Southern Cross Pathology Australia
THALASSAEMIA
1.
What is Thalassaemia?
The thalassaemia syndromes are a
heterogeneous group of inherited diseases characterised by a reduced rate of
production of one or more of the globin chains of haemoglobin.
Typically the haematological phenotype of thalassaemia shows red blood
cell hypochromia and/or microcytosis.
2.
What causes Thalassaemia?
Thalassaemia is caused by mutations in
the globin genes which result in imbalanced globin chain production.
The severity of a thalassaemia phenotype depends on which genes are
affected and which gene mutation or combination of mutations is inherited.
Many thalassaemia causing mutations are
now known and can be detected by DNA analysis.
In a carrier these mutations usually result in reduced red cell indices
but may be silent.
3.
What are the clinical outcomes of Thalassaemia?
The inheritance of a b-thalassaemia
mutation from each parent usually causes the life threatening disease b-thalassaemia
major. This is a severe anaemia
which requires life long treatment consisting of monthly blood tranfusions and
daily iron chelation therapy. Carriers
of a b-thalassaemia
mutation usually show hypochromic, microcytic red blood cell changes with a
diagnostic elevation of the minor adult haemoglobin, HbA2. However
some mutations have a less severe effect on gene expression and indices of
carriers may be borderline or normal with the HbA2 minimally elevated
or even in the normal range.
The genetics of a-thalassaemia
is more complex. Instead of a
single copy on each of a pair of chromosomes the a-globin gene is present as two functional
copies such that normal individuals have four functional a-globin
genes. Clinically a-thalassaemia
ranges from a lethal condition (Bart’s hydrops) in which no a-globin
chains are produced to a silent carrier state in which only one of the four a-globin
genes is non functional.
Hb Bart’s hydrops syndrome not only
leads to the death of the baby but may also adversely affect the mother’s
health during pregnancy. Early
recognition enabling termination of affected pregnancies on medical grounds is
therefore an important aspect of thalassaemia management programs.
Inheritance of two or three a-globin
gene mutations may result in HbH disease with variable severity.
HbH disease is commonly a moderately severe chronic haemolytic anaemia
which can be exacerbated by infection or other oxidant stress.
The clinical outcome of inheriting a
thalassaemia mutation can also be affected by co-inheritance of a mutation
giving rise to a structural haemoglobin variant. For example, the substitution of one particular amino acid in
the b-globin
chain produces the HbS associated with the sickle cell disorders.
Another variant HbE which is particularly common in South East Asian
populations behaves as a mild a b-thalassaemia
mutation. In combination with a b-thalassaemia
gene HbE may cause anything from mild clinical disease to the equivalent of b-thalassaemia
major.
4.
How is the Thalassaemia carrier state identified?
The identification of carriers of
thalassaemia and other clinically significant haemoglobinopathies is a two-stage
process. Initially evidence for the
carrier state is obtained from a full blood examination and Hb electrophoresis.
Iron studies are also required to exclude iron deficiency which also causes
reduced red cell indices. This testing is referred to as a thalassaemia screen.
DNA analysis may then be indicated for the final clarification of the
carrier state.
Normal ranges for the relevant
haematological parameters are shown below.
Reduced Mean Cell Haemoglobin and/or
Mean Cell Volume can indicate a
or b thalassaemia,
a raised Red Cell Count can be found in a
thalassaemia and a raised HbA2 confirms a b
thalassaemia carrier state.
The presence of a variant haemoglobin such as HbS or HbE is detected on
Hb electrophoresis.
Relevant
parameters Normal
ranges (SCPA)
Units
Adult male
Adult female
Hb
g/L
130-180
120-160
RCC
x10^9/L
4.50 – 6.20
3.80 –5.40
MCV
fL
78-98
78-98
MCH
pg
27-34
27-34
HbA2
%
1.8 – 3.5 1.8-3.5
Where the carrier
state has been confirmed for one partner DNA analysis to exclude silent
mutations may be indicated for the other partner even when their haematological
indices fall in the normal range. See
sections 5 & 6.
5.
When is DNA analysis of globin gene mutations appropriate?
An accurate diagnosis of thalassaemia or
haemoglobinopathy may be needed to:
- explain
haematological abnormality or anaemia, not otherwise understood
- confirm
a diagnosis of severe disorders such as sickle cell disease, or b-thalassaemia
major
- characterise
the mutation underlying a thalassaemia carrier state, particularly for a-thalassaemia
where the molecular basis can only be determined by analysis of DNA
- test
for silent mutations which might have clinical significance if inherited
with a mutation from the other parent, for example silent a-
or b-thalassaemia
or coexistent a-thalassaemia
in a b-thalassaemia
or HbE carrier
- provide
accurate genetic counselling to individuals and prospective parents
- identify
serious disorders in the fetus and hence provide the additional option to an
at-risk couple of termination of pregnancy
- fully
characterise a variant haemoglobin
6.
What testing is required to identify and counsel at risk couples?
- Where
one partner is identified haematologically as a b
or
db -thalassaemia carrier (or a carrier of the
haemoglobin variants Hb Lepore, HbE, S, D, C or O). the other partner should
be screened haematologically (ie. FBE and Hb electrophoresis).
If these indices are borderline the b globin gene is sequenced to exclude the
possibility of a silent mutation. DNA
studies to exclude underlying a
thalassaemia are also performed.
- Where
a two gene deletion a-thalassaemia
(--/aa)
is detected in one partner a haematology screen and DNA analysis should be
performed on the other partner to exclude the risk of a child with HbH
disease or Bart’s hydrops syndrome.
- Where
a single gene deletion a-thalassaemia
(-a/aa or
-a/-a) or
a non-deletional a-thalassaemia
(aTa/aa) is
detected in one partner a haematology screen and DNA analysis should be
performed on the other partner to exclude the risk of a child with HbH
disease.
- When
an at risk couple has been identified, DNA analysis to fully characterise
the globin gene mutations of both partners is performed so that informed
counselling and prenatal diagnosis is available to them.
What testing for
thalassaemia is provided in Victoria?
The Clinical Genetics Laboratory at SCPA
is the thalassaemia reference centre for Victoria. It receives blood samples from antenatal clinics, pathology
laboratories and private practitioners throughout the state (and some from
interstate) where haematological indices suggest a thalassaemia/haemoglobinopathy
carrier state.
When there is a current pregnancy the
results of a partner thalassaemia screen are immediately required to determine
the need for DNA analysis for one or both partners. Prenatal genetic diagnosis cannot be performed for at risk
couples until their mutations have been characterised by DNA studies.
The laboratory tests about 800 samples
for thalassaemias/haemoglobinopathies and performs around 30 prenatal diagnoses
each year.
Where can you direct your
questions about thalassaemia and thalassaemia testing?
For clinical information and counselling
appointments contact Assoc. Prof. Don Bowden (head of the Medical Therapy Unit
at Monash Medical Centre) on 03 9594 2756.
For information about testing protocols
contact the Clinical Genetics Laboratory (scientist-in-charge Jan Brasch) on 03
9594 3398 or by email to dnalab@southernhealth.org.au
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To contact us email :
scpathology@southernhealth.org.au