Hemoglobinopathies And Thalassemias

Question 1

Alpha Hb genes

Answer 1

. On chromosome 16
. 2 zeta genes for alpha chains
. Contains gene expressed in early development as an alpha-globin like component of embryonic Hb

Question 2

Beta Hb genes

Answer 2

. Chromosome 11
. Contains epsilon gene expressed in early embryonic development
. 2 gamma gene expression seen in Hb F
. Delta gene for globin chain found in adult HbA2

Question 3

Steps in globin chain synthesis

Answer 3

. Starts in nucleus of blood cell precursors where it’s transcribed
. mRNA produced, 2 introns removed and 2 Econ’s join
. Mature mRNA is translated producing globin chain

Question 4

Hb A

Answer 4

. Contain the alpha and beta tetramer structure

. HbA2 synthesized in low levels

Question 5

Hb F

Answer 5

. Tetramer of 2 alpha and 2 gamma chains

Question 6

Hb synthesis timeline

Answer 6

. 1 month after conception synthesis starts in yolk sac
. After 5th week the Hb synthesis switches to liver then the marrow w/ product Hb F
. Last months Hb F is 60% of rbcs
. Hb A starts in bone marrow at 8th month and gradually replaces Hb F

Question 7

2,3-BPG binding to Hb F

Answer 7

. Weakly binds so f has higher O2 affinity than A

Question 8

Why does Hb F need higher O2 affinity?

Answer 8

To facilitate transfer from maternal circulation across placenta to RBC of fetus

Question 9

Hb A2

Answer 9

. Minor component of normal adult Hb that appears shortly after birth and eventually constitutes 2% total Hb

Question 10

HbA1c

Answer 10

. HbA undergoes glycation
. Glycation dependent on [glucose] in blood plasma
. Inc. amounts found in diabetic patients
. Gives indication of blood glucose level over 120 days (RBC life span)

Question 11

Glycation

Answer 11

NONENZYMATIC addition of glucose to HbA

Question 12

Hemoglobinopathies

Answer 12

. Result from production of Hb w/ altered amino acid sequence

Question 13

Hb S disease

Answer 13

. Sickle cell
. Single point mutation in gene (Val instead of Glu at position 6) for beta-globin making it beta-s
. Mutation makes HbS less negative than HbA
. Autosomal recessive gene

Question 14

Sickle cell prevalence

Answer 14

. 50,000 Mexicans affects
. 1:500 black children
. 1/12 black people heterozygous carriers

Question 15

SIckle cell characteristics

Answer 15

. Infant don’t show symptoms until Hb F is replaced by HbS
. Lifelong episodes of pain, chronic hemolytic anemia, inc. bilirubin, and inc. suspectibility to infection
. Lifespan of RBC w/ HbS is less than 20 days
. Cell looks sickled

Question 16

How do cells look sickled?

Answer 16

. Replacement of Glu for Val forms protrusion on beta-chain
. Fits into complementary site on beta-chain of another Hb molecule
. Low O2, R state of HbS polymerizes inside RBC forming network of insoluble, fibrous polymers that stiffen and distort cell

Question 17

How do sickle cells cause localized anoxia?

Answer 17

. Block blood flow in capillaries causing anoxia, pain, or death of cells

Question 18

How is sickling enhanced?

Answer 18

. Dec. pO2
. Inc. pCO2
. Dec. pH
. Dehydration
. Inc. 2,3-BPG

Question 19

Sickle cell treatment

Answer 19

. Adequate hydration, analgesics, antibody therapy for infection, blood transfusions. Intermittent transfusions packed with RBCS

Question 20

Advantage of being heterozygous for HbS

Answer 20

. Less susceptible for malaria because cell lifespan isn’t long enough for parasite to grow

Question 21

Hb C disease

Answer 21

. Single amino acid substitution in 6th position of beta chain (Lys for Glu)
. Causes HbC to move slower toward anode than HbA and HbS in gel electrophoresis
. Experience mild chronic hemolytic anemia but no crises
. No treatment needed

Question 22

HbSC disease

Answer 22

. Beta globin chains have HbS mutation and other beta-globin genes carry mutation found in HbC
. Individuals affected are compound heterozygous
. Hb levels higher than in Hb levels in sickle cell disease
. Vary in symptoms
. Crises less frequent and less severe than HbS

Question 23

Methemoglobinemia

Answer 23

. Oxidation of heme Fe to Fe 3+ (ferric) causing HbM that can’t bind to O2
. Causes by drugs, ROS, mutations in chains, NADH-cytochrome B5 reductive deficiency

Question 24

Methemoglobinemia symptoms

Answer 24

. Chocolate cyanosis, brownish blue coloring in skin and mucous membranes from dark HbM coloration
. Tissue hypoxia, anxiety, headache, dyspnea, coma, and death (rare)

Question 25

Methemoglobinemia treatment

Answer 25

Methylene blue that reduces Fe 3+ back o Fe2+

Question 26

Thalassemia

Answer 26

. Hereditary hemolytic diseases that cause imbalance in globin chain synthesis
. Most common single gene disorder
. Either alpha or beta chain defective
. Varies in type of mutation causes defect
. Either no type of a globin chain is produced or some are synthesized but at reduced rate

Question 27

Beta-thalassemias

Answer 27

. Synthesis of beta-chain is dec. or gone
. Usually point mutation issue
. Alpha chain is normal, but can’t form stable tetramers resulting in RBC precursor death
. Inc. HbA2 and HbF

Question 28

Type of beta-thalassemia

Answer 28

. Minor: one defective copy of beta-globin gene on chromosome 11
. Cooley anemia (major): 2 defective copies of beta-globin gene on chromosome 11

Question 29

Beta-thalassemia presentation

Answer 29

. Physical manifestations appear several months after birth
. Severely anemia during 1-2 years of life
. Skeletal changes from extramedullary hematopoiesis

Question 30

Beta-thalassemia treatment

Answer 30

. Regular transfusions
. Can result In Fe overload so iron chelation therapy needed
. Only cure is hematopoietic stem cell transplant

Question 31

Alpha-thalassemia

Answer 31

. Synthesis of aloha chain dec. or gone
. Usually deletion mutations
. Chromosome 16 affected by mutations

Question 32

Types of alpha-thalassemia

Answer 32

. 1 defective gene: silent carrier/no symptoms
. 2 defective genes: alpha thalassemia traits
. 3 defective genes: Hb H (B4) disease causing hemolytic anemia of varying severity
. 4 defective genes: Hb Bart (gamma4) causing fetal death because no HbF is made