2 affected genes). Patients
who have alpha thalassaemia trait have smaller (microcytic),
paler (hypochromic) red blood cells and a mild chronic Anaemia
but do not generally experience any symptoms. This is an
Anaemia that does not respond to iron supplements. Diagnosis
of alpha thalassaemia trait is usually by exclusion of other
causes of microcytic Anaemia.
analysis is available but is not routinely done.
• Haemoglobin H Disease (3 affected genes). With this
condition, the large decrease in the amount of alpha globin
chains produced causes an excess of beta chains which then
aggregate into beta4 tetramers (groups of 4 beta chains),
known as Haemoglobin H. HbH disease can cause moderate to
severe Anaemia and splenomegaly (enlarged spleen). The
clinical picture associated with HbH disease is extremely
variable, however. Some individuals are asymptomatic while
others have severe Anaemia. Haemoglobin H disease is found
most often in individuals of Southeast Asian or Eastern
Mediterranean descent.
• Alpha Thalassaemia Major (also called hydrops fetalis, 4
affected genes). This is the most severe form of alpha
thalassaemia. In this condition, no alpha globin is produced,
therefore, no HbA or HbF are produced. Fetuses affected by
alpha thalassaemia major become anemic early in pregnancy.
They become hydropic (retain fluids), and frequently have
enlarged hearts and livers. This diagnosis is frequently made in
the last months of pregnancy when a fetal ultrasound indicates
a hydropic fetus. About 80% of the time the mother will have
toxaemia and can develop severe postpartum hemorrhage.
Fetuses with alpha thalassaemia major are usually miscarried,
stillborn, or die shortly after birth.
Individuals with alpha thalassaemia may be misdiagnosed as
iron deficient by unwary doctors, as iron deficiency also leads to
small pale (microcytic hypochromic) red cells. It is important
that iron therapy in thalassaemic patients is only given when
specific iron tests (LINK TO FERRITIN, SERUM IRON, TIBC
&TRANSFERRIN) have confirmed iron deficiency. This is
especially important in alpha thalassaemia, where there is a
small potential for dangerous iron overload to develop.
Alpha thalassaemia is found most commonly in individuals with
an ethnic background of Southeast Asia, Southern China, the
Middle East, India, Africa and the Mediterranean.
Beta thalassaemia
is due to mutations, in one or both of the beta globin genes.
There are 100 to 200 mutations that have been identified but
only about 20 are common. The severity of the Anaemia caused
by beta thalassaemia depends on which mutations are present
and on whether they decrease beta globin production (called
beta+ thalassaemia) or completely eliminate it (called beta0
thalassaemia). The different types of beta thalassaemia
include:
• Beta Thalassaemia Trait. A person with this condition has
one normal gene and one with a mutation. They will usually
experience no health problems other than microcytosis (small
red blood cells) and a possible mild Anaemia that will not
respond to iron supplements. This gene mutation can be passed
on to an individual’s children.
• Thalassaemia Intermedia. In this condition, an affected
person has two abnormal genes but is still producing some beta
globin. The severity of the Anaemia and health problems
experienced depends on the mutations present. The dividing
line between thalassaemia intermedia and thalassaemia major
is the degree of Anaemia and the number and frequency of
blood transfusions required to treat it. Those with thalassaemia
intermedia may need occasional transfusions but do not require deficiency is causing and/or exacerbating a patient’s
them on a regular basis. Anaemia. One or more of them may also be ordered to
• Thalassaemia Major (also called Cooley's Anaemia). help monitor the degree of iron overload in a patient with
This is the most severe form of beta thalassaemia. The patient thalassaemia.
has two abnormal genes that cause either a severe decrease or 4. Haemoglobinopathy (Hb) evaluation. This test
complete lack of beta globin production, preventing the measures the type and relative amounts of
production of significant amounts of HbA. This condition usually haemoglobins present in the red blood cells.
appears in an infant after 3 months of age and causes life- Haemoglobin A, composed of both alpha and beta
threatening Anaemia. This Anaemia requires lifelong regular globin, is the major normal type of haemoglobin found
blood transfusions and considerable ongoing medical care. Over in adults. A greater percentage of HbA2 and/or HbF is
time these frequent transfusions lead to excessive amounts of usually seen in beta thalassaemia trait. HbH may be
iron in the body. Left untreated, this excess iron can deposit seen in alpha thalassaemia , but only when at two of
into the liver, heart and other organs, and can lead to a the four alpha genes are deleted or mutated.
premature death from organ failure. 5. DNA analysis. This test is used to investigate deletions
Other forms of thalassaemia occur when a gene for beta and mutations in the alpha and beta globin producing
thalassaemia is inherited in combination with a gene for a genes. Family studies can be done to evaluate carrier
haemoglobin variant. (link to Hb Variant page) The most status and the types of mutations present in other
important of these are: family members. DNA testing is not routinely done but
• HbE – beta thalassaemia. HbE is one of the most can be used to help diagnose thalassaemia, and to
common haemoglobin variants, found predominantly in people determine carrier status. It is the only reliable way of
of Southeast Asian descent. If a person inherits one HbE gene diagnosing carriers who have only one of four alpha
and one beta thalassaemia gene, the combination produces genes deleted or mutated.
HbE-beta thalassaemia which causes a moderately severe
Anaemia similar to beta thalassaemia intermedia.
• HbS – beta thalassaemia or sickle cell – beta
thalassaemia. HbS is one of the most well known of the
haemoglobin variants. Inheritance of one HbS gene and one
beta thalassaemia gene results in HbS-beta thalassaemia. The
severity of the condition depends on the amount of beta globin
produced by the beta gene. If no beta globin is produced, the
clinical picture is almost identical to sickle cell disease.
Laboratory Tests
1. FBC (full blood count). The FBC is a snapshot of the cells
and fluid in your bloodstream. Among other things, the FBC
will tell the doctor how many red blood cells are present,
how much haemoglobin is in them, and give the doctor an
evaluation of the size and shape of the red blood cells
present. MCH (mean corpuscular haemoglobin) and MCV
(mean corpuscular volume) are measurements of the
haemoglobin content and size of the red blood cells. A low
MCH or MCV is often the first indication of thalassaemia. If
the MCH or MCV is low and iron-deficiency has been ruled
out, the person may be a thalassaemia trait carrier.
2. Blood film (smear). In this test a thin stained layer of blood
is examined on a slide, under a microscope. The number
and type of white blood cells, red blood cells, and platelets
can be manually counted and be evaluated to see if they
are normal and mature. A variety of disorders affect
normal blood cell production. With thalassaemia, the red
blood cells are often microcytic (small). They may also be:
• Hypochromic (pale – indicating less haemoglobin)
• Vary in size (anisocytosis) and shape (poikilocytosis)
• Be nucleated (not normal in a mature RBC)
• Be distorted to produce “target cells”, which look like a
bull’s-eye under the microscope.
3. Iron studies. These may include: Iron, Ferritin, UIBC, TIBC,
and Percent Saturation of Transferrin. These tests measure
different aspects of the body’s iron storage and usage.
They are ordered to help determine whether an iron