GENETICS DISORDERS thelesemia

1. Professor Naseer ud din.

2.  Thelesemia is genetically heterogeneous disorder caused
by Germ line mutation that decrease the synthesis of either
α globulin or ß globulin leading to anemia, tissue hypoxia
and cell hemolysis related to imbalance of globulin.
 ß thelesemia is caused by deficient synthesis of beta
chains
 α thelesemia is caused by deficient synthesis of α chain.
 thelesemia is caused by mutation that dimnish the
synthesis of ß chain.
 Impaired ß globulin synthesis results in anemia by two
machanisms.
 1.Defecite in HbA synthesis produces hypochromic
microcytic red cells with sub normal oxygen transport
capacity.

4. ß Thelesemia:
 ß thelesemia is caused by mutation that dimnish the synthesis
of ß chain.
 Impaired ß globulin synthesis results in anemia by two
machanisms.
 1.Defecite in HbA synthesis produces hypochromic microcytic
red cells with sub normal oxygen transport capacity.
 2.Deminished survival of red cells and their precursor which
results from imbalance in α and ß globulin synthesis.
 Membrane damage is the proximal cause of most red cell
pathology.
 Most cells succumb to membrane damage and undergo
apoptosis which leads to ineffective erythropoiesis.

5.  Those red cells released from bone marrow also contain
inclusions (α unpaired chain of hemoglobin) have membrane
damage prone to spleenic sequestration and extra vascular
hemolysis.
 Ineffective erythropoiesis create additional problem as
massive erythroid hyperplasia in marrow and extensive extra
medullary hematopoiesis.
 Expanding mass of red cell precursor erodes bone cortex,
impair bone growth and produces skeletal abnormalities.
 Metabolically active erythroid progenitor steal nutrient from
other tissues that are already oxygen starved causing
cachexia.
 In thelesemia marked expansion of erythroid precursor
leads to increase absorption of iron from gut and together
with repeated transfusions leads to severe iron accumulation
(hemachromatosis).

6. CLINICAL SYNDROME:
 Thelesemia depends on genetic defects (B+ or B°).
 Beta thelesemia allele (B+B+, B+B or B°B°) have
severe transfusion dependent anemia called
thelesema major.
 Heterozygotes with one ß thelesemia and one normal
gene (B+/ B, B°/B) usually have mild asymptomatic
microcytic anemia, this condition is called beta
thelesemia minor and the condition is referred as ß
thelesemia trait.

7. ß THELESEMIA MAJOR
 Most common in Mediterranean countries part of
Africa and South east Asia.
 Anemia manifest 6 to 9 month after birth as
hemoglobin synthesis switches from HbF to HbA.
 In transfused patient hemoglobin levels are 3 to 6
grams /dl.
 The red cells completely lack HbA major red cells
hemoglobin is HbF.
 The blood smear shows severe red cells
abnormalities in size (Anisocytosis) and shape
(piokilocytosis) microcytosis and hypochromia.
 Target cells (as hemoglobin collects in center of the
red cells) basophilic stippling and fragmented red
cells also common.
 Reticulocyte elevated.

8. Other major alteration:
 In un transfused patient striking expansion of
hemopoietically active bone marrow.
 Erosion of bone by expanding marrow in face and
skull with new bone formation give rise crew-cut
appearance radiographycally.
 Enlargement of spleen (as much as 1500 grams due
to extra medullary hematopoiesis).
 Secondary hemochromatosis due to continuous
transfusion leads to iron deposition in heart, liver and
pancreas and cause their damage.

9.  Clinical course:
 Untreated children
 1. Growth to retardation
 2.Die at early age
 3.Those survive suffer from cheeks bone deformity.
 4.Hepatospleenomegally due to extra medullary
hematopoiesis.
 secondary hemochromatosis must be treated
with iron chelator.
 With transfusion and iron chelator survival into 3rd
decade is possible.
 Hematopoietic cell transplantation is the only therapy
being used increasingly.
 Prenatal diagnosis possible by molecular analysis.

12. ß THELESEMIA MINOR:
 It is much more common than ß thelesemia major.
 Most patients are heterozygote groups carrier of B+
or B° allele.
 They are usually asymptomatic .
 Mild anemia present
 peripheral blood smear show
 - hypochromia
 - microcytosis
 - basophilic stippling
 - target cell
 Mild erythoroid hyperplasia in bone marrow .
 Hemoglobin electrophoresis reveals increase in
HbA2(α² , delta2) chain reflecting elevated ratio of
delta chain and ß chain synthesis.

13. IMPORTANCE OF DAIGNOSIS OF BETA
THELESEMIA TRAIT
 1. It may be mistaken for iron deficiency anemia.
 2.it has implication for genetic counseling.
 Iron deficiency anemia is excluded by
measurement of serum iron and total iron binding
capacity (TIBC and serum ferritin).
 Increase in HbA2 is diagnostically useful in women of
child bearing age who are at high risk of iron
deficiency

14. α THELESEMIA:
 It is caused by inherited delusion of α chain as a result of
reduced or absent synthesis of Alfa globin chain .
 Normal individuals have 4 α globin chain.
 Severity of thelesemia depends on how many α globin gene
are effected.
 In newborn with α thelesemia there is excess unpaired
gama globin chain form gama4 tetrameres known as
hemoglobin Barts .
 Whereas in older children and adult excess ß globin chain
form B4 tetrameres known as HbH.
 Because free ß chains and gama chains are more soluble
than free α chain therefore form fairly stable homotetramere
.
 Gene deletion is the most common cause of reduced chain
synthesis.

15. CLINICAL SYNDROMES:
 Clinical syndromes are determined by number of
globin gene that are deleted.
 Severity of clinical syndrome is proportional to the
number of a globin gene that are deleted.
Silent carrier state:
 Deletion of α globin gene these individuals are
completely asymptomatic.
α thelesemia trait:
 Caused by deletion of two α globin gene from single
chromosomes (α / α, -/- ) or deletion of α globin gene
from each of two chromosomes (α /-, α /-) thelesemia
trait is identical to ß thelesemia minor that is small red
cell and minimal anemia no abnormal physical sign,
Hba2 are normal or low.

16. HEMOGLOBIN H DISEASE:
 Caused by deletion of 3 α globin.
 Most common in Asians.
 Only 1 α globin present, synthesis of α chains
markedly reduced and tetra mere of ß globin called
HbH form.
 Have extremely high affinity for oxygen therefore not
useful for oxygen delivery leading to tissue hypoxia
disproportionate to the level of hemoglobin.
 HbH is prone to oxidation which causes it to
precipitate and form intra cellular inclusion that
promote red cell sequestration and phagocytosis in
spleen, the result is moderately severe anemia.

17. Hydrops fetalis:
 Most severe form of thelesemia.
 Caused by deletion of all 4 α globulin.
 In fetus excess gama globin chain form gama globin
tetramere (hemoglobin bart).
 Have high affinity for oxygen , deliver little oxygen to
tissue.
 Survival in early development is due to expression of
delta chain an embryonic globin that pairs with gama
chain to form functional delta 2 gama 2 hemoglobin
tretrameres.

18.  Sign of fetal distress become evident by 3rd
trimester of pregnancy may lead to death.
 With intra uterine transfusion infants are now
saved.
 Fetus show severe pallor, generalized oedema
and massive hepatospleenomagally.
 Life long dependence on blood transfusion for
survival with risk of iron overload.
 Haemopoietic stem cells are puritive.