thalassemias Flashcards
Alpha globin cluster is on chromosome
___ 13.3 & consists of an embryonic z gene and duplicate a genes
Alpha globin cluster is on chromosome 16p 13.3 & consists of an embryonic z gene and duplicate a genes
The two alpha a genes are highly homologous and encode an identical protein
yep
Most globin synthesis occurs from
a2 gene
b globin cluster is on chromosome ___ and consists of embryonic e globin gene, duplicate g genes (Ag and Gg), d and b
11
There is one b globin gene per
and the expression of each globin cluster is regulated by
haploid chromosome
and regulated by upstream locus control region (LCR)
Hemoglobin switching
- There are 3 embryonic ___ before the 8th week of life (Gower 1, Gower 2, Portland)
- By month 3 gestation, ___ and ___globin gene expression peak
- ___ and___ globin chains (alpha2gamma2) compose HbF to provide increased O2 transport to fetus
- ____ globin gene expression is down regulated at birth and Hb F levels decline by 6 months of age
- ____ gene is turned on at birth and Hb A2 achieves low steady state levels
- ___ globin levels peak and HbA comes to dominate 6mo post-natal
- There are 3 embryonic Hb before the 8th week of life (Gower 1, Gower 2, Portland)
- By month 3 gestation, a and g globin gene expression peak
- 2 a and 2 g globin chains (alpha2g2) compose HbF to provide increased O2 transport to fetus
- g globin gene expression is down regulated at birth and Hb F levels decline by 6 months of age
- δ gene is turned on at birth and Hb A2 (alpha2δ2) achieves low steady state levels
- ß globin levels peak and HbA (a2b2) comes to dominate 6mo post-natal
what kind of bonds are broken when a single O2 binds to one heme moieties
salt bonds
right shift
decreased affinity of Hb for oxygen
left shift
increased affinity of Hb for oxygen
sickle hemoglobin has low or high O2 affinity
low
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
Hemoglobinopathies
quantative disorder of globin synthesis
thalassemia
Thalassemic syndromes are caused by mutations in globin chains of hemoglobin that lead to ____production of globin chains from the affected allele(s
decreased
decreased or absent beta globin synthesis
Beta thalassemia –
decreased or absent alpha globin synthesis
Alpha thalassemia –
deletion of 4 a globin genes incompatible with life and designated results in
hydrop fetalis
deletion of 3 a globin genes phenotype can be severe (-a/–)
Hb H disease
deletion of 2 a globin genes; mild anemia
alpha talassemia trait/minor
deletion of 2 a globin on the same haploid chromosome
cis
deletion of 2 a globin on alternate chromosomes
trans
deletion of 1 alpha globin gene (a-/aa) microcytosis but no anemia
Alpha thalassemia minima (Silent alpha thalassemia):
Hb Constant Spring
Substitutions in the a2 globin termination codon
- longer and more unstable mRNA transcript
- common in Asia and some U.S. Asian communities
Non-deletional a-thalassemia mutations
Point mutations that inactivate a globin genes or interfere with gene transcription or translation
much less common than deletional mutations
in alpha thalassemia
- what happens in adults with the excess of beta globin chains
- what occurs in utero
- B globin chains forms tetramers that precipitate in red cells and have increased O2 affinity
- in utero there is gamma tetramers called Hb Barts that precipitate
Homozygous and complete loss of b globin gene expression
Beta thalassemia major or Cooley’s anemia: very severe anemia, with transfusion dependency
mutations of both globin alleles but the quantity of normal hemoglobin (Hb A) produced is greater than in thalassemia major
Beta thalassemia intermedia: moderately severe
anemia but not transfusion dependent
mutation of a single b thalassemia allele (b
Beta thalassemia minor: clinically mild or silent
ß thalassemia mutations down-regulate or abolish either the transcription of _____ or translation of ______
ß thalassemia mutations down-regulate or abolish either the transcription of globin genes or translation of globin mRNA
point mutations in Beta-thalassemia (3)
- Mutations in promoter region (common)
- Cap site mutations (mild effect)
- Splice site mutations
the excess of alpha chains in Beta-thalassemia results in
alpha-tetramers precipitate in red cell precursors, damaging red cell membranes and thus there is ineffective erythropoiesis
in beta thalassemia we see peripheral hemolysis which causes s
splenomegaly from work hypertrophy
complications of B-thalassemia major
- bone deformities
- High output heart failure
- infection risk
- hepato-splenomegaly
- severe anemia
- chronic hemolysis
- hepato-splenomegaly
> 50 mutations that can result in both a variant (non-A) hemoglobin and thalassemia phenotype.
Combined hemoglobinopathy & thalassemia
Hb E:
- Caused by one of the most common and important mutations worldwide - _______
- Hb E is a _____ Hb (qualitative) but the mutation activates a cryptic mRNA splice site– ______ synthesis of b-E globin chain & a thalassemia phenotype
- AE (E trait) confers resistance to ________
- Found in
- Co-inheritance with_____ confers a clinical phenotype similar to b thalassemia intermedia or major
- E-b thalassemia affects
- E-b thal is becoming a health problem in
- Caused by one of the most common and important mutations worldwide - b codon 26 GAG>AAG or glu26Lys
- 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
- AE (E trait) confers resistance to Plasmodium falciparum
- Found in Indian subcontinent and SE China, Thailand, Laos, Cambodia, Malaysia, Sri Lanka
- Co-inheritance with b thal confers a clinical phenotype similar to b thalassemia intermedia or major
- E-b thalassemia affects >1 million people worldwide
- E-b thal is becoming a health problem in North America (U.S. west coast Asian communities)
Diagnosis of Thalassemia:
- CBC
a. Hb and Hct
b. MCV
c. red cell count - Peripheral blood smear
a. red cells are
b. polychromasia and basophilic stippling
c. poikilocytosis and target cells/red cell fragments - iron studies
- Hb electrophoresis
a. alpha thalassemia
b. HbH
c. Beta thalassemia - HPLC
- genetic studies
- CBC
a. Hb and Hct is low
b. MCV is low/microcytosis
c. red cell count is high - 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 - iron studies are normal
- 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
treatment of Thalassemia Major
- supportive
- disease modifying (2)
- supportive: Red cell transfusion at birth, folic acid suppl., iron chelation, vax. against hep. virus, endocrine replacement
- (1) bone marrow transplant (2) Gene therapy
