Tay-Sachs disease: Origin and Prevention

Tay-Sachs is an autosomal recessive disease most commonly found in Jews of Ashkenazi descent. Approximately 1 in 30 Ashkenazi Jews in America are carriers for the disease compared to 1 in 300 for the total population.Tay-Sachs is caused by a single mutation in the gene coding for the enzyme beta-hexosaminidase A, resulting in the accumulation of excess ganglioside GM2 in nerve cells of the brain. In the first year of a child’s life they may experience symptoms such as; blindness, deafness, dysphasia, muscular atrophy and paralysis.The child will slowly deteriorate and will most likely die by the age of 4. Another, rarer form emerges later in life and may result in an unsteady gait and neurological deterioration. The characteristic sign of the disease which was noticed by Tay himself is the appearance of ‘cherry-red’ spots in the eyes.

Origin

There are several theories to explain the prevalence of Tay-Sachs in Ashkenazi Jews; one of the more popular theories is the founder effect. In this hypothesis, it is believed there was originally a low incidence of the mutated allele in the Ashkenazi population.Then by a presently unknown cause a large number of people in the population without the allele died. Therefore there was now a higher proportion of people with the defective gene. Once the population re-grew to its original size there was a higher number of people with Tay-Sachs than before. However the founder effect requires certain criteria in order to take place.Firstly, the sudden population decrease must be followed by little or no migration or interbreeding with other societies. Also, being a carrier of the Tay-Sachs allele must not affect a persons chance to reproduce.

A second theory known as heterozygous advantage, is where there is a selective advantage for carriers of the allele. The most widely held theory is that the allele for Tay-Sachs gives the carrier a resistance against Tuberculosis, so those with the alleles have a higher chance of surviving an outbreak of TB. As a result of this resistance the prevalence of the lethal allele increases after every TB outbreak in the Ashkenazi population.

A third theory is genetic drift, which describes random events that cause some alleles to become more prevalent than others, irrespective of environmental or sexual selection . (You may find it interesting to know that Darwin was unaware of genetic drift and therefore evolutionary biologists are no longer known as Darwinists). For example, if by chance carriers in a given generation were to breed more than non-carriers, you‘d expect the prevalence of Tay-Sachs to increase in the next generation.

The final theory is that parents that have a child displaying the Tay-Sachs phenotype may have more children than normal to ensure that they have at least some children that reach a reasonable life expectancy. This means that there may be higher prevalence of the allele in future generations.

There are reasons (which I am about to explain) why most of the theories I have described may not be viable:
Ashkenazi jews have a higher gene frequency of 22 listed genetic disorders, therefore if the founder effect were to be a prevailing theory, early Ashkenazi ancestors must have been carrying several defective genes, this is an unlikely event making the founder effect an untenable theory.
Another problematic theory is heterozygous advantage, in a study by B Spyropoulos et al. data was found that has shown grandparents of Tay-Sachs carriers die from proportionally the same causes as those grandparents of non-carriers. This suggests there is no advantage of being a carrier regarding resistance against any cause of disease, including TB. Also , in another study (Shaw and Smith,1969) it is said that if theTay-Sachs allele offered resistance to TB it would take 300 generations to reach the current frequency of the detrimental allele in the Ashkenazim, who have been a separate group for only 70 generations. In addition one would expect that if TB gave significant resistance, other ethnic groups under comparable conditions would also have a higher prevalence of Tay-Sachs. Similarly, it is doubtful that the genetic drift theory acts alone, because it is unlikely that random chance could produce such a large prevalence of Tay-Sachs in so few generations of Ashkenazi jews compared to the rest of world . A good example of its large prevalence (mentioned earlier), is the united states of America, where the prevalence of Tay -Sachs is 10 times higher is the Ashkenazim than the total population. However, this theory could contribute to other theories and increase their effect.
Finally, with respect to the final theory I described tt is impossible to prove/disprove carrier parents had more children, although it is a seemingly viable hypothesis.
Many theories exist explaining the disease’s prevalence but it is difficult to prove/disprove them. Further research needs to be done but is likely there will never be definite conclusion.

Prevention

Currently, very few methods exists for the prevention of Tay-Sachs. One of the most popular methods for prevention, whilst still having the opportunity to have children, is genetic testing. By receiving information that evaluates the probability of having affected children, parents can make an informed decision as to whether having children is the right decision or not.Pre-natal testing is also available for pregnant women, it allows pregnant women to get tested to see if they are carrying an affected fetus. This gives the pregnant women and her partner the option to have an abortion because they know it is affected.Of course, there are othzer options including abstinence, contraception and chemical castration. Perhaps in the future gene therapy may be a legitimate mode of Tay-Sachs prevention.Research is currently being done by researchers (from 6 prestigious academic institutions) of the Tay-Sachs Gene Therapy Consortium to test whether vectors can be used to transport therapeutic genes into a few diseased cells in the brain. The aim of the therapy is to produce a compensatory amount of Hex B enzyme to be distributed about the entire brain. In practice it should ideally restore the brains ability to function properly.

References

http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1685578&blobtype=pdf
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1685035
http://www-personal.umd.umich.edu/~jcthomas/JCTHOMAS/1997%20Case%20Studies/S.%20Bergeron.html
http://www.curetay-sachs.org/gt.shtml