Screening for would-be marriage partners

By Dhaneshi YATAWARA

Today the entire world focuses on an incurable deadly disease known as Cooley's Anaemia. Never heard of it? Does the word Thalassaemia strike a bell. Cooley's Anaemia is another name or Thalassaemia Major. The word entered medical jargon after American paediatrician Dr. Thomas B. Cooley, who described the disease in 1925.

Today is world Thalassaemia Day. 'Thalassa' in Greek is for the sea and 'Haema' for blood. This easily preventable genetically transferred disease is believed to have originated in the Mediterranean region and today it is prevalent across the world largely affecting communities bringing painful experiences specially to children. Today Thalassaemia has become a major health problem for many developing countries as a result of sticking to certain extreme traditional concepts.

Thalassaemic child with abdominal protrusion

The only cause that spreads Thalassaemia is marriage between two carriers. When marriage is between two blood relatives, the probability is high for both the man and the woman to be carriers.

According to the Ministry of Health annually eighty children are born with Thalassaemia Major. As of today the health sector has to look after 1,600 thalassaemia patients spending approximately Rs. 350,000 million per year. The high risk areas in Sri Lanka are identified as Northwestern, Uva, Northcentral and Western.

Thalassaemia is a disorder in the red blood cells. In these patients red blood cells breakdown premature to its full life-span of 120 days. The actual problem lies in the haemoglobin - the most important constituent in blood carrying oxygen and giving blood its redness.

The Haemoglobin molecule has two components - haem and globin. Globin is a protein. In Thalassaemia globin production gets defective as a result of the changed genetic material. Haemoglobin is made of two proteins: Alpha globin and beta globin. Alpha thalassaemia occurs when a gene or genes related to the alpha globin protein are missing or changed. Beta thalassaemia occurs when similar gene defects affect production of the beta globin protein.

In both these types there are two forms - Thalassaemia Minor and Thalassaemia Major. The individual suffering from Thalassaemia Minor has only one copy of the defective gene together with one perfectly normal gene. Persons with Thalassaemia Minor may almost have a slight lowering of the haemoglobin level in the blood. Similar to a mild iron-deficiency anaemia. However, persons with thalassaemia minor have a normal blood iron level, unless they have iron deficient for other reasons. No treatment is necessary for Thalassaemia Minor.

Patients with Thalassaemia Major has two defective genes for thalassaemia and no normal gene. This causes a striking deficiency in beta chain production and in the production of normal adult haemoglobin. Thalassaemia Major is, therefore, a serious disorder.

In Sri Lanka

Since no one can predict the sequence of genes, Thalassaemia shows a spectrum of conditions depending on the structure of the haemoglobin molecule. "Only two have been observed in Sri Lanka - `beta' Thalassaemia and `E' Thalassaemia," said Dr. Ashok Perera the Medical Officer in Charge of the National Centre for Thalassaemia. Accordingly patients with `beta' Thalassaemia is common. "Red blood cells in Thalassaemia `E' patients shows longer life time - thus, less complications for patients.

These patients live longer than patients with `beta' thalassaemia," he added. The oldest `beta' Thalassaemia patient living in the country is 32-years-old and less number of Thalassaemia `E' patients live longer.

According to Dr. Ashok Perera in `alpha' Thalassaemia the foetus gets affected while in the mother's womb and either results in a miscarriage or a still birth. "We don't have patients with `alpha' thalassaemia since they do not live till birth," Dr. Perera explained.

Haemoglobin is not just one component - in our blood it has three categories. i.e., haemoglobin A, haemoglobin A2 and haemoglobin F (foetus). In a normal adult, haemoglobin A is in high percentage while haemoglobin F is very low. Among normal Thalassaemia patients we mostly find, haemoglobin F at a very high percentage and haemoglobin A is very low. Haemoglobin F gets destroyed very quickly thus shortening the lifespan of a red blood cell. "Hence, we cannot generalise patients. They should be examined and analysed by a special consultant doctors and a specially trained staff," Dr. Perera added.

Treatment

Treatment for Thalassaemia is still under research in the world.

Treatment for patients with Thalassaemia Major includes chronic blood transfusion therapy, iron chelation, splenectomy, and stem cell transplantation. In 2009, a group of doctors and specialists in Chennai and Coimbatore registered the successful treatment of Thalassaemia in a child using a sibling's (brother's) umbilical cord blood. The treatment - a stem cell transplant has helped the girl to get rid of the disease. According to news reports published on the web the stem cells were from two sources - her brother's umbilical cord blood that was harvested during the time of his birth and his bone marrow as the number of stem cells from the cord blood was insufficient.

Since Thalassaemic patients experience anaemia, in order to fill up the deficiency the body tends to produce more haemoglobin even at extraordinary points. Normally red blood cells are produced in the bone marrow at the end of long bones of our body. To meet the demand in a Thalassaemia patient even maxillary bone marrow will start producing red blood cells. The liver and the spleen are the other two organs that get affected due to this excessive haemoglobin production. Hence the two organs enlarge resulting a protruded abdomen. The facial and forehead bones start to overgrow, trying to give more space for the bone marrow. Hence, protrusions of the forehead and cheeks result.

A child would start showing these symptoms five years onwards.

The initial symptoms becomes visible in a child since 4 - 5 months from birth. "Lack of redness under the eye, inadequate weight gain, less active, poor sucking, more prone to infections and eyes get yellow in colour are - these are the most common ones. As the iron deposits under the skins it becomes unusually dark in colour," Dr. Perera explained further.

To provide more space for bone marrow for maximum red blood cell production the cavity enlarges and the shaft becomes thin. This results in fragile bone structure.

Naturally these people have a high iron absorption rate to fill up the deficiency as a natural adaptation of the body. "In addition to keep haemoglobin at an optimum level monthly blood transfusion (2 - 3 days per month) is required. This results in excessive level of iron deposits in the body which needs to be removed using drugs," he added.

Iron is a foreign element to the body, thus it will have a negative impact on the body's most vital organs. The heart tends to get enlarged and later the patient maybe prone to heart failure. As the endocrine system gets affected, i.e. organs like the pituitary gland, pancreas etc. the body faces a hormone imbalance. With the irregular production of insulin Thalassaemic patients are prone to diabetes. Secretion of hormones affecting the secondary sexual growth imbalances, reducing the growth of the child.

However, the final responsibility lies with the man and the woman who are going to marry and produce children. Are we going to continue to carry this burden to the next generation?

As this genetic disease is incurable and the cost of management is very expensive, prevention is the best option for Sri Lanka. If a married couple who are both carriers conceive a child, the couple has to take the painful responsibility of raising a child with Thalassaemia, restricting the right of the child to have a happy life. For a successful prevention program, detection of all the carriers would be ideal. In Sri Lanka if we promote to make sure that either of the partners of a couple is a non carrier the concept will be more flexible.

As it is reiterated by medical professionals, the best option to eradicate Thalassaemia is to prevent the birth of a Thalassaemia child. To treat an adolescent patient the Government spends Rs. 1 - 1.5 million per year per person. "People need to conduct blood screening, specially if they are living in areas with high Thalassaemia prevalence. This is a less complicated method," Dr. Perera said stating that it is a major step in their prevention campaigns.

The first step would be testing for full blood count which could be conducted at any medical lab islandwide, where the volume of red blood cell is measured (MCV - Mean Corpuscular Volume). Three parameters are considered - MCV, MCH (Mean Corpuscular Haemoglobin content ) and MCHC and if these are below normal levels further testing is required to differentiate patients from those having anaemic conditions. "A chemical analysis of the haemoglobin is needed next specifically to identify Thalassaemia patients and this is done through High Performance Liquid Chromatography (HPLC)," Dr. Perera explained.

"A person must identify whether he or she is a carrier or not and that should be a key factor when marriage is concerned. We call it the 21st `porondama' (horoscope factor)," Dr. Perera emphasised. This is a test readily available at any main Government Hospital done free of charge. For the Government it only costs Rs. 40 per test. After testing the blood, a pink card is to be issued for thalassaemia carriers and a green card to non-carriers. The Ministry of Health plans to issue details to marriage registrars of high risk areas such as the North Western, North Central and Uva Provinces. When two pink cardholders turn up to get their marriage registered the registrar will educate them on the risk of having children.

According to doctors two pink cardholders should avoid marriage or having children. Blood Screening Centres are to be set up at the Jaffna Teaching Hospital and Matara General Hospital to identify Thalassaemia carriers in the respective areas. Such centres are already functioning at all high risk areas.

The government's target is to reduce the number of children born with thalassaemia to seven per year by 2015.

Bone deformity gene discovered

The Human Genetics team at The University of Queensland Diamantina Institute have successfully used a new gene-mapping approach for patients affected by severe skeletal abnormalities.

Skeletal dysplasias are a group of diseases that cause abnormalities in the skeleton's growth and function.

This can lead to problems such as abnormal height and/or limb length, difficulty with reproduction and decreased life span. Families affected by skeletal dysplasias are usually very small in number, which can make it difficult to find the disease-causing gene for that family.

Associate Professor Andreas Zankl, a clinical geneticist from The University of Queensland Centre for Clinical Research, developed a Bone Dysplasia registry for patients and their families - the first of its kind in Australia.

Through the registry, the UQDI team of researchers met a family with two young daughters affected by a severe form of dwarfism.

The team used next-generation sequencing to simultaneously study the four immediate family members and compare their exomes - the coding section of the genes - to each other and against the reference sequence from the international Human Genome Project.

They were able to discover which gene within the family caused the abnormality. Impressively, the mapping process took only a few weeks.

The UQDI researchers then successfully determined how the genetic abnormality caused the skeletal disease.

In the past, researchers could only sequence and compare a few genes at a time, which was expensive and time-consuming.

For example, UQDI researchers had spent a decade finding the responsible gene for another type of skeletal dysplasia, fibrodysplasia ossificans progressiva.

In contrast, next-generation sequencing technology can provide more rapid results for mapping genes in these particular types of diseases.

However, despite this breakthrough in progress, Associate Professor Emma Duncan said it was still an intensive process.

"Typically, we all have a number of small genetic differences - we find approximately 20,000 on average just in our coding regions when compared with the Human Genome sequence - so it's still a very involved process to work out which one is the disease-causing mutation," she said.

"For this family, it's been a huge relief to find out why their little girls have this devastating skeletal disorder, and understanding the genetics has helped them in their planning for any future pregnancies," said Professor Matthew Brown.

With the success of their next-generation sequencing approach, the team have also researched another skeletal dysplasia case which involved five unrelated individuals, comparing their exomes with each other and with the Human Genome Project.

By examining just this small number of affected people, the responsible gene has been identified. UQDI researchers will continue to map unknown genes for skeletal dysplasias and for other likely single-gene inherited diseases.

The paper has been published in the Public Library of Science (PLoS).

(Source: The University of Queensland Diamantina Institute)

Measuring medications' effects on the heart

A common component in webcams may help drug makers and prescribers address a common side-effect of drugs called cardiotoxicity, an unhealthy change in the way the heart beats. Researchers at Brigham and Women's Hospital (BWH) have used the basic webcam technology to create a tool to look at the effects of medications in real time on heart cells, called cardiomyocytes. These findings were published in the journal, Lab on a Chip.

Researchers developed a cost-effective, portable cell-based biosensor for real time cardiotoxicity detection using an image sensor from a webcam. They took cardiomyocytes, derived from mouse stem cells, and introduced the cells to different drugs. Using the biosensor, the researchers were able to monitor the beating rate of the cardiomyocytes in real time and detect any drug-induced changes in the beating rates.

The technology provides a simple approach to perform evaluative studies of different drugs effects on cardiac cells. Cardiotoxicity is a significant problem in drug development, with more than 30 percent of drugs withdrawn from the market between 1996 to 2006 related to cardiac dysfunction. "Assessing the toxic effects of new drugs during the early phases of drug development can accelerate the drug discovery process, resulting in significant cost and time savings, and leading to faster treatment discovery," said Ali Khademhosseini, PhD, of the Center for Biomedical Engineering at the Department of Medicine at BWH.

"This technology could also play a role in personalized medicine," said Sang Bok Kim, PhD, a Research Fellow in the Renal Division at BWH. "By first extracting somatic cells from patients which can be reprogrammed to stem cells called induced pluripotent stem (iPS) cells. Then these iPS cells can be differentiated into cardiac cells to be studied, the biosensor can monitor the cardiac cells as they're introduced to a medication, providing a glimpse at how the drugs may affect the individual's heart, and thus shaping the treatment plan for that person."

Monitoring cardiac cells in the past required using expensive equipment that had a limited measurement area. This low cost biosensor is compatible with conventional equipment but will enable reliable, yet faster and more cost-effective studies.

"Our next goal is to combine our detection sensor with our microwell arrays and perform screening studies of thousands of drugs to cardiac cells simultaneously in a fast and reliable manner," said Dr.

Khademhosseini. (Source: Holly Brown-Ayers Brigham and Women's Hospital)