Genetic hemoglobinopathies wk7th11 Flashcards
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
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
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
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
Bone Crisis
Vaso-occlusion of bones
Extremely painful
Persist for days or weeks if untreated
Treatment:
Pain management
Hydration
Oxygen
Prevention:
Hypertransfusion
Additional causes of morbidity and mortality is SS disease
- progressive renal and cardio-pulm failure
(4th-5th decades)
- Parvovirus
- high risk of aplastic anemias
- temporary cessation of erythrocyte production
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
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
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
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
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
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
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
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
