1. THALASSEMIA autosomal recessive blood disease.
the genetic defect results in reduced rate of synthesis of one of the globin chains that make up hemoglobin.
Reduced synthesis of one of the globin chains can cause the formation of abnormal hemoglobin molecules, thus causing anemia,
autosomal recessive blood disease. In thalassemia, the genetic defect results in reduced rate of synthesis of one of the globin chains that make up hemoglobin. Reduced synthesis of one of the globin chains can cause the formation of abnormal hemoglobin molecules, thus causing anemia, the characteristic presenting symptom of the thalassemias.
Thalassemias cause the body to make fewer healthy red blood cells and less hemoglobin (HEE-muh-glow-bin) than normal. Hemoglobin is an iron-rich protein in red blood cells. It carries oxygen to all parts of the body. It also carries carbon dioxide (a waste gas) from the body to the lungs, where it's exhaled.

2. If the body doesn't produce enough of either alpha or beta proteins
Overview
Hemoglobin
oxygen-carrying component of the red blood cells
consists of two different proteins
alpha 
 beta.
If the body doesn't produce enough of either alpha or beta proteins
the red blood cells do not form properly and cannot carry sufficient oxygen.
ANEMIA
Thalassemia is the name of a group of genetic blood disorders. To understand how thalassemia affects the human body, you must first understand a little about how blood is made. Hemoglobin is the oxygen-carrying component of the red blood cells. It consists of two different proteins, an alpha and a beta. If the body doesn't produce enough of either of these two proteins, the red blood cells do not form properly and cannot carry sufficient oxygen. The result is anemia that begins in early childhood and lasts throughout life. Since thalassemia is not a single disorder but a group of related disorders that affect the human body in similar ways, it is important to understand the differences between the various types of thalassemia

3. Alpha Thalassemia
Four genes (two from each parent) are needed to make enough alpha globin protein chains.
commonly found in Africa, the Middle East, India, Southeast Asia, southern China, and occasionally the Mediterranean region.
types
Silent Carrier State.
Alpha Thalassemia Trait or Mild Alpha Thalassemia.
Hemoglobin H Disease.
Hemoglobin H-Constant Spring.
Hydrops Fetalis or Alpha Thalassemia Major
Silent Carrier State. This condition generally causes no health problems because the lack of alpha protein is so small that the hemoglobin functions normally. It is called "silent carrier" because of how difficult it is to detect. Silent carrier state is "diagnosed" by deduction when an apparently normal individual has a child with hemoglobin H disease or alpha thalassemia trait. Hemoglobin Constant Spring. This is an unusual form of Silent Carrier state that is caused by a mutation of the alpha globin. It is called Constant Spring after the region of Jamaica in which it was discovered. As in silent carrier state, an individual with this condition usually experiences no related health problems. Alpha Thalassemia Trait or Mild Alpha Thalassemia. In this condition, the lack of alpha protein is somewhat greater. Patients with this condition have smaller red blood cells and a mild anemia, although many patients do not experience symptoms. However, physicians often mistake mild alpha thalassemia for iron deficiency anemia and prescribe iron supplements that have no effect on the anemia. Hemoglobin H Disease. In this condition, the lack of alpha protein is great enough to cause severe anemia and serious health problems such as an enlarged spleen, bone deformities and fatigue. It is named for the abnormal hemoglobin H (created by the remaining beta globin) that destroys red blood cells. Hemoglobin H-Constant Spring. This condition is more severe than hemoglobin H disease. Individuals with this condition tend to have a more severe anemia and suffer more frequently from enlargement of the spleen and viral infections. Homozygous Constant Spring. This condition is a variation of hemoglobin H-Constant Spring that occurs when two Constant Spring carriers pass their genes on to their child (as opposed to hemoglobin H Constant Spring, in which one parent is a Constant Spring Carrier and the other a carrier of alpha thalassemia trait). This condition is generally less severe than hemoglobin H Constant Spring and more similar to hemoglobin H disease. Hydrops Fetalis or Alpha Thalassemia Major. In this condition, there are no alpha genes in the individual's DNA, which causes the gamma globins produced by the fetus to form an abnormal hemoglobin called hemoglobin Barts. Most individuals with this condition die before or shortly after birth. In some extremely rare cases where the condition is discovered before birth, in utero blood transfusions have allowed the birth of children with hydrops fetalis who then require lifelong blood transfusions and medical care
Cooley's Anemia Foundation, Inc. 

4. PATHOGENESIS OF Alpha THALASSEMIA
relatively fewer α-globin
an excess of β- and γ-globin chains.
These excess chains form
Bart's hemoglobin (γ4) in fetal life
Hb H (β4) after birth.
Prenatally, a fetus with α-thalassemia may become symptomatic because Hb F requires sufficient α-globin gene production,
whereas postnatally, infants with β-thalassemia become symptomatic because Hb A requires adequate production of β-globin genes.
In α-thalassemia, there are relatively fewer α-globin chains and an excess of β- and γ-globin chains. These excess chains form Bart's hemoglobin (γ4) in fetal life and Hb H (β4) after birth. These abnormal tetramers are not as lethal, but lead to extravascular hemolysis. Prenatally, a fetus with α-thalassemia may become symptomatic because Hb F requires sufficient α-globin gene production, whereas postnatally, infants with β-thalassemia become symptomatic because Hb A requires adequate production of β-globin genes.

5. Inheritance Pattern for Alpha Thalassemia
The diagram shows one example of how alpha thalassemia is inherited. The alpha globin genes are located on chromosome 16. A child inherits four alpha globin genes—two from each parent. In this example, the father is missing two alpha globin genes and the mother is missing one alpha globin gene.
Therefore, each child has a 25 percent chance of inheriting two missing genes and two normal genes (thalassemia trait), three missing genes and one normal gene (hemoglobin H disease), four normal genes (no anemia), or one missing gene and three normal genes (silent carrier).

6. Beta Thalassemias
People whose hemoglobin does not produce enough beta protein
It is found in people of Mediterranean descent, such as Italians and Greeks, Arabian Peninsula, Iran, Africa, Southeast Asia and southern China.

7. Pathogenesis of Beta Thalassemia
Inadequate β-globin gene production
leading to decreased levels of normal hemoglobin (Hb A)
imbalance in α- and β-globin chain production.
excess of α-globin chains relative to β- and γ-globin chains;
α-globin tetramers (α4) are formed,
these inclusions interact with the red cell membrane and shorten red cell survival,
leading to anemia and increased erythroid production.
In bone marrow, thalassemic mutations disrupt the maturation of red blood cells, resulting in ineffective erythropoiesis; the marrow is hyperactive, but the patient has relatively few reticulocytes and severe anemia. In β-thalassemias, there is an excess of α-globin chains relative to β- and γ-globin chains; α-globin tetramers (α4) are formed, and these inclusions interact with the red cell membrane and shorten red cell survival, leading to anemia and increased erythroid production. The γ-globin chains are produced in increased amounts, leading to an elevated Hb F (α2γ2). The δ-globin chains are also produced in increased amounts, leading to an elevated Hb A2(α2δ2) in β-thalassemia.

8. Types of Beta Thalassemia
the lack of beta protein is not great enough to cause problems in the normal functioning of the hemoglobin.
A person with this condition simply carries the genetic trait for thalassemia and will usually experience no health problems other than a possible mild anemia.
Thalassemia Minor or Thalassemia Trait.
lack of beta protein in the hemoglobin is great
bone deformities
enlargement of the spleen
patients with thalassemia intermedia need blood transfusions to improve their quality of life, but not in order to survive.
Thalassemia Intermedia.
This is the most severe form of beta thalassemia
complete lack of beta protein in the hemoglobin causes a life-threatening anemia
requires regular blood transfusions and extensive ongoing medical care.
lead to iron-overload which must be treated with chelation therapy
Thalassemia Major or Cooley's Anemia.
Thalassemia Minor or Thalassemia Trait. In this condition, the lack of beta protein is not great enough to cause problems in the normal functioning of the hemoglobin. A person with this condition simply carries the genetic trait for thalassemia and will usually experience no health problems other than a possible mild anemia. As in mild alpha thalassemia, physicians often mistake the small red blood cells of the person with beta thalassemia minor as a sign of iron-deficiency anemia and incorrectly prescribe iron supplements. Thalassemia Intermedia. In this condition the lack of beta protein in the hemoglobin is great enough to cause a moderately severe anemia and significant health problems, including bone deformities and enlargement of the spleen. However, there is a wide range in the clinical severity of this condition, and the borderline between thalassemia intermedia and the most severe form, thalassemia major, can be confusing. The deciding factor seems to be the amount of blood transfusions required by the patient. The more dependent the patient is on blood transfusions, the more likely he or she is to be classified as thalassemia major. Generally speaking, patients with thalassemia intermedia need blood transfusions to improve their quality of life, but not in order to survive. Thalassemia Major or Cooley's Anemia. This is the most severe form of beta thalassemia in which the complete lack of beta protein in the hemoglobin causes a life-threatening anemia that requires regular blood transfusions and extensive ongoing medical care. These extensive, lifelong blood transfusions lead to iron-overload which must be treated with chelation therapy to prevent early death from organ failure.

9. Inheritance Pattern for Beta Thalassemia
The diagram shows one example of how beta thalassemia is inherited. The beta globin gene is located on chromosome 11. A child inherits two beta globin genes—one from each parent. In this example, each parent has one altered beta globin gene.
Therefore, each child has a 25 percent chance of inheriting two normal genes (no anemia), a 50 percent chance of inheriting one altered gene and one normal gene (beta thalassemia trait), or a 25 percent chance of inheriting two altered genes (beta thalassemia major).

10. CLINICAL MANIFESTATIONS
If not treated, children usually become symptomatic as a result of progressive hemolytic anemia,
with profound weakness and cardiac decompensation during the 2nd 6 mo of life.
Most infants and children have cardiac decompensation when the hemoglobin is 4.0 g/dL or less.
children with β-thalassemia usually become symptomatic as a result of progressive hemolytic anemia, with profound weakness and cardiac decompensation during the 2nd 6 mo of life. Depending on the mutation and the degree of fetal hemoglobin production, transfusions in patients with thalassemia major are necessary in the 2nd mo of life or the 2nd yr of life, but rarely later. The decision to transfuse depends on the child's ability to compensate for the degree of anemia. Most infants and children have cardiac decompensation when the hemoglobin is 4.0 g/dL or less. Fatigue, poor appetite, and lethargy are late findings of severe anemia in an infant or child and were common before transfusions were standard therapy. The classic findings in children with severe thalassemia, including typical facies (maxillary hyperplasia, flat nasal bridge, frontal bossing), pathologic bone fractures, marked hepatosplenomegaly, and cachexia, are primarily seen in developing countries. The spleen may become so enlarged that it causes mechanical discomfort and secondary hypersplenism. Features of ineffective erythropoiesis include expanded medullary spaces (with massive expansion of the marrow of the face and skull), extramedullary hematopoiesis, and a huge caloric need ( Fig ). Hepatosplenomegaly may interfere with nutritional support. Pallor, hemosiderosis, and jaundice may combine to produce a greenish brown complexion. As a result of the anemia, there is also an increase in iron absorption from the gastrointestinal tract, with toxicity leading to further complications. Many of these features became less severe and less frequent with transfusion therapy, but the creation of excessive iron stores associated with hemosiderosis is a major concern in individuals with β- thalassemia. Many of the complications of thalassemia seen in developed countries today are the result of increased iron deposition from repeated blood transfusions. Complications can be avoided by the consistent use of an iron chelator. However, chelation therapy also has associated complications. Endocrine and cardiac pathology is often associated with excessive iron stores in patients with thalassemia major who are chronically transfused. Endocrine dysfunction may include hypothyroidism, gonadal failure, hypoparathyroidism, and diabetes mellitus. Congestive heart failure and cardiac arrhythmias are potentially lethal complications of iron stores in individuals with thalassemia.
Figure 462-7  Ineffective erythropoiesis in an untransfused 3 yr old patient with thalassemia major. A, Massive widening of the diploic spaces of the skull as seen on MRI. B, Radiographic appearance of the trabeculae as seen on plain radiograph, and C, obliteration of the maxillary sinuses with hematopoietic tissue as seen on CT scan.

11. Number of affected genes Transfusion dependent
Summary
Number of affected genes
Hemoglobin (g/dL)
MCV (fL)
Transfusion dependent
Alpha Thalassemia
Alpha-thal-2 trait 1
NORMAL
None No
Alpha-thal-1-trait 2
>10
<80
Hemoglobin H 3
7-10
<70
+/-
Hydrops Fetalis 4
Incompatible with Life
Beta-Thalassemia
Beta-Thal Minor (trait)
Beta-Thal intermedia
65-75
Beta-Thal Majot
<7
yes