Tay-Sachs Disease Tay-Sachs disease is a fatal, genetic disorder of the nervous system. There is no treatment. Tay-Sachs was first identified in the 1880’s by two physicians. Dr. Bernard Sachs of the United States has found a “cherry-red” spot in the eyes of a patient.

That patient later died. After searching medical literature, he found Warren Tay of great Britain had also reported this (Information, 1994). The symptoms of Tay-Sachs disease appear after about six months. At first, the patient has an over-exaggerated “startled” reaction to sounds and begins to loose control of its head. Eventually, it cannot roll over or sit without help. Dementia (uncontrolled laughter) may set in and the head grows abnormally large.

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The baby then becomes blind, and dies, usually before its 5th year (Seely et al, 1992). Tay-Sachs disease is an autosomal, recessive disorder caused by a deficiency in B-hexosaminidase A. Being an autosomal recessive disease, Tay-Sachs can only be passed on in its fatal form if both parents are heterozygous for the disease. If both parents are heterozygous for Tay-Sachs, there is a one in four chance of the infant having the disease. If only one parent is heterozygous, the infant has a one in two chance of being a carrier (heterozygous) for the disease(Mahany et al, 1994).

In 1962, researchers found B-hexosaminidase A is responsible for the breakdown of ganglioside (gm2) in nerve cells. Ganglioside is a lipid found in modest levels in nerve cell membranes. It is constantly being synthesized and broken down. Without the B-hexosaminidase A to break down the gm2, the cells swell up and eventually burst( Diamond, 1991). B-hexosaminidase A is composed of two amino acid chains, the alpha and the beta chain(Navon et al, 1989). The gene responsible for the manufacture of B-hexosaminidase A was originally thought to be located on chromosome 7(Gilbert et al, 1975).

It was later determined that the gene for the alpha chain is located on chromosome 15, and the beta chain gene is located on chromosome 5( Chern et al, 1976). In 1991, with the use of a cDNA clone, it was determined the alpha chain gene is located at 15q23-q24(Nakai et al, 1991). All forms of Tay-Sachs disease are caused by mutations in the alpha chain of the enzyme(Navon et al, 1989). The alpha chain of B-hexosaminidase A is about 35 kilobases long and split into 14 exons(Proia and Soravia, 1987). There are at least thirty different mutations that cause Tay-Sachs disease. A majority of the classical (infantile) form of the disease that is found in the Ashkenazi Jewish population is caused by one of two different gene mutations( Triggs-Raine et al, 1990).

The first one, Tay Sachs disease [HexA, 4-BP INS, EX11] accounts for about 70% of heterozygous carriers in the Ashkenazi population. The mutation introduces a 4-basepair insertion into exon 11, which causes a premature termination signal. This results in a deficiency of mRNA. The 4-basepair insertion causes a frameshift which makes a termination codon 9 nucleotides down from the insertion (Myerowitz and Costigan, 1988). This mutation is also prevelant in the southwest Louisiana Cajun population.

In the last three decades, 8 infants from 6 unrelated families have been diagnosed with Tay-Sachs disease. With 12 heterozygous carriers in the 6 families identified, 11 were carriers of the exon 11 mutation. The other mutation was of a form of Tay-Sachs disease found in the French-Canadian populations. The second mutation is Tay-Sachs disease [HexA, IVS< G-C, +1]. It is found in 20% of Ashkenazi patients and carriers. It is a G-C base substitution in the first nucleotide of intron 12.

This results in defective splicing of the mRNA(Arpaia et al, 1988). Another form of Tay-Sachs disease is Adult onset Tay-Sachs [HexA, GLY269SER]. This form of Tay-Sachs is caused by an amino acid substitution in the alpha chain of the B-hexosaminidase A molecule. Glycine is substituted serine at position 269 in the HexA subunit. This is caused by a G to A substitution at the 3-prime end of exon 7 (Navon and Proia, 1989).

Unlike infantile Tay-Sachs disease, Adult onset Tay-Sachs disease is not always fatal. While the former causes a rapid degeneration of the central nervous system, the latter causes a slower degeneration. This makes a normal lifespan possible (LOTSDF, 1995). Some of the symptoms associated with Adult (or Late onset) Tay-Sachs are mild dementia, ataxia, and mild spasticity (Mitsumoto et al, 1985). Other symptoms include muscle cramps, recurrent psychosis, incoordination, and dysarthria (Parnes et al, 1985).

Tay-Sachs appears once in 400,000 births around the world. In Ashkenazi Jews, it appears once in every 3,600 births. This is due to the high frequency of heterozygous carriers in the Ashkenazi population(Diamond, 1991). In a sample of 46,304 North American Ashkenazi Jews, of which 88% were of Polish or Russian ancestry, 1 in 31 were carriers. Jews with Austrian ancestry had a frequency of 1 in 9(Petersen et al, 1983).

Other Jewish groups are also affected by Tay-Sachs disease. In the Moroccan Jewish population, who are a subgroup of Sephardic Jews (Jews from Spain or other Mediterranean countries), an elevated frequency of carriers has been noted(Diamond, 1991). A mutation called Tay-Sachs disease [HexA, PHE304DEL] has been identified. It is a deletion of one of the two phenylalanine codons at position 304 or 305 in the alpha chain. This mutation was identified in one Moroccan patient and three unrelated heterozygous carriers( Drucker et al, 1992).

Tay-Sachs in the French-Canadian population was originally thought to have been introduced by a Jewish fur trader; however, this idea was discarded when the most prevalent mutation in the French-Canadian population was identified. In 1986, a study of 2 Ashkenazi and 2 French-Canadian carriers concluded the populations had different mutations. Tay-Sachs disease [HexA 7.6-kbDEL, EX1] is a deletion mutation. 7.6 kilobases are deleted, including part of intron 1 and all of exon 1. The deletion extends 2000 basepairs past the promoter region of the alpha-chain gene (Myerowitz and Hogikyan, 1987).

This mutation is unique in that it was traced back through an average of 12 generations to the provinces of Normandy and Perche in France. The mutation was not found on French soil, so it is assumed the mutation occurred in Canada. A further search for the ancestral couple was narrowed down to 7 possibilities. The most obvious choice was a man born in 1680 and his wife born in 1683. They had 11 offspring, 5 of whom must have been heterozygous for the mutation, because they had carrier descendants through a total of 14 descendant lines(DeBruekeleer et al, 1992).

A study was done to determine the risk of Tay-Sachs disease for French-Canadians living in northern New England. 372,000 live births between 1977 and 1986 were surveyed to see if any deaths from Tay-Sachs were found. Of 1,860 births with both parents of Ashkenazi Jews, one child was diagnosed with Tay-Sachs. In 41,000 births with both parents of French-Canadian descent, there were no recorded cases of Tay-Sachs disease. The conclusion of the study was heterozygous carriers were not present in the population of northern New England, but this was only a regional variation (Palomaki et al, 1995).