L29: Hemoglobinopathies Flashcards
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?
Methemoglobin
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
