Hereditary Hemolytic Anemia

Where is the alpha globin gene cluster located?

On chromosome 16 (16p13.3)

What is the function of the zeta (ζ) globin gene?

It is an embryonic globin gene that substitutes for alpha-globin very early in development.

When is zeta globin expressed?

During the embryonic stage, specifically in the yolk sac phase (~first 6–8 weeks of gestation).

Which embryonic hemoglobin includes zeta globin?

Hemoglobin Gower I (ζ₂ε₂)

How many alpha globin genes does each person typically have?

Four total (two HBA1 and two HBA2—one set from each chromosome 16)

How are the alpha globin genes arranged on chromosome 16?

HBA1 and HBA2 are aligned one after the other in tandem.

What proportion of alpha-globin chains is produced by each alpha gene?

Each gene contributes approximately 25% of the total alpha-globin chain production.

On which chromosome is the beta globin gene cluster located?

Chromosome 11

What is the sequence of genes in the beta globin cluster (from 5’ to 3’)?

Epsilon (ε), Gamma (Gγ and Aγ), Delta (δ), Beta (β)

Which gene in the beta cluster is expressed during embryonic development?

Epsilon (ε) globin

When is epsilon globin expressed?

During early embryonic development (approximately the first 12 weeks after conception)

Which gene is primarily expressed during fetal development?

Gamma (γ) globin

What type of hemoglobin does gamma globin form during fetal life?

Hemoglobin F (HbF), composed of α₂γ₂

Which gene in the beta cluster produces a small amount of globin in children and adults?

Delta (δ) globin

What hemoglobin is formed with delta globin?

Hemoglobin A₂ (HbA₂), composed of α₂δ₂

Which gene in the beta cluster is most active in adults?

Beta (β) globin, forming HbA (α₂β₂)

Embryonic hemoglobin

1st : zeta(2), epsilon(2)

2nd : alpha(2), gamma (2)

3rd : alpha (2), gamma (2)

Fetal hemoglobin

alpha(2),gamma(2)

Adult hemoglobin

Hemoglobin A :

alpha(2), beta(2)

Hemoglobin A2:

alpha(2), delta(2)

Human adult Hemoglobin coded by

Pathpopgenetic classification of anemia

-Decreased production

- Increased loss/ destruction

Decreased production

Nutrient deficiency

▪ Iron deficincy / megaloblastic

Hemopoietic cell defect:

▪ Anemia of chronic disorders

▪ Aplastic anemia

Increased loss/ destruction

▪ Blood loss anemia: acute/chronic bleeding

▪ Hemolytic anemia: congenital/acquired

congenital hemolytic anemia includes

Defective Hemoglobin: Thalassemia and Sickle cell

Defective Membrane: Spherocytosis

Deficient Enzyme: G6PD deficiency enzyme

Thalassemia

 Inherited genetic disorder that results in reduced rate of synthesis or no synthesis of one of the globin chains that make up hemoglobin

 A quantitative problem of too few globins synthesized

types of thalassemia

alpha thalassemia

beta thalassemia

Alpha Thalassemia

Results from deficient or absent synthesis of alpha globin chain

Alpha Thalassemia genetic mutation

-HBA1 and HBA2 located on chromosome 16

-Mainly deletions, point mutations

Trans

Each chromosome has one affected and one normal gene

(-α/-α)

(striped is affected, - is affected, a is normal)

cis

Both deletions or mutations are on the same chromosome

(--/αα)

Trans X Cis

silent carrier

-/α α/α

Asymptomatic

slight reductions in MCV

and MCH or no changes

Trans X Cis

Cis X cis

what disease happens if 2 genes are deleted

Alpha-thalassemia trait

-/α -/α

-/- α/α

Alpha-thalassemia trait

Asymptomatic

minimal anemia slightly

reduced MCV and MCH

what disease happens if 3 genes are deleted

HbH disease

-/- -/α

HbH disease

microcytic hypochromic hemolytic anemia, splenomegaly, mild jaundice, and sometimes thalassemia-like bone changes

what disease happens if 4 genes are deleted

Hydrops fetalis

-/- -/-

Hydrops fetalis

Die either in utero or shortly after birth because of severe anemia

Alpha Thalassemia pathogenesis

Beta Thalassemia

Characterized by a genetic deficiency in the

synthesis of β polypeptide chains

Beta Thalassemia mutations

HBB gene on chromosome 11 provides instructions for making a protein called beta globin

Mutation in HBB prevent or reduce the production of beta globin

 β0 

The absence of beta globin is referred to as this

β+

A reduced amount of beta globin

Beta-thalassemia minor

beta-thalassemia trait genes

β+/β

βo/β

Beta-thalassemia minor

beta-thalassemia trait clinical features

-Asymptomatic

-Mild microcytic anemia

Beta-thalassemia

intermedia genes

β+/β+

βo/β+

Beta-thalassemia

intermedia clinical features

-Asymptomatic

-Minimal anemia reduced MCV and

MCH

may need occasional transfusions,

e.g., at times of illness or pregnancy,

depending on the severity of their

anemia.

Beta-thalassemia major

(Cooley's anemia) genes

βo/βo

Beta-thalassemia major

(Cooley's anemia) clinical features

presents at a few months of age

with progressive pallor and

abdominal distension; possibly with

poor feeding, decreased activity;

hepatosplenomegaly and bony

abnormalities most often of the skull

(frontal and parietal bossing, and

chipmunk facies).

symptoms of thalassemia

complications of thalassemia

Sickle-cell disease

caused by a gene mutation that leads to the production of Sickle haemoglobin HbS

Qualitative :Production of abnormal chains

sickle cell mutation

Occur in beta globin gene of hemoglobin

Mutation on chromosome 11: single amino

acid change (Point mutation)

Inherited in an autosomal recessive pattern

point mutation

Monogenic disorder caused by an T-to-A point mutation in the 𝛽-globin gene that produces abnormal hemoglobin S (Hb S)

sickle cell disease pathogenesis

combinations

Sickle Cell Trait

HbA/S

~60% HbA, ~40% HbS

Sickle Cell Trait clinical

Carrier state; generally asymptomatic and live normal lives

Sickle Cell Anemia

HbS/S

~100% HbS

Sickle Cell Anemia clinical

Severe form of SCD; frequent vaso-occlusive crises, hemolytic anemia, organ damage

S/β⁰-thalassemia

HbS/β⁰

~100% HbS, 0% HbA, HbF ~1–10%

S/β⁰-thalassemia clinical

Clinically similar to sickle cell anemia (no HbA at all); often severe

S/β⁺-thalassemia

HbS/β⁺

~60% HbS, ~40% HbA

S/β⁺-thalassemia clinical

Milder symptoms than sickle cell anemia; variable severity depending on how much HbA is produced

HbSC Disease

HbS/C

~50% HbS, ~50% HbC, HbA 0%

HbSC Disease clinical

Milder sickle cell disease; fewer complications than HbSS, but still at risk for retinopathy, avascular necrosis

Hereditary Spherocytosis

Familial hemolytic disorder associated with a variety of mutations that lead to defects in red blood cell (RBC) membrane proteins

These proteins allow the cells to change shape without breaking when passing through narrow capillaries.

ANK1, EPB42, SLC4A, SPTA1 AND SPTB gens give the instruction to produce the proteins.

Dysfunctional membrane proteins interfere with the cell's ability to change shape when traveling through the blood vessels.

The misshapen red blood cells, called spherocytes, are removed from circulation and taken to the spleen for destruction.

Spherocytosis inheritance

Inherited as autosomal dominant pattern

Glucose-6-Phosphate Dehydrogenase

deficiency inheritance

X linked recessive disorder

G6PD gene

provides instructions for making an enzyme called glucose-6-phosphate dehydrogenase.

Glucose-6-Phosphate Dehydrogenase function

Beside carbohydrate metabolism, this enzyme involved in protecting red blood cells from the effects of potentially harmful molecules called reactive oxygen species.

If mutations in the G6PD gene reduce the amount of glucose-6- phosphate dehydrogenase or alter its structure, this enzyme can no longer play its protective role.

As a result, reactive oxygen species can accumulate and damage red blood cells.

Factors causing red blood cells to be destroyed faster than the body can replace them.

infections, certain drugs, or ingesting fava beans can increase the levels of reactive oxygen species