Download Variant types of Haemoglobinopathies

VARIANT TYPES OF
HAEMOGLOBINOPATHIES
WHAT ARE HEMOGLOBINOPATHIES?
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A group of inherited disorders characterized by
structural variations of the Hb molecule. They are
Disorders of globin synthesis rather than heme
synthesis.
These may result from :
Synthesis of abnormal Hb
Reduced rate of synthesis of NORMAL α or β globin
chains
Genetic defects of Hb are the most common genetic
disorders worldwide.
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People only have these disorders if they inherit two unusual
hemoglobin genes – one from their mothers, and one from
their fathers.
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People who inherit just one unusual gene are known as
‘carriers’. (Some people call this having a ‘trait’.) Carriers are
healthy and do not have the disorders.
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It is estimated that globally at least : 5% of adults are carriers
for a hemoglobin disorder, 2.9% for thalassaemia and 2.3% for
sickle cell diseases.
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In KSA*, some studies reported the incidence of Hb S for the
studied neonates to be 14.4%, ranged from 0.8% in Najran to
26.4% in Al-Qurayyat
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In the eastern provinces the disease is generally milder
whereas in the western provinces the disease is severe.
*Kuwait Medical Journal 2002, 34 (2):156-160
CLASSIFICATION
Can be classified into three main groups :
1. Variant Haemoglobins.
2. Thalassaemia.
3. Hereditary Persistence of Foetal Haemoglobin (HPFH)
VARIANT HEMOGLOBINS
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Variant Hbs result from substitution of one or more
amino acids in the globin portion of the molecule at
selected positions in the two alpha or two beta
polypeptide chains.
Usually caused by single point mutations.
Although more than 100 variants have been
described, only hemoglobins S, C, and D are
commonly seen.
Hb S
Sickle cell disease.
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Many variant Hbs are hematologically and clinically silent
because the underlying mutation causes no alteration in the
function, solubility, or stability of Hb.
Some structural variants are associated with severe clinical
phenotypes ; these mutations affect the physical or chemical
properties of Hb, resulting in changes in hemoglobin solubility,
stability, or oxygen-binding properties.
COMMON VARIANTS
Hb S
Hb C
Hb E
Hb D-Punjab
Hb O-Arab
Hb G-Philadelphia
Hb Hasharon
Hb Korle-Bu
Hb Lepore
Hb M
Hb AS
Hb AC
Hb ADPunjab
Hb AE
Hb AOArab
THALASSAEMIAS
Result from reduced rate of synthesis of α or β
globin chains.
 These may be due to point mutations or
insertion/deletions.
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HEREDITARY PERSISTENCE OF FOETAL
HAEMOGLOBIN (HPFH)
Benign group of conditions.
 Synthesis of foetal haemoglobin remains raised
throughout life.
 Molecular causes may be deletional or non deletional
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The abnormality in Haemoglobinopathies may occur in the
heterozygous or the homozygous form.
Homo = ‫متشابه‬
Hetero = ‫مختلف‬
Zygosity refers to the similarity of genes for a trait (inherited
characteristic).
If both genes are the same, the person is homozygous for the
trait.
If both genes are different, the person is heterozygous for that
trait
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In the heterozygous form, hemoglobin A and the variant both
appear in the red cell : ( Hb AS, Hb AC). Little or no clinical
manifestation of disease may be present.
In the homozygous form, only the variant hemoglobin is present
(Hb SS, Hb CC), and the characteristic symptoms of that
hemoglobinopathy appear.
Mixed heterozygous forms are also known to occur (Hb SC).
The normal hemoglobin A may be absent, and two or three
hemoglobin variants may be present.
LABORATORY METHODS
Initial tests recommended include:
 Complete blood count (CBC).
 Electrophoresis at pH 9.2
 Tests for solubility and sickling
 Quantification of Hb A2 and Hb F.
 If an abnormal Hb is identified on the initial tests, then further
techniques are recommended to identify the variants. These
techniques include electrophoresis at pH 6.0–6.2, globin chain
separation, and isoelectric focusing (IEF).
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Although electrophoresis at alkaline and acid pH has been
used for many years, cation-exchange HPLC is emerging as the
method of choice for quantification of Hb A2 and Hb F and
identification of Hb variants.
HPLC = High Performance Liquid Chromatography
PCR techniques are used in definition of known globin chain
mutations/deletions, including those for Hb S, E, D, and O, and
several ß-thalassemias.
PCR = Polymerase Chain Reaction