The classical form of Tay-Sachs disease (TSD) is a fatal genetic disorder in children that causes progressive destruction of the central nervous system.
The disease is named for Warren Tay (1843-1927), a British ophthalmologist who in 1881 described a patient with a cherry-red spot on the retina of the eye. It is also named for Bernard Sachs (1858-1944), a New York neurologist whose work several years later provided the first description of the cellular changes in Tay-Sachs disease. Sachs also recognized the familial nature of the disorder, and, by observing numerous cases, he noted that most babies with Tay-Sachs disease were of eastern European Jewish origin.
Tay-Sachs disease is caused by the absence of a vital enzyme called hexosaminidase A (Hex-A). Without Hex-A, a fatty substance or lipid called GM2 ganglioside accumulates abnormally in cells, especially in the nerve cells of the brain. This ongoing accumulation causes progressive damage to the cells. The destructive process begins in the fetus early in pregnancy, although the disease is not clinically apparent until the child is several months old. By the time a child with TSD is three or four years old, the nervous system is so badly affected that life itself cannot be supported. Even with the best of care, all children with classical TSD die early in childhood, usually by the age of five.
A baby with Tay-Sachs disease appears normal at birth and seems to develop normally until about six months of age. The first signs of TSD can vary and are evident at different ages in affected children. Initially, development slows, there is a loss of peripheral vision, and the child exhibits an abnormal startle response. By about two years of age, most children experience recurrent seizures and diminishing mental function. The infant gradually regresses, losing skills one by one, and is eventually unable to crawl, turn over, sit, or reach out. Other symptoms include increasing loss of coordination, progressive inability to swallow and breathing difficulties. Eventually, the child becomes blind, mentally retarded, paralyzed, and non-responsive to his or her environment.
To date, there is no cure or effective treatment for TSD. However, there is active research being done in many investigative laboratories in the U.S. and around the world. The uses of enzyme replacement therapy to provide the Hex-A which is missing in babies with TSD has been explored. Although this approach is promising, scientists still face serious obstacles. Because the disease affects brain cells which are protected by the blood-brain barrier, enzymes like Hex-A are blocked from entering the brain from the blood. Bone marrow transplantation has also been attempted but to date has not been successful in reversing or slowing damage to the central nervous system in babies with TSD.
Although a cure for Tay-Sachs disease does not exist at the present time, support for families of affected children is available through organizations such as the National Tay-Sachs and Allied Diseases Association.
All of us carry genes, in pairs, located along 23 pairs of chromosomes. TSD is controlled by a pair of genes on chromosome 15; these are the genes that code for the enzyme Hex-A. If either or both Hex-A genes are active, the body produces enough of the enzyme to prevent the abnormal build-up of the GM2 ganglioside lipid. Carriers of TSD - people who have one copy of the inactive gene along with one copy of the active gene - are healthy. They do not have Tay-Sachs disease. The only significance of being a carrier is the possibility of passing the inactive gene to one's children.
A carrier has a 50% chance of passing the inactive gene on to his or her children; any child who inherits one inactive gene is a Tay-Sachs carrier like the parent. If both parents are carriers and their child inherits the inactive TSD gene from each of them, the child will have Tay-Sachs disease since he or she has inherited two inactive recessive genes and , therefore, cannot produce any functional Hex-A.
When both parents are carriers of the inactive Tay-Sachs gene, they have a 1 in 4 chance (25%) with each pregnancy that their child will have Tay-Sachs Disease, and a 3 in 4 chance (75%) that their child will be healthy. Of their unaffected children, there is a 2 in 3 chance that each child will be a carrier, like the parents. This pattern of inheritance is called autosomal recessive.
Recessive diseases such as Tay-Sachs often occur more frequently, though not exclusively, in a defined population. A person's chances of being a TSD carrier are significantly higher if he or she is of eastern European (Ashkenazi) Jewish descent. Approximately one in every 27 Jews in the United States is a carrier of the TSD gene. There is also a noticeable incidence of TSD in non-Jewish French Canadians living near the St. Lawrence River and in the Cajun community of Louisiana. By contrast, the carrier rate in the general population as well as in Jews of Sephardic origin is about one in 250.
While there are certain populations known to be at higher risk for carrying an altered Hex-A gene, anyone in any population can be a carrier of TSD. If two such individuals have children, they will have the same one in four chance, with each pregnancy, of having a child with TSD. In fact, over the past 25 years, carrier screening and genetic counseling within high-risk populations have greatly reduced the number of children born with TSD in these groups; at the same time the number of children born with TSD to couples not known a priori to be at high risk of being carriers of TSD has remained more or less constant. Therefore, a great percentage of the babies born with Tay-Sachs Disease today are born to couples who were not previously thought to be at significant risk.
Tay-Sachs most often appears in families with no prior history of the disease. The TSD gene can be carried without being expressed through many generations. Before 1970, the only way to learn if one was a Tay-Sachs carrier was to be the parent of a baby with TSD. Now, safe and reliable carrier testing is available to identify Tay-Sachs carriers. Most important, testing can identify carrier couples who are at risk for bearing a child with TSD - before a tragedy occurs. With this vital information, couples can explore the various options that will enable them to protect their families from this devastating disease.
A simple blood test can distinguish Tay-Sachs carriers from non-carriers. Blood samples can be analyzed by either enzyme assay or DNA studies. The enzyme assay is a biochemical test that measures the level of Hex-A in a person's blood. Carriers have less Hex-A in their body fluid and cells than non-carriers. (Babies with Tay-Sachs disease have a total absence of Hex-A in their cells.) The biochemical test is able to detect all Tay-Sachs carriers of all ethnic backgrounds.
Accurate biochemical testing requires laboratories to be proficient in specialized laboratory procedures and experienced in the interpretation of test results. To ensure accuracy, person seeking such carrier testing for TSD should verify that the analysis is being performed at a laboratory that participates in the Tay-Sachs Quality Control Program supported by NTSAD. A complete list of laboratories affiliated with the Quality Control Program is available on our Web site or through our Home Office.
DNA-based carrier testing looks for specific mutations, or changes, in the gene that codes for Hex-A. Since 1985, when the Hex-A gene was isolated, over 50 different mutations in this gene have been identified. Some are more prevalent than others, and a few are associated with a later-onset form of the disease, rather than with the infantile form described here.
The limitation of DNA-based carrier testing is that not all known mutations in the Hex-A gene are detected by the test, and others have yet to be identified. The tests currently available detect about 95% of carriers of Ashkenazi Jewish background and about 60% of non-Jewish individuals. Therefore, some people who are carriers will not be identified by DNA analysis alone.
DNA testing can provide very important information when used in conjunction with biochemical testing, especially in cases where both members of a couple are determined to be carriers. Knowing information about the mutations carried by each parent, and whether they are classical or Late-Onset Tay-Sachs mutations, is important if a couple chooses to undergo prenatal diagnosis.
Tay-Sachs carrier testing is vital for individuals in high-risk populations who are planning to have children. Even if your childbearing years are over, your carrier status can provide extremely important information. If you are a carrier, your close relatives (children, brothers, sisters, cousins, aunts, uncles) should be alerted to be tested as well. Tay-Sachs carrier testing is also vital for the close relatives of families with an affected child, regardless of ethnic background, since all parents of children with Tay-Sachs are, by definition, carriers.
Note: Some special considerations are involved in carrier testing of pregnant women. The best advice for women is to be tested before pregnancy. The standard biochemical test used to test males and non-pregnant women cannot be used in pregnant women because of changes in serum enzyme levels during pregnancy. Pregnant women must instead be tested using leukocytes (white blood cells). The leukocyte test is as reliable as the blood serum test, but is considerably more complex and costly. Another advantage to testing before pregnancy is that a couple is given time to consider the information they receive. If a couple is found to be at risk, they can review their options and make the necessary decisions about planning and protecting their families.
Tay-Sachs today is a preventable tragedy. Recent medical advances offer high-risk couples the means of having full, healthy families. In 1969, researchers discovered that Tay-Sachs babies lack Hex-A and that carriers of TSD have reduced amounts of Hex-A in their blood. Two years later, Hex-A levels were measured in amniotic fluid, introducing the first prenatal diagnosis for Tay-Sachs Disease.
Today, at-risk couples can choose from two available prenatal diagnostic procedures: amniocentesis and chorionic villus sampling (CVS). Amniocentesis involves removing and testing a small quantity of the fluid that bathes the fetus in the uterus. This procedure is done at approximately the 16th week of pregnancy. If Hex-A is found to be present, the fetus is not affected by TSD. On the other hand, if Hex-A is missing in fetal cells, the infant will have TSD. If the fetus is affected, the family may elect to have a therapeutic abortion. In this way, even at-risk couples can be helped to have children, as many as they wish, who are free of Tay-Sachs disease.
Chorionic villus sampling (CVS) is a newer technique. It is performed earlier in pregnancy, by the 10th week, and usually provides a test answer much sooner than amniocentesis. The cell sample is obtained by withdrawing a small bit of the developing placenta (afterbirth). Because the procedure is performed earlier than amniocentesis - often before the pregnancy shows - CVS offers couples greater privacy in their decision making as well as a safer pregnancy termination, should therapeutic abortion be necessary.
Recently, assisted reproductive technologies have become available to at-risk couples who wish to have children but for whom abortion is not an option. One option is artificial insemination by a non-carrier sperm donor. Another option, available only for couples with identified DNA mutations in the Hex-A gene, involves in-vitro fertilization using the couple's own eggs and sperm. Here, in-vitro fertilization is followed by an analysis of the DNA of the newly formed embryos to determine which carry two copies of the TSD gene and which do not; only those embryos determined not to be affected with TSD are implanted in the woman. This latter method is complex and quite expensive but is sometimes covered by insurance.
Genetic counseling is an important service available to all carrier couples to assist them in assessing their reproductive options. In addition to reviewing the various options for family planning which are currently available to high-risk couples (prenatal diagnosis by amniocentesis or CVS and selective termination of affected fetuses; adopting children; assisted reproductive technologies such as in-vitro fertilization followed by pre-implantation diagnosis or artificial insemination by a non-carrier donor; or taking a 25% risk of bearing a child with TSD), the genetic counselor can help carriers fulfill their responsibility of informing family members that they, too, may be carriers and should be tested.
--A person's chances of being a TSD Carrier are significantly higher if he or she is of Eastern European (Ashkenazi) Jewish descent.
--Tay-Sachs carrier testing is vital for individuals in high-risk populations who are planning to have children and for the close relatives of families with an affected child.
--Recent medical advances offer high-risk couples the means of having full, healthy families.