137 Tay-Sachs Disease

Tay-Sachs disease (TSD) is the best known of the sphingolipidoses, a group of genetic disorders that includes Niemann-Pick disease, Gaucher’s disease, and others. Specifically, TSD is G_m2 (beta) gangliosi­dosis, an autosomal recessive disease with complete penetrance.

History

The British ophthalmologist Warren Tay (1881) first reported some of the early clinical signs of TSD. In the United States, Bernard Sachs (1887) further documented the clinical course and pathology of the disease he later called “amaurotic family idiocy” (Sachs 1896). It was Sachs who first noted the famil­ial nature of the disease, and its seemingly exclusive occurrence in Jewish families. However, reports were soon made of non-Jewish cases. D. Slome (1933) was the first to survey the literature on the popula­tion characteristics of TSD and confirmed the dis­ease’s autosomal recessive mode of transmission as well as the TSD gene’s higher frequency among Jews. E. Klenk (1942) discovered that the nerve cells of individuals who died from TSD contained an ex­cess of a lipid he called ganglioside. L. Svennerholm (1962) later described the specific G_m2 ganglioside.

Clinical Manifestations and Mortality

E. H. Kolodny (1979) gives a concise outline of the symptoms and course of TSD. Between birth and age 6 months, the affected child may begin displaying apathy, hypotonia, and an exaggerated startle reac­tion to noise. Between 6 and 12 months of age, the characteristic cherry-red spot in the eye becomes evident, and the child also displays psychomotor re­tardation, spasticity, and rigidity. From 12 to 18 months of age, the child may have excessive drool­ing, bouts of unmotivated laughter, and convulsions. Between 18 and 24 months, megacephaly, cortical blindness, and quadriplegia commonly occur. After age 2 years, the child is in a vegetative state, and most affected children die sometime during the next 2 years. Until then their condition steadily worsens, with flexor contractures, episodes of autonomic dys­function, neurogenic bladder, and skin yellowing be­ing common signs.

Pathology

B. W. Volk, Schneck, and M. Adachi (1970) and Adachi and Volk (1975) detail the pathology of TSD. The key pathological features of TSD are most appar­ent in the brain and related structures, and become more obvious as the disease progresses. The most striking gross change in the brain is its marked in­crease in weight, especially in individuals who live beyond 2 years of age. Another gross change, most apparent in later stages of the disease, is cerebellar atrophy.

Biochemistry

Gangliosides are a family of acidic complex lipids called glycosphingolipids. Gangliosides are present to some degree in most of the body’s tissues, but are found primarily in the brain (Svennerholm 1980). More than 40 different molecular forms have been discovered, four of which comprise 65 percent to 85 percent of the total ganglioside content of mam­malian brains (Rapport 1981). Though the role of gangliosides in neural physicology is not completely understood, the basic biochemical cause of TSD re­mains straightforward. In persons with TSD, unusu­ally large amounts of G_m2 ganglioside accumulate in the brain and associated tissues, thus disrupting their normal development and function. This accu­mulation is due to the lack of a functional specific enzyme, hex A, that breaks down the G_m2 ganglio­side. Hex A activity can be assessed by a serum enzyme assay (O’Brien et al. 1970). This has led to the discovery by many investigators that hetero­zygous carriers of the TSD gene have roughly only half the hex A activity of individuals homozygous for the normal allele. This is apparently enough, how­ever, for normal catabolism of the G_m2 ganglioside. In fact, G. Bach and colleagues (1976) reported a healthy adult TSD heterozygote woman with only 22 percent hex A activity.

Molecular Genetics

P A. Lalley, M. C. Rattazzi, and T.

Genetic Epidemiology

Certainly contributing to the amount of attention paid to TSD over the last century is the enigma it (and other deleterious genetic disorders such as sickle-cell anemia) presents: How can a lethal gene get to a high frequency in a population? How can that high frequency be maintained? Why is that gene found at a relatively high level in a particular population? In addressing this problem, one first examines in turn the basic evolutionary forces that change gene frequencies: mutation, gene flow, ge­netic drift, and natural selection.

Forces of Evolution Affecting Gene Frequencies

Mutations.

Gene Flow. Gene flow, the movement of genes from one population to another as individuals move, plays a greater or lesser role in the various explanations of the high TSD gene frequency in the Ashkenazim. Gene flow could have its biggest role if the intrigu­ing scenario proposed by A. Koestler (1976) is cor­rect. He suggests that the Ashkenazim are in large part descended from members of the Khazar Empire. The Khazar Empire existed from the seventh to the tenth century A.D. in an area north of the Caucasus Mountains, and during that time some Khazars con­verted to Judaism. It is speculated that after the fall of the Khazar Empire, those converts moved north­westward into areas of central Europe where Jews from western Europe were also emigrating. Thus, if those Khazars carried the TSD genes, they delivered them as part and parcel of their contribution to the Ashkenazi gene pool. As was the case with muta­tion, though, it is unlikely that gene flow in and of itself can account for the high frequency of the TSD genes among Ashkenazi Jews. The reason is that such an explanation would suggest that there was a group (perhaps the Khazars, perhaps some other group) with a high frequency of the TSD gene that provided the Ashkenazi Jewish population with a large number of carriers. There is no evidence of such an occurrence (see Neel 1979), which leaves natural selection and genetic drift as more likely reasons for the high frequency of the TSD genes among Ashkenazi Jews.

Natural Selection. N. C. Myrianthopoulos (1962) and A. G. Knudson and W. D. Kaplan (1962) first suggested that heterozygote carriers of the TSD gene may have a selective advantage over the nor­mal homozygote. Myrianthopoulos and S. M. Aron­son (1966, 1967) calculated that a selective advan­tage of about 1.25 percent on the part of the heterozygous carrier of the TSD allele would be suffi­cient to maintain the allele at its present frequency of approximately 1.3 percent among the Ashke­nazim, despite the loss of TSD genes through the deaths of recessive homozygotes afflicted with TSD. They then showed that over the course of 50 gen­erations (roughly from the time of the Diaspora to the present), a heterozygote-selective advantage of about 4.5 percent would increase the TSD allele frequency from 0.13 percent to 1.3 percent, again despite losses of TSD alleles through the deaths of recessive homozygotes. In order to provide support for their hypothesis, they compared sibship sizes of the parents of TSD offspring to the sibship sizes of a control group. They found the former to be slightly larger than the latter. Although the differences were not statistically significant, they indicated a heterozygote advantage sufficient to result in the observed present-day TSD gene frequency in the Ashkenazi population (assuming that the hetero­zygote advantage had remained more or less con­stant over time).

Two conditions are essential for a natural selec­tion explanation to hold: (1) a selective agent of sufficient magnitude to affect negatively the repro­ductive success of individuals, and (2) a physiologi­cal basis for the advantage one genotype has over the others. Following up on their earlier work, Myrianthopoulos and Arsonson (1972) suggested that heterozygous carriers of the TSD allele were less susceptible to tuberculosis, a disease especially common in many urban centers of Europe during the nineteenth century. Although they found a negative association between indirect estimates of TSD and tuberculosis prevalence, the association was too small to be statistically significant. Furthermore, no physiological basis was offered to explain why heterozygote carriers of the TSD allele might have a selective advantage with regard to tuberculosis. More recently, J. Zlotogora, M. Zeigler, and Bach (1988) have posited that selection is the reason for the high prevalence of not only TSD in the Ashke­nazi population, but also sphingolipid storage disor­ders in general among all Jews. However, they con­clude that the nature of the hypothesized selective forces has yet to be fully elucidated.

Founder Effect and Genetic Drift. G. A. Chase and V. A. McKusick (1972) suggested that founder effect and genetic drift, rather than heterozygote advan­tage and natural selection, explain better the high TSD gene frequencies in the Ashkenazi Jewish popu­lation. D. C. Rao and N. E. Morton (1973) calculated that it was possible that drift could account for the high frequency of the TSD genes in the Ashkenazim, and D. Wagener and colleagues (1978) came to a similar conclusion. T. E. Kelly and colleagues (1975) studied a semi-isolated non-Jewish population with a high frequency of TSD, concluding that founder effect is the most likely cause and suggesting that this case illustrated, in microcosm, how the high frequency of the TSD genes might have occurred. A. L. Fraikor (1977) also favors a genetic drift expla­nation in a detailed study in which genetic drift (broadened to include founder effect as well as some other population processes) is argued to be the most parsimonious explanation for the high TSD gene frequency among the Ashkenazim.

Genetic drift refers specifically to random changes in gene frequencies from one generation to the next (i.e., “sampling errors”). Sampling error is most pro­nounced in small populations in which, simply be­cause of the chance combination of a relatively small number of gametes out of millions of geneti­cally different contenders, the offspring genera­tion’s gene pool may not contain the same genes in the same frequencies as the parental generation’s gene pool. Thus, gene frequencies “drift” up or down through time. Unfortunately, there is no way to tell whether or not genetic drift has occurred in a population. Nonetheless, the probability of genetic drift of a certain magnitude occurring under certain circumstances can be estimated. Population size and changes in population size through time are the most important parameters in these calcula­tions (see Wilson and Bossert 1971). A process re­lated to genetic drift, founder effect, refers to the genetic impact that one or a few individuals may, by chance, have on the genetic structure of a new population after either migration or population de­cline. It is because of the chance factor that founder effect is usually considered in the context of genetic drift.

Fraikor (1977) chronicles the population history of Ashkenazi Jewry and finds that the conditions most conducive for genetic drift (especially small and semi-isolated local populations and large fluctua­tions in overall population size) were present throughout much of Europe for hundreds of years. However, A. Chakravarti and R. Chakraborty (1978) calculate that even in some situations highly condu­cive to genetic drift, the probability of observing the present discrepancies in TSD gene frequencies be­tween the Ashkenazim and non-Ashkenazim is low. They conclude that heterozygote advantage and ge­netic drift should be considered together as the most probable explanation for the high TSD frequency in the Ashkenazi Jewish population. This conclusion serves as a worthwhile reminder that the forces of evolution are not necessarily mutually exclusive ex­planations of genetic variation, a point made explicit by S. Wright (1977) in his “shifting balance” theory of evolution.

Up to now the difference between Ashkenazi Jews and non-Ashkenazi Jews (and non-Jews) in TSD prevalence and gene frequencies has been empha­sized. Indeed, in the extensive literature on TSD, this difference is often the only one considered. There is, however, evidence of considerable disparity among Ashkenazi Jewish groups in the prevalence of TSD. These differences are also important in as­sessing the reasons for the overall high frequency of TSD genes among the Ashkenazim. Aronson (1964) found that the ancestors of the majority of Jewish TSD cases in the United States came from the north­eastern provinces of Poland and the Baltic States. Myrianthopoulos and Aronson (1967) confirmed this finding, stating that with regard to TSD prevalence in central Europe “some variation, as high as five­fold, existed between Ashkenazi communities of these areas and that this variation is not random but shows a definite geographic trend.”

As it happens, these findings can be incorporated into both the natural selection hypothesis and the genetic drift hypothesis. The search for natural selec­tion is made somewhat easier because a selective agent in the environment that might give the hetero­zygote a reproductive advantage no longer needs to exist across Europe, but needs only to be shown to exist in a delimited geographic area. TSD genes spread out from there through gene flow, and it would have been some time before they would have been removed in appreciable numbers through the deaths of the recessive homozygotes; by then the carrier frequency may have become rather high. The case for genetic drift is made somewhat stronger because the Ashkenazim no longer need to be consid­ered a large interbreeding population, but instead can be viewed as a subdivided population made up of a number of smaller semi-isolates in each of which genetic drift is more likely to take place. The TSD genes spread from areas of high frequency to neigh­boring areas of low frequency through gene flow, thus explaining the geographic distribution ob­served by Myrianthopoulos and Aronson (1967) of the ancestors of TSD-affected individuals.

A Combination of Factors. In the absence of much substantive data, and the fact that evolutionary forces most often work in concert, the conclusion reached by Chakravarti and Chakraborty (1978), that a combination of heterozygote advantage and genetic drift is the most probable reason for the high TSD gene frequencies in the Ashkenazim, is appeal­ing. In a similar vein, although not incorporating heterozygote advantage, Fraikor (1977) does not rely solely on genetic drift, but favors a combination of factors. She writes of Ashkenazi Jewish communi­ties over the last few hundred years:

The combination of polygamy, inbreeding, small effective population size, and large numbers of progeny could have elevated the frequency of the TSD allele in the descen­dants of these populations. The subsequent period of seminomadism resulted in numerous individual carriers being scattered in many parts of Eastern Europe. Some carriers probably also remained in Germany or Western Europe. During the Golden Age of the sixteenth century, the rapid population expansion and freedom of migration within the territory of Poland greatly enhanced the chances for carriers to marry noncarriers. Such marriages would further increase the number of carriers in the total population, and selection against the gene would be re­duced because affected homozygotes were not being pro­duced in significant numbers. (Fraikor 1977)

Alternative Theories

Before leaving this issue, we must consider other explanations for the high frequency of TSD in the Ashkenazi Jewish population. One of these, inbreed­ing, was mentioned previously. Inbreeding does not change gene frequencies, but because it increases homozygosity generally (dependent on the level of inbreeding), it increases the probability of deleteri­ous alleles coming together in individuals. In­breeding is, in fact, the likely cause of the high prevalence of other sphingolipid disorders in other Jewish populations (see Zlotogora et al. 1980; Towne 1987; Zlotogora, Zeigler, and Bach 1988), and as Fraikor (1977) hypothesizes, may have played a role in some of the smaller and more iso­lated Ashkenazi Jewish communities.

Finally, Wagener and Cavalli-Sforza (1975) sug­gest that either “hitchhiking” or epistasis may have increased TSD gene frequencies in the Ashkenazim. When two genes are in close proximity to each other on a chromosome, they are likely to be inherited together over the generations. Thus, a deleterious allele may “hitch” an evolutionary ride with a selec­tively favorable allele. With the human genome map becoming more and more detailed, some hitchhiking hypotheses can increasingly be tested. What re­mains to be seen in this case is whether a highly favorable allele can be found in the Ashkenazim that happens to be on chromosome 15 in the area of q23-q24. Epistasis refers to the interactions be­tween unlinked genes. J. V. Neel (1979) notes the following:

[An] epistasis hypothesis is theoretically possible but diffi­cult to visualize as a general explanation for recessive deleterious genes in high frequencies in defined groups, given what we know about the usual heterozygous effects of these genes. Specifically, in the case of TSD, it is diffi­cult to visualize a genetic interaction that converts half­levels of hex-A into a selective advantage.

The Disease in the Future

There has been some debate on whether or not the incidence of TSD is increasing. R. F. Shaw and A. P. Smith (1969) argue that it is, basing their conclusion on a calculation that assumes a heterozygote advan­tage of approximately 5.3 percent, a value slightly higher than that calculated by Myrianthopoulos and Aronson (1966). On the other hand, Myrianthopou- los, A. F. Taylor, and Aronson (1970) doubt that the TSD gene is increasing because the conditions (high prevalences of tuberculosis) that may have offered the heterozygote an advantage in the past are no longer present. Chase and McKusick (1972) suggest that the present high incidence of TSD is “a tran­sient phenomenon due to the chance encounter of recessive genes whose frequency has reached a high level partly as a consequence of diminished inbreed­ing.” It must also be kept in mind, though, that present-day high levels of TSD may be an artifact of better diagnosis and case reporting.

Aside from the continuing study and debate about the different aspects of TSD touched on here, there are some more immediate concerns. At the present time, there is no cure for TSD. However, because heterozygote carriers of a TSD gene can be identi­fied by a clinical test, as can an affected fetus through amniocentesis, individuals have available to them some important options. M. M. Kaback and R. S. Zeiger (1972) conducted the first major effort to identify TSD heterozygote carriers. Kolodny (1979) gives three reasons for the success of this screening program:

1. The testing program was targeted toward a de­fined subgroup of the population, namely, Ashke­nazi Jews in their childbearing years.

2. A relatively simple, accurate, and inexpensive method was available for determining heterozy­gote status in an individual.

3. An in utero test for Tay-Sachs disease existed.

Kolodny (1979) went on to note that as a result of this and other screening programs more than IOO TSD births had been averted. Kaback and col­leagues (see his 1979, 1981) present detailed infor­mation and updates on various aspects of TSD screening programs. D. A. Greenberg and Kaback (1982) report that at the time of their writing, over 200,000 adults in the United States had been screened for TSD carrier status. Estimates of TSD carrier frequencies vary somewhat from one study to another. O’Brien (1983) predicts a U.S. Ashkenazi Jewish population carrier frequency of 2.6 percent, whereas Kolodny (1979) estimates the frequency to be 3.7 percent.

Bradford Towne I would like to thank Dr. Jean W. MacCluer for her comments and suggestions on this article.

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