Genetic hemoglobinopathies wk7th11 Flashcards Preview

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Flashcards in Genetic hemoglobinopathies wk7th11 Deck (15):
1

Hereditary persistence of fetal hemoglobin

- clinically benign

- mutations impair the perinatal switch from gamma to beta synthesis

- at least one gamma gene intact

- increase gamma production-> increased HbF

 

2

Sickle cell mutation

- single nucleotide substitution in the 2nd position of the 6th codon of the beta globin gene

- GAG-> GTG

- Glu (neg charge) to val (hydrophobic)

- Malaria resistance among AS heterozygotes

- Lower density of parasites in AS cells

3

Clinical feature of SS disease

- presentation typically in first 2 years of life 

- infections

- anemia

- failure to thrive

- splenomegally

- dactylitis: plainful swelling of hands and feet from capillary occlusion in small bones

4

Vaso-occlusive infarctions

Strokes
Acute chest syndrome
Renal papillary necrosis
Autosplenectomy
Leg ulcers
Priapism
Bone aseptic necrosis
Visual loss
As many as 70% of affected people have no symptoms

5

Bone Crisis

Vaso-occlusion of bones
Extremely painful
Persist for days or weeks if untreated

Treatment:
Pain management
Hydration
Oxygen

Prevention:

Hypertransfusion

6

Additional causes of morbidity and mortality is SS disease

1. progressive renal and cardio-pulm failure

(4th-5th decades)

2. Parvovirus

- high risk of aplastic anemias

- temporary cessation of erythrocyte production

7

Sickling in sickle cell disease

HbS

- soluble HbS functions nomrally in O2 binding

- solubility 20% of HbA in deoxygenated blood

- aggregates into rodes or fibers, distorts shapes

- sickled: less deformable, block blood flow, cause ischemia

8

Thalassemias

overview

- Reduced synthesis of alpha- or beta-globin chains

- Relative imbalance of alpha:beta chains


- Globin chain produced in normal amount is in relative excess

- Excess normal chains eventually precipitate in the red cell

- Cell membrane is damaged

- Premature RBC destruction occurs

Results in hypochromic microcytic anemia and tissue iron overload

9

Alpha thalasemmias

Disorders of alpha-globin production

- Affect formation of both fetal and adult hemoglobins

-Cause intrauterine and postnatal disease

In absence of alpha-globin chains, chains from beta-globin gene cluster are free to form a homotetrameric hemoglobin

gamma4: Hb Bart’s
beta4: Hb H

- homologous parining and unequal crossover messes up genes

10

HB Bart's and Hb H

- Cannot release oxygen to tissues normally

- Ineffective oxygen carriers

Severe alpha-thal and high levels of Hb Bart’s:
- Marked intrauterine hypoxia
- Hydrops fetalis: massive generalized fluid accumulation in utero

Milder alpha-thal
- Anemia develops because of gradual precipitation of Hb H in erythrocytes

11

Hydrops fetalis

Due to absence of alpha chains: - -/- -

Although alpha-thal seen in many groups, hydrops fetalis is largely restricted to Southeast Asia

- High gene frequency (up to 15%)
- Predominant form of alpha-thal trait in SEA: - -/alpha2
- Therefore, at risk for - -/ - -

Contrast with predominant form elsewhere
- alpha/- alpha

- Virtually impossible to see hydrops fetalis phenotype  

12

Beta thal

Not apparent until a few months after birth

Excess alpha chains
- Insoluble
- Precipitate in erythrocyte precursors
- Erythrocyte precursors destroyed in bone marrow
- Ineffective erythropoiesis

13

Beta that heterozygotes

beta-Thal Minor: hypochromic, microcytic and may be misdiagnosed as iron deficiency anemia

HbA2 elevation unique to beta-thal heterozygotes
- alpha2delta2
- delata gene is intact and HbA2 production continues

HbF is also increased
- Not due to reactivation of gamma-globin gene switched off at birth
- Increased selective survival and possibly also increased production of minor population of HbF-containing adult RBCs

14

Beta Thal major

description and tx

- Usually genetic compounds
- Severe anemia with phenotype due to combined effects of two alleles
- beta0-thal: No HbA present
- beta+-thal: HbA present
- Severe hypochromic anemia

TX:
Blood transfusion and iron chelation
Bone marrow transplantation if appropriate match

15