T7 hemoglobinopathies & thalassemia

hemoglobinopathies - cause

qualitative defects in Hb structure

thalassemia - cause

quantitative defects of globin chains

Hb qualitative defect - cause

inherited amino acid substitution in globin chains

thalassemia - results in

ineffective erythropoiesis and hemolysis

Hb quantitative defects leads to…

excess amount of normally produced chain

most common thalassemia in thailand

Hb E

thalassemia - mode of inheritance

autosomal recessive

alpha thalassemia - location

chromosome 16

number of alpha globin genes

4

alpha thalassemia leads to…

excess beta / gama → abnormal Hb

abnormal tetramers

high O2 affinity → cannot deliver O2 effectively

alpha thalassemia - normal - genotype

αα/αα

alpha thalassemia - silent carrier - genotype

-α/αα

-α/αα

heterozygous alpha thal-2

alpha thalassemia trait (minor) - genotype

-α/-α OR --/αα

-α/-α

homozygous alpha thal-2

--/αα

heterozygous alpha thal-1

alpha thalassemia - HbH - genotype

--/-α

--/-α

heterozygous alpha thal-1 thal-2

alpha thalassemia - Hb bart’s (hydrops fetalis - genotype

--/--

--/--

homozygous alpha thal-1

alpha thalassemia trait (minor) - blood smear

mild microcytic hypochromic anemia

Hb H disease - blood smear

microcytic hypochromic RBCs, poikilocytosis, target cells, inclusion bodies (golf ball)

Hb bart’s hydrops fetalis - blood smear

severe anisopoikilocytosis, numeraous nucleated RBCs

Hb bart’s hydrops fetalis - clinical features

intrauterine or perinatal death, severe hypoxia, edema, ascites, cardiomegaly, hepatosplenomegaly

alpha or beta more toxic accumulation and deposition

alpha

type of thalassemia that is more severe

beta thalassemia

beta thalassemia - location

chromosome 11

beta thalassemia - symptoms when?

after birth when HbA replace HbF

beta thalassemia - ineffective erythropoiesis

destruction of erythroblasts from alpha chain precipitates

beta thalassemia - extravascular hemolysis

RBCs with alpha chain inclusion are destroyed in spleen

mutation in beta globin gene leads to…

decrease transcription → abnormal RNA processing → decrease translation

beta+ thalassemia - what is it

reduced beta globin production

beta+ thalassemia - cause

mutations in promoter, UTRs, introns, poly-A site

beta0 thalassemia - what is it

no beta globin production

beta0 thalassemia - cause

initiation codon mutations, splicing defects, frameshift, nonsense mutations

beta thalassemia minor - features

mild microcytic hypochromic anemia

beta thalassemia major - features

severe anemia, starts in infancy, lifelong transfusion-dependent

beta thalassemia minor - genotypes

β⁺ / β & β⁰ / β

β⁺ / β

heterozygous beta+ thalassemia

β⁰ / β

heterozygous beta0 thalassemia

beta thalassemia major - genotypes

β⁰ / β⁰, β⁺ / β⁺, β⁰ / β⁺

β⁰ / β⁰

homozygous beta0 thalassemia

β⁺ / β⁺

homozygous beta+ thalassemia

β⁰ / β⁺

heterozygous β⁰/β⁺ thalassemia

beta thalassemia minor - blood smear

microcytic hypochromic RBCs, target cells, elliptocytes, basophilic strippling, mild anemia

beta thalassemia minor - symptoms

asymptomatic, worsen during pregnancy, infection, folate deficiency

beta thalassemia major - onset

early infancy

beta thalassemia major - blood smear

hypochromic microcytic RBCs, marked polikocytosis, target cells, teardrop cells, NRBCs

beta thalassemia major - bone marrow expansion

hair on end skull x ray appearance & mongoloid facies

beta thalassemia major - complications

iron overload, alloimmunization, transfusion-transmitted infections

thalassemia - imbalance globin chain synthesis

decrease production of one chain & excess of the other

thalassemia - excess normal globin chains

forms insoluble precipitates in developing RBCs

thalassemia - toxic effects

precipitation & degradation of globin chains → free radical release, oxidative stress

thalassemia - cellular damage

lipid peroxidation, loss of deformability, loss of lipid asymmetry

thalassemia - ineffective erythropoiesis

RBC precursors die due to intracellular toxcity

indications of stem cell transplants

transfusion-dependent beta thalassemia major, transfusion-dependent HbE/beta-thal, severe alpha thalassemia (surviving Hb bart’s hydrops)

hemoglobinopathies - what is it

inherited disorders from production of abnormal globin chains

hemoglobinopathies - abnormal globins

differ in structure & function

hemoglobinopathies - results from

point mutation in globin gene

HbS - beta or alpha variant

beta

HbS - AA change

glutamic acid → valine

HbS - clinical note

found in africans → sickel cell anemia

HbS - codon mutation

6

HbE - AA change

glutamic acid → lysine

HbE - beta or alpha variant

beta

HbE - codon mutation

26

HbE - blood smear

mild chromatic hemolytic anemia, target cells

HbE - activates what

cryptic splice site → reduce mRNA

Hb constant spring - codon mutation

142

Hb constant spring - AA change

stop codon (UAA) → glutamine

HbC - beta or alpha variant

beta

HbC - AA change

glutamic acid → lysine

HbC - codon mutation

6

HbC - blood smear

mild chronic hemolytic anemia, crystals, target cells