Thalassemia

Thalassemia
Heterogenous group of inherited disorders,
characterized by diminished synthesis of
structurally normal globin chains.
Decreased chains thalassemia ;
chains thalassemia
Other uncommon variants: ,, ,
thalassemias

Thalassemia
Traditionally considered as a quantitative
abnormality of hemoglobin synthesis.
However may be a/w mutations resulting
in production of structural variants(Hb
Lepore ,Hb E) or hyperunstable Hb
variants with thalassemic phenotype
(thalassemic hemoglobinopathy)
Both beta and alpha thalassemia may
occur in a/w structural variants

 Imbalance between the synthesis of globin

chains leads to
Ineffective erythropoeisis (intramedullary
destruction of RBC precursors)

Hemolysis (peripheral destruction of cells)

Reduced production of Hb tetramers leads

to hypochromia and microcytosis

 Clinical severity depeds upon

The degree to which globin chain synthesis is
impaired
Altered synthesis of other globin chains
Co-inheritance of other abnormal globin
alleles

Homozygotes for B thal

Beta
Heterozygotes
for B thal

alpha
Alpha thal

Beta
Imbalance
Balance

HPFH

Balance

alpha
Imbalance

Excess alpha chains

Unstable
Hb

Hb A tetramer

globin

globin

globin

globin

 Thalassemia
First described by Thomas Cooley in 1925.
a.k.a Cooleys anemia, Mediterranean anemia.

Diminished synthesis of normal -globin chains

Unimpaired synthesis of chains

 Thalassemia molecular
pathogenesis

Single gene on ch 11.

0 thal : total absence of chain
+ thal : reduced chain synthesis
Single gene/both genes may be
affected

Mutations
Any step in the pathway of globin chain
expression may be affected
Transcription defects
M-RNA processing defects
Translational defects
Post translational modification of the beta
globin poplypeptide chain

Mutations:
PROMOTER REGION
Point mutation
Prevents RNA polymerase
binding
75% in transcription
+ thal

CHAIN TERMINATOR
Premature termination of mRNA
translation
1) Creation of new stop codon within an
exon
2) Frame shift mutations
Globin not synthesized
0 thal

SPLICING (COMMONEST)
Introns / Exons : 2 types
Ectopic splice junction
In introns
Abnormal splice junctions :
Normal and abn splicing occurs
Unspliced mRNA degraded in nucleus Normal and abn globins
0 thal
produced
+ thal

 Thalassemia
-pathogenesis

Crew cut appearance on x-ray

 Thalassemia major - course

Chronic hemolysis
Insidious anemia in I yr of life
Hepatosplenomegaly by 3 years
Iron overload with repurcussions on organ systems
Hepatosplenomegaly , prominent cheek bones
(Mongoloid facies), cardiac disease CCF, 2dary
hemochromatosis
Untreated children growth retardation, die of
anemia
Transfusion dependant improves anemia
BMT/gene therapy

Lab diagnosis

Hb : 3-6gm/dl,
RBC count : Normal / increased
RBC Indices :
MCV,MCH,MCHC
PS : RBC :
Marked anisopoikilocytosis, MCHC
Target cells
Basophilic stippling
nRBCs +
Fragmented RBCs
WBC : Slight shift to left,
Platelets : Normal
Reticulocyte count :
URINE
Dark Brown
Hemosiderinuria

Lab diagnosis
BM :
Hypercellular ,
Erythoid : :

Micronormoblast :

Very little cytoplasm,

Uneven cytoplasmic membranes,

Basophilic stippling
chain inclusions in normoblasts
Iron stores
Osmotic Fragility :
Alkali denaturation test
Globin chain synthesis analysis
Beta globin gene analysis
Prenatal diagnosis :

DNA by Chorionic Villous Biopsy/

amniocentesis
Biochemistry :

Haptoglobin, Hemopexin :

Bilirubin, Iron, Ferritin, Uric acid :

HPLC/Hb electrophoresis

00
HbA : Nil
HbF : >90%,
HbA2 : N/

+ +
HbA : >50%,
HbA2 : 2.5 %,
HbF : 20-40%

Disorder

HbA

HbA2

HbF

Beta thal minor

90-95

3.5-7

1-5

Beta thal major

(+)

10-90

1.5-4

10-90

Beta thal major

(0)

1.5-4

98

HPFH

60-85

1-2

15-35

PS:

PS:

 Thalassemia minor

More common
Heterozygous , protection from falciparum malaria
Asymptomatic
Anemia mild
PS same, lesser degree, BM- mild hyperplasia
Hb A2 (N- 2.5%), Hb F N/ slight

Recognition is imp :1. IDA, 2. genetic counseling

 Thalassemia
Reduced or absent synthesis of chains
4 -globin genes (ch 16), severity depends on
no. of genes affected
Children : 4 tetramer forms Hb barts,
Adults : 4 tetramer forms HbH (fast Hb)
Free & chains more soluble than free
chains hence IE is less severe than in thal

Clinical & genetic classification of

-Thalassemias

 Thalassemia
thal trait : / -/- (Asian) or /- /- (African);
III to thal minor,
/ -/- : can result in progeny with HbH or Hydrops
fetalis
Hb H disease : Deletion of 3 globulin genes. Increased 02 affinity hypoxia, prone for oxidation
inclusions by vital stains, III to thal inter.
Hydrops fetalis : Deletion of all 4 globulin genes.
Most severe form, Hb barts having 02 affinity ,
fetus : severe pallor, generalised edema, massive
hepatosplenomegaly

Hb H Prep with thalassemia

Brilliant cresylHydrops
blue
fetalis

MCV >78 fl
MCH >27pg

MCV <78 fl
MCH <27pg

HbA2 <3%
HbF <1.5%

HbA2 <3.5%
HbF <1.5%

Normal

MCV <78 fl
MCH <27pg
HbA2 > 3.5%
HbF 1-5%

Iron Deff Alpha-thal

Anemia
Alpha-beta-trait
Beta-thal
carier

MCV <<78 fl
MCH <<27pg
HbA2 <3%
HbF 5-20%%

DeltaBeta-thal
HPFH

???