Tay-Sachs and Sandhoff diseases are inherited diseases of the central nervous system. These diseases have the same symptoms, though they are caused by mutations (changes) in different genes. A form of each disease affects babies and is fatal.

What are the symptoms of Tay-Sachs and Sandhoff diseases?
Babies with the classic (infantile) forms of Tay-Sachs and Sandhoff diseases appear healthy at birth and seem to develop normally for the first few months of life. Symptoms generally appear by about 6 months of age when an apparently healthy baby gradually stops smiling, crawling, turning over and reaching out. The baby continues to lose skills gradually and eventually becomes blind, paralyzed and unaware of surroundings. Babies with Tay-Sachs disease usually die by age 5, and those with Sandhoff disease by age 3 (1, 2).

What causes the symptoms of these diseases?
Babies with classic Tay-Sachs and Sandhoff diseases lack an enzyme (protein) called hexosaminidase. There are two versions of this enzyme, hex A and hex B. Babies with Tay-Sachs disease do not make hex A, and babies with Sandhoff do not make either hex A or hex B. A small number of babies with Tay-Sachs disease (AB variant) make both versions of the enzyme, but lack another protein that is needed for these enzymes to work properly.

Hexosaminidase is necessary for breaking down certain fatty substances (called GM2 gangliosides) in cells of the brain. Without this enzyme, these fatty substances build up and gradually destroy brain cells, until the entire central nervous system stops working.

Are there other forms of Tay-Sachs and Sandhoff diseases besides the classic type that affects babies?
There are also late-onset forms of these diseases, referred to as juvenile and adult-onset disease, depending on the nature of the symptoms and when they begin.

While babies with classic Tay-Sachs do not produce any hex A, individuals with the late-onset forms produce very small amounts of the enzyme. This is probably why their symptoms begin later in life and generally are milder than in the classic form.

Children with juvenile Tay-Sachs disease develop symptoms between 2 and 10 years of age that resemble those of the classic form (3). Although the course of the disease is slower, death generally occurs by age 15 (3).

Individuals with adult-onset Tay-Sachs disease (also called chronic Tay-Sachs disease) have far milder symptoms than children with the classic or juvenile forms. Symptoms usually begin between adolescence and the mid-30s, although they can begin in childhood (4). Affected individuals usually do not lose vision or hearing. Some individuals may have loss of certain mental abilities, including problems with memory and comprehension. Symptoms vary greatly in severity and can include slurred speech, muscle weakness, muscle cramps, tremors, unsteady gait and sometimes mental illness. Life expectancy is variable, and in some cases appears to be unaffected (4, 5).

Rare late-onset forms of Sandhoff disease appear to share many of these symptoms.

Is there any treatment for these diseases?
There is currently no treatment that will prevent these diseases from running their course. Affected children can only be made as comfortable as possible and given other supportive care.

Researchers are investigating whether stem cell transplants (sometimes called bone marrow transplants) could help babies with classic Tay-Sachs and Sandhoff diseases. Stem cells are immature blood cells that produce all other kinds of blood cells. Stem cells are obtained from umbilical cord blood or from the bone marrow of a donor. Unfortunately, stem cell transplantation has not yet been successful in stopping or reversing brain damage in Tay-Sachs or Sandhoff diseases, and this treatment poses a high risk of death in affected babies (6).

Doctors are also studying the effectiveness of drug treatments (including a drug called miglustat, which is approved by the Food and Drug Administration to treat a related disorder) in helping to reduce the build-up of fatty substances in brain cells in individuals with these diseases (7, 8).

Who is at risk for Tay-Sachs and Sandhoff diseases?
Tay-Sachs disease occurs most frequently in descendants of Central and Eastern European (Ashkenazi) Jews. About 1 out of every 30 American Jews carries a mutation in the gene that codes for hex A (9). Some non-Jewish individuals of French-Canadian ancestry (from the St. Lawrence River Valley of Quebec) and members of the Cajun population in Louisiana are also at increased risk (9). Individuals in other ethnic groups in this country have about a 1 in 300 chance of carrying a mutation in this gene (9).

Sandhoff disease can occur in any ethnic group, though it is uncommon. Individuals not of Jewish ancestry are more likely to carry one of the gene mutations that causes Sandhoff disease than those of Jewish ancestry (1 in 600 vs. 1 in 1,000) (2).

How are the diseases transmitted?
All forms of Tay-Sachs and Sandhoff diseases are inherited. Tay-Sachs disease is caused by mutations in a gene on chromosome 15 that codes for hex A, while Sandhoff disease is caused by mutations in a gene on chromosome 5 that codes for hex B. Both diseases are passed on through parents who carry one of these mutations. A carrier does not have the illness. However, when two carriers become parents:

There is a 25 percent (1-in-4) chance that any child they have will inherit a gene mutation from each parent and have the disease.
There is a 25 percent chance (1-in-4) that the child will inherit the normal gene from each parent. The child will not have the disease and will not be a carrier.
There is a 50 percent (2-in-4) chance that the child will inherit one normal and one abnormal gene. The child will not have the disease but will be a carrier like the parents.

If only one parent is a carrier, none of that person's children can inherit the disease. However, each child has a 50 percent chance of inheriting the gene mutation and being a carrier.

Carrier screening is commonly performed before or during pregnancy for adults in populations who are at risk for these disorders.

Can these diseases be diagnosed before birth?
Yes. Prenatal tests called amniocentesis and chorionic villus sampling (CVS) can diagnose these diseases before birth. Amniocentesis usually is done between the 15th and 20th week of pregnancy. In this test, the doctor inserts a needle into the mother's abdomen to take a sample of fluid that surrounds the fetus. The fluid contains fetal cells, which the lab tests to see if they contain hex A (when testing for Tay-Sachs) or hex A and hex B (when testing for Sandhoff).

CVS is generally done between the 10th and 12th weeks of pregnancy. In CVS, the doctor retrieves a sample of cells from the developing placenta either through a thin tube inserted through the vagina or by inserting a needle through the mother's abdomen. The placenta contains cells that are genetically identical to those of the fetus, and these cells are examined for the presence of the enzyme.

If prenatal testing shows that only hex A is missing, the baby will have classic Tay-Sachs disease. If both hex A and hex B are missing, the baby will have classic Sandhoff disease. In a small number of cases, the doctor may recommend DNA-based genetic testing to look for known mutations in the hex A gene or hex B gene that cause the late-onset forms of the diseases. This type of test can determine whether the fetus has classic or a late-onset disease, and possibly how severely affected the child may be.

Some medical centers have begun offering genetic testing to carrier couples who undergo in vitro fertilization (a process in which eggs are removed from a woman's ovaries and fertilized in the laboratory with her partner's sperm). The embryos are tested for a genetic disease, and only healthy ones are implanted in the mother. This is called pre-implantation genetic testing.

How can people find out if they are carriers?
An individual can take a test that measures the amount of hexosaminidase in the blood. Tay-Sachs carriers have about half as much of hex A as noncarriers, but this is plenty for the carrier's own needs. Similarly, carriers of Sandhoff disease have reduced but adequate amounts of both hex A and hex B.

A blood sample also can be used to perform DNA-based genetic testing for known mutations in the hex A or hex B genes. This kind of testing may be recommended if the results of the carrier screening test are uncertain.

Where is carrier screening for Tay-Sachs and Sandhoff diseases available?
Carrier screening is available from a genetic services center or clinic. A health care provider can provide referrals to local sites where testing is available, as can the National Tay-Sachs and Allied Diseases Association.

The genetic services center performs the carrier screening test that can determine whether one or both partners carry mutations that can cause these diseases. Trained genetic counselors will explain the test results so that individuals know whether or not their children will be at risk for the disease.

What research on Tay-Sachs and Sandhoff diseases is being conducted by March of Dimes grantees?
March of Dimes grantees helped pinpoint mutations in the hex A gene that are responsible for late-onset forms of Tay-Sachs disease. Information about specific mutations leads to improved diagnosis and carrier screening for all forms of Tay-Sachs disease.

A recent grantee has been attempting to develop a drug treatment that may prevent the production of certain fatty substances that build up and impair brain cells in affected individuals. This approach eventually may help prevent the early deaths and loss of central nervous system function associated with Tay-Sachs and Sandhoff diseases.

How can someone learn more about Tay-Sachs and Sandhoff diseases?
The National Tay-Sachs and Allied Diseases Association provides information and referrals (2001 Beacon St., Suite 204, Brookline, MA 02135, (800) 906-8723).

References

1. National Tay-Sachs and Allied Diseases Association, Inc. Tay-Sachs Disease (Classical Infantile Form), accessed 1/30/06.

2. Online Mendelian Inheritance in Man. Sandhoff Disease #268800. Updated 10/12/05, http://www.ncbi.nlm.nih.gov/.

3. Online Mendelian Inheritance in Man. Tay-Sachs Disease #272800. Updated 5/7/02, http://www.ncbi.nlm.nih.gov/.

4. National Tay-Sachs and Allied Diseases Association, Inc. Late Onset Tay-Sachs Disease, accessed 1/30/06..

5. Chicago Center for Jewish Genetic Disorders. Tay-Sachs Disease, updated 1/10/03.

6. Desnick, R., and Kaback, M. (eds.). Tay-Sachs Disease. Academic Press, Advances in Genetics, volume 44, October 2001.

7. Patterson, M.C. and Johnson, W.G. Lysosomal and Other Storage Diseases, in: Rowland, L.P. (ed.), Merritt's Neurology 11th Edition, Philadelphia, Lippincott, Williams & Wilkins, 2005.

8. Bembi, B., et al. Substrate Reduction Therapy in the Infantile Form of Tay-Sachs Disease. Neurology, volume 66, January 2006, pages 278-280.

9. American College of Obstetricians and Gynecologists (ACOG). Screening for Tay-Sachs Disease. ACOG Committee Opinion, volume 318, October 2005.

July 2006