Thalassaemias · PDF fileThalassemia • Thalassemia is an inherited autosomal recessive...

Thalassaemias

Thalassemia

• Thalassemia is an inherited autosomal recessive blood disease.

• Associated with absence or reduction in a or b globin chains.

• Reduced synthesis of one of the globin chains can cause the

formation of abnormal hemoglobin molecules, thus causing anemia.

• The thalassemias are classified according to which chain of the hemoglobin molecule is affected.

• In α thalassemias, production of the α globin chain is affected,while in β thalassemia production of the β globin chain is affected.

• In adults, the predominant Hb (HbA) molecule has four chains: two α and two β chains.

• In thalassemias, the synthesis of either the α or

the β chains is reduced or absent, thus preventing

the formation of a normal Hb molecule.

• In α thalassemias the α chain is reduced or absent, whereas in β thalassemias the β chain is reduced or absent.

Genetics of thalassemia

• β globin chains are encoded by a single gene on chromosome 11. • α globin chains are encoded by two closely linked genes on chromosome 16. • Normal person has two copies of each chromosome. • Therefore, there are two loci encoding the β chain: one inherited from the mother and one from the father. • There are four loci encoding the α chain: 2 from the mother and 2 from the father.

α thalassemia

• Decreased α-globin production, therefore fewer α-globin chains are produced, resulting in an excess of β chains in adults and excess γ chains in newborns.

• Free beta chains form aggregates and produce unstable Hb.

• Red blood cells with such Hb have short life span and destroyed early in the spleen = anaemia.

Alpha thalssemia

• One defective gene:There is minimal effect. Three α-globin alleles are enough to permit normal Hb production, and there are no clinical symptoms. They have been called silent carriers. They may have a slightly reduced MCV and MCH. • Two defective genes: The condition is called alpha thalassemia trait. Two alleles permit nearly normal erythropoiesis, but there is a mild microcytic hypochromic anemia. The disease in this form can be mistaken for iron deficiency anemia and treated inappropriately with iron.

Alpha thalssemia

• Three defective genes: The condition is called Hemoglobin H disease. Two unstable hemoglobins are present in the blood: Hemoglobin Barts (tetrameric γ chains) and Hemoglobin H (tetrameric β chains). • Both of these unstable hemoglobins have a higher affinity for oxygen than normal hemoglobin, resulting in poor oxygen delivery to tissues. • There is a microcytic hypochromic anemia with target cells and Heinz bodies (precipitated HbH) on the peripheral blood smear, as well as splenomegaly. The disease may first be noticed in childhood or in early adult life, when the anemia and splenomegaly are noted. • Four defective genes: The fetus cannot live once outside the uterus and most such infants are dead at birth with hydrops fetalis, and those who are born alive die shortly after birth. The hemoglobin that is present is all tetrameric γ chains (hemoglobin Barts).

• in β-thalassemias the β globin chain is either absent (β0 form) or reduced amount (10-20%) of globin chain is produced (β+ form).

• The cause of the abnormal production of β globin chain is a defect in the genes encoding for the β globin molecule (gene mutations or gene deletion).

• β0 form: HbA is absent, levels of HbF are raised, and HbA2 has a variable concentration.

• β+ form: variable amount of HbA, normal HbA2, and raised levels of HbF.

β-THALASSEMIAS

• If you have one altered gene, you're a carrier. • This condition is called beta thalassemia trait or beta thalassemia minor. It causes mild anemia. • If both genes are altered, you will have beta thalassemia intermedia or beta thalassemia major (also called Cooley's anemia). • The intermedia form of the disorder causes moderate anemia. • Beta thalassemia major form causes severe anaemia.

Beta thalassemia major

• Both beta globin genes are affected. • Clinical symptoms begin about 4–6 months after birth when HbF is normally replaced by HbA. • In β-thalassemia, there will be excess α chains and HbF persists • Excess α chains precipitate in erythroblasts and in mature red cells causing the severe ineffective erythropoiesis and haemolysis. • The greater the α-chain excess, the more severe the anaemia.

Beta thalassemia clinical features

• Severe anaemia becomes apparent at 3-6 months after birth. • Enlargement of the liver and spleen occurs as a result of excessive red cell destruction, extramedullary haemopoiesis, and iron overload. • Expansion of bones caused by intense marrow hyperplasia leads to a thalassaemic facies and to thinning of the cortex of many bones. • Blood transfusions can improve the symptomps but iron overload caused by repeated transfusions is inevitable unless iron chelation therapy is given. • Iron damages the heart, the liver and the endocrine organs with failure of growth, delayed or absent puberty, diabetes mellitus, hypothyroidism and hypo-parathyroidism. • Increased susceptibility to infections. • Death may occur on the second decade due to heart failure.

Lab tests for β-thalassemia major

• Blood film: severe hypochromic, microcytic anaemia, reticulocytosis with normoblasts, target cells and basophilic stippling in the blood film • Haemoglobin electrophoresis: absence or almost complete absence of Hb A, with almost all the circulating haemoglobin Hb F. • An iron overload is indicated by elevated iron and ferritin levels in the serum and an increased saturation of the serum ironbinding capacity (liver biopsy may be used). • The molecular defect can be identified by Southern blotting or PCR.

Treatment

• 1) Regular blood transfusions are needed to maintain the Hb over 10 g/dL at all times. 2-3 units every 4-6 weeks are required.

• 2) Regular folic acid (e.g. 5 mg/day) is given if the diet is poor.

• 3) Iron chelation therapy to treat iron overload.

• 4) Splenectomy after the age of 6 years.

• 5) Prophylactic antibiotics.

• 6) Bone marrow transplantation.