View
542
Download
1
Category
Preview:
Citation preview
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.
9
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.
10
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.
11
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
14
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.
23
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.
24
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.
25
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.
27
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.
28
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.
30
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.
31
Alpha Thalassemia
34
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
37
Silent Carrier State►Deletion of one alpha gene, leaving
three functional alpha genes.
►Alpha/Beta chain ratio nearly normal.
►No hematologic abnormalities present.
38
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.
39
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
40
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.
41
Thanks
Recommended