Hemoglobinopathies

Question 1

Hb Composition

Answer 1

4 polypeptide subunits (2 alpha and 2 beta) + 4 heme groups w/ FE++ at center of ea heme group

alpha encoded by HBA genes of chromosome 16
beta encoded by HBB genes of chromosome 11

Question 2

Fetal Hemoglobin (HbF)

Answer 2

2 alpha globulins and 2 gamma globulins

gamma globulin prod dec at birth but persists until about 7-8 months then only trace amounts

Question 3

3 Main Types of Hemoglobinopathies

Answer 3

1- qualitative (structural chain varieties - sickle cell)
2-quantitative (disrupt synthesis of globin - thalassemia)
3-Regulatory (impair switching from gamma to betta globin- persitence of fetal hemoglobin)

Question 4

Sickle Cell Disease Basics

Answer 4

• autosomal recessive
• beta subunit of HBB has missense mutation –> sub valine (NOW HYDROPHOBIC) for glutamic acid
• mutant Hb is HBSS for homozygous and HBBS for heterozygous (HbS)
• when deoxygenated hydrophobic part –> aggregates (polymerizes) –> sickle RBCs

Question 5

Sickle Cell Carriers

Answer 5

HbC- does not polymerize as easily as HbS (no anemia)

• resistance to falciparum malaria
• “sickle cell trait”
• just possible symptoms under stress (serious exercise, hypoxia, anesthesia when pregnant

Question 6

alpha- thalassemia

Answer 6

-usually caused by deletion
-2 types…
absolutely no alpha hemoglobin –>hydrops fetalis (build up of fluid in utero) all gamma hemoglobin in fetus
Hb Bart

some alpha –>excess beta hemoglobin –> HbH disease (sometimes not noticed)

Question 7

beta-thalassemia

Answer 7

-usually caused by point mutations
-2 types…
absolutely no beta –> “thal major”–> need constant transfusions

some beta –>beta + –>compatible w/ life

Question 8

Thalassemia Minor

Answer 8

Carriers of 1 beta-thal allele

May suffer from anemia, microcytic RBCs, hypochromic

Question 9

Methemoglobin

Answer 9

One or more iron atoms is in ferric state (Fe+++) which is incapable of reversible oxygenation

Methemoglobin is spontaneously formed w/in RBCs in all people so kept from accumulating by methemoglobin reductase

BUT…Mutation can make heme pocket resistant to methemoglobin reductase (genetic or toxic causes)

Question 10

Changes in Hb During Development

Answer 10

Fetal Hb (HbF) - 2 alpha and 2 gamma

At time of birth- gamma prod dec and beta prod inc

Fetal Hb persists until about 7/8 mo after birth

Question 11

Why can gamma Hb be used as potential therapy for sickle cell?

Answer 11

Gamma Hb is similar to beta Hb (which has mutation in sickle patients)

You can re-activate the gene that produces gamma Hb as therapy option