Presented to: Dr Lesley Johnson Human disease=Beta Thalassemia

Presented to: Dr Lesley Johnson

Human disease=Beta ThalassemiaPresenter Name: Khazeema Yousaf12-10308By PresenterMedia.com

Diagnosis, Prevention, treatment,

What causes which type? What is hemoglobin(structure)?Basic ideaTreatment and prevention of Thalassemia in PakistanBeta-Thalassemia major, intermedia, minorSummary LayoutWhat thalassemia is? How the word was coined?Pattern of inheritance, Importance, Treatment and prevention & pioneering work in Pak.Diff. techniques, What can be done as biotechnologist? Ethical issues

Facts and theoriesTypes of ThalassemiaFurther classificationPopulation affected

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

Hemoglobin structureWhat is Thalassemia?

Types of Beta-thalassemia

-Beta-thalassemia (Thalassemia major, Thalassemia intermedia, Thalassemia minor)- Beta-thalassemia with associated Hb anomalies (HbC, HbE, HbS/Beta-thalassemia (clinical - Hereditary persistence of fetal Hb and beta-thalassemia- Autosomal dominant forms- Beta-thalassemia associated with other manifestations

HemoglobinOxygen carrying tetrameric molecule consisting of two alpha and two beta subunit (22)

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Mutation in 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 RBCsDecreased amounts of hemoglobin A (HbA).Molecular Basispoint mutations in the promoter, translational initiation codon, polyadenylation signal and an array of mutations leading to splicing abnormalities.

What is Beta-thalassemia?

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 IdeaExcess alpha globin left unbound clump inside of cells membrane Clumps kill the 95% cells itself Survived RBCs lack hemoglobin do not last longer as normal RBCs left untreated causes bone marrow for increase production of RBCs vast majority dies increased production of RBCs causes bone marrow grows up and bones to grow outward deformed body structure Damaged RBCs overwhelm the spleen (increase in size) removal of spleen, lower some stress on body Without blood transfusion, patient will die prematurely

Beta-Thalassemia major/ Cooleys anemia 0(zero) =complete absence of -globin protein+thalassemia=partial production of -globin proteinMust inherit the defective gene from both parents to develop thalassemia major

Beta-thalassemia minor: Carries are actually known as having thalassemia minor. Patient may harbor a mild anemia but they a usually asymptomatic-thalassemia Intermedia: Occurs when both -globin genes express decreased amount of protein or where 1 gene makes decreased amount and the other produced none.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

Epidemiology

Pattern Of inheritance

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 includeoutgrowth of the skull, depression of the bridge of the nose and hypertrophy of the maxillae due to which upper teeth got expose

Signs and symptoms

In Pakistan NIBGE national institute of biotechnology and genetic engineering has done pioneering work on thalassemia.Characterization of mutations by ARMS-PCR(amplification refractory mutation system) 50,000 registered cases of transfusion dependent about 5,000 Transfusion dependent children are born every year in PakistanAli Zaib Blood Transfusion Center, NIBGE, Fatmid Foundation Multan

Whats the Importance in Pakistan?What is being done and what is needed?

No satisfactory treatment available for -thalassemia 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 ARMS-PCR, radioactive and non-radioactive dot-blot or ASO (allele specific oligonucleotide) hybridization, DGGE (denaturing gradient gel electrophoresis), restriction endonuclease analysisMolecular genetics testing:Targeted mutation analysis, Sequence analysis, Deletion/duplication analysisHematologic DiagnosisRBC indices, Peripheral blood smear, hemoglobin analysis:Qualitative and quantitative Hb analysis

Blood transfusions Bone marrow transplantationcord 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.

Worlds first successful treatment= 21 years old Frenchman for thalassemia with GENE therapy in 2007 and was published in Nature. Mediterranean Institute of Hematology has dealt with advanced cases of thalassemia successfully.TreatmentGenetic counselingAvoiding cousin marriages having disease historyPre-natal diagnosisCarrier screening

Prevention 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.

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!!!!!!

THANKSQuestions

Ethical issue