- gamma (γ): two types of y chains produced (differ in the 136th position)

1. G gamma (Gγ) 2. A gamma (Aγ)

THALASSEMIA Flashcards by Arriane Cyrel (MTI)

▪ results of impaired (deficient) globin chain synthesis

THALASSEMIA

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▪ may affect either the alpha or beta chain synthesis

THALASSEMIA

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THALASSEMIA ▪ diverse group of genetic disorders due to:

a. quantitative reduction in globin chain synthesis for hemoglobin

b. formation of structurally abnormal hemoglobins formed from normal globin chains or parts of normal chains

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a. quantitative reduction in globin chain synthesis for hemoglobin

• alpha (a)
• beta (ß)
• gamma (y)
• delta (δ)

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b. formation of structurally abnormal hemoglobins formed from normal globin chains or parts of normal chains

• Hb H (ß4)
• Hb Barts (y4)
• Hb Lepore
• Hb Constant Spring (presents with a thalassemic clinical picture)

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▪ decreased or non-existent production of one or more globin chain type

THALASSEMIA

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• most common thalassemias:

α-thalassemia: ↓ α-chain(s)
ß-thalassemia: ↓ ß-chain(s)

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▪ human hemoglobin may contain any of seven different globin polypeptide chains

alpha (α)
beta (ß)
G gamma (G γ)
A gamma (A γ)
delta (δ)
epsilon (ɛ)
zeta (ζ)

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▪ globin rearrangement usually occurs in:

• chromosome 11

• chromosome 16

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• chromosome 11:

beta (ß)
gamma (γ)

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• chromosome 16:

alpha (α)
zeta (ζ)

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gamma (γ): two types of y chains produced (differ in the 136th position)

G gamma (Gγ)
A gamma (Aγ)

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amino acid: glycine

G gamma (Gγ)

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amino acid: alanine

A gamma (Aγ)

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delta (δ) - epsilon (ɛ)

A gamma (Aγ)

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141

alpha

zeta

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unknown

theta

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146

beta

delta

gamma

epsilon

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4; Ch 16

alpha

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2; Ch 11

beta

delta

gamma

epsilon

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2; Ch 16

zeta

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double

alpha

gamma

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single

beta

delta

epsilon

zeta

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: embryonic chains

*Epsilon and zeta

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: embryonic counterpart of alpha

*Zeta

: embryonic counterpart of beta, delta, and gamma

*Epsilon

▪ 1 globin

GLOBIN STRUCTURE

▪ protein portion composed of 2 sets (dimer) of 2 different polypeptide chains

GLOBIN STRUCTURE

▪ determines the type of hemoglobin

GLOBIN STRUCTURE

2 ζ 2 ɛ

Gower I

embryonic Hbs

Gower I Gower II Portland 2

2 α 2 ɛ

Gower II

ζ 2 γ

Portland 2

2 α 2 γ

Fetal (Hb F)

2 α 2 ß

major Hb A1

A2 2 α 2 δ

minor Hb

newborns and adults

Fetal (Hb F) major Hb A1 minor Hb A2

Hemoglobin concentrations in adults

major Hb A1: 92-95% Hb A2: 2-3% Hb F: 1-2%

• most potential Hb incorporated on RBCs to transport oxygen to the tissues

major Hb A1: 92-95%

• compensation in cases of abnormalities affecting Hb A1

Hb A2: 2-3%

▪ [?] anemia

microcytic and hypochromic

▪ RBC count:

elevated (↑)

▪ abnormalities:

• nucleated RBCs • microcytosis • hypochromia • anisocytosis • poikilocytosis • polychromasia • basophilic stippling • target cells (predominant) • leukocytes and platelets

- variations in the shades of cell colors

• polychromasia

- caused by a combination of the affinity of hemoglobin ribosomal RNA

• polychromasia

(predominant)

• target cells

: not affected- display of diffused bluish-gray tint of RBCs

• leukocytes and platelets

▪ concurrent iron deficiency in thalassemia causes:

• lower concentrations of Hb A2 and Hb H • lower serum iron and iron stores

- may mask diagnosis of heterozygous ß thalassemia and Hb H disease, respectively

• lower concentrations of Hb A2 and Hb H

- Hb H inclusions may be more difficult to detect in red cells

• lower concentrations of Hb A2 and Hb H

▪ diagnosis: in cases of iron deficient individuals, [?] should first be repleted before performing diagnostic tests for thalassemia

iron deficient iron stores

▪ on the short arm of chromosome 16

1. ALPHA GENES

: 4 genes (2 genes each inherited from parents)

▪ (αα/αα)

• 2 copies of α-globin gene per chromatid =

4 genes per diploid cell (αα/αα)

▪ nomenclature:

• 1 gene deletion: -α • 2 gene deletion: (--) • 3 gene deletion: --/-α or α-/-- • 4 gene deletion: --/-- • non-functional α-genes: present but nonfunctional hence do not code for globin synthesis (partially suppressed gene)

• 1 gene deletion:

-α

• 2 gene deletion:

(--)

• 3 gene deletion:

--/-α or α-/--

• 4 gene deletion:

--/--

: present but nonfunctional hence do not code for globin synthesis (partially suppressed gene)

• non-functional α-genes

• non-functional α-genes:

- + superscript (+ ) - example: αα+

: -α - α-thalassemia 2 or α+ thalassemia

• 1 gene deletion

- αα/-α or α-/αα

• 1 gene deletion

: (--) - α-thalassemia 1 or αo thalassemia

• 2 gene deletion

- homozygous:

αα/-- or --/αα

- heterozygous (1 α-gene deleted per parent):

α-/α- or -α/-α

▪ deficiency in the synthesis of alpha-globin chains

ALPHA THALASSEMIA

▪ each individual has two sets of two alpha genes

ALPHA THALASSEMIA

▪ usual mechanism of suppression: gene deletion

ALPHA THALASSEMIA

• causes suppression of all four genes leading to complete suppression of alpha chain synthesis

gene deletion

• 2 haplotypes:

1. one gene deletion: α-thalassemia 2 or α+ thalassemia 2. double gene deletion: αthalassemia 1 or αo thalassemia (more severe)

: α-thalassemia 2 or α+ thalassemia

1. one gene deletion

: αthalassemia 1 or αo thalassemia (more severe)

2. double gene deletion

Alpha Thalassemia Variants

1. Silent carrier/α-Thalassemia minor 2. α-Thalassemia trait/α-Thalassemia minor 3. Hb H Disease 4. Bart’s Hydrops fetalis (Hb Barts)

▪ 1/4 α-gene deleted

1. Silent carrier/α-Thalassemia minor

▪ heterozygous: α-/αα (α+ )

1. Silent carrier/α-Thalassemia minor

▪ remaining 3 α-genes are still able to regulate the synthesis of normal amounts of α-chains

1. Silent carrier/α-Thalassemia minor

▪ no signs and symptoms observed

1. Silent carrier/α-Thalassemia minor

▪ 2/4 α-genes deleted

2. α-Thalassemia trait/α-Thalassemia minor

2. α-Thalassemia trait/α-Thalassemia minor ▪ genotypes:

• homozygous: αα/-- or --/αα • heterozygous: α-/α- (1 gene deleted per parent)

▪ can still synthesize α-chains but insufficient

2. α-Thalassemia trait/α-Thalassemia minor

▪ MILD signs and symptoms

2. α-Thalassemia trait/α-Thalassemia minor

▪ 3/4 α-genes deleted

3. Hb H Disease

• α 0 / α+ (--/-a)

3. Hb H Disease

▪ remaining 1 gene is unable to dictate the synthesis of the required concentration of α-chain

3. Hb H Disease

▪ ↓ α-chain = ↑ ß-chain → tetramer ß4 of hemoglobin

3. Hb H Disease

• 1 Hb consists of 4 ß-chains

▪ Hb H

• unstable

▪ Hb H

• leads to formation of Heinz bodies which makes RBCs become rigid and destroyed by spleen

▪ Hb H

: supravitally stained with brilliant cresyl blue (BCB)

Heinz bodies

• phenotype similar to Hb H disease

▪ Hb H-Constant Spring Disease (Hb H/CS)

- inheritance of Hb CS causes a deficit in normal α chains, and when it is inherited along with a double a-gene deletion, it produces a disorder similar to Hb H disease

▪ Hb H-Constant Spring Disease (Hb H/CS)

• caused by compound heterozygous inheritance of Hb Constant Spring (Hb CS) and α 0 thalassemia (--/α CSα)

▪ Hb H-Constant Spring Disease (Hb H/CS)

• more severe hemolysis than in the typical threeα gene deletion Hb H disease

▪ Hb H-Constant Spring Disease (Hb H/CS)

▪ 4/4 α-genes deleted (--/--) (α0 )

4. Bart’s Hydrops fetalis (Hb Barts)

▪ no synthesis of α-chains resulting in the production of Hb Barts (tetramer γ4)

4. Bart’s Hydrops fetalis (Hb Barts)

: x α-chains

• Hb F

↑ γ-chains

• Hb F

: has a high affinity for oxygen and thus will not effectively release it to the tissues (no oxygen delivered)

• Hb Barts

- suffers still-birth

• fetus

- does not survive (dies inside the uterus)

• fetus:

: swollen (enlarged) head

- hydrops fetalis

▪ can be manifested in as early as the fetal life

4. Bart’s Hydrops fetalis (Hb Barts)

• no synthesis of Hb A and Hb F

4. Bart’s Hydrops fetalis (Hb Barts)

Classifications of Alpha Thalassemia

One-gene deletion (αα/α) Two gene deletion (-α/α; αα/--) Three-gene deletion (-α/-)

Silent Carrier/ α-Thal minor

One-gene deletion (αα/α)

▪ hematology: normal with few target cells and elliptocyte

One-gene deletion (αα/α)

▪ asymptomatic

One-gene deletion (αα/α) Two gene deletion (-α/α; αα/--)

AlphaThalasse mia Trait/ αThal minor

Two gene deletion (-α/α; αα/--)

▪ mild anemia

Two gene deletion (-α/α; αα/--)

▪ microcytic hypochromic

Two gene deletion (-α/α; αα/--) Three-gene deletion (-α/-)

▪ elliptocytes

Two gene deletion (-α/α; αα/--)

▪ target cells

Two gene deletion (-α/α; αα/--)

▪ Hb A (60%)

Two gene deletion (-α/α; αα/--)

▪ Hb Barts (5- 10%)

Two gene deletion (-α/α; αα/--)

Hb H Disease

Three-gene deletion (-α/-)

▪ Hb H inclusions (Heinz bodies)

Three-gene deletion (-α/-)

▪ high retics

Three-gene deletion (-α/-)

▪ 30% Hb H (ß4) – precipitated into Heinz bodies

Three-gene deletion (-α/-)

▪ Constant Spring disease (Hb H/CS)

Three-gene deletion (-α/-)

– precipitated into Heinz bodies

▪ 30% Hb H (ß4)

• 6% Hb Barts

α-Thal minor (one & two gene deletion)

- asymptomatic (accidentally discovered) in adults (not diagnostic)

α-Thal minor (one & two gene deletion)

- considered diagnostic in newborns

α-Thal minor (one & two gene deletion)

▪ short arm of chromosome 11

2. BETA GENES

▪ one copy per chromatid

2. BETA GENES

• total: 2 ß-genes per diploid cell

2. BETA GENES

• ß/ß

2. BETA GENES

: gene cannot fully synthesize required number of ß-chains (decreased production but not fully deficit)

▪ + superscript (+ )

: deleted gene (no production)

▪ 0 superscript (0 )

: reduced ß-chain production

▪ ß +

: no ß-chain production

▪ ß 0

: δ and ß-gene deletion

▪ (δß)0

: Hb Lepore designation

▪ (δß)Lepore

• nonhomologous meiotic crossing over between δ and ß globin genes (exchanging of genetic material or traits) on chromosome 11

▪ (δß)Lepore

▪ unbalanced globin chain synthesis due to a lack of, or to the reduced production of, ß chains

BETA THALASSEMIA

• causes an excess of α chains (very unstable)

BETA THALASSEMIA

- normally, production of α and ß chains should be proportionate (equal production for them to be paired -- Hb A1)

BETA THALASSEMIA

BETA THALASSEMIA • minor imbalance:

unpaired α chains are simply removed by proteolysis during erythroid maturation

BETA THALASSEMIA • major imbalance:

overwhelmed/massive number of unpaired α chains (excess free α chains) precipitate (results to Heinz bodies), causing severe erythrocyte dysfunction (rigid RBCs)

- defective red cells are destroyed by bone marrow macrophages causing ineffective erythropoiesis and a massively enlarged erythron

BETA THALASSEMIA

▪ characterized by a deficiency in Beta-globin chain synthesis

BETA THALASSEMIA

▪ each individual has one set of two beta genes

BETA THALASSEMIA

▪ suppression or absence of these beta genes results to deficient beta chain synthesis

BETA THALASSEMIA

Classifications of Beta Thalassemia

ß-Thal Minor/Trait (Cooley’s Trait) ß-Thal Intermedia ß-Thal Major (Cooley’s Anemia)

ß 0 /ß0

ß-Thal Major (Cooley’s Anemia)

severe

ß-Thal Major (Cooley’s Anemia)

ß/ß+ or ß/ß0

ß-Thal Minor/Trait (Cooley’s Trait)

silent

ß-Thal Minor/Trait (Cooley’s Trait)

ß + /ß+ or ß+ /ß0

ß-Thal Intermedia

moderate

ß -Thal Intermedia

▪ 1/2 normal ß-gene: still able to synthesize at least enough ß-chains

ß-Thalassemia Minor/Cooley’s Trait (ßO /ß)

• other ß-gene: either deleted or suppressed

ß-Thalassemia Minor/Cooley’s Trait (ßO /ß)

▪ still able to produce sufficient quantities of HbA1

ß-Thalassemia Minor/Cooley’s Trait (ßO /ß)

▪ hemoglobin levels: slightly low

ß-Thalassemia Minor/Cooley’s Trait (ßO /ß)

ß-Thalassemia Minor/Cooley’s Trait (ßO /ß) ▪ blood smear:

• shows similar morphology as in Thalassemia Major or Intermedia • mild microcytic-hypochromic anemia • basophilic stippling • target cells

ß-Thalassemia Minor/Cooley’s Trait (ßO /ß) ▪ Hb F level: ▪ Hb A2 level: ▪ Hb A1 level:

▪ Hb F level: 2-3% ▪ Hb A2 level: elevated ▪ Hb A1 level: decreased

▪ caused by a partial suppression of the Beta genes

ß-Thalassemia Intermedia (ß+ /ß+ )

▪ lesser production of Hb A1

ß-Thalassemia Intermedia (ß+ /ß+ )

▪ symptoms are similar with that of Beta Thalassemia major, but depend on the extent of gene suppression

ß-Thalassemia Intermedia (ß+ /ß+ )

▪ milder than Beta Thalassemia major

ß-Thalassemia Intermedia (ß+ /ß+ )

ß-Thalassemia Intermedia (ß+ /ß+ ) ▪ genotypes:

• homozygous: ß + /ß+ • heterozygous: ß + /ß0

▪ complete lack of Beta globin production