Flashcards in Chapter 6: Genetic hemaglobin abnormalities Deck (59):
What proportion of the world's population is affected by mutations in the globin genes?
7% of the world population is affected by mutations in the globin genes
What are the structures of various types of Hgb?
Hgb A is alpha2beta2.
Hgb A2 is apha2delta2
Hgb F is alpha2gamma2
What kinds of mutations can lead to thalassemias?
Any mutation that alterers the structure, regulation or processing of globin genes can potentially lead to thalassemia.
What is the locus control region?
It is a genetic regulatory element situated a long way upstream of the globin genes that controls transcription.
What transcription factors influence expression of globin genes?
GATA-1, FoG, NF-E2
When is fetal hemoglobin production overtaken by adult hemoglobin production?
3-6 months after birth gamma chain production for fetal hemoglobin is decreased while beta chain production for adult hemoglobin is increased. (switch from fetal to adult)
What are the two basic categories of hemoglobin abnormalities?
(1) Synthesis of an abnormal hemoglobin
(2) reduced synthesis of normal alpha or beta chains ( the thalassemias)
What are the abnormal hemaglobin diseases?
They are caused usually by point mutations in globin genes that result in unstable cyrstalline hemaglobins.
(1) Hgb S
(2) Hgb C
(3) Hgb D
(4) Hgb E
What secondary effects can be caused by abnormal hemaglobins?
Where is beta-thalassemia the most common?
Beta-thalassemia is most common in mediterranean ethnic groups.
Where is alph-thalassemia most common?
Alpha thalassemia is most common among far eastern ethnic groups.
What are thalassemias?
Disorders characterized by a reduced rate of synthesis of alpha or beta genes.
How many alpha globin genes are there?
There are two alpha globin genes on each chromosome for a total of 4 alpha genes.
What is hydrops fetalis?
Hydrops fetalis is caused by deletion of all four alpha globin genes. This condition is lethal in utero.
What is Hgb H disease?
Hgb H disease is caused by deletion of 3 alpha globin genes. This condition is characterized by
(3) anemia (Hgb 7-11 g/dL)
(5) Hgb H which is beta4 hemaglobin
What are the alpha-thalassemia traits?
Deletion of 1 or 2 alpha thalassemia genes will result in slightly lowered MCV and MCH , but there is not anemia and electrophoresis is normal.
What causes beta thalassemia major?
beta thalassemia is caused by point mutations in beta globin genes that result in very little (beta+) or no (beta0) beta globin being produced.
What determines the severity of the thalassemia major?
The greater the alpha chain excess over the beta chain the more severe the anemia?
What is Lepore syndrome?
beta thalassemia major caused by a delta-beta fusion gene.
Is anemia present in beta thalassemia major?
Yes anemia will become apparent at 3-6 months of age once Hgb F has switched to Hgb A.
What anatomical findings are seen clinically with beta thalassemia major?
(1) splenomegaly (from red cell destruction)
(2) hepatomegaly (from red cell destruction)
(3) Expansion of bones (from bone marrow hyperplasia)
What is the result of repeated blood transfusions for beta thalassemia major?
Iron overload precipitated by ineffective erythropoiesis and inappropriately low hepcidin levels.
What effects does beta thalassemia major have on the endocrine system?
Iron overload causes damage to the endocrine organs.
(3) delayed puberty
What is the effect on the skin of beta thalassemia major?
pigmentation due to excess melanin, hemosiderin, giving a grey appearance.
What is the effect of beta thalassemia major on the immune system?
those with beta thalassemia major have increased risk for infections. (particularly with splenectomy and transfusions)
What is the effect of beta thalassemia major on the skeletal system?
Osteoporosis is common in diabetic and well transfused patients.
What is the most dangerous adverse effect of iron overload?
Iron overload damages the heart.
What are cellular lab abnormalities seen with beta thalassemia major?
(3) increased reticulocyte count
(4) Normoblasts, target cells, and basophilic stippling on PBS.
What is the result of hemoglobin electorphoresis in beta thalassemia major?
(1) almost complete absence of hemoglobin A
(2) larger amounts of Hgb F.
HPLC is most commonly used to diagnose beta thalassemias.
How should iron status be assessed in beta thalassemia major?
iron status should be assessed by monitoring serum ferritin. However, T2 MRI imaging is required to asses iron mediated damage to the heart. Urine iron excretion with chelators and liver biopsy can also be used to monitor iron status.
How is beta-thalassemia treated?
(1) Regular blood transfusions maintain hemoglobin levels above 10g/dL
(2) Folic acid supplementation
(3) Iron chelation therapy
(4) Endocrine therapy to compensate for iron damaged organs.
(5) Immunization against hepatitis in transfusions
(6) Vitamin C (Improves iron excretion)
(7) splenectomy in patients over 6yo.
(8) BM transplant (definitive treatment, effective in 80% of patients)
What is beta-thalassemia minor?
The carrier trait for beta thalassemia
What are the characteristics of beta thalassemia?
(1) hypochromic, microcytic blood film
(2) HIgh red cell count
(3) mild anemia (hgb 10-12)
How is beta thalassemia minor diagnosed?
A raised Hgb A2 confirms beta thalassemia minor diagnosis.
What is thalassemia intermedia?
thalassemias of moderate severity with Hgb between 7-10 g/dL
What is delta-beta thalassemia?
Thalassemia cuased by reduced amount of beta and delta chains. typically exhibits increased Hgb F.
What kind of thalassemia is caused by hemaglobin lapore?
Homozygotes exhibit thalassemia intermedia while heterozygotes exhibit thalassemia trait.
What is hereditary persistence of fetal hemaglobin?
Genetic conditions caused by deletions or cross overs affecting the production of beta and gamma chains.
What is the result of beta-thalassemia combined with Hgb E trait?
It presents like thalasemia major.
What is the result of beta thalassemia with Hgb S trait?
It presents like sickle cell disease.
What is the result of beta-thalassemia trait with Hgb D?
Hypochromic, microcytic anemia of varying severity.
What are the three forms of sickle cell disease?
(1) Hgb SS (sickle cell disease)
(2) Hgb SC (double heterozygote presents like sickle cell disease)
(3) Hgb SBetathalassemia (presents like sickle cell disease)
What mutation causes sickle cell disease?
A Val for Glu substitution at position 6 of the beta globulin gene. Causes hemoglobin to polymerize under low oxygen tension.
What is the primary sign of SS disease?
severe hemolytic anemia
Why are symptoms of anemia mild in comparison to the severity of the anemia?
Because Hgb S gives up oxygen more readily than Hgb A shifting the O2 dissociation curve to the right.
What is the primary symptoms of SS disease?
Frequent and severely painful vaso-occlusive crises.
What can precipitate vaso-occlusive crises in SS disease?
Infection, acidosis, dehydration, or deoxygenation.
What are the potential complications of vaso-occlusive crises?
infarction of the bones, lung, spleen and brain (most serious).
What are visceral sequestration crises?
sickling of cells within organs leading to pooling of blood (Chest syndrome in lungs - must give oxygen and transfusion.)
What are the different kinds of crises seen in SS disease?
(2) visceral sequestration
(3) Aplastic crisis
What are aplastic crises?
aplastic crises are caused by parvovirus infection or folate deficiency and are characterized by a fall in reticulocyte and hemoglobin counts.
What are hemolytic crises?
Increased rate of hemolysis characterized by fall in Hgb and rise in reticulocytes
What are the clinical features of SS disease?
(1) Ulcers in the lower legs (due to stasis)
(3) Pulmonary hypertension
(4) liver damage
(5) Bilirubin gallstones
(6) renal infarctions
What is the hemoglobin level in SS disease?
Hgb is low 6-9 g/dL
What are the cellular morphological findings in SS disease?
sickle cells, target cells, Howell-Jolly bodies (splenic atrophy)
How can SS disease be treated?
(1) Folic acid
(2) Pneumococcal, haemophilus, and meningicoccal vaccination and prophylactic penicillin prevent infection.
(3) Transfusions with iron chelators in patients with frequent crisis
(4) Hydroxyurea (increases Hgb F)
(5) stem cell transplant
What is hemoglobin C disease?
A genetic defect in which lysine is substitiuted for Glu at the 6 position of beta globin.
(1) cells with rhomboid crystals
What are the characteristics of Hgb D disease?
Mild hemolytic anemia