Rbc disorders-5

Thalassemia Syndromes

Dr.CSBR.Prasad, M.D.,

• They are QUANTITATIVE defects in globin chain synthesis

• Heme synthesis is normal

Thalassemias

Porphyrias

Name some diseases involving heme synthesis?

Cooley’s anemia

Usual types of HGBs in adults

• Different types of HGBs seen in adults

– Hb A (α2 β2) (97%)

– Hb A2 (α2 δ2) (1.5-3.5%)

– Hb F (α2 γ2) (<1%)

Fetal hemoglobin - HbF

• The main oxygen transport protein in the fetus during the last seven months of development in the uterus and

• After birth HBF levels gradually fall reaching adult levels by the age of 6-9 months

Oxygen dissociation curve

Facial abnormalities

Organomegaly

Hemoglobin

• HbA (α2β2)

• FOUR α-globin genes on chr 16

• TWO β-globin gene on chr 11

Globin genes

Thalassemia

• Inherited genetic disorder of globin chain synthesis of HbA (α2β2)

• AR

• Decreased synthesis may involve α or β globin chain

α-Thalassemias [↓ α-chain]

β-Thalassemias [↓ β-chain]

Normal HGB

• Hb A - α2β2

• α : β = 1:1 (+/- 0.05)

• Disproportionate synthesis is associated with relative excesses of the other

Figure 1. The two chromosomes #11 have one beta globin gene each (for a total of two genes). The two chromsomes #16 have two

alpha globin genes each (for a total of four genes).

Hemoglobin protein has two alpha subunits and two beta subunits. Each alpha globin

gene produces only about half the quantity of protein of a

single beta globin gene. This keeps the production of protein subunits equal.

Thalassemia occurs when a globin gene fails, and the

production of globin protein subunits is thrown out of

balance.

Thalassemia

• Low HGB levels

• Relative excess of unimpaired chains form insoluble inclusions Hemolysis

β-Thalassemia

β-Thalassemia

• ↓ Synthesis of structurally normal β globin chain with unimpaired synthesis of α globin chain

• β globin chain is coded by two globin genes located on Ch 11

• α globin chain is coded by two pairs of globin genes located on Ch 16

β-Thalassemia

• β0 Thalassemia – Total absence of β globin chain in homozygous state

• β+ Thalassemia – reduced β globin chain synthesis in homozygous state

β-Thalassemia

• More than 100 different causative MUTATIONS • Point mutations – most common • Promoter region mutations

– Reduces transcription rate by 75-80% - Β+ Thalassemia

• Chain terminator mutation – Premature chain termination - Β0Thalassemia

• Splicing mutation – More common cause of Β+ Thalassemia

β-Thalassemia

• Thalassemia major – Homozygous for β-Thalassemia genes – Genotype β0 / β0 or β+ / β+

– Severe tranfusion dependent anemia

• Thalassemia minor – Heterozygous with one thalassemia gene and one normal

gene β0 / β or β+ / β

• Thalassemia intermedia – Genetically heterogenous group with milder variant of β0 /

β0 or β+ / β+ and severe form of heterozygous thalassemia β0 / β or β+ / β

Thalassemia major

• Mediterranean, Africa and south east Asia • Manifest 6-9 months after birth • Hb – 3-6 gm/dl • PBS

– Anisocytosis - microcytes, – poikilocytosis, target cells, basophilic stippling, fragmented

RBC, NRBCs – Reticulocytosis – ↑ ↑ Hb F – Hb A2 - N, ↑, ↓

Transfusion dependent anemia

Hereditary - AR

Microcytic hypochromic RBCs

Target cells

NRBs and Punctate basophilia

Thalassemia major

• Morphology

• Bone marrow hyperplasia – “CREW CUT” appearance on skull X ray

• Splenomegaly – upto 1500 gms

• Hemosiderosis and secondary hemochromatosis – due to repeated blood transfusion and ↑ absorption of dietary iron – affects heart, liver and pancreas

• Early death in untreated cases

“CREW CUT” appearance

on skull X ray

Thalassemia minor

• More common

• Heterogenous carrier of β0 or β+ gene

• Asymptomatic / mild anemia

• PBS – Microcytic hypochromic RBCs, basophilic stippling

• ↑ Hb A2 ; 4-8% (N 2.5%)

• DD – Iron deficiency anemia

α Thalassemia

Demographics: Thalassemia

• Found most

frequently in the

Mediterranean, Africa,

Western and

Southeast Asia, India

and Burma

• Distribution parallels

that of Plasmodium

falciparum

Classification & Terminology

Alpha Thalassemia

• Terminology

• Silent carrier

• Minima

• Minor

• Intermedia

• Major

Symbolism Alpha Thalassemia

• Greek letter used to designate globin

chain:


/ : 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


- : Indicates a gene deletion:

-/


Alpha Thalassemia

• Normal /

• Silent carrier - /

• Minor -/-

--/

• Hb H disease --/-

• Barts hydrops fetalis --/--

Symbolism Other Thalassemia

• Greek letter used to designate globin

chain:


+: Indicates diminished, but some

production of globin chain by gene:

+


0 :Indicates no production of globin chain by

gene:

0


Superscript T denotes nonfunctioning gene:

T


Beta Thalassemia

• Normal /

• Minor /0

/+

• Intermedia 0/+

• Major 0/0

+/+

Special Cases Thalassemia

• Hb Lepore: fusion seen in some types

of thalassemia

• Hb Constant Spring

• chain with 31 additional amino acids

• --/cs

• Hereditary persistence of fetal hemoglobin

(HPFH)

Special Cases: Thalassemia

• Hb H

• 4 tetramer

• Associated with --/- thalassemia

Special Cases: Thalassemia

• Hb Barts & hydrops fetalis

• Barts is a 4 tetramer

• Associated with --/--

• Lethal

• High concentrations are capable of sickling

Different types of HGBs seen in adults

• Hb A (α2 β2) 97%

• Hb A2 (α2 δ2) (1.5-3.5%)

• Hb F (α2 γ2) <1%

• Adult HbH (β4)

• Neonate Barts (γ4)

α Thalassemia

• Reduced or absent synthesis of α globin chains

• Excess of non α chain –ß, γ, δ

– Hb A (α2 β2)

– Hb A2 (α2 δ2)

– Hb F (α2 γ2)

α Thalassemia

• New born – formation of γ4 tetramer – Hb Barts

• Adults – ß4 tetramer – HbH

• Free ß, & γ chains are more soluble than α chains – hemolysis is less severe

α Thalassemia

• Sevearity varies depending on number of α globin genes affected

• DELETION of α- globin genes are more common

• Hydrops fetalis -/- -/-

• HbH disease -/- -/ α

• α Thalassemia trait -/- α/ α (asian)

-/ α -/ α ( black african) • Silent carrier -/ α α/ α

Figure 3. People of Asian ancestry often have two alpha globin genes deleted on the same chromosome #16. The parents each

have the mild thalassemia that results with two functioning alpha globin genes. The

offspring that inherits the double deletion from one parent and the single from the

other will have Hemoglobin H disease (Scenario 1). The offspring who inherits no alpha genes from the parents dies in utero

(Scenario 2; hydrops fetalis).

Figure 4. People of African ancestry usually

have only one alpha globin gene deleted per

chromosome. The parents each have the mild thalassemia that

results with two functioning alpha globin genes. The

offspring can, at most, inherit the relatively mild condition of the

parents.

Hb H disease

• Tetramer of β globin chain

• High affinity for oxygen

• Unstable HbH form precipitates

• Resemble β-Thalassemia intermedia

HBH inclusions

HPLC pattern of a patient with HbH disease. The peaks of the different hemoglobins are indicated

Hydrops fetalis

• Hb barts – tetramer of γ globin chains

• ζ2 γ2 -Severe tissue anoxia

• Pallor, generalised edema, massive hepatosplenomegaly

• High mortality

Hydrops fetalis

Other causes for Hydrops fetalis

• Rh incompatibility

• Hypoplastic left heart syndrome

Common mechanism

• Alfa thal- Deletion

• Beta thal – Mutation

Gamma gene can be induced to function by some drugs

• What is the clinical implication of this finding?

END

Dr.CSBR.Prasad, M.D.,

Associate Professor of Pathology,

Sri Devaraj Urs Medical College,

Kolar-563101,

Karnataka,

INDIA.

[email protected]

Documents

Rbc disorders-5