Transcript huaman disease Presentation

Presented to: Dr Lesley
Johnson
Human disease=Beta
Thalassemia
Presenter Name:
Khazeema Yousaf
12-10308
By PresenterMedia.com
•Summary Layout
Facts and
theories
What thalassemia is? How the word was coined?
Types of
Thalassemia
What causes which type? What is
hemoglobin(structure)?Basic idea
Further
classification
Beta-Thalassemia major, intermedia,
minor
Population
affected
Diagnosis,
Prevention,
treatment,
Treatment
and prevention
of Thalassemia
Pattern
of inheritance,
Importance,
Treatmentin
and prevention & pioneering
Pakistan work in Pak.
Diff. techniques, What can be done as
biotechnologist? Ethical issues
•What is Thalassemia?
•
Hemoglobin structure
•
•
Inherited blood disorder, recessive trait
name thalassemia =George Whipple and the
William Bradford from the Greek thalassa for sea
and -emia, meaning the blood.
Types of Thalassemia
Types of Beta-thalassemia
-Beta-thalassemia
(Thalassemia major,
Thalassemia intermedia, Thalassemia
minor)
- Beta-thalassemia with associated Hb
anomalies (HbC, HbE, HbS/Betathalassemia (clinical - Hereditary
persistence of fetal Hb and betathalassemia
- Autosomal dominant forms
- Beta-thalassemia associated with
other manifestations
Hemoglobin
,
Oxygen carrying tetrameric
molecule consisting of two alpha and
two beta subunit (α2β2)
What is Beta-thalassemia?
Mutation in β globin gene leads to reduce or absent
synthesis of Beta globin protein resulting in beta
thalassemia
results in microcytic hypochromic
anemia (microcytic= small size RBCs, hypochromic=
Light in color)
• Irregular peripheral blood smear which has
nucleated RBCs
• Decreased amounts of hemoglobin A (HbA).
Molecular Basis
point mutations in the promoter, translational initiation
codon, polyadenylation signal and an array of
mutations leading to splicing abnormalities.
•
Cytogenetic location of HBB gene
HBB gene is on the short arm of chrm#
11 (11p15.5), Gene causing beta
thalassemia: Mutations in the HBB gene
Basic Idea
•
Excess alpha globin left unbound
clump inside of
cell’s membrane
Clumps kill the 95% cells itself
Survived RBC’s lack hemoglobin
do not last
longer as normal RBC’s
left untreated causes
bone marrow for increase production of RBC’s
vast majority dies
increased production of RBC’s
causes bone marrow grows up and bones to grow
outward
deformed body structure
Damaged RBC’s overwhelm the spleen (increase
in size) removal of spleen, lower some stress on body
Without blood transfusion, patient will die prematurely
Beta-Thalassemia
major/ Cooley’s
anemia
β0(zero)
=complete
absence of βglobin protein
• β+thalassemia=
partial production
of β-globin protein
Must inherit the
defective gene
from both parents
to develop
thalassemia major
•
•
Β-thalassemia
Intermedia: Occurs
when both βglobin genes
express decreased
amount of protein
or where 1 gene
makes decreased
amount and the
other produced
none.
Betathalassemia
minor: Carries
are actually
known as having
thalassemia
minor. Patient
may harbor a
mild anemia but
they a usually
asymptomatic
Epidemiology
•
•
•
predominant in Mediterranean countries, Central
Asia, Middle East, India, Southern China, countries
along the north coast of Africa.
Highest rate is in Cyprus= 14%, Sardinia =10.3%, and
Southeast Asia as well.
carriers =80-90 million
Pattern Of inheritance
•Signs and symptoms
•
•
Diarrhea, enlargement of abdomen because of
hepatosplenomagly and jaundice. If the patient left
untreated heart failure, leg ulcers, extra medullary
hematopoiesis and skeletal deformities. Skeletal
changes are due to expansion of the bone marrow.
Skeletal deformities include
outgrowth of the skull, depression of the bridge of the
nose and hypertrophy of the maxillae due to which
upper teeth got expose
What’s the Importance in Pakistan?
What is being done and what is
needed?
•
•
•
•
In Pakistan NIBGE national institute of
biotechnology and genetic engineering has
done pioneering work on thalassemia.
Characterization of mutations by ARMSPCR(amplification refractory mutation system)
50,000 registered cases of transfusion
dependent about 5,000 Transfusion dependent
children are born every year in Pakistan
Ali Zaib Blood Transfusion Center, NIBGE, Fatmid
Foundation Multan
• No satisfactory treatment available for βthalassemia
• Regular Blood Transfusion required to sustain life
• Iron Chelation Therapy (Annual cost
US$4,400/patient, Annual average income in
Pakistan US$420)
• Bone Marrow Transplant (Not affordable)
• Gene Therapy (Not affordable)
THE ONLY AFFORDABLE SOLUTION IS
Prevention through
• Carrier Screening
• Genetic Counseling
• Characterization of Mutations
• First Trimester Prenatal Diagnosis by CVS
Diagnosis
Screening =mutations Monoplex
ARMS-PCR (amplification refractory
mutation system), Multiplex ARMSPCR, radioactive and non-radioactive
dot-blot or ASO (allele specific
oligonucleotide) hybridization, DGGE
(denaturing gradient gel electrophoresis),
restriction endonuclease analysis
Molecular genetics testing:
Targeted mutation analysis, Sequence analysis,
Deletion/duplication analysis
Hematologic Diagnosis
RBC indices, Peripheral blood smear,
hemoglobin analysis:Qualitative and
quantitative Hb analysis
Treatment





Blood transfusions
Bone marrow transplantation
cord blood and bone marrow transplant is more successful)
chelation therapy to remove excess iron from the
body.Transfusional iron overload is treated with Deferiprone,
Deferasirox,Exjade( chelator administered orally.) Ferriprox.
World’s first successful treatment= 21 years old Frenchman for
β thalassemia with GENE therapy in 2007 and was published in
Nature.
 Mediterranean Institute of Hematology has dealt with
advanced cases of thalassemia successfully.
Prevention
1.
2.
3.
4.
Genetic counseling
Avoiding cousin marriages having disease history
Pre-natal diagnosis
Carrier screening
What can be done as biotechnologist?
 Replacement of hemapoietic cells that do not
have the defective beta globin gene.
 To replace defective beta globin gene in the
bone marrow cells, this can avoid graft
rejection.
 Alternate form of treatment is presence of beta
like chain i.e. Hb F (fetal hemoglobin). The
genes are still present but they got inactive, if
they can be reactive, patient with thalassemia
can be cured.
Ethical issue

After prenatal diagnosis, if the fetus is 100% expected to be diseased,
termination of pregnancy is recommended, which as Muslim we
believe is a murder. So issue arises here!!!!!!
 THANKS
 Questions