ENZYMES

A protein with catalytic properties due to its power of specific

activation

© 2007 Paul Billiet ODWS

The Thalassemias

Objectives By the end of this lecture the student should be able to:  Understand the normal stucture of Haemoglobin• Know the Diverse group of disorders which manifest as anemia of

varying degrees. • Know the defective production of globin portion of hemoglobin

molecule. • Know the Distribution of disease worldwide. • Describe the disease either homozygous or heterozygous defect. • Know the Defect results from abnormal rate of synthesis in one of

the globin chains. 

 

Hemoglobin Review

• Each complex consists of :– Four polypeptide chains, non-covalently bound

– Four heme complexes with iron bound

– Four O2 binding sites

Globin Chains• Alpha Globin

– 141 amino acids– Coded for on Chromosome 16– Found in normal adult hemoglobin, A1 and A2

• Beta Globin– 146 amino acids– Coded for on Chromosome 11, found in Hgb A1

• Delta Globin – Found in Hemoglobin A2--small amounts in all adults

• Gamma Globin– Found in Fetal Hemoglobin

• Zeta Globin– Found in embryonic hemoglobin

Normal Haemoglobin

• HbA - α2β2

• HbA2 - α2δ2

• HbF – α2γ2

Each goblin chain have separate genetic control

α –thalassaemia affect α-chain synthesis

β –thalassaemia affect β -chain synthesis

Thalassemia►Diverse group of disorders which manifest

as anemia of varying degrees. ►Result of defective production of globin

portion of hemoglobin molecule. ►Distribution is worldwide. ►May be either homozygous defect or

heterozygous defect. ►Defect results from abnormal rate of

synthesis in one of the globin chains. 

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Thalassemia►Results in overall decrease in amount of

hemoglobin produced and may induce hemolysis.

►Two major types of thalassemia: – Alpha (α) - Caused by defect in rate of synthesis

of alpha chains. – Beta (β) - Caused by defect in rate of synthesis in

beta chains. ►May contribute protection against malaria.

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Genetics of Thalassemia►Adult hemoglobin composed two alpha and

two beta chains. ►Alpha thalassemia usually caused by gene

deletion;  ►Beta thalassemia usually caused by mutation. ►Results in microcytic, hypochromic anemias

of varying severity.

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GeneticTypes of Thalassaemia :

There are two basic groups of thalassaemia.

Alpha ( )Thalassaemia

Beta ( )Thalassaemia

Demographics: Thalassemia

• Found most frequently in the Mediterranean, Africa, Western and Southeast Asia, India and Burma.

Beta Thalassemia

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β-Thalassaemia

An absence or deficiency of β-chain synthesis of adult HbA

β Chain synthesis

Hb-A

γ and δ chain

Hb-A = α2β2

On the basis of synthetic ability β-genes are designated as

• β gene – can synthesize normal amount of β-chain

• β+ gene – can synthesize reduced amount of β-chain

• β0 gene – cannot synthesize β-chain

Pathophysiology of β-Thalassaemia

Various mutation in β-gene

Complete or partial absence of β-chain

Decreased adult HbA

α-chain synthesis remain normal

Free complementary α-chain – unstable and precipitate within normoblasts as insoluble

inclusionsCell membrane damage & impaired DNA synthesis

apoptosis i.e. ineffective erythropoeisis

70-80% marrow normoblasts undergo apoptosis

Inclusion bearing red cells undergo sequestration & destruction in spleen

Partial or lack of HbA synthesis ↓MCHC & MCH Hypochromia & microcytosis

Normal

Thalassaemia

↑Haemolysis ↑demands of phagocytic function hyperplasia of phagocytes

Hepatosplenomegaly

To compensate anaemia extramedullary haemopoiesis in liver, spleen & brain

Organomegaly

↑Erythropoiesis marrow expansion & thinning of cortex of skull bone Thalassaemia facies

Classification & Terminology Beta Thalassemia

• Normal /• Minor/0

/+

• Intermedia 0/+

+/+

• Major 0/0

+/+

0/+

Classical Syndromes of Beta Thalassemia

►Silent carrier state – the mildest form of beta thalassemia.

►Beta thalassemia minor - heterozygous disorder resulting in mild hypochromic, microcytic hemolytic anemia.

►Beta thalassemia intermedia - Severity lies between the minor and major.

►Beta thalassemia major - homozygous disorder resulting in severe transfusion-dependent hemolytic anemia.

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Silent Carrier State for β Thalassemia

►Are various heterogenous beta mutations that produce only small decrease in production of beta chains.

►Patients have nearly normal beta/alpha chain ratio and no hematologic abnormalities.

►Have normal levels of Hb A2.

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Beta Thalassemia Minor

►Caused by heterogenous mutations that affect beta globin synthesis. 

►Usually presents as mild, asymptomatic hemolytic anemia unless patient in under stress such as pregnancy, infection, or folic acid deficiency.

►Have one normal beta gene and one mutated beta gene. ►Hemoglobin level in 10-13 g/dL range with normal or

slightly elevated RBC count. 

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Beta Thalassemia Minor

►Anemia usually hypochromic and microcytic with slight aniso and poik, including target cells and elliptocytes;  May see basophilic stippling.

►Rarely see hepatomegaly or splenomegaly. ►Have high Hb A2 levels (3.5-8.0%) and normal to

slightly elevated Hb F levels. ►Are different variations of this form depending upon

which gene has mutated. ►Normally require no treatment.  ►Make sure are not diagnosed with iron deficiency

anemia. 26

Beta Thalassemia Intermedia

►Patients able to maintain minimum hemoglobin (7 g/dL or greater) without transfusions. 

►Expression of disorder falls between thalassemia minor and thalassemia major.  May be either heterozygous for mutations causing mild decrease in beta chain production, or may be homozygous causing a more serious reduction in beta chain production.

►See increase in both Hb A2 production and Hb F production.

►Peripheral blood smear picture similar to thalassemia minor.

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Beta Thalassemia Intermedia

►Have varying symptoms of anemia, jaundice, splenomegaly and hepatomegaly.

►Have significant increase in bilirubin levels.  ►Anemia usually becomes worse with infections,

pregnancy, or folic acid deficiencies. ►May become transfusion dependent as adults. ►Tend to develop iron overloads as result of increased

gastrointestinal absorption. ►Usually survive into adulthood.

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Beta Thalassemia Major 1 of 3

►Characterized by severe microcytic, hypochromic anemia. 

►Detected early in childhood: – Infants fail to thrive.  – Have pallor, variable degree of jaundice, abdominal

enlargement, and hepatosplenomegaly. ►Hemoglobin level between 4 and 8 gm/dL. ►Severe anemia causes marked bone changes due to

expansion of marrow space for increased erythropoiesis.►See characteristic changes in skull, long bones, and

hand bones.  29

Beta Thalassemia Major 2 of 3

►Have protrusion upper teeth and Mongoloid facial features. 

►Physical growth and development delayed. ►Peripheral blood shows markedly hypochromic,

microcytic erythrocytes with extreme poikilocytosis, such as target cells, teardrop cells and elliptocytes.  See marked basophilic stippling and numerous NRBCs. 

►MCV in range of 50 to 60 fL. ►Low retic count seen (2-8%). ►Most of hemoglobin present is Hb F with slight

increase in Hb A2.

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Beta Thalassemia Major 3 of 3

►Regular transfusions usually begin around one year of age and continue throughout life. 

►Excessive number of transfusions results in tranfusional hemosiderosis; Without iron chelation, patient develops cardiac disease.

►Danger in continuous tranfusion therapy: – Development of iron overload. – Development of alloimmunization (developing antibodies to

transfused RBCs). – Risk of transfusion-transmitted diseases.

►Bone marrow transplants may be future treatment, along with genetic engineering and new drug therapies.

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Alpha Thalassemia

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Classification & TerminologyAlpha Thalassemia

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

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

Alpha Thalassemias• Result from gene deletions• One deletion—Silent carrier; no clinical

significance• Two deletions— Thal trait; mild hypochromic

microcytic anemia• Three deletions—Hgb H; variable severity, but

less severe than Beta Thal Major• Four deletions—Bart’s Hgb; Hydrops Fetalis; In Utero or early neonatal death

Alpha Thalassemia 2 of 2

►Predominant cause of alpha thalassemias is large number of gene deletions in the alpha-globin gene.

►Are four clinical syndromes present in alpha thalassemia: – Silent Carrier State – Alpha Thalassemia Trait  (Alpha Thalassemia Minor) – Hemoglobin H Disease – Bart's Hydrops Fetalis Syndrome

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Silent Carrier State►Deletion of one alpha gene, leaving

three functional alpha genes.

►Alpha/Beta chain ratio nearly normal.

►No hematologic abnormalities present.

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Alpha Thalassemia Trait (Alpha Thalassemia Minor)

►Also called Alpha Thalassemia Minor. ►Caused by two missing alpha genes.  May be

homozygous (-a/-a) or heterozygous (--/aa). ►Exhibits mild microcytic, hypochromic anemia. ►May be confused with iron deficiency anemia. ►Although some Bart's hemoglobin (γ4) present at birth,

no Bart's hemoglobin present in adults.

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Hemoglobin H Disease 1 of 2

►Second most severe form alpha thalassemia. ►Usually caused by presence of only one gene producing

alpha chains (--/-a).  ►Results in accumulation of excess unpaired gamma or

beta chains. Born with 10-40% Bart's hemoglobin (γ4).   Gradually replaced with Hemoglobin H (β4). In adult, have about 30-50% Hb H.

γ4 β4

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Bart’s Hydrops Fetalis Syndrome

► Most severe form.  Incompatible with life.  Have no functioning alpha chain genes (--/--).

► Baby born with hydrops fetalis, which is edema and ascites caused by accumulation serous fluid in fetal tissues as result of severe anemia.  Also see hepatosplenomegaly and cardiomegaly.

► Predominant hemoglobin is Hemoglobin Bart, along with Hemoglobin Portland and traces of Hemoglobin H.

► Hemoglobin Bart's has high oxygen affinity so cannot carry oxygen to tissues.  Fetus dies in utero or shortly after birth. At birth, see severe hypochromic, microcytic anemia with numerous NRBCs.

► Pregnancies dangerous to mother.  Increased risk of toxemia and severe postpartum hemorrhage.

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Thanks