Hemoglobinopathy

Genetic disorders
of haemoglobin
Hemoglobinopathy
• Hemoglobinopathy refers to a disease state (“opathy”)
involving the hemoglobin (Hb) molecule.
• All hemoglobinopathies result from a genetic
mutation in one or more genes that affect hemoglobin
synthesis.
• The genes that are mutated can code for
• either the proteins that make up the hemoglobin
molecule (globin chains)
• or the proteins involved in synthesizing or regulating
synthesis of the globin chains
Classification
• Hemoglobinopathies affect hemoglobin synthesis in one of two ways:
qualitatively or quantitatively
Qualitative
• hemoglobin molecule has an altered amino acid sequence within the
globin chains
• (structural defect) and its function (qualitative defect)
Quantitative
• reduced rate of haemoglobin synthesis (quantitative) but do not
affect the amino acid sequence of the globin chains.eg thalassemias
GLOBIN GENES
• six functional human globin genes located on two different
chromosomes
• globin genes, α and ζ, are located on chromosome 16 and
are referred to as α-like genes
• The remaining four globin genes, β, γ, δ, and ε, are located
on chromosome 11 and are referred to as β -like genes.
• Each globin gene codes for the corresponding globin chain:
• the α-globin gene is used as the template to synthesizethe α-
globin chain, the β-globin gene codes for the β-globin chain,
and so forth
HEMOGLOBIN SYNTHESIS
• Each human hemoglobin molecule is composed of four
globin chains, a pair of α-like chains and a pair of β-like
chains
• During the first 3 months of embryonic life, only one α-like
gene (ζ) and one β-like gene (ε) are activated,
• ζ and ε chains that pair to form a haemoglobin type called
Gower-1 (ζ2ε2)
• Shortly thereafter, α and γ chain synthesis begins, which
leads to the production of Hb Gower-2 (α2ε2) and Hb
Portland (ζ2γ2).
 HEMOGLOBIN SYNTHESIS
• Later in fetal development, ζ and ε synthesis ceases;
this leaves α and γ chains, which pair to produce Hb F
(α2γ2), also known as fetal haemoglobin
• During the 6 months after birth, γ chain synthesis
gradually decreases and is replaced by β chain
• HbA (α2β2), also known as adult haemoglobin
produced
 HEMOGLOBIN SYNTHESIS

• globin gene, δ, becomes activated around birth,

producing δ chains at low levels
• δ chains with α chains to produce the second adult
hemoglobin, called Hb A2 (α2δ2).

• Normal adults produce Hb A (95%), Hb A2 (less than

3.5%), and Hb F (less than 1% to 2%)
 Sickle Cell Anemia

• The term sickle cell diseases is used to describe a group of

symptomatic hemoglobinopathies that have in common
sickle cell formation and the associated crises

• Patients with SCD are either homozygous for Hb S (SS) or are

compound heterozygotes expressing Hb S in combination
with another haemoglobin β chain mutation like Hb C or β-
thalassemia
 Molecular pathology of sickle cell
anaemia.
• There is a single base change in the DNA coding for the
amino acid in the sixth position in the β - globin chain
(adenine is replaced by thymine).
• This leads to an amino acid change from glutamic acid to
valine
• Hb S (Hb α 2 β 2 S ) is insoluble and forms crystals when
exposed to low oxygen tension
• Deoxygenated sickle haemoglobin polymerizes into long
fibres, each consisting of seven intertwined double strands
with cross – linking
Molecular pathology of sickle cell
anaemia
Inheritance Pattern
• Patients with SCD (Hb SS), Hb SC, or Hb S–β-thal have
inherited a sickle (S) gene from one parent and an S,
C, or β-thalassemia gene from the other.

• Among patients with SCD, individuals who are

homozygotes (Hb SS) have more severe disease than
individuals who are compound heterozygotes for Hb S
(Hb SC or Hb S–β-thal).
Clinical features

• severe haemolytic anaemia punctuated by crises

• some patients having an almost normal life free of
crises
• Others develop severe crises even as infants and may
die in early childhood or as young adults
• Crises may be vaso-occlusive, visceral, aplastic or
haemolytic
 Visceral sequestration crisis
• These are caused by sickling within organs and pooling of
blood, often with a severe exacerbation of anaemia
• The acute sickle chest syndrome is a feared complication and
the most common cause of death after puberty
• Patients present with dyspnoea, falling arterial P O 2 , chest
pain and pulmonary infiltrates on chest X – ray
• Hepatic and girdle sequestration crises and splenic
sequestration may lead to severe illness requiring exchange
transfusions
• enlarging spleen, falling haemoglobin and abdominal pain
Aplastic crises
• These occur as a result of infection with parvovirus or
from folate deficiency
• characterized by a sudden fall in haemoglobin
• transfusion be required
• fall in reticulocytes as well as haemoglobin
Haemolytic crisis
• These are characterized by an increased rate of
haemolysis
• fall in haemoglobin
• rise in reticulocytes
• usually accompany a painful crisis.
Other clinical features
• Ulcers of the lower legs are common, as a result of
vascular stasis and local ischaemia
• The spleen is enlarged in infancy and early childhood
• later is often reduced in size as a result of infarcts
(autosplenectomy)
• Pulmonary hypertension
• Chronic damage to the liver
painful swollen fingers (dactylitis) in a child
Sickle cell anaemia
Laboratory findings
• The haemoglobin is usually 6 – 9 g/dL – low in comparison to
symptoms of anaemia.
• Sickle cells and target cells occur in the blood
• Features of splenic atrophy (e.g. Howell – Jolly bodies) may also be
present.
• Screening tests for sickling are positive when the blood is
deoxygenated (e.g. with dithionate and Na 2 HPO 4 ).
• HPLC or haemoglobin electrophoresis
Tube solubility screening test for the presence
of haemoglobin S
Peripheral blood film for an SCD patient
 Treatment
• Prophylactic – avoid those factors known to precipitate crises,
especially dehydration, anoxia, infections, stasis of the circulation
and cooling of the skin surface
• Folic acid (e.g. 5 mg once weekly).
• Good general nutrition and hygiene.
• Pneumococcal, Haemophilus and meningococcal vaccination and
regular oral penicillin
• Crises – treat by rest, warmth, rehydration by oral fluids and/or
intravenous normal saline (3 L in 24 hours) and antibiotics if
infection
 Haemoglobin C disease

• substitution of lysine for glutamic acid in the β - globin

chain at the same point as the substitution in Hb S
• Hb C tends to form rhomboidal crystals and in the
homozygous state
• there is a mild haemolytic anaemia with marked target
cell formation
• cells with rhomboidal shape and microspherocytes.
• The spleen is enlarged.
Peripheral blood film for a patient with
hemoglobin (Hb) C