thalassemias

Question 1

Alpha globin cluster is on chromosome

___ 13.3 & consists of an embryonic z gene and duplicate a genes

Answer 1

Alpha globin cluster is on chromosome 16p 13.3 & consists of an embryonic z gene and duplicate a genes

Question 2

The two alpha a genes are highly homologous and encode an identical protein

Answer 2

yep

Question 3

Most globin synthesis occurs from

Answer 3

a2 gene

Question 4

b globin cluster is on chromosome ___ and consists of embryonic e globin gene, duplicate g genes (Ag and Gg), d and b

Answer 4

11

Question 5

There is one b globin gene per

and the expression of each globin cluster is regulated by

Answer 5

haploid chromosome

and regulated by upstream locus control region (LCR)

Question 6

Hemoglobin switching

1. There are 3 embryonic ___ before the 8th week of life (Gower 1, Gower 2, Portland)
2. By month 3 gestation, ___ and ___globin gene expression peak
3. ___ and___ globin chains (alpha2gamma2) compose HbF to provide increased O2 transport to fetus
4. ____ globin gene expression is down regulated at birth and Hb F levels decline by 6 months of age
5. ____ gene is turned on at birth and Hb A2 achieves low steady state levels
6. ___ globin levels peak and HbA comes to dominate 6mo post-natal

Answer 6

1. There are 3 embryonic Hb before the 8th week of life (Gower 1, Gower 2, Portland)
2. By month 3 gestation, a and g globin gene expression peak
3. 2 a and 2 g globin chains (alpha2g2) compose HbF to provide increased O2 transport to fetus
4. g globin gene expression is down regulated at birth and Hb F levels decline by 6 months of age
5. δ gene is turned on at birth and Hb A2 (alpha2δ2) achieves low steady state levels
6. ß globin levels peak and HbA (a2b2) comes to dominate 6mo post-natal

Question 7

what kind of bonds are broken when a single O2 binds to one heme moieties

Answer 7

salt bonds

Question 8

right shift

Answer 8

decreased affinity of Hb for oxygen

Question 9

left shift

Answer 9

increased affinity of Hb for oxygen

Question 10

sickle hemoglobin has low or high O2 affinity

Answer 10

low

Question 11

are caused by mutations in alpha and beta globin genes of hemoglobin protein that lead to a structural or qualitative change in the hemoglobin; also referred to as variant hemoglobins

Answer 11

Hemoglobinopathies

Question 12

quantative disorder of globin synthesis

Answer 12

thalassemia

Question 13

Thalassemic syndromes are caused by mutations in globin chains of hemoglobin that lead to ____production of globin chains from the affected allele(s

Answer 13

decreased

Question 14

decreased or absent beta globin synthesis

Answer 14

Beta thalassemia –

Question 15

decreased or absent alpha globin synthesis

Answer 15

Alpha thalassemia –

Question 16

deletion of 4 a globin genes incompatible with life and designated results in

Answer 16

hydrop fetalis

Question 17

deletion of 3 a globin genes phenotype can be severe (-a/–)

Answer 17

Hb H disease

Question 18

deletion of 2 a globin genes; mild anemia

Answer 18

alpha talassemia trait/minor

Question 19

deletion of 2 a globin on the same haploid chromosome

Answer 19

cis

Question 20

deletion of 2 a globin on alternate chromosomes

Answer 20

trans

Question 21

deletion of 1 alpha globin gene (a-/aa) microcytosis but no anemia

Answer 21

Alpha thalassemia minima (Silent alpha thalassemia):

Question 22

Hb Constant Spring

Answer 22

Substitutions in the a2 globin termination codon

• longer and more unstable mRNA transcript
• common in Asia and some U.S. Asian communities

Question 23

Non-deletional a-thalassemia mutations

Answer 23

Point mutations that inactivate a globin genes or interfere with gene transcription or translation

much less common than deletional mutations

Question 24

in alpha thalassemia

1. what happens in adults with the excess of beta globin chains
2. what occurs in utero

Answer 24

1. B globin chains forms tetramers that precipitate in red cells and have increased O2 affinity
2. in utero there is gamma tetramers called Hb Barts that precipitate

Question 25

Homozygous and complete loss of b globin gene expression

Answer 25

Beta thalassemia major or Cooley’s anemia: very severe anemia, with transfusion dependency

Question 26

mutations of both globin alleles but the quantity of normal hemoglobin (Hb A) produced is greater than in thalassemia major

Answer 26

Beta thalassemia intermedia: moderately severe

anemia but not transfusion dependent

Question 27

mutation of a single b thalassemia allele (b

Answer 27

Beta thalassemia minor: clinically mild or silent

Question 28

ß thalassemia mutations down-regulate or abolish either the transcription of _____ or translation of ______

Answer 28

ß thalassemia mutations down-regulate or abolish either the transcription of globin genes or translation of globin mRNA

Question 29

point mutations in Beta-thalassemia (3)

Answer 29

1. Mutations in promoter region (common)
2. Cap site mutations (mild effect)
3. Splice site mutations

Question 30

the excess of alpha chains in Beta-thalassemia results in

Answer 30

alpha-tetramers precipitate in red cell precursors, damaging red cell membranes and thus there is ineffective erythropoiesis

Question 31

in beta thalassemia we see peripheral hemolysis which causes s

Answer 31

splenomegaly from work hypertrophy

Question 32

complications of B-thalassemia major

Answer 32

1. bone deformities
2. High output heart failure
3. infection risk
4. hepato-splenomegaly
5. severe anemia
6. chronic hemolysis
7. hepato-splenomegaly

Question 33

> 50 mutations that can result in both a variant (non-A) hemoglobin and thalassemia phenotype.

Answer 33

Combined hemoglobinopathy & thalassemia

Question 34

Hb E:

1. Caused by one of the most common and important mutations worldwide - _______
2. Hb E is a _____ Hb (qualitative) but the mutation activates a cryptic mRNA splice site– ______ synthesis of b-E globin chain & a thalassemia phenotype
3. AE (E trait) confers resistance to ________
4. Found in
5. Co-inheritance with_____ confers a clinical phenotype similar to b thalassemia intermedia or major
6. E-b thalassemia affects
7. E-b thal is becoming a health problem in

Answer 34

1. Caused by one of the most common and important mutations worldwide - b codon 26 GAG>AAG or glu26Lys
2. Hb E is a variant Hb (qualitative) but the mutation activates a cryptic mRNA splice site  reduced synthesis of b-E globin chain & a thalassemia phenotype
3. AE (E trait) confers resistance to Plasmodium falciparum
4. Found in Indian subcontinent and SE China, Thailand, Laos, Cambodia, Malaysia, Sri Lanka
5. Co-inheritance with b thal confers a clinical phenotype similar to b thalassemia intermedia or major
6. E-b thalassemia affects >1 million people worldwide
7. E-b thal is becoming a health problem in North America (U.S. west coast Asian communities)

Question 35

Diagnosis of Thalassemia:

1. CBC
   a. Hb and Hct
   b. MCV
   c. red cell count
2. Peripheral blood smear
   a. red cells are
   b. polychromasia and basophilic stippling
   c. poikilocytosis and target cells/red cell fragments
3. iron studies
4. Hb electrophoresis
   a. alpha thalassemia
   b. HbH
   c. Beta thalassemia
5. HPLC
6. genetic studies

Answer 35

1. CBC
   a. Hb and Hct is low
   b. MCV is low/microcytosis
   c. red cell count is high
2. Peripheral blood smear
   a. red cells aresmall and hypochromic
   b. polychromasia and basophilic stippling- reflect increased reticulocytosis
   c. poikilocytosis and target cells/red cell fragments- variable cell shape
3. iron studies are normal
4. Hb electrophoresis identifies varian Hb with altered state of migration of the Hb in an electric field
   a. alpha thalassemia- electrophoresis shows HbA only

b. HbH- a fast migrating band formed by tetramers of beta (HbH) is present in addition to HbA
c. Beta thalassemia- HbA2 & HbF levels are increased because the excess alpha chains form tetramers with d and g globin chains respectively
5. HPLC- separates Hb on basis of their hydrophobicity
6. genetic studies- PCR or gene sequencing

Question 36

treatment of Thalassemia Major

1. supportive
2. disease modifying (2)

Answer 36

1. supportive: Red cell transfusion at birth, folic acid suppl., iron chelation, vax. against hep. virus, endocrine replacement
2. (1) bone marrow transplant (2) Gene therapy