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Genetics of Thalassemia
- 1. Families and Thalassemia Mariam Alosfoor
- 2. Case study Eight years later, she tells you that she is happily married with a Saudi person from Hofuf. They decided to start a family. Remarkably, several family members of her husband living in the city need regular blood transfusions. She wonders whether her children might have an increased risk of genetic disorder causing anemia.
- 3. Objectives Hemoglobin Types Thalassemia Genetics of Thalassemia What is your advise to this patient and her husband?
- 4. Hemoglobin types HbA α2β2 Normal HbF α2γ2 Fetal HbH β4 α thalassemia HbA2 α2δ2 β thalassemia Hb Barts γ4 α thalassemia
- 5. Thalassemia Defects in production of the α or β chains of hemoglobin Resulting imbalance in globin chains leads to hemolysis in the spleen or bone marrow Increase severity with increasing number of alleles involved
- 6. Microcytic Anemia Hb Heme Fe++ Iron deficiency anemia Anemia of chronic disease Protoporphyrin Sideroblastic anemia Globin α chain α thalassemia β chain β thalassemia = +
- 7. Genetics of Thalassemia 4 α genes in total; 2 on each copy of chromosome 16 2 β genes in total; 1 on each copy of chromosome 11
- 8. Thalassemia α thalassemia 1 gene Asymptomatic 2 genes Mild anemia 3 genes Severe anemia 4 genes Lethal β thalassemia Minor (β/β+) Asymptomatic Major (β0/β0) Severe anemia
- 9. Advice Confirm parents blood condition Lab work Genetic testing Genetic Counseling
- 10. Lab work Complete Blood Count (CBC) Hb, MCV, Fe, RBC count Microscopy Hb electrophoresis
- 11. Thalassemia A thalassemia 1 gene Asymptomatic HbA 2 genes Mild anemia HbA 3 genes Severe anemia HbH 4 genes Lethal Hb Barts B thalassemia minor Asymptomatic HbA major Severe anemia HbF Hb Electrophoresis
- 12. Genetic Counseling Communication process of providing information and support to individuals and families with a diagnosis and/or risk of occurrence of an inherited disorder. Genetic counseling is needed: at diagnosis and during adolescence prior to and after any genetic testing prior to pregnancy and/or as early in pregnancy as possible Annual follow-ups are needed to reinforce teaching.
- 14. Summary What have we been talking about?
- 15. References St. Jude Children’s Research Hospital, article Cooley’s Anemia Foundation, article Northern California Comprehensive Thalassemia Center, article Torronto notes 2012 Pathoma notes
Notes de l'éditeur
- α thalassemia = gene deletions 2 genes: trans deletions or cis deletions worse for the offsprings with a carrier spouse 3 genes: deficiency in α chains β chains bind together to form the hemoglobin HbH damages RBS 4 genes: NO α chains NO β chains in fetus YET γ chains bind together to form hemoglobin Hb Barts damages RBC fetus does not survive ---- β thalassemia = gene mutations (point mutations/ splicing site) β thalassemia major: - most severe form severe anemia a few months after birth; high HbF (a,y,) at birth is temporarily protective. α4 aggregate and damage RBCs ineffective erythropoiesis (RBC damage in bone marrow) + extravascular hemolysis (removal of circulating RBCs by the spleen). Severe anemia erythropoietin from kidneys Massive erythroid hyperplasia (bone marrow expansion) expansion of hematopoiesis into the skull and facial bones ('chipmunk faciei’) + extra medullary hematopoiesis with hepatosplenomegaly, - Chronic transfusions are often necessary; leads to risk for secondary hemochromatosis Smear showrs microcytic, hypochromic RBCs with target cells and nucleated red blood cells. Electrophoresis shows little or no HbA with increased HbA2 and HbF.
- Microscopy: microcytic target cells
- Critical components of genetic counseling include: obtaining a three-generation genetic family history (pedigree) assessing risk for thalassemia in family members identifying risk factors impacting medical management (e.g., family history of other hemoglobin traits or diseases, hereditary hemochromatosis, G6PD deficiency, inherited thrombophilia, cardiovascular disease or its risk factors, diabetes, renal disease, allergies, ethnicity, consanguinity) incorporating psychosocial information impacting the family system and relationships (e.g., location of residence, disclosure/nondisclosure of diagnosis, reliable source of emotional/social support) assisting patients in conveying information about genetic risk to other family members providing informed consent, pre-, and post-counseling for all genetic testing