Path-Thal/G6PD
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| HbA are encoded by an identical pair of α-globin genes on chromosome____, while the two β chains are encoded by a single β-globin gene on chromosome____. | 16, 11
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| hematologic consequences of diminished synthesis of one globin chain stem not only from hemoglobin deficiency but also from... | a relative excess of the other globin chain, particularly in β-thalassemia.
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| Thalassemia syndromes are endemic in the... | Mediterranean basin, the Middle East, tropical Africa, the Indian subcontinent, and Asia, and in aggregate are among the most common inherited disorders of humans.
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| The β-thalassemias are caused by mutations that diminish the synthesis of... | β-globin chains.
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| β0 mutations, associated with ____ ______synthesis; β+ mutations, characterized by _____ ______ synthesis. | absent β-globin synthesi; reduced β+ mutations
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| What are some causative mutations of beta-thalassemia? | splicing mutations(+/0), promoter region mutations(+), chain terminator mutations
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| What are the most common causes of beta(+)-thalassemia? | splicing mutations (most lie in introns while a few are within exons)
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| What are the most common causes of beta(0)-thalassemia? | chain terminator mutations
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| Describe chain terminator mutations. | The most common type creates a new stop codon within an exon; the second introduces small insertions or deletions that shift the mRNA reading frames (frameshift mutations). Both block translation and prevent the synthesis of any functional β-globin
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| In severe β-thalassemia, ineffective erythropoiesis creates several additional problems. How? | Erythropoietic drive during severe anemia lds to erythroid hyperplasia and extramedul.hematopoiesis. Inc mass red cell precursors erode bony cortex, impair bone growth, and skel. abnormalities. Active erythroid prog. steal nutrients from tissues -cachexia
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| In addition to skeletal abnormalities and cachexia, another serious complication of ineffective erythropoiesis is... | excessive absorption of dietary iron
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| How does ineffective erythropoiesis cause excessive absorption of dietary iron? | Ineffective erythropoiesis suppresses levels of hepcidin. Dec hepcidin and iron load of repeated blood transfusions lead to severe iron overload. Secondary injury to parenchymal organs, particularly liver occurs, secondary hemochromatosis possible.
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| In general, individuals with what β-thalassemia alleles have β-thalassemia major? | (β+/β+, β+/β0, or β0/β0)
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| Heterozygotes with one βthalassemia gene and one normal gene (β+/β or β0/β) usually have ... | a mild asymptomatic microcytic anemia. This condition is referred to as β-thalassemia minor or β-thalassemia trait
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| Some patients with β-thalassemia intermedia have... | two defective β-globin genes and an α-thalassemia gene defect, which lessens the imbalance in α- and β-chain synthesis.
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| In beta-thalassemia, blood smears show severe red cell abnormalities, including... | marked variation in size (anisocytosis) and shape (poikilocytosis), microcytosis, and hypochromia.
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| Describe intial course of beta-thalassemia. | anemia 6 to 9 months fol birth w/ switch from HbF to HbA. (In untransfused pts, Hb levels are 3 to 6 gm/dL.) Red cells may lack HbA (β0/β0 genotype) or contain small amts (β+/β+ or β0/β+ genotypes). HbF is inc. HbA2 levels may inc but usually norml or low
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| In beta-thalassemia, blood smears show marked variation in size (anisocytosis) and shape (poikilocytosis), microcytosis, and hypochromia as well as... | Tgt cells (Hb cell center), baso. stipping, and frag. red cells common. Inclusions α chains removed by spleen, not seen. Reticulocytes elevated, but lower than expected for severe anemia due to ineffective erythropoiesis. Var.#s poor normoblasts in blood
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| What are major alterations involving the bone marrow and spleen in beta-thalassemia? | In untransfused pt - expansion of hematopoietically active marrow. Face/skull bone marrow erodes existing cortical bone and induces new bone formation - “crew-cut” x-ray. Spleen, liver and the lymph nodes be enlarge by extramedullary hematopoiesis.
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| Beta-thalassemia can often cause iron overload which leads to which to conditions? Deposited iron impacts what organs? | Hemosiderosis and secondary hemochromatosis; The deposited iron often damages organs, most notably the heart, liver, and pancreas.
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| The clinical course of β-thalassemia major is brief unless... | blood transfusions are given
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| The only therapy offering a cure for beta-thalassemia. | Bone marrow transplantation
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| β-Thalassemia Minor patients are usually... | asymptomatic
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| Recognition of β-thalassemia trait is important for two reasons: | (1) differentiation from the hypochromic microcytic anemia of iron deficiency and (2) genetic counseling
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| In newborns with α-thalassemia, excess unpaired γ-globin chains form γ4 tetramers known as _______whereas in older children and adults excess β-globin chains form β4 tetramers known as ____. | hemoglobin Barts,HbH
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| Since free β and γ chains are more soluble than free α chains and form fairly stable homotetramers, hemolysis and ineffective erythropoiesis are ________than in β-thalassemias. | less severe
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| A variety of molecular lesions give rise to α-thalassemia, but _______is the most common cause of reduced α-chain synthesis. | gene deletion
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| Silent Carrier State: | This is associated with the deletion of a single α-globin gene, which causes a barely detectable reduction in α-globin chain synthesis. These individuals are completely asymptomatic, but they have slight microcytosis.
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| α-Thalassemia Trait: | del. of 2 α-globin genes from a single chrom. (α/α α/α), or del.of 1 α-globin gene from each chrom. (α/—α α/—α). Former common in Asian, latter in Africa. Both ->sim. def. of α-globin, clinically same but have diff. implications for aff.offspring
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| Both genotypes of alpha-thalassemia trait produce similar quantitative deficiencies of α-globin and are clinically identical, but have different implications for the children of affected individuals. What are these? | Inc risk of clinically significant α-thalassemia (HbH disease or hydrops fetalis) only when one parent has the α/—α haplotype. Symptomatic α-thalassemia is relatively common in Asian populations, rare in black African populations.
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| The clinical picture in α-thalassemia trait is identical to that described for β-thalassemia minor. What is it? | small red cells (microcytosis), minimal or no anemia, and no abnormal physical signs. HbA2 levels are normal or low.
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| Hemoglobin H Disease: | Asians. 3 α-globin genes del, 1 norm gene, α chains syn reduced, β-globin tetra, HbH->high aff O2 ->poor O2 deliv.-> hypoxia w/ norm Hb level, prone to oxidation, precip. out - form intracell. inclusions-> rbc sequest./phago- spleen -> mod/severe anemia
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| Hydrops Fetalis: | Most severe α-thalassemia caused by deletion of 4 α-globin genes. In fetus, excess γ-globin chains form tetra. (Hb Barts) w/ high affinity for O2 -> dec tissue deliv. Early dev. survival due ζ chains, embryonic form ζ2γ2 Hb tetra.
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| What is the tx/result of hydrops fetalis? | In past, severe anoxia-> death in utero/after birth; w/ intrauterine transfusion ->saved. Fetus ->severe pallor, gen. edema, hepatosplenomegaly. Lifelong blood transfusions for survival, w/ risk of iron overload. BM transplantation can be curative.
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| What is G6PD? | protects erythrocyte hemoglobin from oxidation and denaturation. Def. ->susceptible to hemolytic episodes following oxidant stress to their red cells. In Mediterranean, deficiency, acute hemolysis initiated by the ingestion of fava beans.
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| The most common enzyme defect involves ... | glucose-6-phosphate dehydrogenase (G6PD), which catalyzes conversion of glucose-6-phosphate to 6-phosphogluconate.
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| G6PD deficiency is ... | an X-linked disorder in which abnormal red cell sensitivity to oxidative stress manifests as hemolytic anemia.
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| G6PD helps to recycle ... | reduced glutathione, red cell deficient in this enzyme are susceptible to oxidative stress (e.g., infections, drugs, or fava bean ingestion [favism]).
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| Oxidation of hemoglobin leads to formation of ... | methemoglobin, in which Fe2+ ions are converted to ferric (Fe3+) ions. Methemoglobin cannot transport oxygen, is unstable and precipitates in the cytoplasm as Heinz bodies. Precipitated methemoglobin increases cell rigidity and leads to hemolysis.
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| In quiescent periods, erythrocytes in G6PD deficiency appear normal. However, in hemolytic episode w/ oxidative stress,_____can be demonstrated by supravital staining. After passage through spleen, circulating red cells have membrane part removed forming_ | Heinz bodies; bite cells
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| Full expression of G6PD deficiency is seen only in_____, with ____ being asymptomatic carries. | males; females
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