IN THE NAME OF ALLAH, THE MOST MERCIFUL,
THE MOST BENEFICIENT
‫اﻟﺤﻤﺪ ﷲ رب اﻟﻌﻠﻤﻴﻦ واﻟﺼﻠﻮة واﻟﺴﻼم‬
‫ﻋﻠﻰ ﺳﻴﺪاﻻوﻟﻴﻦ واﻻﺧﺮﻳﻦ‬
Blood Genetic Disorders in
Saudi Arabia
Arjumand Warsy
Department of Biochemistry
College of Science, KSU, Riyadh
[email protected]
Lecture Outline
• Introduction to BGD
– Types of BGD
– Associated problems
• BGD in Saudi Arabia
Jordan
Ar
ab
ia
n
North
G
ulf
East
West
Central
U.A.E
South
Al K
Rab
n
me
e
Y
i
hal
Om
an
ea
dS
Re
– Types identified
– Distribution
– Inheritance
– Presentation
– Control and Prevention
bian
Ara
Sea
Blood Genetic Disorders?
• Genetic disorders
• A diverse group
• Affect different components
of blood
• Most frequently encountered
genetic diseases in many
populations
• A major cause of morbidity
and mortality
Types of Blood Genetic Disorder
• Affecting Blood Cells
– Erythrocytes (RBC)
– Leucocytes (WBC)
– Thrombocytes (Platelets)
• Affecting Plasma proteins
–
–
–
–
–
Carrier proteins-Wilson’s disease
Protease inhibitors-α1 AT def.
Clotting factors-Hemophilia
Immunoglobulin-Ig def.
Complement- C3 def.
1. Disorders of
the Erythrocytes
i. Membrane defects
Elliptocytosis
Poikilocytosis
Stomatocytosis
• ii. Haemoglobin Defects
Thalassaemias
Sickle
Cell Anaemia
Hb Structural
Biosynthetic
Hb
Defects
defects
• iii. Enzyme defects
Glucose-6-phosphate
Pyruvate Kinase
dehydrogenase
Deficiency
deficiency
2. Disorders of
the
Thrombocytes
Platelet
clumping
Wiskott
Aldrich
Syndrome
Giant Platelets
3. Disorders of
the Leucocytes
Leucocyte
Chronic granulomatous
adhesion
disease
deficiency
Problems Associated with Blood Genetic
Disorders
- Erythrocyte
abnormalities
- Leucocyte
abnormalities
- Thrombocyte
abnormalities
- Clotting factor
deficiencies
-α1 AT def.
-Anaemia
-Skeletal defects
-Splenomegaly
-Blood transfusion requirement
-Painful crises
- Severe life threatening infections
- Abnormal blood clotting
-Delayed clotting
- Emphysema
Blood Genetic
Disorders are
frequent in almost
all populations of
the World, some
(thalassaemias,
HbS, G-6-PD def.)
are particularly
common in malaria
endemic region
Blood Genetic Disorders (BGD) in
Saudi Arabia
• BGD were identified in all
regions of Saudi Arabia
• Constitute a major health
problem
• Two broad groups:
•
•
Polymorphic (common)
Rare disorders.
• Mutation causing common
disorders confer selective
advantage to carriers,
resistance to
– Malaria (Plasmodium
falciparum).
Blood Genetic
GeneticDisorders
Disordersin
inSaudi
SaudiArabia
Arabia
Blood
Polymorphic
Polymorphic
Structural
••Structural
HbSS
••Hb
Biosynthetic
••Biosynthetic
Thalassaemias(α
(α
••Thalassaemias
andββ)
and
)
Enzymopathies
--Enzymopathies
deficiency
••GG-6-PD
-6-PD deficiency
• Hb E,
• Hb E,
• Hb C,
• Hb C,
•Hb Riyadh
•Hb Riyadh
•Hb O-Arab
•Hb O-Arab
• Haemophilia A & B
• Haemophilia A & B
• α-1AT deficiency
• α-1AT deficiency
• others
• others
Jordan
Ar
ab
ia
n
G
East
u
North
West
ea
dS
Re
Sout
h
Central
Al K
Rab
n
me
e
Y
lf
U.A.E
i
hal
Om
an
- Haemoglobinopathies:
- Haemoglobinopathies:
Non-polymorphic
Non
-polymorphic
(Rare)
(Rare)
Sea
n
a
i
b
Ara
Haemoglobinopathies in
Saudi Arabia
Genetic Disorders affecting
Haemoglobin
Sickle Cell
Haemoglobin (HbS)
α
β
β
GAG
6
Glu
β
GTG
Val
α
Haemolysis
HbS Soluble in
Lungs in
oxygenated state
HbS becomes
precipitated in
deoxygenated state
and form sickle cells
Inheritance of Sickle Cell Anaemia (AR)
AS
AS
AS
SS
AA
AS
Family tree of Sickle Cell Anaemia/
Thalassaemias
A family with SCA
Hb Electrophoresis
AA
AS
SS
Sickle cell anaemia
Hemolysis
Anaemia
Sickled cells block narrow blood
capillaries
• Leading to severe painful crises
(abdomen, hand-foot, limbs, other organs
• Crises may be precipitated by:
dehydration, cold, fever, infection
Jordan
North
Om
an
Ar
a
Eastbia
n
G
West Central U.A.E
ui
hallf
K
l
South b A
Ra n
SickleCell
CellGene
Genein
inSaudi
SaudiArabia
Arabia
Sickle
ea
dS
Re
Sea
me
n
a
e
i
b
Y
Ara
Occursalmost
almostin
in
Occurs
allregions
regionsat
at
all
variablefrequency
frequency
variable
Coexists with
with
Coexists
otherabnormal
abnormal
other
genes
genes
αα−Thal.
−Thal.
Frequencyof
ofHbS
HbS
Frequency
correlateswith
with
correlates
pastor
orpresent
present
past
endemicityto
to
endemicity
malaria
malaria
+HbS/
β
+
HbS/ β Thal
Thal
+ - & βoβ
+
β - & βoThal.
Thal
.
oHbS/
β
o
HbS/ β Thal
Thal
Prevalence of Hb AS and Hb SS
in different Regions of Saudi Arabia
NP (%)
Hb AS = 1.3
Hb SS = 0.1
Jordan
NWP (%)
Hb AS = 7.54
Hb SS =0.88
Ar
ab
ian
EP (%)
Hb AS = 21.28
Hb SS = 3.82
Gu
lf
U.A.E
Ar
Om
a
ea
dS
en
m
e
Y
n
Re
SWP(%)
Hb AS = 11.97
Hb SS = 1.67
i
hal
K
l
A
Rab
ea
S
n
abi a
CP (%)
Hb AS = 0.83
Hb SS = 0.09
Hb S Gene
Frequency in Saudi Arabia
NP
<1.0 – 3.0
Jordan
Ar
ab
ian
NWP
<1.0 – 8.3
EP
< 5.3 – 17.4%
Gu
lf
CP
< 1.0 – 1.4
U.A.E
Ar
Om
a
ea
dS
en
m
e
Y
n
Re
SWP
<1.0 – 15.11
i
hal
K
l
A
Rab
ea
S
n
abi a
Micro-distribution of HbS in Saudi Arabia
Samples screened= 32,000
NWP
(%)
NP
Jordan
Ar
ab
ia
n
North
East
West
SWP
Al K
Rab
n
me
Ye
G
EP
(%)
AlQateef-----17.4
Al-Hafouf----15.0
Dammam----5.2
ulf
CP
Central
South
ea
dS
Re
Qunfuda---.11.48
Bisha-------8.31
Najran------1.83
Jaizan------ 10.3
Sabya------ 8.88
Samtah--- -4.15
Abu-Areeh-8.68
Farasan--- -0.0
Baish------ 6.25
Fifa-------- 15.11
Al-Baha-- - 18.7
Mahayel--- 12.09
Abha------- 12.81
Majarda--- 12.31
(%)
Hail-----------0.3
Tabuk--------3.0
Arar----------0.59
Qurayet------0.0
Al-Jouf-------0.0
U.A.E
i
hal
Om
an
(%)
Al-Ula ---8.1
Khaiber—8.3
Yanbu----1.55
Makkah---2.74
bian
Ara
Sea
(%)
Riyadh-----------0.5
Qaseem----------0.1
Buraidah--------0.16
Al-Russ----------0
Al-Unaiza-------0
Al-Mesnab------0
Bkaria-----------0
Sulayel-----------1.4
Harf Al Batin—0.37
WadiDawasir--0.65
Clinical Presentation of SCD in
Saudi Arabia
Variable-Two major forms
Mild (benign)
Presentation
Severe
Presentation
Jordan
Ar
ab
ia
East n G
West
South
ea
dS
Re
Mainly in the
Western province;
Also some in EP
Central
A
Rab
ulf
U.A.E
ali
l Kh
n
me
e
Y
Om
an
North
ea
nS
a
i
b
Ara
Mainly in the
Eastern province
Two forms of SCD in Saudi Arabia Haematological Parameters
Severe SCD
mean±SD Jordan
North
2.6 ±0.6*
Hb (g/dl)
8.3 ±1.1*
PCV (l/l)
0.22 ±0.04*
MCV (fl)
87.6 ±7.9*
MCH (pg)
31..7 ±4.8
MCHC (g/dl)
36.9 ±2.81
HbA2 (%)
3.0 ±0.75*
HbF (%)
9.9 ±6.4
Parameter
mean±SD
RBC(x1012/l)
4.0 ±0.74*
Hb (g/dl)
10.5 ±2.0*
PCV (l/l)
ea
S
n
bia
Ara
MCV (fl)
0.3 ±0.05*
Ar
ab
ia
East n G
West
Central
South
ea
dS
Re
RBC(x1012/l)
A
Rab
ulf
U.A.E
ali
l Kh
n
me
Ye
(* p< 0.05)
Om
an
Parameter
Mild SCD
74.7 ±9.3*
MCH (pg)
26.2 ±4.4
MCHC (g/dl)
34.7 ±3.1
HbA2 (%)
2.9 ±0.48*
HbF (%)
11.1 ±5.7
Two forms of SCD in Saudi Arabia –
Clinical Presentation
Severe SCD
Mild SCD
Sign/Symptoms
(%)
Sign/Symptoms
(%)
Anaemia
100
Anaemia
56.1
Jaundice
13.2
Jaundice
17.1
Splenomegaly
77.4
Splenomegaly
31.7
Hepatomegaly
66.0
Hepatomegaly
36.6
Hand/foot Synd.
33.9
Jordan
North
Ar
ab
East ian
Hand/foot Synd.
Nil
Om
an
G
ulf
West Central U.A.E
i
hal
South
Al K
b
Ra
Crises
n
ea - Vasoocclusive
me
nS
a
i
Ye
b
Ara
- Infective
- Haemolytic
75.5
9.4
18.9
Hospitalization
96.2
Hospitalization
41.5
Blood
Transfusion
-2-5 times/year
84.9
Blood
Transfusion
-2-5 times/year
48.8
43.4
ea
dS
Re
Crises
- Vasoocclusive
- Infective
- Haemolytic
Rare
Rare
Rare
---
The Thalassaemias
The Thalassaemias
Genetic disorders resulting from
decreased synthesis of globin chains
of haemoglobin.
Types of Thalassaemias
α- Thalassaemia
γ- Thalassaemia
β-Thalassaemia
δ- Thalassaemia
γδβ- Thalassaemia
Frequently Encountered Thalassaemias
in Saudi Arabia
In α- Thalassaemia
α- Thalassaemia
Decreased
production
of α- chains
Normal α= β
α
α- Thalassaemia
In β- Thalassaemia
Accumulation of β
β
α
β Decreased
β
production
β
of β- chains
- Decreased α/β ratio
Normal α= β
β-Thalassaemia
α
β- Thalassaemia
β
Increased α/β ratio
Accumulation of α
α
α
α
β
The Thalassaemias in
Saudi Arabia
Jordan
Ar
ab
ia
n
North
G
ulf
East
West
Central
U.A.E
ea
dS
Re
Al K
Rab
n
me
e
Y
Om
an
South
i
hal
bian
Ara
Sea
Frequency (%) of α-thalassaemia in
Saudi Arabia
NP
<1.0
EP
45.0
Jordan
Ar
ab
ia
n
NWP
19.0
East
West
Central
South
ea
dS
Re
A
Rab
ulf
U.A.E
ali
l Kh
n
me
e
Y
SWP
55.0
G
Om
an
North
Sea
n
a
i
b
Ara
CP
<1.0
Types of mutations producing α-thalassaemia
in Saudi Arabia
Chromosome 16
Mainly deletions
αα/αα
Normal
-α/αα
-α/-α
--/αα
--/-α
--/--
α-thal 2 α-thal 2 α-thal 1 HbH Hydrops
hetero homo hetero Disease fetalis
Introns
Chromosome 16
exon1
exon2
exon3
Point Mutations ?
The α-2 globin gene
AATAAA→AATAAG
Poly A signal
Mutation
Frequency(%) of β-Thalassaemia in
Saudi Arabia
Jordan
Ar
ab
ia
n
Al-Ula
11.95
East
West
Central
South
ea
dS
Re
Al K
Rab
n
me
e
Y
Khaiber
4.0
Jaizan
5.9
G
ulf
U.A.E
i
hal
Om
an
North
Riyadh
3.6
Sea
n
a
i
b
Ara
Najran
15.3
Clinical Presentation of β-Thalassaemias
• Symptomatic
– β-Thalassaemias intermedia• Moderate anaemia, hypochromic microcytic, high A2, may
require transfusion for correction of anaemic state. Mild to
moderate growth retardation and skeletal defects
– β-Thalassaemias major• Identified early in life, severe transfusion dependent anaemia,
hypochromic microcytic, severe growth retardation and skeletal
changes, jaundice, splenomegaly etc
• Assymptomatic
– Silent carriers
• Microcytosis, elevated HbA2, no anaemia,
– β-Thalassaemias
• Mild anaemia, microcytosis
Glucose-6-Phosphate
dehydrogenase deficiency in
Saudi Arabia
Jordan
Ar
ab
ia
n
North
G
ulf
East
Central
U.A.E
South
ea
dS
Re
A
Rab
ali
l Kh
n
me
e
Y
Om
an
West
ea
nS
a
i
b
Ara
Glucose-6-Phosphate
Dehydrogenase Deficiency
G-6-PD Deficiency
• Deficiency of G-6-PD leads to hemolytic
anaemia under oxidative stress(e.g.
antimalarial drugs, fava beans, infections,
diabetic acidosis)
• Favism
Vicia fava
Hemolysis
divicine
Malarial parasite and G-6-PD
deficiency
Plasmodium falciparum
Red cells infested with
malarial parasite
Malarial parasite cannot
survive in G-6-PD deficient
red cells
Requires NADPH to survive
in red blood cells
Family Tree in G-6-PD deficiency
G-6-PD def
G-6-PD def
Deficiencyin
inSaudi
SaudiArabia
Arabia
GG-6-PD
-6-PD Deficiency
Alters clinical
Alters clinical
presentation
presentation
of SCD
of SCD
• Most frequent
• Most frequent
G-6-PD deficient
G-6-PD deficient
variant is G-6-PDvariant is G-6-PDmediterranean
mediterranean
• Others identified:
• Others identified:
• G-6-PD-A+ +
• G-6-PD-A • G-6-PD-A
• G-6-PD-A• G-6-PD-Khartoum
• G-6-PD-Khartoum
Jordan
Ar
ab
ia
East n G
ulf
West Central
U.A.E
ali
South
l Kh
A
Rab
North
ea
dS
Re
G-6-PD deficiency
G-6-PD deficiency
correlates with
correlates with
past or present
past or present
history of malaria
history of malaria
endemicity
endemicity
Frequently coexists
Frequently coexists
with Hb S
with Hb S
Om
an
Occurs in almost
Occurs in almost
all regions of
all regions of
Saudi Arabia at
Saudi Arabia at
a variable frequency
a variable frequency
n
Sea
me
n
e
a
i
b
Y
Ara
FREQUENCY (%) OF G-6-PD DEFICIENCY IN
DIFFERENT REGIONS OF SAUDI ARABIA
Jordan
Ar
a
North
bi
a
n
East
West
South
ea
dS
Re
WP
M F
8.6 5.3
EP
M F
25.5 12.6
Central
G
ul
f
U.A.E
Om
an
NP
M F
1.5 0.8
ali
l Kh
A
Rab
n
me
e
Y
S
ian
b
a
Ar
SWP
M
F
12.4
5.0
ea
CP
M F
2.7 1.3
Many Problems are associated with the Common BGD
Moderate to
severe
anaemia
Growth
retardation
Multiple
organ
damage
Psychological
burden
• Patient
• Family
Structural
defects
Frequent
hospitalization
Decrease
productivity
Blood
transfusion
requirements
Requirements for
chelation therapy
Infections
Economic
burden
• Family
• Community
Increased
morbidity
Early
death
It is essential to adopt steps to control
and prevent the occurrence of the severe
forms of the Blood Genetic Disorders
So what needs to be done?
• Adopt methods to prevent the birth of
children suffering from blood genetic
disorders (Primary Prevention)
• Premarital screening programme
• Better care programmes (Secondary
and Tertiary Prevention)
• Improve awareness
Thank you for listening