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Tay-Sachs Disease

Tay-Sachs Disease

Tay-Sachs disease is a severe genetic disease of the nervous system that is nearly always fatal, usually by three to four years of age. It is caused by mutations in the HEXA gene, which codes for a component of the enzyme β-hexosaminidase A or "Hex A." The resulting accumulation of a brain lipid called GM2 ganglioside produces brain and spinal cord degeneration. It is a rare disease that is found in all populations, but it is particularly prevalent in Ashkenazi Jews of Eastern European origin. There is no treatment, but research aimed at treating the disease by blocking synthesis of the affected molecules has been ongoing since the late 1990s. Carriers can be identified by DNA or enzyme tests and prenatal diagnosis is available to at-risk families.

History and Disease Description

In 1881 Warren Tay, a British ophthalmologist, observed a "cherry red spot" in the retina of a one-year-old child with mental and physical retardation. Later, in 1896 Bernard Sachs, an American neurologist, observed extreme swelling of neurons in autopsy tissue from affected children. He also noted that the disease seemed to run in families of Jewish origin. Both physicians were describing the same disease, but it was not until the 1930s that the material causing the cherry-red spot and neuronal swelling was identified as a ganglioside lipid and the disease could be recognized as an "inborn error of metabolism." The term "ganglioside" was coined because of the high abundance of the brain lipid in normal ganglion cells (a type of brain cell). In the 1960s, the structure of the Tay-Sachs ganglioside was identified and given the name "GM2 ganglioside" (Figure 1).

Gangliosides are glycolipids. The lipid component, called ceramide, sits in the membranes of cells. Attached to it and sticking out into the extra-cellular space is a linked series of different sugars, the "glyco" portion of glycolipid. The basic function of gangliosides is not well understood, but they appear to have roles in biological processes as diverse as cell-to-cell recognition, differentiation, and in the repair of damaged neurons.

Gangliosides, like most cell components, are broken down and regenerated as part of normal cellular metabolism. The breakdown or "catabolism" of gangliosides occurs in the lysosome, a specialized vesicle that is analogous to the vacuole of plants. In the lysosome a series of acid hydrolases (degradative enzymes) removes each sugar, one at a time, until the ceramide lipid is all that remains. In Tay-Sachs disease, one of the lysosomal hydrolases, Hex A, is defective or completely absent, so the degradative process is blocked before completion. The result is the accumulation of GM2 ganglioside, the last molecule before the Hex A block in the catabolic sequence.

Since breakdown is blocked while synthesis continues, the result is a progressive accumulation of GM2 ganglioside and massive swelling of the lysosomes and hence of the neurons containing them. This is the basis of the neuron swelling observed by Sachs and the cherry-red spot described by Tay. The cherry-red spot is due to the white appearance of swollen neurons of the retina surrounding the normally red fovea centralis (central depression in retina and site of maximum vision acuity) in the back of the eye (Figure 2).

Newborns with Tay-Sachs disease appear normal at birth. By six months of age, parents begin to notice that their infant is becoming less alert and is less responsive to stimuli. The affected infant soon begins to regress and shows increasing weakness, poor head control, and inability to crawl or sit. The disease continues to progress rapidly through the first years of life, with seizures and increasing paralysis. The child eventually progresses to a completely unresponsive vegetative state. Death is often caused by pneumonia because of the child's weakened state. Some forms of Tay-Sachs disease are much milder with onset of the disease later in childhood or even adulthood. We now know that these forms of the disease are caused by less severe mutations in the HEXA gene.

Molecular Biology: Understanding Tay-Sachs Disease

Hex A is composed of two polypeptide subunits, one called α and one called β (Figure 1). One other form of the enzyme, Hex B, is composed of two β subunits. In Tay-Sachs disease, it is the α subunit that is mutated so that patients have a defective Hex A, while Hex B remains unaffected. However, Hex B is not active toward GM2 ganglioside and can not substitute for Hex A. Some patients have a disease similar to Tay-Sachs, with the absence of both Hex A and Hex B. This condition, now called Sandhoff disease, was first described by Konrad Sandhoff in the 1960s and is due to mutations in the β subunit.

One more protein is involved in the disease. It is called the GM2 activator and is essential to the breakdown of GM2 ganglioside. The protein forms a complex with the GM2 ganglioside, converting the GM2 from a hydrophobic, membrane-liking molecule to one that is hydrophilic (water loving) so that it can be successfully hydrolyzed by Hex A in the lysosome. Mutations in the GM2 activator gene, called GM2A, can also cause a Tay-Sachs-like disease, although it is exceedingly rare.

In sum, mutations in any of three genes can cause the disease: HEXA, HEXB, or GM2A. As a group, patients with any of these diseases are said to have GM2 gangliosidosis. Tay-Sachs disease refers specifically to the most common form of the disease, caused by mutations in the HEXA gene.

The HEXA gene is one of about 30,000 to 70,000 genes in the human genome. It is of average size at about 35,000 base pairs in length and contains fourteen exons. The remainder of the gene is made up of thirteen introns that separate the exons from one another. Extensive research has given us a clear picture how the enzyme is synthesized, processed through the endoplasmic reticulum and Golgi network of the cell, and sent to the lysosome. This understanding of the cell biology of Hex A has had an important impact on our understanding of mutations in Tay-Sachs disease. Some affect enzyme function, that is, they occur near the "active" site of the enzyme and block its activity, while others affect the biosynthetic processing of the protein. The latter type of mutations may not affect enzyme activity at all. but causes disease because the enzyme fails to reach the lysosome to carry out its biological role.

Mutations and Founder Effect

To date, nearly 100 mutations have been identified in Tay-Sachs disease. Ashkenazi Jews have two common mutations that cause the severe, infantile form of the disease. One, accounting for 80 percent of mutant alleles carried in the population, is the loss of four nucleotides in exon 11 of the gene. This causes a "frameshift" in the reading of the genetic code and the inability to generate a complete protein. The second mutation, accounting for about 15 to 18 percent of mutations, is a splice junction mutation, a defect in processing nuclear RNA to form the mature messenger RNA that makes its way to the cytoplasm to direct protein synthesis. When this mutation is present, splicing of intron 12 fails to occur properly, and a functional protein fails to be synthesized. In both cases, the result is the absence of the α subunit and hence Hex A.

Ashkenazi Jews and other populations also have mutations that cause amino acid substitutions. One such mutation, accounting for about 3 percent of mutations in Ashkenazi Jews, results in a glycine to serine substitution in exon 7. This mutant α subunit is synthesized and an abnormal Hex A is produced. It is sufficiently active so that patients with this mutation as one of their two mutant alleles have sufficient "residual" Hex A activity to produce a mild, adult form of the disease.

This finding of three predominant mutations causing Ashkenazi Jewish Tay-Sachs disease was unexpected. Most medical scientists thought a single mutation would have acted as a "founder" mutation and over time increased in frequency to the level at which it is found today. It is believed that the first Tay-Sachs mutation may have entered the population about 1000 years ago. It increased in frequency either by random genetic drift or possibly through selection for presence of the gene in heterozygous carriers. This latter interpretation is controversial, but it has been suggested that carriers might have been more resistant to tuberculosis than normal individuals so that they had a greater chance of surviving the epidemics of centuries ago, thereby resulting in a steady increase in the frequency of the mutant allele in Ashkenazi Jews. Another group with a founder mutation, a large deletion of the 5 ("five prime," or front) end of the gene, are French Canadians from the Lac Saint-Jean region of Quebec.

Carrier Testing and Prenatal Diagnosis

One in thirty Ashkenazi Jews is a carrier of one of the Tay-Sachs mutations. This is about ten times the frequency of carriers in non-Jews. Until 1970 it is estimated that about one in 4,000 births among Ashkenazi Jews was of a Tay-Sachs baby. This produced a great desire to develop a carrier and prenatal test shortly after the enzyme defect was identified. Michael Kaback spearheaded a carrier testing program that, by 2000, had tested well over 1 million Ashkenazi Jews, mainly in North America and Israel. This led to a drop in the incidence of Tay-Sachs disease to less than one-tenth of its previous level.

The testing program has been so successful because it is organized through Jewish community groups, with the active participation of geneticists who conduct the tests. During the 1970s and 1980s the test measured the level of Hex A activity in serum or white blood cells. With the identification of the Ashkenazi mutations, DNA testing came into use. Many geneticists prefer to conduct both types of tests, especially for non-Jews. They find DNA testing useful for its simplicity and exceedingly low error rate, but also recommend enzyme testing to guard against the involvement of a previously undetected mutation that would be missed by the mutation-specific DNA tests.

Future Prospects

In the 1990s laboratories in the United States, Canada, and France developed mouse models of Tay-Sachs disease, Sandhoff disease and GM2 activator deficiency. These investigations led to a much better understanding of the brain pathology and progression of the diseases. A significant outcome has been the use of the mouse models to experiment with approaches to therapy. A promising approach is based on partially blocking the synthesis of gangliosides with drugs so that accumulation of GM2 ganglioside becomes minimal. In addition to "substrate deprivation," as this blocking action is called, other laboratories are trying gene therapy and drug-based methods for bypassing the Tay-Sachs defect. The combination of carrier testing and prenatal diagnosis to assure the birth of healthy babies, and the more recent prospects for treating affected patients are major advances since the discovery of a cherry-red spot described in the first infant known to have been born with Tay-Sachs disease.

see also Cell, Eukaryotic; Disease, Genetics of Founder Effect; Gene; Genetics of Disease; Heterozygote Advantage; Metabolic Disease; Mutation; Population Screening; Prenatal Diagnosis; Proteins; RNA Processing; Rodent Models.

Roy A. Gravel

Bibliography

Gravel, Roy A., et al. "The GM2 Gangliosidoses." In The Metabolic and Molecular Bases of Inherited Diseases, 8th ed., Charles R. Scriver, Arthur L. Beaudet, William S. Sly and David Valle, eds. New York: McGraw-Hill, 2001.

Internet Resources

"HEXA Locus Database." <http://data.mch.mcgill.ca/gm2-gangliosidoses>.

"Tay-Sachs Disease." National Center for Biotechnology Information, Division of Online Mendelian Inheritance in Man. <http://www.ncbi.nlm.nih.gov:80/entrez/dispomim.cgi?id=272800>.

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Tay-Sachs Disease

Tay-Sachs disease

Definition

Tay-Sachs disease is a genetic disorder caused by a missing enzyme that results in the accumulation of a fatty substance in the nervous system. This disease causes disability and death.

Description

Gangliosides are fatty substances necessary for the proper development of the brain and nerve cells (nervous system). Under normal conditions, gangliosides are continuously broken down, so that an appropriate balance is maintained. In Tay-Sachs disease, the enzyme necessary for removing excess gangliosides is missing. This situation allows gangliosides to accumulate throughout the brain and is responsible for the disability associated with the disease.

Demographics

Tay-Sachs disease is particularly common among Jewish people of Eastern European and Russian (Ashkenazi) origin. About one out of every 2,500 to 3,600 babies born to Ashkenazi Jewish couples have the disease. In the general population about one out of every 320,000 babies born has Tay-Sachs disease. Approximately one in 30 Ashkenazi Jews is a carrier of the gene that causes the disease. Tay-Sachs is also more common among certain French-Canadian, Pennsylvania Dutch, and Cajun families.

Causes and symptoms

Tay-Sachs is caused by a defective gene. Genes are located on chromosomes and serve to direct specific developments and processes within the body. The genetic defect in Tay-Sachs disease results in the lack of an enzyme called hexosaminidase A. Without this enzyme, gangliosides cannot be broken down. They build up within the brain, interfering with nerve functioning. Because Tay-Sachs is a recessive disorder, only people who receive two defective genes (one from the mother and one from the father) will actually have the disease. People who have only one defective gene and one normal gene are called carriers. They carry the defective gene and thus the possibility of passing the gene and/or the disease onto their offspring.

When a carrier and a non-carrier have children, none of their children will actually have Tay-Sachs. The statistical probability is that 50 percent of their children will be carriers themselves. When two carriers have children, their children have a 25 percent chance of having normal genes, a 50 percent chance of being carriers of the defective gene, and a 25 percent chance of having two defective genes. Only the individual with two defective genes actually has the disease.

Classic Tay-Sachs disease strikes infants around the age of six months. Up until this age, the baby appears to develop normally. When Tay-Sachs begins to show itself, the baby stops interacting with other people and develops a staring gaze. Normal levels of noise startle the baby to an abnormal degree. By about one year of age, the baby has very weak, floppy muscles and may be completely blind. The head is quite large. Children with Tay-Sachs also have other symptoms, such as loss of peripheral (side) vision, inability to breathe and swallow, and paralysis as the disorder progresses. Seizures become a problem between ages one and two, and the baby usually dies by about age four.

A few variations from this classical progression of Tay-Sachs disease are possible:

  • Juvenile hexosaminidase A deficiency: Symptoms appear between ages two and five; the disease progresses more slowly, with death by about 15 years.
  • Chronic hexosaminidase A deficiency: Symptoms may begin around age five or may not occur until between 20 and 30 years of age. The disease is milder. Speech becomes slurred. The individual may have difficulty walking due to weakness, muscle cramps , and decreased coordination of movements. Some individuals develop mental illness. Many have changes in intellect, hearing, or vision.

When to call the doctor

If the child has any noticeable problems that might be associated with Tay-Sachs disease or appears to stop developing normally after a period of normal development, the doctor should be consulted.

Diagnosis

Examination of the eyes of a child with Tay-Sachs disease reveals a characteristic cherry-red spot at the back of the eye in an area called the retina. Tests to determine the presence and quantity of hexosaminidase A can be performed on the blood, specially treated skin cells, or white blood cells. A carrier has about half the normal level of hexosaminidase A present, while an individual with the disease has no hexosaminidase A at all.

Treatment

Providing good, supportive care and treating the symptoms as they arise is the only way to treat Tay-Sachs; there is no way to treat the disease itself.

Prognosis

The prognosis for a child with classic Tay-Sachs disease is death. Because the chronic form of Tay-Sachs was discovered near the end of the 2000s, prognosis for this type of the disease was, as of 2004, not completely known.

Prevention

There is no known way to prevent Tay-Sachs disease. It is, however, possible to identify carriers of the disease and provide them with genetic counseling and appropriate information concerning the chance of their offspring having Tay-Sachs disease. When the levels of hexosaminidase A are half the normal level, a person is a carrier of the defective gene. Blood tests of carriers reveal reduction of hexosaminidase A.

When a woman is already pregnant, tests can be performed on either the cells of the fetus (amniocentesis ) or the placenta (chorionic villus sampling) to determine whether the baby will have Tay-Sachs disease.

Parental concerns

If parents are thinking of having a child and believe they might be carriers of Tay-Sachs, they should be screened so that they can assess their options. Children born with infantile Tay-Sachs, even with the best available care, usually die before the age of five. Children born with juvenile Tay-Sachs usually die before the age of 15.

KEY TERMS

Ganglioside A fatty (lipid) substance found within the brain and nerve cells.

Resources

BOOKS

Behrman, Richard E., Robert M. Kliegman, and Hal B. Jenson. Nelson Textbook of Pediatrics, 17th ed. Philadelphia: Saunders, 2004.

Desnick, Robert, and Michael M. Kaback, eds. Tay-Sachs Disease. San Diego, CA: Academic, 2001.

ORGANIZATIONS

March of Dimes Birth Defects Foundation. 1275 Mamaroneck Avenue, White Plains, NY 10605. Web site: <www.modimes.org>.

National Tay-Sachs and Allied Diseases Association. 2001 Beacon Street, Suite 204, Brighton, MA 02135. Web site: <www.ntsad.org>.

Tish Davidson, A.M.

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Tay-Sachs Disease

Tay-Sachs disease

Definition

Tay-Sachs disease is a genetic disorder caused by a missing enzyme that results in the accumulation of a fatty substance in the nervous system. This results in disability and death.

Description

Gangliosides are a fatty substance necessary for the proper development of the brain and nerve cells (nervous system). Under normal conditions, gangliosides are continuously broken down, so that an appropriate balance is maintained. In Tay-Sachs disease, the enzyme necessary for removing excess gangliosides is missing. This allows gangliosides to accumulate throughout the brain, and is responsible for the disability associated with the disease.

Tay-Sachs disease is particularly common among Jewish people of Eastern European and Russian (Ashkenazi) origin. About one out of every 3,600 babies born to Ashkenazi Jewish couples will have the disease. Tay-Sachs is also more common among certain French-Canadian and Cajun French families.

Causes and symptoms

Tay-Sachs is caused by a defective gene. Genes are located on chromosomes, and serve to direct specific development/processes within the body. The genetic defect in Tay-Sachs disease results in the lack of an enzyme, called hexosaminidase A. Without this enzyme, gangliosides cannot be degraded. They build up within the brain, interfering with nerve functioning. Because it is a recessive disorder, only people who receive two defective genes (one from the mother and one from the father) will actually have the disease. People who have only one defective gene and one normal gene are called carriers. They carry the defective gene and thus the possibility of passing the gene and/or the disease onto their offspring.

When a carrier and a non-carrier have children, none of their children will actually have Tay-Sachs. It is likely that 50% of their children will be carriers themselves. When two carriers have children, their children have a 25% chance of having normal genes, a 50% chance of being carriers of the defective genne, and a 25% chance of having two defective genes. The two defective genes cause the disease itself.

Classic Tay-Sachs disease strikes infants around the age of six months. Up until this age, the baby will appear to be developing normally. When Tay-Sachs begins to show itself, the baby will stop interacting with other people, and develop a staring gaze. Normal levels of noise will

startle the baby to an abnormal degree. By about one year of age, the baby will have very weak, floppy muscles, and may be completely blind. The head will be quite large. Patients also present with loss of peripheral (side) vision, inability to breath and swallow, and paralysis as the disorder progresses. Seizures become a problem between ages one and two, and the baby usually dies by about age four.

A few variations from this classical progression of Tay-Sachs disease are possible:

  • Juvenile hexosaminidase A deficiency. Symptoms appear between ages two and five; the disease progresses more slowly, with death by about 15 years.
  • Chronic hexosaminidase A deficiency. Symptoms may begin around age five, or may not occur until age 20-30. The disease is milder. Speech becomes slurred. The individual may have difficulty walking due to weakness, muscle cramps, and decreased coordination of movements. Some individuals develop mental illness. Many have changes in intellect, hearing, or vision.

Diagnosis

Examination of the eyes of a child with Tay-Sachs disease will reveal a very characteristic cherry-red spot at the back of the eye (in an area called the retina). Tests to determine the presence and quantity of hexosaminidase A can be performed on the blood, specially treated skin cells, or white blood cells. A carrier will have about half of the normal level of hexosaminidase A present, while a patient with the disease will have none.

Treatment

There is no treatment for Tay-Sachs disease.

Prognosis

Sadly, the prognosis for a child with classic Tay-Sachs disease is certain death. Because the chronic form of Tay-Sachs has been discovered recently, prognosis for this type of the disease is not completely known.

Prevention

Prevention involves identifying carriers of the disease and providing them with appropriate information concerning the chance of their offspring having Tay-Sachs disease. When the levels of hexosaminidase A are half the normal level a person is a carrier of the defective gene. Blood tests of carriers reveals reduction of Hexosaminidase A.

When a woman is already pregnant, tests can be performed on either the cells of the baby (amniocentesis) or the placenta (chorionic villus sampling) to determine whether the baby will have Tay-Sachs disease.

Resources

BOOKS

Behrman, Richard, ed. Nelson Textbook of Pediatrics. Philadelphia: W. B. Saunders, 1996.

PERIODICALS

Motulsky, Arno G. "Screening for Genetic Disease." New England Journal of Medicine, 336, no. 18 (May 1, 1997): 1314+.

Rosebush, Patricia I. "Late-Onset Tay-Sachs Disease Presenting as Catatonic Schizophrenia: Diagnostic and Treatment Issues." Journal of the American Medical Association 274, no. 22 (December 13, 1995): 1744.

ORGANIZATIONS

Late Onset Tay-Sachs Foundation. 1303 Paper Mill Road, Erdenheim, PA 19038. (800) 672-2022.

March of Dimes Birth Defects Foundation. National Office. 1275 Mamaroneck Avenue, White Plains, NY 10605. (888) 663-4637. resourcecenter@modimes.org. <http://www.modimes.org>.

National Tay-Sachs and Allied Diseases Association, Inc. 2001 Beacon Street, Suite 204, Brighton, MA 02146. (800) 906-8723. Fax: 617-277-0134. NTSAD-Boston@worldnet.att.net. <http://www.ntsad.org>.

Laith Farid Gulli, MD

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Tay-Sachs Disease

Tay-Sachs Disease

Definition

Tay-Sachs disease is a genetic disorder caused by a missing enzyme that results in the accumulation of a fatty substance in the nervous system. This results in disability and death.

Description

Gangliosides are fatty substances necessary for the proper development of the brain and nerve cells (nervous system). Under normal conditions, gangliosides are continuously broken down, so that an appropriate balance is maintained. In Tay-Sachs disease, the enzyme necessary for removing excess gangliosides is missing. This allows gangliosides to accumulate throughout the brain, and is responsible for the disability associated with the disease.

Tay-Sachs disease is particularly common among Jewish people of Eastern European and Russian (Ashkenazi) origin. About one out of every 3,600 babies born to Ashkenazi Jewish couples will have the disease. Tay-Sachs is also more common among certain French-Canadian and Cajun French families.

Causes and symptoms

Tay-Sachs is caused by a defective gene. Genes are located on chromosomes, and serve to direct specific development/processes within the body. The genetic defect in Tay-Sachs disease results in the lack of an enzyme called hexosaminidase A. Without this enzyme, gangliosides cannot be degraded. They build up within the brain, interfering with nerve functioning. Because Tay-Sachs is a recessive disorder, only people who receive two defective genes (one from the mother and one from the father) will actually have the disease. People who have only one defective gene and one normal gene are called carriers. They carry the defective gene and thus the possibility of passing the gene and/or the disease onto their offspring.

When a carrier and a non-carrier have children, none of their children will actually have Tay-Sachs. It is likely that 50% of their children will be carriers themselves. When two carriers have children, their children have a 25% chance of having normal genes, a 50% chance of being carriers of the defective gene, and a 25% chance of having two defective genes. The two defective genes cause the disease itself.

Classic Tay-Sachs disease strikes infants around the age of six months. Up until this age, the baby will appear to be developing normally. When Tay-Sachs begins to show itself, the baby will stop interacting with other people and develop a staring gaze. Normal levels of noise will startle the baby to an abnormal degree. By about one year of age, the baby will have very weak, floppy muscles, and may be completely blind. The head will be quite large. Patients also present with loss of peripheral (side) vision, inability to breath and swallow, and paralysis as the disorder progresses. Seizures become a problem between ages one and two, and the baby usually dies by about age four.

A few variations from this classical progression of Tay-Sachs disease are possible:

  • Juvenile hexosaminidase A deficiency. Symptoms appear between ages two and five; the disease progresses more slowly, with death by about 15 years.
  • Chronic hexosaminidase A deficiency. Symptoms may begin around age five, or may not occur until age 20-30. The disease is milder. Speech becomes slurred. The individual may have difficulty walking due to weakness, muscle cramps, and decreased coordination of movements. Some individuals develop mental illness. Many have changes in intellect, hearing, or vision.

Diagnosis

Examination of the eyes of a child with Tay-Sachs disease will reveal a characteristic cherry-red spot at the back of the eye (in an area called the retina). Tests to determine the presence and quantity of hexosaminidase A can be performed on the blood, specially treated skin cells, or white blood cells. A carrier will have about half of the normal level of hexosaminidase A present, while a patient with the disease will have none.

Treatment

There is no treatment for Tay-Sachs disease.

Prognosis

Sadly, the prognosis for a child with classic Tay-Sachs disease is certain death. Because the chronic form of Tay-Sachs has been discovered recently, prognosis for this type of the disease is not completely known.

Prevention

Prevention involves identifying carriers of the disease and providing them with appropriate information concerning the chance of their offspring having Tay-Sachs disease. When the levels of hexosaminidase A are half the normal level, a person is a carrier of the defective gene. Blood tests of carriers reveals reduction of hexosaminidase A.

KEY TERMS

Ganglioside A fatty (lipid) substance found within the brain and nerve cells.

When a woman is already pregnant, tests can be performed on either the cells of the baby (aminocentesis) or the placenta (chorionic villus sampling ) to determine whether the baby will have Tay-Sachs disease.

Resources

ORGANIZATIONS

Late Onset Tay-Sachs Foundation. 1303 Paper Mill Road, Erdenheim, PA 19038. (800)672-2022.

March of Dimes Birth Defects Foundation. 1275 Mamaroneck Avenue, White Plains, NY 10605. (888) 663-4637. resourcecenter@modimes.org. http://www.modimes.org.

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Tay-Sachs disease

Tay-Sachs disease (tā´-săks´), rare hereditary disease caused by a genetic mutation that leaves the body unable to produce an enzyme necessary for fat metabolism in nerve cells, producing central nervous system degeneration. The disease is named for a British ophthalmologist, Warren Tay, who first described the disease, in 1881, and a New York neurologist, Bernard Sachs, who first described the cellular changes and the genetic nature of the disease, in 1887. In infants, it is characterized by progressive mental deterioration, blindness, paralysis, epileptic seizures, and death, usually between ages three and five. Late-onset Tay-Sachs occurs in persons who have a genetic mutation that is similar but allows some production of the missing enzyme. There is no treatment for Tay-Sachs.

Course of the Disease

The enzyme involved in Tay-Sachs is called hexosaminidase A. Its absence allows a lipid called GM2 ganglioside to build up in the brain, destroying the nerve cells. The process starts in the fetus; the disease is clinically apparent in the first few months of life. Initial symptoms vary, but usually include a general slowing of development and loss of peripheral vision. By the age of one, most children are experiencing convulsions. The damage to the nervous system progresses inexorably, bringing with it an inability to swallow, difficulty in breathing, blindness, mental retardation, and paralysis.

In late-onset Tay-Sachs, which is often misdiagnosed, the symptoms (ataxia, dysarthria, and muscle weakness) usually become apparent late in childhood or early in adulthood. About 40% of the patients display symptoms of bipolar disorder. Life expectancy does not appear to be affected.

Genetic Basis and Screening

Tay-Sachs disease occurs primarily among Jews of Eastern European descent but is also found in French Canadians whose roots are in the St. Lawrence region, certain Cajuns in Louisiana, and some Amish communities. Tay-Sachs is an autosomal recessive disorder; a person must have two defective genes (one from each parent) in order for the disease to occur. Carriers, people with only one gene for the disorder, are physically unaffected. When both parents are carriers, each child has a 25% chance of getting the disease. If only one parent is a carrier, there is no chance that the child will get the disease, but there is a 50% chance that the child will be a carrier. The gene may be carried by many generations without a manifestation. For this reason, plus the historical lack of accurate diagnosis and routinely high infant mortality of past generations, there is often no known family history of the disease.

Genetic screening (see genetic testing) for the disease has been possible since the early 1970s and is encouraged in high-risk populations. Blood tests of carriers reveal a reduced amount of the hexosaminidase A. If a couple elects to go forward with a pregnancy, fetal status (again utilizing hexosaminidase A levels) can be ascertained via chorionic villus sampling or amniocentesis. Genetic screening and counseling has greatly reduced the incidence of the disease.

Bibliography

See M. M. Kaback, ed., Tay-Sachs Disease: Screening and Prevention (1977); W. Stockton, Altered Destinies (1979).

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Tay-Sachs Disease

TAY-SACHS DISEASE

DEFINITION


Tay-Sachs disease (pronounced tay-SACKS) is a genetic disorder that can lead to paralysis, blindness, convulsions, mental retardation (see mental retardation entry) and death. A genetic disorder is a medical problem passed down from one generation to the next. The disorder occurs because of a faulty gene. Genes are the chemical units in all cells that tell cells what functions they should perform. When those genes are absent or faulty, cells do not function properly and a medical disorder results.

DESCRIPTION


Gangliosides (pronounced GANG-glee-uh-SIDES) are fatty substances needed for the proper development of the brain and nerve cells. Under normal conditions, gangliosides are continuously broken down so that the correct amount of gangliosides is always present.

The chemical required to break down gangliosides is an enzyme. Enzymes are chemical compounds present in all cells. These compounds make possible thousands of different reactions needed to keep cells operating normally. In a person with Tay-Sachs disease, the enzyme needed to break down gangliosides is missing. As a result, gangliosides continue to build up in the brain. When the brain becomes clogged with this fatty material it is no longer able to function normally.

Tay-Sachs is especially common among Jewish people of eastern European and Russian origin, sometimes referred to as Ashkenazic Jews. About 1 in every 3,600 babies born to Ashkenazic Jewish couples will have Tay-Sachs disease. The disease is also relatively common among certain French-Canadian and Cajun French families. Tay-Sachs disease is quite rare in families of other ethnic backgrounds.

CAUSES


Every child receives two sets of genes, one from its mother and one from its father. These genes may be either dominant or recessive. A dominant gene is "stronger" than a recessive gene and controls the way a cell is going to function.

If a recessive gene is paired with a dominant gene, the recessive gene has no effect on the way a cell functions. The dominant gene overcomes the recessive gene. The only way a recessive gene has any effect on a cell if it is paired with another recessive gene. In such cases, the two recessive genes work together to direct a cell's operation.

Tay-Sachs is caused by a recessive gene. A child with one recessive gene shows no effect as a result of having the gene. The child is a carrier for the disease. A carrier is a person who has one recessive gene for a characteristic. The carrier can pass the gene on to his or her children even though the carrier does not have the disease.

A child with a pair of these recessive genes, however, will show the symptoms of Tay-Sachs disease because the child will lack a normal gene to makes the enzyme needed to break down gangliosides.

SYMPTOMS


Tay-Sachs disease normally shows up at about the age of six months. Prior to that time, the baby acts normally. Once the symptoms of Tay-Sachs begin to appear the baby stops interacting with other people. It may develop a staring gaze. Normal levels of noise tend to startle the baby to an abnormal degree.

Tay-Sachs Disease: Words to Know

Dominant gene:
A form of a gene that predominates over a second form of the same gene.
Enzymes:
Chemicals present in all cells that make possible the chemical reactions needed to keep a cell alive.
Ganglioside:
A fatty substance found in brain and nerve cells.
Gene:
A chemical unit that carries instructions as to the functions a cell should perform.
Genetic disorder:
A medical problem caused by one or more defective genes.
Recessive gene:
A form of a gene that does not operate in the presence of a dominant form of the same gene.

By the time the baby is one year old, it has weak, floppy muscles. The baby may be completely blind, and will usually have a large head. Seizures become a problem between the ages of one and two years and the baby usually dies by the age of four.

DIAGNOSIS


A preliminary diagnosis for Tay-Sachs disease can usually be made by looking into the baby's eyes. If a baby has Tay-Sachs a characteristic cherryred spot can be seen at the back of the eye.

In order to confirm this diagnosis, blood tests are performed that measure the amount of enzyme needed to break down gangliosides. If the level is very low, the baby has Tay-Sachs disease.

TREATMENT


There is currently no treatment for Tay-Sachs disease. Scientists hope to develop some type of treatment eventually. The treatment would involve providing babies with Tay-Sachs disease new genes. These genes would take

over the job of making the enzyme the babies currently lack. While this technology is now being investigated, no technique has yet been shown to work satisfactorily.

PROGNOSIS


At the present time, the prognosis for a baby born with Tay-Sachs disease is certain death. Nothing can be done to keep the baby alive.

PREVENTION


Once a baby receives recessive genes from both parents, it is destined to develop Tay-Sachs disease. The only way to prevent this condition from happening, then, is to make sure no baby receives two recessive genes.

Parents from ethnic groups at risk for Tay-Sachs have the option of being tested for recessive genes. If only one parent has a recessive gene, the baby will not develop Tay-Sachs disease. If both parents have the recessive gene, the child will develop the disorder. Couples can use this kind of information to decide whether or not to have children.

Prenatal testing can also provide information about Tay-Sachs disease. A pregnant woman can be tested to see if her child has Tay-Sachs disease. She and her partner can then decide whether or not to continue with the pregnancy.

FOR MORE INFORMATION


Organizations

Late Onset Tay-Sachs Foundation. 1303 Paper Mill Rd., Erdenheim, PA 19038. (800) 6722022.

March of Dimes Birth Defects Foundation. National Office. 1275 Mamaroneck Ave., White Plains, NY 10605. http://www.modimes.org.

National Tay-Sachs and Allied Diseases Association, Inc. 2001 Beacon St., Suite 204, Brookline, MA 02146. (800) 6722022.

Web sites

"Ask NOAH About: Neurological Problems." NOAH: New York Online Access to Health. [Online] http://www.noah.cuny.edu/neuro/neuropg.html#TAYSACHS (accessed on October 31, 1999).

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Tay-Sachs Disease

Tay-Sachs Disease

What Is Tay-Sachs Disease?

How Does Tay-Sachs Disease Affect the Body?

How Do People Get Tay-Sachs Disease?

Is There α Cure for Tay-Sachs Disease?

Resources

Tay-Sachs disease is a rare inherited disorder that results in slow destruction of the central nervous system (brain and spinal cord).

KEYWORDS

for searching the Internet and other reference sources

Hexosaminidase A (Hex-A)

Neurology

What Is Tay-Sachs Disease?

Tay-Sachs disease is a rare metabolic disorder with severe neurologic (nervous system) symptoms. Metabolic refers to the bodys chemical processes that produce protein and other substances, and break down nutrients to release energy. Tay-Sachs disease is a metabolic disorder because it is caused by the absence of the enzyme (a type of protein) hexosaminidase A (Hex-A). Hex-A is necessary for breaking down fatty substances called lipids. Without Hex-A, these lipids build up in, and eventually destroy, the nerve cells in the brain. Ultimately, the nervous system stops functioning properly.

How Does Tay-Sachs Disease Affect the Body?

Classical Tay-Sachs

The most common form of Tay-Sachs disease (classical Tay-Sachs) affects children and usually is fatal. It is caused by a complete lack of Hex-A. Destruction of nerve cells begins before birth, but an affected baby does not begin to lose nerve function until he or she is about six months old. By age two, the child may have seizures* and begins to lose skills such as crawling, sitting, turning over, and reaching for things. Eventually, the child will be blind, paralyzed, and mentally retarded. Children with this form of Tay-Sachs disease do not live past age five.

* seizures
are sudden attacks of disease, often referring to some type of violent spasms.

A variation of this scenario is when children develop symptoms between the ages of two and five rather than as an infant. The same symptoms emerge, but the disease progresses more slowly. Children with this form usually die by age 15.

Late onset Tay-Sachs (LOTS)

Late onset Tay-Sachs disease (LOTS) is less common than the infantile form. It affects teenagers and adults in their twenties and thirties by causing a gradual loss of nerve function. People with LOTS have low levels of Hex-A rather than a complete lack of it. As LOTS develops, people affected by it may grow clumsy, uncoordinated, and moody. They may experience muscle weakness, twitching, slurred speech, and intellectual impairment. The symptoms vary in type and severity from person to person. Because this form develops so gradually, life expectancy of affected people seems to be similar to that of unaffected people.

How Do People Get Tay-Sachs Disease?

Tay-Sachs disease is caused by a mutation (abnormal change) in the gene that codes for Hex-A, and it is a recessive trait. This means that people will have the disease if they have two copies of the defective gene, but they will not have the disease if they have at least one unaffected copy. People with one normal copy and one defective copy are called carriers, because they can pass the disease on to their children.

Just about anyone can be a carrier of the gene for Tay-Sachs disease. In the general population, about 1 in 250 people carries the gene.

Whats in a Name?

Tay-Sachs disease was named for two scientists working on opposite sides of the Atlantic Ocean.

Warren Tay (1843-1927) was a British eye doctor. In 1881, he described a patient with a cherry red spot on the retina of eye (the structure inside the eye that receives light). This spot is characteristic of the classical form of the disease.

An American neurologist (nerve and brain specialist) named Bernard Sachs (1858-1944) described the changes in cells caused by the disease. He also recognized that it was an inherited condition that ran in families and that most babies with the disease were of eastern European Jewish descent.

However, some populations of people include more carriers than others. For example, 1 in 27 people of eastern European Jewish (Ashkenazi) descent in the United States is a carrier. People of French-Canadian ancestry from one part of Quebec and the Cajun population in Louisiana also have a higher than usual risk of carrying the Tay-Sachs gene.

Is There α Cure for Tay-Sachs Disease?

Although researchers are actively looking for a way to prevent or treat Tay-Sachs disease, currently no treatment or cure exists. However, tests have been developed that allow people to find out if they carry the defective gene. Blood tests can determine the level of Hex-A in peoples blood (carriers have about half as much as noncarriers) and DNA tests may find evidence of mutations in the Hex-A gene. Testing is particularly useful for people who have had relatives with Tay-Sachs disease and for people in high-risk populations. Finding out about risk before having a baby can prevent the anguish of watching a child develop and then die from Tay-Sachs disease.

Prenatal tests also exist for women who already are pregnant. The amniotic fluid (the fluid in which the fetus develops) or the chorionic villus (structures inside the mothers uterus) both contain fluid from the developing baby that can be sampled and tested for the presence of Hex-A. If Hex-A is present, that means that the fetus does not have Tay-Sachs disease.

See also

Genetic Diseases

Resources

National Tay-Sachs and Allied Diseases Association, Inc., 2001 Beacon Street, Suite 204, Brookline, MA 02146. Telephone 800-906-8723 http://www.ntsad.org/

Late Onset Tay-Sachs Foundation, 1303 Paper Mill Road, Erdenheim, PA 19038. Telephone 800-672-2022

March of Dimes Foundation, 1275 Mamaroneck Avenue, White Plains, NY 10605. Telephone 888-663-4637 http://www.modimes.org/

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Tay-Sachs disease

Tay-Sachs disease (amaurotic familial idiocy) (tay-saks) n. an inherited disorder of lipid metabolism (see lipidosis) in which abnormal accumulation of lipid in the brain leads to blindness, mental retardation, and death in infancy. [ W. Tay (1843–1927), British physician; B. Sachs (1858–1944), US neurologist]

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