NHLBI, CDC launch surveillance and research program for inherited blood diseases

Courtesy by: physorg.com

Medical researchers are developing a new surveillance system to determine the number of patients diagnosed with a family of inherited blood disorders known as hemoglobinopathies, including sickle cell disease, thalassemias, and hemoglobin E disease.

The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health is funding the four-year pilot project, which will involve the Centers for Disease Control and Prevention and six state health departments, to create ways to learn more about the extent of hemoglobinopathies in the United States.
Data collected from the $27 million Registry and Surveillance System in Hemoglobinopathies (RuSH) project will help researchers determine the most effective plans for developing future hemoglobinopathy registries. Research findings based on data from disease registries may provide new ideas for drug therapies and can spur the development of tests that can determine severity of diseases over the lifespan.

To manage the surveillance efforts, the NHLBI has entered into an interagency agreement with the CDC’s National Center on Birth Defects and Developmental Disabilities. As part of the project, the CDC has developed cooperative agreements to create surveillance programs with state health departments in California, Florida, Georgia, Michigan, North Carolina, and Pennsylvania.

Hemoglobinopathies involve problems with hemoglobin, the vital blood component responsible for transporting oxygen throughout the body. Production of abnormal hemoglobin, which occurs in the family of sickle cell diseases and hemoglobin E, or production of too little hemoglobin, which occurs in the thalassemias, can cause organ damage and shorten lifespan. While all states now test newborns for some of these diseases, there is no system to track the diseases nationally. In addition, patients born before screening programs began or those who have immigrated to the United States are not tracked. These statistical gaps make it difficult to know the true impact of hemoglobinopathies in this country. RuSH will help determine how many people are affected by hemoglobinopathies. Such data are essential for public health agencies to allocate adequate resources to meet the medical and social service needs of hemoglobinopathy patients.

“While we have made great strides in developing treatments for patients with sickle cell disease and other hemoglobinopathies, RuSH stands as the first major surveillance and registry program to gather comprehensive demographic and other information on people with these life-threatening diseases,” said NHLBI Acting Director Susan B. Shurin, M.D., a hematology researcher.

Hemoglobinopathies cause health problems when abnormal hemoglobin genes are inherited from both parents. Individuals who inherit a single abnormal gene, which is called carrying a trait, have few of these health problems.

The hemoglobinopathies are most common in areas where malaria has been endemic. Sickle cell disease is the most common hemoglobinopathy in the United States and the condition affects millions worldwide. Of the estimated 70,000 to 100,000 people in the United States with sickle cell disease, most are thought to have African ancestry, although the gene also occurs among people from the Mediterranean and Middle East. The abnormal hemoglobin molecules of sickle cell disease deform red blood cells, causing them to clump together and block blood flow through blood vessels, leading to painful sickle cell crises, organ damage, anemia (lack of red blood cells), and premature death.

Life-threatening complications include infections, acute chest syndrome, stroke, and pulmonary hypertension (increased blood pressure in the lung arteries). Painful crises are the leading cause of emergency room visits and hospitalizations of people who have sickle cell disease. Life expectancy has increased dramatically with state newborn screening programs and early treatment, which can include daily penicillin treatment for patients age five and younger as well as immunizations for other diseases to prevent complications.

Patients with thalassemia syndromes produce less hemoglobin than normal, and the red blood cells that are produced are rapidly destroyed. Signs and symptoms of thalassemia can include severe anemia; slowed growth and delayed puberty; bone problems; and enlarged spleen, liver, and heart. Severely affected individuals require frequent and repeated blood transfusions and treatments to reduce the accumulation of iron in the body. Thalassemia genes are widespread across the Mediterranean, Middle East, Africa, the Indian subcontinent, and Southeast Asia.

Hemoglobin E diseases are most common among persons with ancestors from Southeast Asia. Affected individuals produce a smaller than normal number of red blood cells. Red blood cells in these individuals are smaller than normal and misshapen. These abnormal red blood cells carry less oxygen to organs. Milder forms of hemoglobin E disease may not need treatment, although affected individuals may have mild anemia. Severe forms of hemoglobin E disease can cause significant anemia, bone pain, and other complications.

Through surveillance under the initial phase of the RuSH pilot program, researchers hope to determine the prevalence of the hemoglobinopathies among screened newborns and patients not identified through newborn screening. The data should help determine the prevalence of the various conditions. The research will also help describe the demographic characteristics of individuals with these conditions as well as their geographic distribution. Researchers will also examine the existing health care resources available for patients with hemoglobinopathies.

“The data gathered through our RuSH surveillance efforts will provide critical knowledge about the current state of care available for patients who have hemoglobinopathies,” said Hani Atrash, M.D., M.P.H, director of the Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities at the CDC.

Who should consider genetic testing?

Coutresy by: wfaa.com

Inherited diseases such as cystic fibrosis often occur in families with no known risk of them.

Gene mutations can pass silently for generations until two carriers mate; then children have a one-in-four chance of getting the disease. Some insurers cover genetic testing to see if parents carry a gene, and prenatal testing to see if a baby has a disease or a condition like Down syndrome.

The risk of certain genes varies by racial and ethnic groups.

The American College of Medical Genetics says that women who are pregnant or considering pregnancy should be offered testing for cystic fibrosis, a lung disease, and spinal muscular atrophy, a relatively common and devastating neurological disorder.

If you’re an Ashkenazi, or Eastern European Jew, testing for nine diseases is recommended, including the neurological disorders Tay-Sachs, familial dysautonomia and Gaucher disease. Blacks should consider testing for sickle cell disease.

Blacks, Hispanics, Asians and Mediterranean people are more likely than other groups to carry genes that cause thalassemia, a serious blood disorder. All pregnant women should be offered testing for Down syndrome, which is caused by an extra chromosome, not hereditary genes.

Turning back the clock in inherited anaemia

Courtesy by: virtualmedicalcentre.com

Researchers at Children’s Hospital Boston and Dana-Farber Cancer Institute have identified a way to get red blood cells to produce a form of haemoglobin normally made only before birth or by young infants. This could potentially transform sickle-cell disease and beta-thalassemia – life-threatening inherited anaemia – into benign or nearly benign conditions. The findings were published by the journal Science, in its online Science Express, on December 4.
After birth, babies gradually switch from producing foetal haemoglobin (HbF) to an adult form. From population studies, it’s been known for many years that people who retain the ability to produce HbF have much milder forms of anaemia. Attempts to develop therapies to reactivate HbF directly have been hampered by a lack of understanding of how HbF production is switched off. The drug hydroxyurea often raises HbF in patients, but responses are not uniform and there are potential side effects.

Seeking a better approach, researchers Stuart Orkin, MD, a Howard Hughes Medical Institute investigator at Children’s Hospital Boston, and Vijay Sankaran, an MD-PhD student in Orkin’s lab, in collaboration with researchers at the Broad Institute of Harvard and MIT, capitalised on comprehensive gene association studies that identified DNA sequence variants (altered strings of genetic code) that correlate with HbF levels. In a study published last July, they identified five variants that influence HbF levels and disease severity in a group of 1600 patients with sickle-cell disease, the most common inherited blood disorder in the United States.

The variant with the largest effect on HbF levels contains a gene called BCL11A. Located on chromosome 2, it encodes a transcription factor, a protein that regulates activity of other genes. This turned out to be a valuable lead.

In the new study, led by Orkin and Sankaran, the team showed that BCL11A directly suppresses HbF production. When the researchers suppressed BCL11A itself in human red-blood-cell precursors, the cells began making HbF in large amounts.

“This is one of very few instances in the gene association field where one has been able to take a candidate gene and figure out what it’s doing,” says Orkin, the study’s senior investigator who is also a professor of paediatrics at Harvard Medical School and chair of paediatric oncology at Dana-Farber. “It’s pretty clear that this gene is a silencer of foetal haemoglobin. If you could knock it down to a low level, you could turn on foetal haemoglobin.”

“The discovery of a single gene that profoundly affects foetal haemoglobin levels represents a major breakthrough in the quest for effective therapies for sickle cell disease and thalassemia,” notes Elizabeth G. Nabel, MD, director of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health, which helped support the study. “Researchers can now direct their efforts at developing novel therapies aimed at a specific target that could dramatically alter the course of these often devastating blood disorders. This news should bring great hope to the millions of people worldwide affected by sickle cell disease and thalassemia.”

Increasing levels of HbF would compensate for abnormal or insufficient adult haemoglobin in sickle-cell anaemia or thalassemia, easing symptoms and in some cases achieving a virtual cure, the researchers say. The drug hydroxyurea, used in some patients with haemoglobin disorders, often raises HbF levels, but the increases are modest, it doesn’t work in all patients, it can cause toxicity, and no one knows how it works.

“While it’s been demonstrated that increased levels of HbF ameliorate the severity of sickle cell disease and beta-thalassemia, no direct strategies have yet been developed to increase HbF in these diseases,” says Sankaran. “By reducing BCL11A expression or activity, we may be able to develop targeted therapies.”

Haemoglobin is the protein in red blood cells that carries oxygen to the body’s tissues. In sickle-cell disease, haemoglobin is abnormal, forming long chains that make red blood cells stiff and sickle-shaped. In thalassemia, the body’s ability to produce haemoglobin is severely compromised. The hallmark of both disorders is anaemia that can range from mild to life-threatening. Sickle-cell disease can cause severe pain and eventual organ damage as the abnormal, sickle-shaped cells block blood vessels, robbing tissues of their blood supply; beta-thalassemia requires frequent blood transfusions and then chelation therapy to rid the blood of excess iron that also leads to organ failure.

At birth, HbF comprises between 50 to 95 percent of a child’s haemoglobin before the switch to adult haemoglobin production. The foetal form is thought to be an adaptation to the low oxygen in the foetal environment. Foetal haemoglobin has a higher affinity for oxygen, enabling it to pull oxygen more easily from the mother’s circulation.

Are there potential side effects from boosting foetal haemoglobin levels? No, the researchers say. “Some people with rare genetic deletions have 100 percent foetal haemoglobin, and they’re perfectly normal,” says Orkin.

Orkin and Sankaran are conducting further studies to figure out how the switch from foetal to adult haemoglobin production occurs and how to target BCL11A therapeutically. “Improved understanding will permit the design of therapies for reactivation of HbF in patients with sickle-cell disease or thalassemia,” says Orkin.

(Source: Science: Children’s Hospital Boston: December 2008)

In quest of comprehensive treatment facilities

Courtesy by: TheDailyStar.net

Thalassaemia is an inherited blood disease. In thalassemia, the genetic defect results in the formation of abnormal haemoglobin molecules, and this in turn causes the anaemia which is the characteristic presenting symptom of the thalassemias.

Other consequences of the disease are deposition of iron from the haemoglobin affecting the reticuloendothelial system of the body.

So the mainstay of thalassaemia treatment is blood transfusion at a regular interval and removing of iron from body by iron chelating agents.

If this can be maintained strictly, thalassaemia patients can also lead almost a normal and productive life. But most of the cases it does not happen. There remains various causes behind it.

First of all, patients seriously lack from proper knowledge about how to manage the disease and other important issues. Secondly comes the crisis of quality blood frequently. Sometimes patients get infected from poor quality blood. Thirdly, many patients cannot maintain the iron chelating agents. Sometimes availability of drug is a problem, while most often not maintaining a proper guideline is the serious issue.

Above all, handling all these issues from the childhood, patients and their families are very exhausted. Many patients are quite in a fix what to do, where to go and with many more questions.

During treatment, proper evaluation and monitoring of the patients are very crucial which are not maintained very often.

To handle all these crises of the thalassaemaia patients, Bangladesh Thalassaemia Foundation (BTF) has come forward with their comprehensive thalassaemia treatment centre named “Asha Thalassaemia Centre” in the capital.

Dr Abdur Rahim, Secretary General of Bangladesh Thalassaemia Foundation informed Star Health that they have opened the centre with a view to mitigate the problems of the patients from one stop centre. At this centre, they maintain a database of their registered patients by which they monitor their status and communicate with them in time.

“Patients in our country are not properly aware of this disease properly. We are also trying to make them aware of it so that they can cope with the disease easily”, told Dr Rahim in a brief interview at his centre.

BTF offers the source of quality blood to their patients, provides iron chelating agents from the centre, monitor the health status of the patients by the doctors at the centre, manage discounted tests from renowned laboratory. Above all they communicate with their patients frequently and when needed.

For the awareness about the disease, BTF provide proper guideline for medical care and counseling not only to the patients, but also to the physicians.

Each thalassemia patient has his or her own specific needs. Staffs of BTF hope that their comprehensive services will make a meaningful difference in both the quality and quantity of life of thalassaemia patients in the country.

The Asha Thalassaemia Center is located at 44/2, Chamelibag, Shantinagar, Dhaka 1217, Bangladesh. Phone 88-02-8332481, 01190840191 email: info@thals.org web: http://www.thals.org