hemoglobinopathies thalassemia

HEMOGLOBINOPATHIES

ThalassemiasDr Vijay Shankar S

Definition Clinical diseases that result from a

genetically determined abnormality of the STRUCTURE or SYNTHESIS of the hemoglobin molecule.

The abnormality is associated with the globin chains

The heme portion of the molecule is normal.

GLOBIN ABNORMALITY

QUALITATIVE QUANTITATIVE

• Occurs as a result of genetic mutations involving globin protein chain

• Aminoacid deletions or substitutions

• These mutations cause structural variations of the globin chains

• Hb S, Hb C, Hb M etc..

• Occurs as a result of genetic defects that cause reduced synthesis of globin chains

• The globin chains are structurally normal.

• Collectively known as THALASSEMIAS

What is thalassemia?

Thalassemia is a group of inherited disorders of hemoglobin synthesis characterized by a reduced or absent output of one or more of the globin chains of adult hemoglobin .

The name is derived from the Greek words Thalasso = Sea" and "Hemia = Blood" in reference to anemia of the sea.

Type of Hemoglobin Hb A Hb A2 Hb F Hb H Hb Bart’s

α2β2

α2δ2

α2γ2

β4

γ4

Demographics: Thalassemia• Found most

frequently in the Mediterranean, Africa, Western and Southeast Asia, India and Burma

• Distribution parallels that of Plasmodium falciparum

Types of Thalassemia

thalassemia: There are four types categorized according to the severity of their effects on persons with thalassemia.

ß thalassemia: There are 3 types categorized according to severity: Thalassemia minor Thalassemia intermedia Thalassemia major

Alpha ( ) thalassemia

It appears when an individual do not produce enough alpha chains for hemoglobin.

It is mainly prevalent in the Africa,

the Middle East , India, and occasionally in Mediterranean region countries.

Beta (ß) thalassemia

It appears when an individual does not produce enough beta chains for hemoglobin.

It is mainly prevalent in the Mediterranean region countries , such as Greece, Cyprus, Italy, Palestine and Lebanon.

Classification & TerminologyAlpha Thalassemia

• Terminology• Silent carrier• Minima• Minor• Intermedia• Major

SymbolismAlpha Thalassemia

• Greek letter used to designate globin chain:

SymbolismAlpha Thalassemia

/ : Indicates division between genes inherited from both parents:

/

• Each chromosome 16 carries 2 genes. Therefore the total complement of genes in an individual is 4

SymbolismAlpha Thalassemia

- : Indicates a gene deletion:

-/

Classification & TerminologyAlpha Thalassemia

• Normal / • Silent carrier - / • Minor -/-

--/• Hb H disease --/-• Barts hydrops fetalis --/--

SymbolismOther Thalassemia

• Greek letter used to designate globin chain:

SymbolismOther Thalassemia

0 :Indicates no production of globin chain by gene:

0

SymbolismOther Thalassemia

+ :Indicates reduced but detectable production of globin chain by gene:

+

SymbolismOther Thalassemia

Superscript T denotes nonfunctioning gene:

T

Classification & Terminology Beta Thalassemia

• Normal /• Minor /0

/+

• Intermedia 0/+

• Major 0/0

+/+

Genetics of ß thalassemia

Monogenic disorder: a single gene disorder

ß thalassemia result from mutations of the ß globin gene that result in the absence or a decrease in the ß globin chains

Transmission of ß thalassemia

- If a carrier (thalassemia minor) marries a non-carrier, on average half of their children will be carriers, but none will develop thalassemia major.

-However if two carriers marry, in each pregnancy there is a 25% chance of a non-carrier child, a 50% chance of a carrier child (thalassemia minor), and a 25% chance of a child with thalassemia major.

Thalassemia Major (Cooley's Anemia).

Caused by the unavailability of beta chains in hemoglobin leading to a very severe and fatal if left untreated anemia.

It requires regular blood transfusions leading to iron-overload which is treated with chelation therapy to prevent death from organ failure.

In ß-thalassemia point mutations or a partial deletions of chromosome 11 cause defective synthesis of the ß chain. Over 100 mutations have been identified.

Mutations in the promoter affect transcription. Mutations in the coding regions, splice sites, or termination codons affect RNA processing and translation.

Normally a and b globin chains are made in roughly equal amounts.

When ß-globin chains are in short supply or absent, as in ß-thalassemia, a-chains are in excess. The excess a-chains combine with other available ß-family globin chains ( d or g) to form increased amounts of Hgb A2 (a2 d2) and Hgb F (a2 g 2).

Hgb Barts ( g 4) or tetramers of excess gamma chains may also form.

CLINICAL FEATURES

Clinical manifestations are not seenuntil about six months of life when

globin production would normally change from predominantly g -chain to ß-chain

ß-thalassemia major patients have severe, transfusion dependent anemia. Nearly all patients have hepatomegaly and splenomegaly.

Expansion of the marrow by erythroid hyperplasia causes enlargement of bones. The life span of patients with ß-thalassemia major is short, most dying before adulthood.

Ironover load, secondary to transfusion dependency, results in damage to the heart, liver and endocrine organs.

Skull bossing due to expansion of the diploe ( red bone marrow in the skull)

Laboratory findings Anemia , usually severe

PBS shows severe anisocytosis and poikilocytosis,many microcytes, targets, elliptocytes, teardrops, and NRBCs.

Serum bilirubin is raised.

reticulocytosis present

MCV, MCHC & MCH reduced.

Osmotic fragility : shows increased resistance to saline hemolysis.

OSMOTIC FRAGILITY IS DECREASED

HEMOGLOBIN ELECTROPHORESIS

Increased amounts of HbF

Increased amounts of HbA2

Complete absence or presence of variable amounts of HbA

Skull X ray - Hair on end appeareance

ß-Thalassemia Trait /0 /+

In ß-thalassemia trait (aka ß-thalassemia minor) defective ß-chain synthesis results in mildly reduced production of ß+ chains

The RBCs are microcytic and hypochromic; often with associated erythrocytosis. The anemia is usually mild.

High Hemoglobin A2 levels are classic for ß-thalassemia trait. Hemoglobin F levels are mildly increased.

People with ß-thalassemia trait are heterozygous for either ß o or for ß+.

If both parents have ß--thalassemia trait their offspring have a 25% chance of being normal; a 50% chance of having ß-thalassemia trait; and a 25% chance of having ß-thalassemia major.

In thalassemia minor, the severity of disease expression may only be seen as mild anemia and a microcytic state.

It thus may be difficult to distinguish from iron deficiency.

Differentiating features include the following: Thalassemias are more apt to demonstrate reticulocytosis and basophilic stippling in the peripheral blood.

ß-Thalassemia Intermedia 0/+

In ß-thalassemia intermedia ß+ chains are made in amounts intermediate to the major and minor forms.

Summary

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