L29: Hemoglobinopathies

Question 1

What chromosome are alpha globin genes on?

Answer 1

Chromosome 16

Question 2

What chromosome are beta globin genes on?

Answer 2

Chromosome 11

Question 3

What mode of inheritance occurs in hemoglobinopathies?

Answer 3

Autosomal recessive

Question 4

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

Answer 4

Sickle cell disease - qualitative

Thalassemias - quantitative

Question 5

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

Answer 5

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

Question 6

What form of globin is incapable of reversible oxygenation?

Answer 6

Methemoglobin

Question 7

What causes thalassemia?

Answer 7

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

Question 8

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

Answer 8

Single nucleotide substitution

Beta chain: Glu6Val

Question 9

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

Answer 9

Single nucleotide substitution

Beta chain: Glu6Lys

Question 10

What is the pathophysiological effect of Hb S mutation?

Answer 10

Deoxygenated Hb S polymerizes

Sickled RBCs cause vascular occlusion and hemolysis

Question 11

What is the pathophysiological effect of Hb C mutation?

Answer 11

Oxygenated Hb C tends to crystallize, mild hemolysis

Question 12

What are the symptoms of sickle cell disease?

Answer 12

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)

Question 13

What symptoms are part of vaso-occlusive disease?

Answer 13

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)

Question 14

How is sickle cell diagnosed?

Answer 14

Hb electrophoresis

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

Question 15

What is therapy for sickle disease?

Answer 15

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

Question 16

Hb H

Answer 16

4 beta chains

Question 17

Hb Barts

Answer 17

4 gamma chains

Question 18

What does alpha thalassemia lead to?

Answer 18

Formation of Hb H

Hydrops fetalis

Question 19

What does beta thalassemia lead to?

Answer 19

Alpha chain tetramers

Causes anemia with wide spectrum of severity

Question 20

What are alpha thalassemias most often caused by?

Answer 20

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

Question 21

What leads to predisposition alpha thalassemias?

Answer 21

There are 2 alpha-globin genes on each chromosome 16

This predisposes to chromosome deletion due to unequal crossing over

Question 22

What is the clinical condition of αα/α- ?

Answer 22

Silent carrier

Question 23

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

Answer 23

α-Thalassemia trait (mild microcytosis)

Question 24

What is the clinical condition of α-/–?

Answer 24

Hb H (β4) disease - moderate hemolytic anemia

Question 25

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

Answer 25

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

Question 26

What is the clinical presentation of beta thalassemia?

Answer 26

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

Question 27

What are beta-thalassemias most commonly caused by?

Answer 27

Point mutations

Question 28

How are beta mutant alleles classified?

Answer 28

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

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

Question 29

Which beta-thalassemias are transfusion dependent? Why?

Answer 29

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

To maintain adequate Hb levels

Question 30

What kinds of β-globin point mutations occur?

Answer 30

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

Small deletions

All kinds of different mutation

Question 31

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

Answer 31

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