Download alpha thal - Thalassemia Dubai

GENETICS OF a THALASSEMIA AMONG
UAE NATIONALS
Three Normal Hemoglobins
Hb A
a 2 2
96%
Hb A2
a 2 2
3%
Hb F
a 2 2
1%
Developmental expression of the globin chains
• embryonic
z 2 e2
a 2 e2
z 2 2
• fetal
hemoglobins
• the arrangement of the a-like genes and
the -like genes reflects their order of
developmental expression
a2 a1
z
hemoglobins
a 2 2
• adult
HbF
hemoglobins
a2 2
a 2 2
HbA2
e
G
A

developmental time from
HbA
embryo to adult

a-Thalassemia
a
a
FAILURE OF a-GLOBIN LEADS TO:
Hb F
a 2 2
Hb A2
a 2 2
Hb A
a 2 2
(4) Hb Barts
(4) Hb H
a-Thalassemia
• One of the most common human genetic
diseases
• Distribution: Africa, Mediterranean,
Middle East, South Asia
• Definition: Decreased synthesis of aglobin chain.
Transcription
Termination
Transcription
Initiation
‘CAT ‘TATA’
Box
Box
Exon 1
Exon 3
Exon 2
5’
Promoter
region
3’
Intron 1
Translation
Initiation
Codon
(ATG)
Intron 2
Translation
Termination
Codon (TAA)
Polyadenylation
Signal
The a-Globin Gene Cluster
two a-genes are highly similar
with few structural divergences.
The
Their protein
product is identical.
a2-globin gene have a
dominant expression.
The
of a-thals are due to the
deletion of a-globin gene.
95%
The
remainder affect other levels of
gene processing:
Abnormal
RNA processing.
Abnormal or unstable protein
products
Silent Carrier State (a-Thal -2)
• Very common in Mediterranean, Middle
East, Southeast Asia.
• 30% of African-Americans carry this
trait.
• Diagnosis: DNA studies (hematologic
studies are normal).
a-Thalassemia - 1 in Trans
•
•
•
•
•
Single gene deletion on both chromosomes
Very common in our area
Patients are microcytic hypochromic
Normal hemoglobin electrophoresis
No risk of hemoglobin Bart’s hydrops
fetalis
a -Thalassemia - 1 in CIS
• Deletion of both a genes on one
chromosome.
• Common in Southeast Asian, Filipino.
• Fortunately is not recorded in our area.
• Diagnosis: Microcytic hypochromic, normal
Hb electrophoresis, DNA studies
• Risk of transmission of Hb Bart’s hydrops
fetalis
Deletional Hb H Disease
• 3 a genes are detected (-a/--)
• Parents has to be -a/aa & --/aa
• This type is common in South Asia and
not common in our locality.
• Fairly severe anemia with hemolysis.
Hb H Disease among UAE
Nationals Attending Dubai
Thalassemia Centre
No. of Pts. = 17
Hb H Disease:
 Deletional/Non-deletional
PA-1
3.7
•9 cases
a
a/-a
CS
3.7
•3 cases
a a/-a
 Non-deletional
•3 cases
a PA-1a/ a PA-1a
•3 cases
aCSa/aCSa
Polyadenylation I Mutation
‘CAT ‘TATA’
Box
Box
AATAAA-->AATAAG
Exon 1
Exon 2
Exon 3
5’
Promoter
region
3’
Intron 1
Intron 2
Polyadenylation
Signal
Hb Constant Spring (Hb CS)
141
Normal a gene
142
UAA
Terminator
141 142
CS a gene
CAA
Glu
172
173
UAA
Terminator
Mean Hb Values of Hb H Disease
(UAE Nationals-Thalas Centre)
a
a a
a a a
a
aa
a aa a
a
Clinical Presentation of Hb H disease
in UAE Patients
• 8 patients with aPA-1a/-a3.7 were discovered on
routine family screening and were all
asymptomatic, leading a normal active life.
• The homozygous poly A mutation presents
with moderate to severe course and one of the
3 patients was transfusion dependent.
• The homozygous constant spring patients
vary in their presentation from mild to
moderate.
a-gene status among UAE Nationals
(Cord Blood)
Research done by:
Prof. Salah El-Kalla
Erol Baysal
Thalassemia and Clinical Genetic Center
Department of Health & Medical Services
 418 consecutive cord blood
samples were analyzed:
214 (51%) were normal aa/aa
204 (49%) were having a-gene
problem
Types of a-gene problem in the
affected 204 UAE Newborn
 140 (68.6%) Heterozygous for 3.7 Kb deletion
(-a3.7/aa)
 46 (22.6%) Homozygous for 3.7 Kb deletion
(-a3.7/-a3.7)
 5 (2.5%) Heterozygous for 4.2 Kb deletion
(-a4.2/aa)
 1 (0.5%) Compound heterozygous 3.7 and
4.2 Kb deletion
(-a3.7/-a4.2)
 12 (5.9%) Non-deletional aT mutation
The 12 non-deletional a mutations in Cord Blood among
UAE Nationals
• Polyadenylation 2 mutation (AATAAA->AATGAA)
• Polyadenylation 1 mutation (AATAAA->AATAAG)
• Constant spring mutation
(TAA -->CAA)
• Five nucleotide deletion (GAGGTGAGG-->GAGG)
CORD BLOOD
RESEARCH
CONCLUSIONS
• 418 cord blood samples
collected from UAE nationals.
• 204 (49%) having a-gene
defect.
• 214 (51%) normal a-genes
204 with a-gene Defect
• 192 (94%) are of the deletion
type
• 12 (6%) are non-deletion
192 with a-gene Deletion
• 186 (97%) is of the a3.7 kb
deletion
• 6 (3%) is of the a4.2 kb deletion
12 with Non-deletion Defect
• 3 Polyadenylation -1
• 1 Polyadenylation -2
• 3 Constant spring
• 6 a-5nt del
Our findings show that a-thal is
a very common genetic disorder
in the UAE nationals and that
Hb H disease has a mild to
moderate presentation.
All Hb H cases are nondeletional type