The Mystery of Tay-Sachs as a “Jewish Disease”

Jewish genetic diseases like Tay-Sachs disease (TSD) are called “Jewish” because they are found more frequently in the Ashkenazi Jewish population than in other populations. ¹Goodman, Richard. Genetic Disorders Among the Jewish People. Johns Hopkins University Press, 1979. But the big question that is always asked about Jewish genetic disease is: why the Jews?

In 1980, I was working for the Tay-Sachs disease prevention program in Los Angeles. This program tested people, principally Ashkenazi Jews, for being carriers of Tay-Sachs Disease. Being a carrier means that if you have children with another carrier, you could have a child with Tay-Sachs disease. ²Stoll, Ira. “How the Jews Nearly Wiped out Tay-Sachs.” Jewish Telegraph Agency, 11 Aug. 2017 Dr. Michael Kaback helped develop the test, ³Rochman, Bonnie. “How The Jews Beat Tay-Sachs.” The Forward, 23 April 2017 and also had the foresight and the chutzpah to start the testing program and get it funded by the state of California. He came to me, the resident mathematical geneticist, with a question to answer.

In the course of screening something on the order of, back then, 20,000 people for Tay-Sachs carrier status, he came across one adult who tested positive for Tay-Sachs disease. I don’t mean this person tested as being a carrier of Tay-Sachs disease – this person appeared, based on the test, to have Tay-Sachs disease.  But here he was, a walking, talking adult. It was only children, it was thought, who could have Tay-Sachs disease, and such children seldom lived past the age of five. This man appeared entirely normal.

In order to understand the problem that Dr. Kaback was asking me to solve, I needed to know more about Tay-Sachs disease, its course, and why it is found almost – and I emphasize almost ⁴Peter Hechtman, Feige Kaplan, Janet Bayleran, Bernard Boulay, Eva Andermann, Marc de Braekeleer, Serge Melanson, Marie Lambert, Michel Potier, Richard Gagne, Edwin Kolodny, Carol Clow, Aniceta Capua, Claude Prevost, Charles Scriver. More than One Mutant Allele Causes Infantile Tay-Sachs Disease in French-Canadians. Am. J. Hum. Genet. 47:815-822, 199 – exclusively in the Ashkenazi Jewish population.

First of all, the pain and devastation for a family that has a child with Tay-Sachs disease is really terrible. The children are born healthy, and develop normally for about six months – so parents have the expectation of raising a healthy, normal child. But children with Tay-Sachs disease stop reaching normal milestones at about six months of age, and then the milestones that they have achieved slowly disappear. They lose the ability to smile, to crawl, to sit up, to see, to move. They become bedridden and require constant care. They become comatose and develop seizures. They die between the ages of two and five. ⁵Rochman

Tay-Sachs is a disease of the nervous system. ⁶Goodman It occurs because a specific waste product builds up in nerve cells, causing them to not work properly. This substance is called GM2 ganglioside and is usually gotten rid of by an enzyme, hexosaminidase A (HEX A). (Enzymes are a class of proteins, little machines inside the cell, that do all kinds of jobs, an important one of which is to get rid of waste products.) When there is none of this particular enzyme, the child develops Tay-Sachs disease.

On the left side of this picture⁷ Chen, H. (2016). Tay-Sachs. Disease Atlas of Genetic Diagnosis and Counseling, Springer, New York,  NY are what normal nerve cells look like under the microscope. On the right are cells from a TSD brain. You can see how enlarged and abnormal these cells are – and they do not transmit nerve impulses properly. The GM2 ganglioside accumulates gradually after birth, and the nerve cells gradually stop working.

Now, like all proteins, enzymes are “gene products.” That is, the instructions for how to make them are found in the DNA. The enzyme beta-hexosaminidase A is missing in Tay-Sachs, because those children born with the disease inherited genetic material from their parents that could not produce that enzyme or would produce a form of hexosaminidase A that didn’t work.

Some basic genetics: On each chromosome are specific locations where the instructions for making specific gene products are stored. These locations are the same in every human being. These “addresses” on chromosomes are called loci, or locations. The specific DNA that is found at these locations are called “alleles” and there are two alleles at each of the 23,000 or so loci found in humans. These loci and alleles determine our genetically-based characteristics.

There can be a large variety of alleles in a population that can exist at each of the many loci that we have. A person’s parents might have any of those alleles (that they get from their parents) and pass them on to their children. That variety depends on the population their parents come from. But for some loci, there will not be many different alleles, because the job done by the gene products of those loci is too important to tolerate much variation. For example, there are a variety of eye colors and it doesn’t much matter which one you have. But an enzyme like HEXA must work right. Such important loci are called “essential”. That is the case with HEXA. DNA changes happen, and such mutations can cause an allele to produce a gene product that is faulty and doesn’t do its job. That is what happened with TSD. At some point in the distant past, which we will talk about, a HEXA allele on chromosome 15, in some ancestor’s sperm or ovary, got broken and the code changed. That change would produce an enzyme that would not work. People who inherited this change became carriers of Tay-Sachs disease.

After the screening and prevention programs spearheaded by Dr. Kaback became established in 1970, ⁸Rochman the number of Tay-Sachs cases in the Ashkenazi Jewish population plummeted to the point where there are said to be more Tay-Sachs carriers who are non-Jews than among Ashkenazi Jews. There once was a section of Kingsbrook Jewish Medical Center in Brooklyn, whose job it was to essentially warehouse Tay-Sachs disease children. ⁹Stoll It could accommodate 15 or so children, and it was often full – with a waiting list. New patients were accepted only after someone else’s child had died. The need for that clinic is now gone – even though there is still no treatment for Tay-Sachs disease.

Now I will get back to the story that I started with, about a young man who looked like he had Tay-Sachs disease based on a carrier test. At least in those days, the test for carrier status was to take a bit of a person’s blood and mix it with the test chemical that showed how well the HEXA enzyme was working. But this chemical used in the test was not 100% like the natural target of the enzyme, the GM2 ganglioside – just close enough to be able to tell if the enzyme was working. If it worked 100% correctly, that would show that someone was not a carrier; if 50%, it would show someone was a carrier of TSD. If the test showed 0%, it would mean that the person being tested actually had Tay-Sachs disease. Such a person would not show up at a testing center as an adult, and yet that’s what this young man did.

So how can we explain this phenomenon of the young man who appeared to have Tay-Sachs disease, but was an adult? As you may have surmised, the young man in my story did not have the usual beta-HEXA alleles. He had one typical Tay-Sachs disease allele, but the other allele was unusual. It produced a HEXA enzyme that broke down the GM2 ganglioside just enough to prevent nerve cells from shutting down for many years. But this variety of the HEXA enzyme didn’t work with the chemical used in the test, which is why the young man looked like he had TSD. Thus, it took about 18 years before he showed symptoms, which he unfortunately eventually did. It also showed that there are other pathological variants of the Tay-Sachs allele.

The task Dr. Kaback gave me at the time was to figure out how frequently these alleles appeared in the population. ¹⁰David A. Greenberg and Michael M. Kaback. Estimation of the Frequency of Hexosaminidase A Variant Alleles in the American Jewish Population. Am J Hum Genet 34:444-451 (1982). ¹¹Michael M. Kaback. Population-based genetic screening for reproductive counseling: The Tay-Sachs disease model. Eur J Pediatr 1:59 [Suppl 3]: S192-S195 (2000). ¹²Gustavo H. B. Maegawa, Tracy Stockley, Michael Tropak, Brenda Banwell, Susan Blaser, Fernando Kok, Roberto Giugliani, Don Mahuran, Joe T. R. Clarke. The Natural History of Juvenile or Subacute GM2 Gangliosidosis: 21 New Cases and Literature Review of 134 Previously Reported Cases, Pediatrics. 2006 November; 118(5): e1550–e1562 (November 2006). Eventually, five variants of the Tay-Sachs alleles were identified, each of which leads to a somewhat different phenotype (observable characteristics). They are:

1. classical Tay-Sachs disease,
2. juvenile-onset Tay-Sachs disease that starts later than classical Tay-Sachs, but by the age of 10 is fatal.
3. Chronic GM2 gangliosidosis, which continues into adulthood with muscle involvement, but apparently without other symptoms like seizures.
4. Adult-onset Tay-Sachs disease that starts in the second to fourth decade of life and has motor and mental involvement, which the young man that I talked about apparently had.

And,

5. an allele that does not produce any disease. It acts like a TSD allele on the test, but seems to work just fine on GM2 ganglioside, and is called HEX A minus allele.

These variant alleles are not just curiosities; they affect real people. Late-onset Tay-Sachs disease exists in the population and causes real suffering.

So again: why the Jews? There are at least two possible answers to this question. One possible reason is heterozygote advantage, in which being the carrier of a recessive genetic disease is actually good for survival — classic natural selection, as described by Darwin. The second possible reason is genetic drift, or population bottleneck: a large population suddenly becomes a small population. Genetic drift, by the way, is another way of saying “by chance,” but it sounds more scientific if you say “genetic drift.” Reduced population size leads to reduced genetic diversity, which leads to the proliferation of certain alleles.

So first – heterozygote advantage. Heterozygote advantage happens when people who carry a recessive disease-causing allele survive and reproduce better than people who do not carry the allele. In this scenario, the fact that people who are born with two copies of the bad allele die early is more than balanced by the increased survival of the carriers.

Sickle cell anemia is the foremost example of this kind of advantage. In sickle cell anemia, it’s the hemoglobin allele that’s bad. ¹³Michael Aidoo, Dianne J Terlouw, Margarette S Kolczak, Peter D McElroy, Feiko O ter Kuile, Simon Kariuki, Bernard L Nahlen, Altaf A Lal, Venkatachalam Udhayakumar. Protective effects of the sickle cell gene against malaria morbidity and mortality. The Lancet 359 (April 13, 2002). The hemogloblin locus contains DNA that codes for the protein that makes red blood cells red and carries oxygen from the lungs to the rest of the body. Before the advent of modern medicine, inheriting two copies of the sickle cell allele used to lead to sickness and early death. But if one was merely a carrier of the sickle cell trait, the likelihood of surviving and reproducing are much greater than for non-carriers if one lives in certain environments. The reason has to do with protection against malaria. ¹⁴Frédéric B. Piel, Anand P. Patil, Rosalind E. Howes, Oscar A. Nyangiri, Peter W. Gething, Thomas N. Williams, David J. Weatherall, Simon I. Hay, Global distribution of the sickle cell gene and geographical confirmation of the malaria hypothesis, Nature Communications 1:104 (2010).

However, none of the so-called “Jewish genetic diseases” show a geographically-related disease association as does sickle cell. It’s been speculated that carrying the Tay-Sachs disease allele is a protection against tuberculosis. However, the evidence for that protection does not hold up to scrutiny. Tuberculosis has been around for a very long time, and is widespread, but no other population shows evidence of a protective effect of the TSD-causing allele.

Thus, we can turn to the other explanation: genetic drift or population bottleneck. Population bottlenecks play havoc with the frequency of alleles. Rare alleles can become more frequent and common alleles can decrease in frequency and, unlike heterozygote advantage, it has nothing to do with natural selection. ¹⁵Montgomery Slatkin. A Population-Genetic Test of Founder Effects and Implications for Ashkenazi Jewish Diseases. Am. J. Hum. Genet. 75:282–293 (2004). As can happen in when there is population reduction after disastrous occurrences, inbreeding can also become more common, and the consequences can be unusual changes in allele frequencies, in defiance of the accepted laws of population genetics. More evidence for a bottleneck as the reason for the high frequency of Tay-Sachs disease in Ashkenazi Jews is the fact that a majority of Jewish carriers of Tay-Sachs disease have the same identical allele, suggesting they all came from the same origin. ¹⁶Amos Frisch, Roberto Colombo, Elena Michaelovsky, Mazal Karpati, Boleslaw Goldman, Leah Peleg. Origin and spread of the 1278insTATC mutation causing Tay-Sachs disease in Ashkenazi Jews: genetic drift as a robust and parsimonious hypothesis. Hum Genet (2004) 114: 366–376. However, among non-Jewish populations, there are many different Tay-Sachs disease-causing alleles with different mutations, meaning they all arose more or less independently, with different origins. Certainly, the Jews have experienced no shortage of population reduction due to disasters. What was the specific population reduction that led to this disease among Jews?

The genome has a sort of built-in clock, called linkage disequilibrium, that has given us some possible insight. A paper published by Dr. Neil Risch ¹⁷Neil Risch, Hua Tang, Howard Katzenstein, and Josef Ekstein. Geographic Distribution of Disease Mutations in the Ashkenazi Jewish Population Supports Genetic Drift over Selection Am. J. Hum. Genet. 72:812–822 (2003). some years ago used genetic information and linkage disequilibrium to show that the Tay-Sachs disease allele increased due to two bottlenecks, one occurring about 100 CE, and the other about 500 years ago, about the year 1650.

The first disaster one can only speculate about – the one that occurred (according to Dr. Risch) in 100 CE – was the Bar Kochba rebellion. But we have no data on the extent of the supposed reduction in population then. The reduction about 500 years ago would probably have been a result of the Chmielminitski massacres. In 1648, Bogdan Chmielminitski, a Cossack hetman, led a revolt of the Russian peasantry against the Polish aristocracy – but Jews were a prime target. ¹⁸Rosenthal, Herman. “Cossacks’ Uprising.” JewishEncyclopedia.com, The Kopelman Foundation, 1906.  https://jewishencyclopedia.com/articles/4685-cossacks-uprising   ¹⁹Shaul Stampfer. Maps of Jewish settlement in Ukraine in 1648. Jewish History 17: 107–114, 2003. ²⁰Shaul Stampfer, What actually happened to the Jews of Ukraine in 1648? Jewish History 17: 207–227 (2003).

This was probably the worst disaster for the Ashkenazi Jewish community between the Bar Kochba rebellion and the Holocaust. Even the most conservative estimates are that the Jewish population was reduced to half or less of what it was – leaving as few as 20,000 people in the entire region. As many as 10,000 Jewish communities were destroyed.

This map gives you some idea of the breadth of the disaster. Each of the towns listed in this map suffered massacres during the revolt. They’re hard to see, but you can see the extent of how far-reaching the Jewish community was and how it then shrank back to very few.

What is the take-home message from all this information? The most important thing to bear in mind is that for all the success there has been in making Tay- Sachs disease less of a problem, it still cannot be cured, its cause has not been eliminated, and there is still no treatment. It remains a threat. The screening, testing, pregnancy-termination or avoided-relationship tactics we employ in order to get around the devastation to families does not eliminate the fundamental problem. And the underlying cause continues to lurk in the Ashkenazi Jewish population. And those unfortunates with the uncommon late-onset forms continue to suffer.

Second, the evil that people did hundreds or thousands of years ago is still with us. To quote William Faulkner: “The past is never dead. It isn’t even past.” That the product of those evils persists after generations is enough reason to do everything we can to fight forces that foster genocide and mass murder — not just pay lip service to opposing them. One cannot anticipate how these evils will revisit mankind again in some transmogrified form.

And finally, if we consider the benefit what medical science has brought to the world, from smallpox vaccine hundreds of years ago to organ transplants today, from antibiotics to the simple understanding of how our bodies work, knowledge that has increased the span of our lives and our health, we should be in awe. The fact that Tay-Sachs disease has been essentially eliminated from the population in which it was most frequent is glowing testimony to what we can do when we try.

(This post is part of Sinai and Synapses’ project Scientists in Synagogues, a grass-roots program to offer Jews opportunities to explore the most interesting and pressing questions surrounding Judaism and science. This article summarizes a presentation by Dr. Greenberg, “Exploring Tay-Sachs and Other Jewish Genetic Diseases,” at Congregation Tifereth Israel in Columbus, OH).

Additional Bibliography

Joel Charrow. Ashkenazi Jewish genetic disorders. Familial Cancer 3:201–206 (2004).

Inbal Kedar-Barnes and Paul Rozen. The Jewish people: their ethnic history, genetic disorders and specific cancer susceptibility. Familial Cancer 3: 193–199, (2004).

Barbara Mahany. “Tay-Sachs Test Eases The Fears Of Orthodox Jews” Chicago Tribune, Feb 07, 1994.

Rachel Myerowitz. Tay-Sachs Disease-Causing Mutations and Neutral Polymorphisms in the Hex A Gene. Human Mutation 9:195-208 (1997).

Carlos R. Ferreira, William A. Gahl. Lysosomal storage diseases. Translational Science of Rare Diseases 2 1–71 (2017).