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
Tay–Sachs disease is a genetic disorder that results in the destruction of nerve cells in the brain and spinal cord. The most common type, known as infantile Tay–Sachs disease, becomes apparent around three to six months of age with the baby losing the ability to turn over, sit, or crawl.
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-cellularspace 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 ofthe 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.
![Tay-sachs disease pictures Tay-sachs disease pictures](/uploads/1/2/4/2/124276289/130191230.jpg)
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 theAshkenazi 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>.