Thalassemia Flashcards
alpha gene cluster
chromosome 16
beta gene cluster
chromosome 11
disorder of globin chain synthesis (quantitative)
thalassemia
T or F. we need correct proportions of each globin chain in order to have normal levels of each type of hemoglobin
T, pathologic effects arise from imbalance of globin-chain synthesis
most common monogenic diseases in humans
thalassemia
this classically follows malaria distribution
thalassemia
- selective pressure due to protection of heterozygotes from malaria
beta thalassemia
- one beta gene on each copy of chrom 11
- autosomal recessive inheritance
- deletional/non-deletional
beta zero
mutations resulting in no beta chain production
beta +
mutations resulting in partial deficiency of beta chains
beta silent
very mild deficiency; little to no clinical impact
B/B+ or B/Bsilent
b-thal silent carrier
=> no hematologic or clinical abnormalities
B/B0
b-thal minor/trait
- microcytosis, mild hemolytic anemia
- no clinical symptoms
B0/B+ or B+/B+
b-thal intermedia
- microcytosis, mild to moderate hemolytic anemia
- moderate clinical symptoms; may require occasional transfusions but not dependent
B0/B0
- homozygotes or compound heterozygotes; little to no beta globin production
- severe microcytosis and hemolytic anemia
- severe, transfusion dependent
Beta thal major
- B0/B0
- homozygous for non-functional B globin muttons
- no production of HbA
- increased HbA2, often increased HbF due to slight upreg of delta and gamma chains but usually insufficient to fully compensate
- severe anemia starting ~ 6 mos of age (transfusion dependent)
Untreated B thal major lab features
- Hgb below 70 g/L
- MCV = 50-70 fL
- MCH = 12-20 pg
- marked microcytosis and hypochromia
- marked poikilocytosis
- RBC inclusions
- polychromasia - nucleated RBCs
iron precipitates
Pappenheimer bodies
B thal poikilocytosis and RBC inclusions
poikilocytosis: target cells, tear drops, elliptocytes
inclusions: Basophilic stippling, Howell-Jolly bodies, Pappenheimer bodies
B thal minor/trait
- B/B0
- generally asymptomatic, mild hematologic changes
=> may have mild symptoms of anemia
=> maybe have exacerbations of anemia during pregnancy - often identified incidentally
=> family studies, routine CBC
B thal minor/trait lab features
- elevated HbA2, increased HbF usually
- Hgb = 90-110 g/L (normal); out of proportion w degree of microcytosis
- MCV = 50-70 fL
- MCH = 20-22 pg
- RBC count elevated
Blood film for B thal minor/trait
- mild to moderate microcytosis and hypochromia
- moderate poikilocytosis: target cells, few elliptocytes
- RBC inclusions: sometimes basophilic stippling
two alpha globin chains on each copy of this chromosome
16 (4 genes total)
alpha chain mutations
- reduced or absent alpha chain production from chromosome
- deletional, non-deletional (pt mutations, indels, splice sites, mRNA processing, etc.)
alpha^0
deletion involving both alpha-globin genes on a chromosome
- no alpha chain production from a chromosome
- (–) haplotype
- HS-40 deletion
HS-40 deletion
(alpha^0)
important regulatory sequence 40kb upstream of zeta locus, required for alpha chain expression
alpha^+
deletions or mutations affecting only one of the alpha genes on a chromosome
- reduced alpha-globin production from that chromosome
- (- alpha OR alpha -) haplotype; deletional
- (alpha T alpha OR alpha alpha T) haplotype; non-deletional
alpha thalassemia clinical syndromes depends on…
how many of the four genes are affected
alpha thal silent carrier
- (-a/aa) or aT/aa)
- asymptomatic, little to no hematologic abnormalities
- slight microcytosis?
alpha thal minor/trait
- (–/aa) or (-a/-a)
- usually asymptomatic, mild hematologic abnormalities
- microcytic anemia
alpha thal intermedia
- Hb H disease
- (–/-a)
- severe microcytic anemia
Hb Bart’s hydrops fetalis syndrome
- alpha thal major
- (–/–)
- severe, incompatible w life
survival with Hb Bart’s
requires intrauterine transfusions and lifetime transfusion dependence
this syndrome is a high risk of maternal complications at delivery due to very large placenta
Hb Bart’s (a thal major)
loss of all 3 alpha genes or homozygous for severe non-deletion
Hb H disease
–/-a) or (aTa/aTa
Mentzer index
- MCV/RBC
- <13 = thal trait likely
- > 13 = thal less likely
