L29: Hemoglobinopathies Flashcards Preview

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Flashcards in L29: Hemoglobinopathies Deck (31)

What chromosome are alpha globin genes on?

Chromosome 16


What chromosome are beta globin genes on?

Chromosome 11


What mode of inheritance occurs in hemoglobinopathies?

Autosomal recessive


What are the main types of hemoglobinopathies? Are they quantitative or qualitative?

Sickle cell disease - qualitative

Thalassemias - quantitative


What are 2 mutant hemoglobins that are associated w/ hemolysis but are NOT unstable?

Hb S and Hb C

They are not unstable and have normal oxygen association/dissociation but cause the mutant hemoglobin to polymerize and deform the RBC


What form of globin is incapable of reversible oxygenation?



What causes thalassemia?

Variants due to mutation in the globin genes that reduce the abundance or function of one of the globin polypetides


What is the molecular basis of mutation in Hb S? What is the resulting change in polypeptide?

Single nucleotide substitution

Beta chain: Glu6Val


What is the molecular basis of mutation in Hb C? What is the resulting change in polypeptide?

Single nucleotide substitution

Beta chain: Glu6Lys


What is the pathophysiological effect of Hb S mutation?

Deoxygenated Hb S polymerizes

Sickled RBCs cause vascular occlusion and hemolysis


What is the pathophysiological effect of Hb C mutation?

Oxygenated Hb C tends to crystallize, mild hemolysis


What are the symptoms of sickle cell disease?

Anemia by 4 - 5 months (normocytic, normochromic)

Infection (most common complication; occurs in 15 - 30% w/o penicillin prophylaxis) - functional asplenia

Vaso-occlusive disease (in 50% <1 year; most <6 years)


What symptoms are part of vaso-occlusive disease?

Painful bone/joint crisis (most common ER complaint)

Pulmonary crisis (in 50%; 15 % of hospital admissions)

Painful abdominal crises (also splenic sequestration)

Cardiac (10 - 30% of death 2nd to congestive heart failure)

CNS (CVA in 11% of kids; "silent infarcts" in another 17%; aneurysm; subdural hematoma)


How is sickle cell diagnosed?

Hb electrophoresis

Molecular detection of S and C mutant alleles, especially for prenatal dx


What is therapy for sickle disease?

Preventative: penicillin prophylaxis (prevents 80% of strep); vaccination; oral hydration; folate supplements; avoidance of hypoxia, exhaustion, temperature extremes

Hydroxyurea to induce HbF (reduces sicklin, improves RBC survival) results in fewer pain crises and ACS (but not lower CNS risk); lower transfusion dependence

Chronic RBC transfusion to keep HbS<30%

Analgesics for pain crises


Hb H

4 beta chains


Hb Barts

4 gamma chains


What does alpha thalassemia lead to?

Formation of Hb H

Hydrops fetalis


What does beta thalassemia lead to?

Alpha chain tetramers

Causes anemia with wide spectrum of severity


What are alpha thalassemias most often caused by?

Loss of alpha-globin genes by deletion, not point mutations


What leads to predisposition alpha thalassemias?

There are 2 alpha-globin genes on each chromosome 16

This predisposes to chromosome deletion due to unequal crossing over


What is the clinical condition of αα/α- ?

Silent carrier


What is the clinical condition of αα/-- or α-/α- ?

α-Thalassemia trait (mild microcytosis)


What is the clinical condition of α-/--?

Hb H (β4) disease - moderate hemolytic anemia


What is the clinical condition of --/-- (no alpha)?

Hydrops fetalis or homozygous α-thalassemia (Hb Bart's)


What is the clinical presentation of beta thalassemia?

Microcytic anemia

Alpha chain inclusion body formation in erythroid precursor cells in the bone marrow

Inefficient erythropoiesis - transfusion dependent by about 1 year

Splenc enlargement with intramedullary destruction of RBCs

Hyperbilirubinemia; gall stones

Iron overload

Only residual Hb F in beta thalassemia


What are beta-thalassemias most commonly caused by?

Point mutations


How are beta mutant alleles classified?

β+: some partially functional β-globin is made, e.g. missense mutations

β0: no functional β-globin is made, e.g. nonsense mutations


Which beta-thalassemias are transfusion dependent? Why?

β0/β0 and β0/β+ individuals are transfusion dependent

To maintain adequate Hb levels


What kinds of β-globin point mutations occur?

Mutations in transcription, Cap site, RNA splicing, frameshifts, in exon 3 which causes unstable hemoglobin

Small deletions

All kinds of different mutation


β-thalassemia vs. HPFH (Hereditary persistence of fetal hemoglobin)

In HPFH, deletions are large than those that caused β-thalassemias (which are more severe)

Deletion is so large that it includes the site of transition from the fetal hemoglobin gamma chain to the beta chain

Will have fetal hemoglobin bc production of gamma chains is not turned off