Social Issues

Impact of Thalassaemia on the author:
Positive Impact:
• Learn to appreciate life
o Intense passion for living and a deep appreciation for health
o To be the best person that he can be
• Inspiration to continue life
• Quality of life of life is more meaningful than quantity.
• Instil determination and strong will
• Strengthens family dynamics
o Having a supportive family
• Able to understand and share the feelings of others (empathetic)
o Treasure loved ones, family and friends.

Negative Impact:
• Frustration
o Have to deal with chronic illness that consumes an exorbitant amount of time
• Financial difficulties
o Expensive insurance coverage.
• Affect Marital relationship
• Doctor’s appointments, medical procedures, and surgeries are a routine part of life
• Heightened awareness of own mortality

MRI TESTING

An MRI (or magnetic resonance imaging) scan is a radiology technique that uses magnetism, radio waves, and a computer to produce images of body structures. The MRI scanner is a tube surrounded by a giant circular magnet. The patient is placed on a moveable bed that is inserted into the magnet. The magnet creates a strong magnetic field that aligns the protons of hydrogen atoms, which are then exposed to a beam of radio waves. This spins the various protons of the body, and they produce a faint signal that is detected by the receiver portion of the MRI scanner. The receiver information is processed by a computer, and an image is produced.

Magnetic resonance imaging (MRI) provides a noninvasive, quantitative method of estimating parenchymal iron levels. In principle, MRI can be used to quantify iron stores wherever they exist in the body. In practice, MRI has been investigated in the assessment of hepatic, cardiac, and anterior pituitary iron stores.

How MRI measures iron stores

MRI measures tissue iron concentration indirectly via the detection of the paramagnetic influences of storage iron (ferritin and hemosiderin) on the proton resonance behavior of tissue water (1). The longitudinal (R1) and transverse (R2) nuclear magnetic relaxation rates of nearby solvent water protons can then be calculated. Both R1 and R2 rates are increased when interacting with paramagnetic particles such as iron. R2 (or spin-echo imaging) is preferable to R1 for determining LIC, since ferritin enhances the relaxation of both R1 and R2, while hemosiderin only has a strong R2 relaxation accelerating effect. Gradient echo imaging produces images for calculating T2* and R2*, where R2* = 1000/T2*. A T2* of 20 ms is equivalent to an R2* of 50 Hz.

MRI detection of hepatic iron overload

MRI provides a non-invasive alternative to liver biopsy, and may actually be more accurate in patients with heterogeneous liver iron deposition (such as those with cirrhosis) since it measures iron in the whole organ. In addition, the pathologic status of the liver can also be assessed using MRI.

(i couldnt put the picture up)

MRI detection of hepatic iron overload

An MRI image (R2 map, inverse, false color) clearly displays iron-overloading in the liver. 

Evaluation of cardiac iron

MRI remains the only noninvasive modality in clinical use with the ability to detect cardiac iron deposition. T2* MRI is rapidly becoming the new standard for measuring cardiac iron levels. (cant put the picture)

A cardiac T2* MRI image shows myocardial iron stores. The lighter ventricle walls in the left image indicate heavy iron loading. Used with permission from Anderson, et al (2). © 2001 Oxford University Press. MRI detection of cardiac iron overload.

http://www.irontoxicity.com/hcp/diagnosis/imaging_studies/magnetic.jsp

Imaging Studies

·   Skeletal survey and other imaging studies reveal classic changes of the bones that are usually encountered in patients who are not regularly transfused.

·          

o The striking expansion of the erythroid marrow widens the marrow spaces, thinning the cortex and causing osteoporosis. These changes, which result from the expanding marrow spaces, usually disappear when marrow activity is halted by regular transfusions. Osteoporosis and osteopenia may cause fractures, even in patients whose conditions are well-controlled.

o In addition to the classic "hair on end" appearance of the skull, which results from widening of the diploic spaces and observed on plain radiographs , the maxilla may overgrow, which results in maxillary overbite, prominence of the upper incisors, and separation of the orbit. These changes contribute to the classic "chipmunk facies observed in patients with thalassemia major.

o Other bony structures, such as ribs, long bones, and flat bones, may also be sites of major deformities. Plain radiographs of the long bones may reveal a lacy trabecular pattern. Changes in the pelvis, skull, and spine become more evident during the second decade of life, when the marrow in the peripheral bones becomes inactive while more activity occurs in the central bones.

o Compression fractures and paravertebral expansion of extramedullary masses, which could behave clinically like tumors, more frequently occur during the second decade of life.

o MRI and CT scanning are usually used in diagnosing such complications.

·   Chest radiography is used to evaluate cardiac size and shape.

·   MRI and CT scanning can be used as noninvasive means to evaluate the amount of iron in the liver in patients receiving chelation therapy.

·   A newer noninvasive procedure involves measuring the cardiac T2 with cardiac magnetic resonance (CMR). This procedure has shown decreased values in cardiac T2 due to iron deposit in the heart. Unlike liver MRI, which usually correlates very well with the iron concentration in the liver measured using percutaneous liver biopsy samples and the serum ferritin level, CMR does not correlate well with the ferritin level, the liver iron level, or echocardiography findings. This suggests that cardiac iron overload cannot be estimated with these surrogate measurements. This is also true in measuring the response to chelation therapy in patients with iron overload. The liver is clear of iron loading much earlier than the heart, which also suggests that deciding when to stop or reduce treatment based on liver iron levels is misleading.

http://www.medrat.com/info/thalassemia/doc019.php

Benefits

• MRI is a noninvasive imaging technique that does not involve exposure to radiation.
• MR images of the soft-tissue structures of the body—such as the heart, liver and many other organs— is more likely to identify and characterize abnormalities and focal lesions than other imaging methods. This detail makes MRI an invaluable tool in early diagnosis and evaluation of many focal lesions and tumors.
• MRI has proven valuable in diagnosing a broad range of conditions, including cancer, heart and vascular disease, and muscular and bone abnormalities.
• MRI enables the detection of abnormalities that might be obscured by bone with other imaging methods.
• MRI allows physicians to assess the biliary system noninvasively and without contrast injection.
• The contrast material used in MRI exams is less likely to produce an allergic reaction than the iodine-based materials used for conventional x-rays and CT scanning.
• MRI provides a fast, noninvasive alternative to x-ray angiography for diagnosing problems of the heart and blood vessels.

Risks

• The MRI examination poses almost no risk to the average patient when appropriate safety guidelines are followed.
• If sedation is used there are risks of excessive sedation. The technologist or nurse monitors your vital signs to minimize this risk.
• Although the strong magnetic field is not harmful in itself, medical devices that contain metal may malfunction or cause problems during an MRI exam.
• There is a very slight risk of an allergic reaction if contrast material is injected. Such reactions usually are mild and easily controlled by medication.
• Nephrogenic systemic fibrosis is currently a recognized, but rare, complication of MRI believed to be caused by the injection of high doses of MRI contrast material in patients with poor kidney function.

What are the limitations of MRI of the Body?

High-quality images are assured only if you are able to remain perfectly still while the images are being recorded. If you are anxious, confused or in severe pain, you may find it difficult to lie still during imaging.

A person who is very large may not fit into the opening of a conventional MRI machine.

The presence of an implant or other metallic object often makes it difficult to obtain clear images and patient movement can have the same effect.

Breathing may cause artifacts, or image distortions, during MRIs of the chest, abdomen and pelvis. Bowel motion is another source of motion artifacts in abdomen and pelvic MRI studies.

Although there is no reason to believe that magnetic resonance imaging harms the fetus, pregnant women usually are advised not to have an MRI exam unless medically necessary.

MRI may not always distinguish between cancer tissue and edema fluid.

MRI typically costs more and may take more time to perform than other imaging modalities

http://www.radiologyinfo.org/en/info.cfm?pg=bodymr

Summary of Thalassaemia

Thalassaemia Summary

Main types – alpha thalassaemia
- severe types- Hb Barts (all alpha haemoglobin genes abnormal/missing)
- Hb H disease (3 missing alpha haemoglobin genes, mild persistent anaemia)

- beta thalassaemia
- severe types – beta thalassaemia major ( 2 beta thalassaemia genes, most haemoglobin does not work)
- beta thalassaemia intermedia (2 beta thalasaemia genes, some haemoglobin works)
- Thalassaemia minor

Epidemiology

-carried by 150 million or 3% of world population
-Beta thalassaemia more common in Mediterranean countries

In Malaysia, mostly among Malays and Chinese. Only small percentage of Indians
-Carrier for B.Thalassaemia is 3 to 5%
-In 1995, 8000 affected with HbE beta Thalassaemia, 8000 affected with homozygous beta Thalassaemia.
-2140 in Malays
-2240 in Chinese

For alpha thalassaemia, 15.8% of pregnant women in 2005 are carriers.

Predisposing Factors
Factors that increase risk
-family history
-ancestry

Inheritance
Alpha thalassaemia
-4 genes needed to make alpha globin protein chain
-if one or more gene missing, alpha thalassaemia trait

Beta Thalassaemia
-2 genes needed to make beta globin protein chain
-one or both altered, beta thalassaemia


Pathogenesis and genetics
Alpha thalassaemia
-silent carrier state(one gene deletion)
-loss of two genes
-imbalance causes accumulation of beta chains. Beta chains begin to associate in groups of four producing abnormal haemoglobin(hemoglobin H)
-hydrops fetalis-hemoglobin barts

Beta Thalassaemia
-one gene affected, one normal. Degree of imbalance depend on residual production capacity of defective beta globin gene.
-two gene affected.

Thalassemia minor
-small red cells and mild anaemia

Thalassaemia intermedia
-significant anaemia
-able to survive without blood transfusion
-Hb of below 7 or 8 gm/dl

Thalassaemia major
-severe anaemia
-can survive but terrible deformities
-blood transfusion causes iron overload

Signs and Symptoms
Alpha thalassaemia silent carriers
-no symptoms

Alpha of Beta Thalassaemia trait
-mild anemia

Beta Thalassaemia Intermedia
-mild to moderate anemia
-slowed growth
-bone problems
-enlarged spleen

Beta Thalassaemia major
· Pale appearance
· Poor appetite
· Dark urine
· Slowed growth and delayed puberty
· Jaundice(a yellowish color of the skin or whites of the eyes)
· Enlarged spleen ,liver, heart
· Bone deformities (especially bones in the face)
· Pallor
· Fatigue
· Tiredness
· Weakness
· Shortness of breath
· Blood in urine
· Skull deformity
· Skeleton deformity
· Thickening skull
· Thickening facial bone
· lack of beta globin causes a life-threatening anemia
· Therefore requires regular blood transfusions
· Life long transfusions lead to iron overload
· Must be treated with chelation therapy to prevent early death from organ failure.
Haemoglobin H disease
— Severe anemia
— Fatigue
— Pale appearance
— Poor appetite
— Dark urine
— Slowed growth and delayed puberty
— Jaundice(a yellowish color of the skin or whites of the eyes)
— Enlarged spleen
— Bone deformities (especially bones in the face)

E Beta Thalassaemia
-similar to Beta Thalassaemia but may be severe to Beta Thalassaemia Major

Complications
-Iron Overload
-Infections
-Bone deformities
-Splenomegaly
-Anaemia
-Still Birth

Screening and Diagnosis
-Complete Blood Count
-Haemoglobin electrophoresis
-Family genetic study
-Antenatal test
-Genetic studies
-Iron test
-Modified osmotic fragilty test
-Modified dichlorophenolindophenol test
Treatment and Management
-Gene Therapy
-Genetic Counselling
-Chelation Therapy
-Blood Transfusion

Ethical/Legal Issues for Savior Baby
-Read Majids thing. Its quite summarized already. =)

Complications

Iron Overload
People with thalassaemia can get too much iron in their bodies, either from the disease of from the blood transfusions. Too much iron will damage the heart, liver and endocrine system, which includes glands that produce hormones that regulate processes throughout the body. This is the main cause of death in people who have thalassaemia. Heart diseases include congestive heart failure, arrythmias(irregular heartbeat), heart attack

Infection
Infections are a key cause of illness and second most common cause of death. Thalassaemia increases the risk of developing a blood-borne infection related to blood transfusions, such as hepatitis which can damage the liver.

Bone deformities
Thalassaemia can make your bone marrow expand which causes bones to widen. This can result in abnormal bone structure. Abnormalities include skeleton and skull deformality, thickening skull and facial bones. Bane marrow expansion also makes bones thin and brittle, increasing the chance of broken bones, especially the spine. Spine fractures can result in compression of the spinal cord. This also causes osteoporosis which is a condition where the bones are weak, brittle and break easily.

Splenomegaly (Enlarged Spleen)
Spleen helps the body to fight infections and filter unwanted materials like old or damaged blood cells. Thalassaemia often destroys a large number of red blood cells, making the spleen work harder, causing it to enlarge. Splenomegaly can worsen anaemia and can reduce the life of transfused red blood cells. If the spleen is too big it may need to be removed.

Anemia
Thalassaemia can cause anemia which is a condition where there is a deficiency of hemoglobin. Hemoglobin carries oxygen from lungs to the tissues, so lack of hemoglobin causes hypoxia. Anemia can also lead to anisocytosis which is a blood abnormality where the red blood cells are of unequal sizes. Anemia can cause a child’s growth to slow down. Children with severe thalassaemia will rarely reach a normal adult height. Puberty may also be delayed because of endocrine problems.

Still Birth
Still birth is when a woman delivers a child who is dead. This happens when the patient has homozygous alpha thalassaemia.

Pathogenesis and genetics of thalassemia.

The two main forms of the disease, α-thalassemia and β-thalassemia, result from mutations in genes encoding the respective globin chains (α-globin: genes HBA1 and HBA2; β-globin: gene HBB on chromosome [1]). Both forms are inherited as recessive alleles. Individuals with α-thalassemia have reduced production of α-globin chains, which leads to a relative excess of β-globin chains and, in turn, to the formation of unstable tetramers that have abnormal oxygen dissociation curves. In β-thalassemia, for which more than 200 gene mutations have been identified [2], a reduction in β-globin production occurs, which leads to a relative excess of α-globin chains. These chains do not, however, form tetramers. Instead, they bind to erythrocyte membranes causing membrane damage and, at higher concentrations, have the tendency to form toxic aggregates. The severity and required treatment regimen of both diseases depends upon the type of mutation and whether the carrier is heterozygous or homozygous to the disease.
Alpha Thalassemia
Alpha thalassemia occurs when one or more of the four alpha chain genes fails to function. Alpha chain protein production, for practical purposes, is evenly divided among the four genes. Alpha thalassemia has four manifestations that correlate with the number of defective genes. Since the gene defect is almost invariably a loss of the gene, there are no "shades of function" to obscure the matter as occurs in beta thalassemia.
(i) Silent carrier state. This is the one-gene deletion alpha thalassemia condition. People with this condition are hematologically normal. They are detected only by sophisticated laboratory methods. The loss of one gene diminishes the production of the alpha protein only slightly. A person with this condition is called a "silent carrier" because of the difficulty in detection.
(ii) The loss of two genes (two-gene deletion alpha thalassemia) produces a condition with small red blood cells, and at most a mild anemia. People with this condition look and feel normal. The condition can be detected by routine blood testing, however. It is called mild alpha-thalassemia. These patients have lost two alpha globin genes.
(iii) Patients with this condition have a severe anemia, and often require blood transfusions to survive. The severe imbalance between the alpha chain production (now powered by one gene, instead of four) and beta chain production (which is normal) causes an accumulation of beta chains inside the red blood cells. Normally, beta chains pair only with alpha chains. With three-gene deletion alpha thalassemia, however, beta chains begin to associate in groups of four (tetramers), producing an abnormal hemoglobin, called "hemoglobin H". The condition is called "hemoglobin H disease". Hemoglobin H has two problems. First it does not carry oxygen properly, making it functionally useless to the cell. Second, hemoglobin H protein damages the membrane that surrounds the red cell, accelerating cell destruction. The combination of the very low production of alpha chains and destruction of red cells in hemoglobin H disease produces a severe, life-threatening anemia. Untreated, most patients die in childhood or early adolescence. The result is a severe anemia, with small, misshapen red cells and red cell fragments. These patients typically have enlarged spleens. Bony abnormalities particularly involving the cheeks and forehead are often striking. The bone marrow works at an extraordinary pace in an attempt to compensate for the anemia. As a result, the marrow cavity within the bones is stuffed with red cell precursors. These cells gradually cause the bone to "mold" and flair out. Patients with hemoglobin H disease also develop large spleens. The spleen has blood forming cells, the same as the bone marrow. These cells become hyperactive and overexpand, just as those of the bone marrow. The result is a spleen that is often ten-times larger than normal. Patients with hemoglobin H disease often are small and appear malnourished, despite good food intake. This feature results from the tremendous amount of energy that goes into the production of new red cells at an extremely accelerated pace. The constant burning of energy by these patients mimics intense aerobic exercise; exercise that goes on for every minute of every day.

(iv) Hydrops fetalis. The loss of all four alpha genes produces a condition that is incompatible with life. Hemoglobin Barts develops in fetuses with four-gene deletion alpha thalassemia. During normal embryonic development, the episilon gene of the alpha globin gene locus combines with genes from the beta globin locus to form functional hemoglobin molecules. The episolon gene turns off at about 12 weeks, and normally the alpha gene takes over. With four-gene deletion alpha thalassemia no alpha chain is produced. The gamma chains produced during fetal development combine to form gamma chain tetramers. These molecules transport oxygen poorly. Most individuals with four-gene deletion thalassemia and consequent hemoglobin Barts die in utero (hydrops fetalis). The abnormal hemoglobin seen during fetal development in individuals with four-gene deletion alpha thalassemia was characterized at St. Bartholomew's Hospital in London. The hospital has the fond sobriquet, St. Barts, and the hemoglobin was named "hemoglobin Barts."


Beta Thalassemia

The fact that there are only two genes for the beta chain of hemoglobin makes beta thalassemia a bit simpler to understand than alpha thalassemia. Unlike alpha thalassemia, beta thalassemia rarely arises from the complete loss of a beta globin gene. The beta globin gene is present, but produces little beta globin protein. The degree of suppression varies. Many causes of suppressed beta globin gene expression have been found. In some cases, the affected gene makes essentially no beta globin protein (beta-0-thalassemia). In other cases, the production of beta chain protein is lower than normal, but not zero (beta-(+)-thalassemia). The severity of beta thalassemia depends in part on the type of beta thalassemic genes that a person has inherited.
(i) one-gene beta thalassemia has one beta globin gene that is normal, and a second, affected gene with a variably reduced production of beta globin. The degree of imbalance with the alpha globin depends on the residual production capacity of the defective beta globin gene. Even when the affected gene produces no beta chain, the condition is mild since one beta gene functions normally. The red cells are small and a mild anemia may exist. People with the condition generally have no symptoms. The condition can be detected by a routine laboratory blood evaluation. (Note that in many ways, the one-gene beta thalassemia and the two-gene alpha thalassemia are very similar, from a clinical point of view. Each results in small red cells and a mild anemia).
(ii) two-gene beta thalassemia produces a severe anemia and a potentially life-threatening condition. The severity of the disorder depends in part on the combination of genes that have been inherited: beta-0-thal/ beta-0-thal; beta-0-thal/ beta-(+)-thal; beta-(+)-thal/ beta-(+)-thal. The beta-(+)-thalassemia genes vary greatly in their ability to produce normal hemoglobin. Consequently, the clinical picture is more complex than might otherwise be the case for three genetic possibilities outlined.
Features

(i) Thalassemia minor, or thalassemia trait. These terms are used interchangeably for people who have small red cells and mild (or no) anemia due to thalassemia. These patients are clinically well, and are usually only detected through routine blood testing. Physicians often mistakenly diagnose iron deficiency in people with thalassemia trait. Iron replacement does not correct the condition. The primary caution for people with beta-thalassemia trait involves the possible problems that their children could inherit if their partner also has beta-thalassemia trait. These more severe forms of beta-thalassemia trait are outlined below.
(ii) Thalassemia intermedia. Thalassemia intermedia is a confusing concept. The most important fact to remember is that thalassemia intermedia is a description, and not a pathological or genetic diagnosis. Patients with thalassemia intermedia have significant anemia, but are able to survive without blood transfusions. The factors that go into the diagnosis are:
• The degree to which the patient tolerates the anemia.
• The threshold of the physician to transfuse patients with thalassemia.
With regard to the tolerance of the anemia, most patients with thalassemia have substantial symptoms with a Hb of much below 7 or 8 gm/dl. With hemoglobins of this level, excess energy consumption due to the profound hemolysis can produce small stature, poor weight gain, poor energy levels, and susceptibility to infection. Further, the extreme activity of the bone marrow produces bone deformities of the face and other areas, along with enlargement of the spleen. The long bones of the arms and legs are weak and fracture easily. Patients with this clinical condition usually do better with regular transfusions. The need for regular transfusions would then place them under the heading of thalassemia major (see below). On the other hand, some patients with marked thalassemia can maintain a hemoglobin of about 9 to 10 gm/dl. The exercise tolerance of these patients is significantly better. The question then becomes whether the accelerated bone marrow activity needed to maintain this level of hemoglobin causes unacceptable side-effects such as bone abnormalities or enlarged spleen. This is a judgment decision. A given patient at the critical borderline would be transfused by some physicians to prevent these problems, even if they are slight. The patient then would be clinically classified as having thalassemia major. Another physician might choose to avoid the complications of chronic transfusion. The same patient then would be clinically classified as thalassemia intermedia. The patient has thalassemia that is more severe than thalassemia trait, but not so severe as to require chronic transfusion as do the patients with thalassemia major.
A patient can change status. The spleen is enlarged in these patients. The spleen plays a role in clearing damaged red cells from the blood stream. Since all of the red cells in patients with severe thalassemia have some degree of damage, clearance by the spleen accelerates the rate of cell loss. Therefore the bone marrow has to work harder to replace these cells. In some patients, removal of the spleen slows the rate of red cell destruction just enough, that they can manage without transfusion, and still not have the unacceptable side-effects. In this case, the patient converts clinically from thalassemia major to thalassemia intermedia.
(iii) Thalassemia major. (also known as Cooley's anemia) This is the condition of severe thalassemia in which chronic blood transfusions are needed (3). In some patients the anemia is so severe, that death occurs without transfusions. Other patients could survive without transfusions, for a while, but would have terrible deformities. While transfusions are life-saving in patients with thalassemia major, transfusions ultimately produce iron overload.Chelation therapy, usually with the iron-binding agent, desferrioxamine (Desferal), is needed to prevent death from iron-mediated organ injury.

Savior Siblings Ethically, Socially and Legaly

Savior Siblings Ethically, Socially and Legally

(Summary)

Ethically and socially

Against

- Dealing with children as means (commodity).

- Lead to the acceptance of other bad things (designer babies).

- Damage to the welfare of a child (physical and psychological).

- Creating children isn’t wrong so much as sacrificing other lives.

- What if it didn’t work?

- Consent issues

For

-In many cases parents use children as means (save a marriage, being a playmate for an existing child, delighting grandparents) the problem really is using them as mere means.

- the reason differ in designer babies than in saviour siblings. the later is to save a life unlike the former.

- maybe it will get the siblings closer together and they will feel proud to have saved their brothers. their parents still can love them as much.

- welfare of the family as a whole.

- well do we consider the zygotes as lives at this stage?

- what do you expect from a mother watching her child dying? she would do what ever possible !

Legally

It is a controversial issue and some countries allow it, others don’t.

Generally it is not allowed.

In the UK, they started to allow it for serious illnesses only.

Treatment (Gene Therapy)

by Farhana

Gene Therapy for Thalassemia Major
An Introduction to Gene Therapy for Thalassemia Major
Thalassemia research scientists are working to develop a gene therapy that may offer a cure for thalassemia. They are currently looking at two gene therapy treatments:

•Beta-globin gene and stem cells
•Medications and fetal hemoglobin.

Gene Therapy for Thalassemia Major: Beta-Globin and Stem Cells
This type of gene therapy for thalassemia major might involve inserting a normal beta-globin gene (the gene that is abnormal in this disease) into the patient's stem cells, which are the immature bone marrow cells that are the precursors of all other cells in the blood.

Gene Therapy for Thalassemia Major: Medications and Fetal Hemoglobin
Another form of gene therapy for thalassemia major could involve using drugs or other methods to reactivate the patient's genes that produce fetal hemoglobin, which is the form of hemoglobin found in fetuses and newborns. Scientists are seeking ways to activate these genetic switches so that they can make the blood cells of individuals with beta thalassemia produce more fetal hemoglobin to make up for their deficiency of adult hemoglobin.

Scientists hope that spurring production of fetal hemoglobin will compensate for the patient's deficiency of adult hemoglobin.


For beta thalassemia(but not available yet)
Thalagen™: Gene Therapy Treatment for Thalassemia
Thalagen™ is the brand name for EGT's gene therapy treatment for beta thalassemia, also referred to as Cooley's anemia. To date there is no curative therapy for thalassemia, a disease characterized by the cells of the bone marrow having an inability to produce normal hemoglobin. Currently, patients are treated with transfusion therapy, which aims to correct the anemia, suppress massive erythropoiesis and inhibit gastrointestinal absorption of iron. However, transfusion therapy worsens the iron overload, which over time is lethal if not treated.
Gene therapy is considered by most expert blood specialists as the most promising, long-term and cost-effective treatment of thalassemia. The objective of gene therapy is to insert the "normal" gene for hemoglobin into the DNA of the patient's bone marrow cells. The putative treatment procedure requires the collection of bone marrow hematopoietic stem cells from the thalassemic patient in the hospital followed by the treatment of these cells in the laboratory with the virus vector containing the gene for the production of normal hemoglobin. The treated bone marrow cells are then returned to the patient to begin the production of red blood cells with normal hemoglobin.
The proprietary EGT technology of Thalagen™ is anticipated to be:
•Erythroid-specific for elevated expression of the inserted human β-globin gene
•Long-term, producing sustained expression of the human β-globin gene
This method has been approved in April 2007.

Links:
1. http://blood.emedtv.com/thalassemia-major/gene-therapy-for-thalassemia-major.html
2. http://organizedwisdom.com/helpbar/index.html?return=http://organizedwisdom.com/Gene_Therapy_for_Thalassemia&url=www.errantgene.com/Product_Pipeline-Thalagen.shtml
3. http://organizedwisdom.com/helpbar/index.html?return=http://organizedwisdom.com/Gene_Therapy_for_Thalassemia&url=www.marchofdimes.com/pnhec/4439_1229.asp#head8

Genetic Counselling

Genetic Counselling

What is genetic counselling?
process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease.

This process integrates the following:
-Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence.
- Education about inheritance, testing, management, prevention, resources and research.
- Counseling to promote informed choices and adaptations to the risk or condition.
- Diagnostic, carrier, predictive and presymptomatic genetic testing where appropriate

Who does it?
- clinical geneticist (with medical expertise, especially in making diagnosis)
- genetic counsellors (graduate health professionals with certified special training)
- social workers (special interest in genetics – works with geneticist, counsellors and support groups)

Indications for Genetic Counselling
- child born with a possible genetic problem
- parents or other family members who are concerned with well being of future children
- repeated miscarriages
- increasing maternal age
- family history of genetic disorders
- consanguineous couple
- concern about exposure to environmental agents such as drugs, medication, chemicals or radiation that might cause birth defects.

Process for Genetic Counselling
1.Assessment: Gathering information
-Explore with the patient and family their perceptions
(refer to site for more info)
-Gather history
-Pedigree analysis
-Review family’s social history (education, employment)
-Sources of psychosocial support
-Identify potential ethical issues (confidentiality, insurability, discrimination)
-Perform physical examination as needed.

2.Evaluation: Interpreting medical and family history, results of physical examination and tests
-Consult relevant references.
-Compare patient's history and exam to known diagnoses.
-Discuss diagnostic impression.
~Clear diagnosis - Share information about the condition
~Differential diagnosis - Suggest further tests or evaluations
~Unknown diagnosis - Discuss what known diagnoses are ruled out, follow over time

3.Communication: Sharing information about the condition (within the family's ability to understand the information)
Review the details about the disorder in question including:
-Expected course of the disease
-Management issues, and possible treatments or interventions
-Underlying genetic cause if known, including pattern of inheritance
-Describe risks to family members compared with general population risks.
-Discuss reproductive options

4. Support: Helping the family cope
-Recognize and discuss the emotional responses
-Explore strategies for communicating information to others, especially family members who may be at risk.

5.Follow-up: Maintaining ongoing communication
-Arrange for follow-up diagnostic testing or management appointments
-Document the content of the consultation
-Contact the patient to assess level of understanding and response to decisions made.
-Be available to answer future questions.

Interpretation of Risk
By pedigree analysis, genetic testing.

Predictive Testing
use of a genetic test in an asymptomatic person to predict future risk of disease (eg. Huntingtons)
The hope underlying such testing is that early identification of individuals at risk of a specific condition will lead to reduced morbidity and mortality through targeted screening, surveillance, and prevention.

Issues: individual versus family
Current versus future

Links
http://www.genetics.com.au/pdf/factsheets/fs03.pdf
http://kidshealth.org/parent/medical/genetic/genetic_counseling.html?tracking=P_RelatedArticle#
http://www.bmj.com/cgi/content/full/322/7293/1052

Predisposing factors (risk factors) and Inheritance of Thalassemia

Most thalassemias are very common in and originate from the regions surrounding the Mediterranean Ocean, including parts of the European coast, Middle East, and Africa, regions of the world that are most ancient. Thalassemias have been around for a long time, and there is no single "carrier" who is responsible for being the first; rather, several people probably received mutations randomly. The Mediterranean regions are known for giving rise to new genetic syndromes, possibly because the areas are ancient, population dense, and near the equator(it is a theory that exposure to more UV light can cause more mutations in a population).  

Factors that increase your risk of thalassemia include: 

1) Family history. Thalassemia is passed from parents to children through defective haemoglobin genes.  

2) Ancestry The list of risk factors mentioned for Thalassemia in various sources includes: • Italian descent • Greek descent • Mediterranean descent • North African descent • South-East Asian descent • Chinese • Southern European In recent years, thalassemias have become more common in the United States, largely due to increasing numbers of immigrants from Southeast Asia.  

Inheritance 

Alpha Thalassemias  

Four genes (two from each parent) are needed to make enough alpha globin protein chains. If one or more of the genes is missing, you will have alpha thalassemia trait or disease. This means that you don't make enough alpha globin protein. If you have only one missing gene, you're a silent carrier and won't have any signs of illness. If you have two missing genes, you have alpha thalassemia trait (also called alpha thalassemia minor). You may have mild anemia. If you have three missing genes, you likely will have hemoglobin H disease (which a blood test can detect). This form of thalassemia causes moderate to severe anemia. Very rarely, a baby will have all four genes missing. This condition is called alpha thalassemia major or hydrops fetalis. Babies with hydrops fetalis usually die before or shortly after birth.

 

Beta Thalassemias 

Two genes (one from each parent) are needed to make enough beta globin protein chains. If one or both of these genes are altered, you will have beta thalassemia. This means that you don't make enough beta globin protein. • 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. The major form causes severe anemia.

Inheritance patterns: 

There are various clear patterns common to any autosomal recessive genetic disease:

· Children of an affected person will typically not have the disease (except in the rare case that they too marry someone who is also affected or a carrier of exactly the same disease), but the odds are 100% the child will be a carrier. The affected parent has two bad copies of the gene, so the child gets a bad gene from that parent, but usually a good second copy from the other unaffected parent.  

· If only one parent is a carrier (and the other unaffected), the child cannot get the disease, but might still be a carrier (typically 50% chance of being a carrier).  

· If both parents are a carrier, there is a 25% chance that their child will have the disease. There is also a 50% chance the child will be a carrier, and only 25% chance the child will be neither diseased nor carrier. The situation where both parents are carriers is the most likely way that children with the disease are born.  

· If one parent has the disease, and the other is a carrier, a child has a 50% chance of getting the disease, and 50% chance of being a carrier. The child definitely gets one bad gene from the diseased parent, and has a 50% chance of getting a second one from the carrier parent.  

· Other children: If parents have one affected child, the odds of a second are usually 25%. If parents have a child with the disease, this almost always means that they are both carriers. The chances a second child will also have the disease are the same as above for two parent carriers: 25% chance of disease, 50% chance the second child is a carrier, and 25% chance of neither disease nor carrier. Note that genetic testing can often detect the rarer case where a child gets a genetic disease without both parents being carriers (perhaps only one is a carrier). 

 

· Gender bias: Male or females get the disease equally, because an autosomal error is unrelated to the sex chromosomes. · Inheritance patterns tend to be "horizontal", which a generation being affected (i.e. many siblings of the same parents), but not their parents nor their own children. Parents and next-generation children will usually be carriers.  

Sporadic cases: A genetic disease that occurs when neither parent has any genetic defect is called asporadic genetic disease. These cases arise via random genetic mutations in the DNA. A sporadic genetic mutation is not likely as a cause of an autosomal recessive disease, because it would require two identical random mutations (one in each copy of the gene) at the same time.

http://www.mayoclinic.com/health/thalassemia/DS00905/DSECTION=risk-factors

http://www.wrongdiagnosis.com/t/thalassemia/inherit.htm

http://www.healthscout.com/ency/68/477/main.html

http://yourtotalhealth.ivillage.com/thalassemias.html?pageNum=4#4

http://en.allexperts.com/q/Genetics-1795/thalassemia-1.htm

Types of thalassaemia

What are the different types of thalassaemia?

The main types of thalassaemia are called alpha thalassaemia and beta thalassaemia. (The alpha and beta refer to which haemoglobin gene is affected, and which of the haemoglobin chains is faulty.) There are some rarer types too.

Each type of thalassaemia (alpha and beta) is then classified into more types, according to how severe the condition is. This mainly depends on how many thalassaemia genes are involved. The mildest types are called thalassaemia trait (or thalassaemia minor). The more severe beta types are beta thalassaemia major and beta thalassaemia intermedia. The more severe alpha forms are Hb Barts (very severe) and Hb H disease (moderate). These are explained below. There are also some rarer types of thalassaemia such as delta beta thalassaemia, or combinations of a beta thalassaemia gene with another abnormal haemoglobin gene such as HbE.

Thalassaemia trait (thalassaemia minor)

This means that you carry a thalassaemia gene, but can still make enough normal haemoglobin. So, you will not have any symptoms or problems from the thalassaemia. You will not know you have it unless you have a special blood test. However, it can be useful to know your diagnosis because:

• Some types of thalassaemia trait give you a very mild type of anaemia, where your red blood cells are smaller and paler than usual (described in lab reports as 'microcytic and hypochromic'). This can be mistaken for iron deficiency.
• Your children can inherit the gene. By itself this is not a problem. However, if your partner also has a similar gene, your children might get a double dose of the abnormal haemoglobin gene and could inherit a severe form of thalassaemia. It is possible to arrange tests for parents or for an unborn baby, to see whether the baby could be affected.

There are three types of thalassaemia trait:

• Alpha plus thalassaemia trait. This means that you have one missing alpha haemoglobin gene. (Normally there are four of these genes.) This trait can ONLY cause a problem if your partner has alpha zero thalassaemia trait - in which case your children might inherit Hb H disease (explained below). Apart from that situation, it will not affect you or your children.
• Alpha zero thalassaemia trait. This means you have two missing alpha haemoglobin genes (out of the normal four alpha genes). It will not make you ill, but if your partner also has alpha zero thalassaemia trait, your children might inherit a severe condition called Hb Barts (explained below). Or, if your partner has alpha plus thalassaemia trait, then your children might inherit Hb H disease (see below).
• Beta thalassaemia trait. This means you have one abnormal beta haemoglobin gene (out of the normal two beta genes). It will not make you ill. But, if your partner also has beta thalassaemia trait, then your children could inherit beta thalassaemia major or beta thalassaemia intermedia (see below). Beta thalassaemia trait can also interact with other abnormal haemoglobin genes which are not thalassaemias. For example, if your partner has a gene for sickle cell anaemia, then your children might inherit a serious condition called sickle cell/beta thalassaemia (see below).

Beta thalassaemia major

A person with beta thalassaemia major has two beta thalassaemia genes. Most of their haemoglobin is abnormal and does not work. This causes severe anaemia starting around the age of 4-6 months. Before that, the baby is not affected. This is because until age 3-6 months the baby makes a different type of haemoglobin called fetal haemoglobin which is not affected by the thalassaemia gene. With beta thalassaemia major, you need regular blood transfusions, plus other treatment to prevent complications.

Beta thalassaemia intermedia

As the name suggests, this type is less severe than beta thalassaemia major. You have two beta thalassaemia genes but can make some haemoglobin which works reasonably well. This may be because your particular combination of thalassaemia genes is (in effect) less severe, or because of some other protective factor. Although less severe than thalassaemia major, thalassaemia intermedia does need regular monitoring for life and often needs some treatment to prevent complications.

Sickle cell/beta thalassaemia

This can occur if one parent has a beta thalassaemia gene, and the other parent carries a gene for a different haemoglobin disorder called sickle cell anaemia. If their child inherits one of each gene, the combination is called sickle cell/beta thalassaemia - also called 'sickle cell disease'. This condition behaves like sickle cell anaemia (not like thalassaemia) and is treated in the same way as sickle cell anaemia. See separate leaflet called 'Sickle Cell Disease and Sickle Cell Anaemia' for more detail.

Hb H disease

This is a type of alpha thalassaemia. It is due to having three missing alpha haemoglobin genes (normally each person has 4 of these genes). This can happen if one parent has alpha plus thalassaemia and the other has alpha zero thalassaemia. It usually causes a mild but persistent anaemia. Sometimes Hb H causes more symptoms and is similar to beta thalassaemia intermedia (explained below). Some people with Hb H disease need blood transfusions.

Hb Barts

This is the most severe form of thalassaemia, where all the alpha haemoglobin genes are abnormal or missing. It occurs if a baby inherits two alpha zero thalassaemia genes. In this condition, no normal haemoglobin can be made, even before birth. It is the most serious form of thalassaemia - so serious that the baby will usually die in the womb from severe anaemia. There have been rare cases where the baby was saved by giving blood transfusions in the womb, and then continuing the transfusions after birth.

Link : http://www.patient.co.uk/showdoc/23068993/

INCIDENCE & PREVALENCE OF THALASSAEMIA

 

Thalassaemia is carried by 150 million or 3% of the world population. It is clinically apparent in 15 million people. It is particularly associated with people of Mediterranean origin, Arabs, and Asians. Certain types of thalassaemia are more common in specific parts of the world.

Alpha thalassaemia is common in those parts of the world where malaria is endemic.

Beta thalassaemia is much more common in Mediterranean countries such as Greece, Italy, and Spain. Many Mediterranean islands, including Cyprus, Sardinia, and Malta, have a significantly high incidence of severe beta thalassaemia, constituting a major public health problem. For instance, in Cyprus, 1 in 7 individuals carries the gene, which translates into 1 in 49 marriages between carriers and 1 in 158 newborns expected to have beta thalassaemia major.

Beta thalassaemia is also common in North Africa, the Middle East, India, and Eastern Europe. On the other hand, alpha thalassaemia is more common in Southeast Asia, India, the Middle East, and Africa.

The carrier rates for thalassaemia are:

• 1 in 7 Cypriots
  
• 1 in 12 Greeks
  
• 1 in 10 Gujeratis
  
• 1 in 10 Sindhis
  
• 1 in 20 South Indians
  
• 1 in 25 Pakistanis
  
• 1 in 15 to 1 in 30 Punjabis and Bangladeshis
  

In Malaysia, thalassaemia is a public health problem among the Malays and Chinese where Indians form only a small percentage of those with thalassaemia.

• Hb E and β thalassaemia are the most common inherited hematologic disorders. The carrier rate for beta thalassaemia is around 3 to 5 percent.
  
• Estimated number of beta-thalassaemia carriers is 60,000.
  
• Estimated number of beta-thalassemia major and HbE beta-thalassemia are 5000.
  
• There is also an estimated 120 to 240 new cases of beta thalassaemia major each year and about 61 with Hb Barts hydrops fetalis.
  

In 1995, about 40% of Hb E beta thalassaemia and beta thalassaemia were dependent on regular blood transfusions for survival. Since there is no national screening policy, national Thalassaemia trait (carrier) registry or registry of beta Thalassaemia major patients, the current figures available are presumptive, derived from population studies data of various research workers in the country. Based on an estimated population of 22.7 million, the number of cases afflicted with beta Thalassaemia major is 2140 among Malays and 2240 among Chinese. Sabah appears to have a higher incidence of Thalassaemia major, with 676 cases registered with the Thalassaemia Association of Sabah.

For alpha thalassaemia, a study done by University of Malaya in 2005 on 650 pregnant women shows that

• 15.8% of the pregnant women were confirmed as α-thalassaemia carriers.
  
• The double Southeast Asian (--SEA) double alpha-globin gene deletion was significantly higher in the Chinese (15%) compared to the Malays (2.5%) and not detected in the Indians studied.
  

http://www.moh.gov.my/MohPortal/DownloadServlet?id=727&type=2

http://www.medic.upm.edu.my/FPSK/Penyelidikan/

http://www3.interscience.wiley.com/journal/118666291/abstract?CRETRY=1&SRETRY=0

http://www.patient.co.uk/showdoc/40001022/

http://emedicine.medscape.com/article/958850-overview

 

Signs and symptoms of Thalassemia

SIGNS AND SYMPTOMS OF THALASSEMIA
Signs and symptoms of thalassemias are due to lack of oxygen in the bloodstream. This occurs because the body doesn't make enough healthy red blood cells and hemoglobin. The severity of symptoms depends on the severity of the disorder
Alpha thalassemia silent carriers
· generally those who are the silent carriers have no signs or symptoms of the disorder. This is because the lack of alpha globin protein is so small that hemoglobin works normally.
Alpha or Beta Thalassemia trait
· can result in mild anemia
· Mild anemia can make you feel tired
· However most people with this type of thalassemia have no signs or symptoms.
Beta Thalassemia Intermedia
· Can result in mild to moderate anemia
· Also associated with other health problems such as:
· Slowed growth and delayed puberty. Anemia can slow down a child's growth and development.
· Bone problems. Thalassemia may make bone marrow (the spongy material inside bones that makes blood cells) expand. This causes wider bones than normal. Bones also may be brittle and break easily.
· An enlarged spleen. The spleen is an organ that helps your body fight infection and remove unwanted material. When a person has a thalassemia, the spleen has to work very hard. As a result, the spleen becomes larger than normal. This makes anemia worse. If the spleen becomes too large, it must be removed.









Beta thalassemia major
· Pale appearance
· Poor appetite
· Dark urine
· Slowed growth and delayed puberty
· Jaundice(a yellowish color of the skin or whites of the eyes)
· Enlarged spleen ,liver, heart
· Bone deformities (especially bones in the face)
· Pallor
· Fatigue
· Tiredness
· Weakness
· Shortness of breath
· Blood in urine
· Skull deformity
· Skeleton deformity
· Thickening skull
· Thickening facial bone
· lack of beta globin causes a life-threatening anemia
· Therefore requires regular blood transfusions
· Life long transfusions lead to iron overload
· Must be treated with chelation therapy to prevent early death from organ failure.
Haemoglobin H disease
— Severe anemia
— Fatigue
— Pale appearance
— Poor appetite
— Dark urine
— Slowed growth and delayed puberty
— Jaundice(a yellowish color of the skin or whites of the eyes)
— Enlarged spleen
— Bone deformities (especially bones in the face)
E Beta Thalassemia
— Has similar symptoms to Beta Thalassemia Intermedia but at times the symptoms can be as severe to Beta Thalassemia Major

Screening and Diagnosis

How are Thalassemia diagnosed :

ž Complete blood count (CBC)

ž Haemoglobin electrophoresis

ž Family genetic study

ž Antenatal test : Amniocentesis

Complete Blood Count (CBC)

ž Test using electronic blood cell counter

ž Blood is drawn from vein In

— Arm

— Fingerstick

— heelstick

ž Automated count of the cells in the blood.

ž Provide information of WBC, RBC and platelet populations present

— Number

— Type

— Size

— Shape

ž Compare to normal ranges of blood populations and abnormalities are noted

ž Mean Corpuscular Volume (MCV)

— Smaller than normal

ž Mean Corpuscular Haemoglobin (MCH)

— Weight lighter than normal RBC

— Paler than normal RBC

ž Test for total conc. of haemoglobin

— Lower conc. of haemoglobin

Haemoglobin Electrophoresis Test

ž Identifies abnormal Hb proteins by the way they migrate in an electric field.

ž Separating the Hb from each other

— Allow the identification of diff. types of Hb.

ž Eg. Beta-thalassemia

— X Hb A

— High level of Hb F

ž Thalessamia intermidiate

— More Hb A than affected person but lower than unaffected person

— Higher Hb F

ž Carrier of thalessemia

— Normal level of Hb A

— Low level of Hb F

Amniocentesis (antenatal test)

ž Take a sample of amniotic fluid of placenta

ž Test done on the fluid to show whether the baby has thalassemia and how severe it it.

Genetic Studies

ž Help diagnose genetic disorder in family

— Thalassemia are passed from parents to children

ž This involves

— Taking medical history

— Doing blood tests on family members

○ To show whether there is any missing or altered Hb gene

Alternative method :

ž Modified osmotic fragility (OF) test

ž Modified dichlorophenolindophenol (DCLP) test

— They are carried together

— Less effective

— Cheaper

Iron test

ž Test on the amount of iron in the blood

— To find out whether the anaemia is due to iron deficiency or thalassemia

ž Iron-deficiency anaemia – X enough iron to make Hb

ž Anaemia in thalassemia

— Problem in alpha globin chain or beta globin chain of the Hb, not because of a lack of iron.