Neurologic genetic diseases of Jewish people

Biomed

& Pltnnnocorl~er

( 1994) 48, 39 I-397

391

0 Elsevier, Paris

Neurologic

genetic diseases of Jewish people AD Korczyn

Sackler

Fucult~

of Medicine.

Tel At’iv

University

69978

Ramor

Aviv,

Israel

Summary - Three important dominantly-inherited neurological diseases were discovered to be particularly common among various Jewish ethnic groups. For idiopathic torsion dystonia (ITD), previously thought to be recessively transmitted among Ashkenazi Jews, we have established an autosomal dominant mode of inheritance. This finding resulted from a country-wide survey of ITD in Israel and its subsequent genetic analysis. In Creutzfeldt-Jakob disease (CJD) the focus among Libyan Jews was previously thought to be related to culinary habits; a point mutation of the prion-protein gene was first described by us. The factors leading to the perservation of these disadvantageous genes in the communities are however unknown. Genetic analysis shows reduced penetrance in ITD and age-related expression in CJD. Factors leading to the expression of the genes were looked for. Data for ITD suggest that laterality of onset depends on motor dominance. Data on anticipation are presented. Factors possibly involved in the expression of the CJD codon 200 mutation are also discussed. A focus of myotonic dystrophy was documented among Yemenite Jews. The preservation of this disadvantageous, dominantly-inherited gene (which leads to diminished reproductive abilities), was found to be social rather than biological, related to reduced age of marriage and number of offspring in this ethnic group. These data show an interaction between genetic and other biological and external factors in the expression of these three diseases. human

genetics

/ neurological

diseases

I Jewish

people

/ torsion

Unusual diseases are not rare in people who were isolated from other communities by reasons of geography, religion or prejudice. Several disorders are known to occur with an unusually high frequency among Jews [29]. The scientific study of these diseases has been hampered for many years by the fear -among Jewish scholars - of contributing fuel to prevailing predjudice, and among non-Jews by fear of being suspected of antisemitic motives. Still, the recognition and understanding of such diseases is of considerable scientific interest and obvious practical importance. Recent years have evidenced a change in the understanding of anthropological genetics of Jewish people [8, 281. At the beginning of the 20th century, there was an emphasis on physical anthropology, that is of body features distinguishing Jews from other ethnic groups. Jews, particularly Ashkenazi Jews, were regarded as having unique physical characteristics, different from those of other Europeans, to the extent of justifying their distinction as a separate “race”. This

dystonia

I Creutzfeldt-Jakob

disease

/ myotonic

dystrophy

was the context which has led to the concept of the “Jewish nose” and other phenotypic features. In reaction to this approach and its horrifying consequences, leading to the extermination of millions of Jews in Europe during the Nazi era, many geneticists shied away from the further study of “Jewish genetics”. The traditional anthropological measures used were of parameters such as height, color or intelligence, which - as we now know - change in a continuous manner and are controlled by several genes (as well as by environmental factors). However newer studies have employed biochemical or genetic markers - firstly blood groups and later also HLA phenotypes, glucose6-phosphate dehydrogenase isoenzymes and many other parameters. These studies have led to a better understanding of genetic similarities and differences among Jewish communities as well as between the Jews and non Jews residing in the same countries [8]. In parallel with these developments, several genetic diseases which have a predominantly high

392 frequency among some Jewish ethnic groups were identified [1, 2, 5, 6, 12, 13, 19, 27, 35, 36, 41, 43, 501, and several of those with neurological aspects are enumerated in table I. Some diseases with specific neurological relevance will be discussed below. The high prevalence of certain genetic disease among Jews may be the result of different causes, and a few examples will be reviewed. In Israel, the Ashkenazi Jewish population of European origin comprises 49% of the Jewish population. The prevalence of myotonic dystrophy (MyO) among them is 2.8 per 100,000, consistent with worldwide rates for the Caucasoid groups. Sephardi Jews originating in the Middle East and the Mediterranean basin comprise 46% of the population, and have a prevalence of 5.7 per 100,000. Another small subgroup, Yemenite Jews, comprise 3% of the Jewish population, and have a prevalence rate of 17 per 100,000. Most phenotypic expressions of MyD are similar among ethnic subgroups. However, an analysis of the fertility rates for each ethnic group has determined that the increased number of Yemenite patients could be accounted for by the normal number of progeny of the male Yemenite patients, as compared to the reduced number of progeny of the male patients of other ethnic groups [41]. A relative increased fecundicity, noted in the Yemenite male patients was also reported from the Suguenay-Lac St. Jean region of Quebec, Canada [52]. The reasons for the fact that increased fertility among the Yemenite patients is not decreased, as should be expected by the testicular atrophy, and as observed in other ethnic groups, is still under investigation. However, the explanation seems to be a sociological one. Ye-

menite Jews tended to get married at a very early age. Because the testicular changes responsible for reduced fertility (fibrosis of seminiferous ducts) develop insidiously over 2-3 decades or more, progeny may not necessarily be seriously reduced if marriage occurs early. Several lysosomal diseases are more frequent among Ashkenazi Jews. These include Tay Sachs disease, Niemann Pick disease, Gaucher disease and mucolipidosis type IV. All are recessively inherited disorders and the occurrence of all of them in a single ethnic group (East-European Ashkenazi Jews) is hard to explain. Although many are lethal diseases, the mutant genes persist and reach a high frequency. This has suggested a selective advantage of the recessive gene carrier. These hypotheses are difficult to test experimentally and conflicting views may well persist for long periods.

Creutzfeldt

Jakob

disease

Creutzfelt Jakob disease (CJD) is the most common human spongiform encephalopathy (SE), a unique group of diseases (table II), which have recently been a focus of interest. Epidemiological studies of CJD indicate that it is quite rare in Europe and north America, with an annual incidence of about 1: 106. It is one of the rare causes of dementia, either pre-senile or senile. Most commonly it presents sporadically, although about 10% of index cases report additional affected individuals in their families. The successful transmission of CJD to experimental animals [21] has led to the suspicion that CJD is a “viral” disease [20]. Several cases of apparent humanto-human transmission of CJD [ 10, 14, 531 have

Table I. Genetic neurologic diseases of Jews. Ethnic

Congenital myasthenia Quadriceps-sparing myopathy Oculopharyngeal muscle dystrophy Tay Sachs disease Torsion dystonia Familial dysautonomia Creutzfeldt Jakob disease Myotonic dystrophy Huntington’s disease Cerebrotendinous xanthomatosis 3-Methylglutaconic Aciduria

group

Irani-Iraqi Jews Iranian Jews Bukhara Jews East European Jews East European Jews East European Jews Libyan Jews Yemenite Jews Karaite Jews Moroccan Jews Iraqui Jews

W

[501

[511 [521 [61 [I21 191

[lOI 1111 1531 141 [541

393 Table II. Unusual I. 2. 3. 4. 5. 6.

characteristics

of spongiform

encephalopathies

Transmission by inoculating tissues from affected individuals Accumulation of specific proteins (PrP) in the brains of affected individuals Infecting material consisting primarily or exclusively of protein; no evidence No inflammatory tissue response in recipients’ blood, brain or CSF Genetic mutations of the PRNP gene may result in “spontaneous” SE Exceptional cases of well-documented human-to-human transmission of SE

resulted in an impression that CJD is, in fact, an infective disorder. During the early 1970’s a cluster of CJD patients was identified in Israel among Jewish immigrants from Libya [4, 261. This focus was of great interest since until then no other focus of this disease was described, and consequently it was extensively studied [33]. It was found that all Jews belonging to the focus had emmigrated from Libya in one wave during 1950-51. Since then, cases of CJD were also discovered in a relatively high frequency among North African Jews who have emmigrated to France [3]. It was first suggested that the high frequency of CJD among Libyan Jews was due to a shared environmental factor, and specifically that it resulted from exposure to scrapie in Libya (table III). Thus, it was thought that the inhabitants of Libya consumed the brains [l] or eyeballs [30] of sheep which were infected by scrapie. Since the local custom among Jews in North Africa was to grill brains, it was hypothesized that the infective material could be inactivated by cooking but not by light grilling (which may be true for the scrapie agent). This hypothesis assumed that scrapie in fact existed in Libya, but whether this is true, is still unknown today. Noteworthy, figures concerning the frequency of CJD among non-Jewish Libyans are hard to obtain. In addition, customary habits were not obviously different among Jews of Libya and other North African origins [22]. Yet, CJD was not seen in the much larger Jewish population who have em-

Table III. I. 2. 3. 4. 5.

(SE).

Spongiform

encephalopathies

for nucleic

acids

migrated to Israel from Morocco. On the other hand, it was obvious that familiarity exists among cases of North African origin, but never in other Jewish CJD patients in Israel. A formal study confirmed the high familial predisposition, but suggested that this reflected shared environmental factors (eg exposure to scrapie) rather than, for example, a genetic predisposition [45]. Obviously the popular and widely accepted concepts about transmissibility of the CJD agent have obscured alternative explanations. The assumption of natural transmission of SE in humans (at least in the Libyan focus in Israel) suffered a strong blow when we encountered a CJD patient, who was born in Israel to parents who had emmigrated from Libya [46]. He could not have been exposed to scrapie in Israel (which he had never left) since scrapie does not exist in Israel. Obviously a new explanation had to be provided. Because of the known familiarity of CJD in Libyan Jews, the most likely explanation was that CJD in this ethnic group is transmitted genetically in a pattern similar to that of another human spongiform encephalopathy, GerstmannStraussler-Scheinker disease (GSS) [31]. Another cluster of CJD was reported from Slovakia [42]. This focus was investigated but an environmental factor could not be detected. However, molecular genetic studies revealed the presence of a G-to-A point mutation in codon 200 of the prion protein gene [23, 241. We have subsequently confirmed the existence of the same point mutation among the Libyan patients

(SE): transmission.

All SE can be transmitted experimentally to suitable experimental animals Transmissibility is modified by species barriers and by genetic heterogeneity in recepients Among human SE, only Kuru had frequently been transmitted from victims to healthy subjects Transmission of SE from CJD patients to healthy subjects were reported anecdotally and extremely rarely CJD clusters are infrequent, and can probably always be explained by genetic factors rather than by natural infection 6. Coniugal CJD is practically non existent, and CJD among health (or cattle) workers is exceptionally rare

394

[25, 381 and these findings were later confirmed by others [32]. This then is a clear example of a situation where a disease was originally thought to be due to environmental exposure, but later proven to result from a genetic mutation [ 12, 351. The specific Libyan mutation exists in several other parts of the world. It was first recognized, as mentioned above, in Slovakia [24], even before the Libyan focus was recognized as being due to a genetic mutation. In Slovakia, the focus occurs in two separate villages. Recently, the same mutation was also discovered in Chile. The question then posed itself as to whether all three foci, the Slovakian, the Jewish Libyan and the Chilean, resulted from a single mutation, spreading to these respective areas through genetic drift. It was suggested that the mutation first occurred in Spain over 5 centuries ago, possibly in a Jewish person. The expulsion of Jews from Spain in 1492 was assumed to have caused the mutation to spread with founders contributing the mutated gene to different communities. Several lines of thought make this hypothesis unlikely. The majority of Jews who have left Spain emmigrated to the various Mediterranean countries, largely to North Africa, Italy and Turkey. Yet, the codonmutation CJD has never been documented among Italian or Turkish Jews. There are several cases of the codonmutation CJD cases among Tunisian Jews and this probably reflects the close connections which have always existed between the Jewish ethnic communities in Libya and Tunisia. The same explanation might account for the single Greek Jewish case [25] and for one non-Jew identified by us in Sicily (unreported). The codon 200 mutation CJD focus among Jews in the South of France [3] is obviously related to Jewish emmigration from Tunisia. Following the expulsion of Jews from Spain, Jews have also emmigrated to the Netherlands and other northern European countries, and these immigrants could have carried genetic mutations with them, and presumably could have “seeded” the Slovak focus. However, it must be realized that 500 years ago it would have been quite difficult for a wandering Jew to marry into a Christian family in central or eastern Europe, whereas these immigrants were easily accepted and integrated by the local Ashkenazi communities in these countries. The absence of codon 200 mutation CJD cases among Ashkenazi Jews thus makes the suggestion that this specific mutation drifted from Spain to Slovakia highly unlikely,

since it implies that only one person carrying the mutation ended up in central or eastern Europe, and this person happened to marry a non-Jew. Even less likely is the suggestion that Jews have been responsible for the Chilean focus, although for similar reasons. The Chilean families, like the Slovak ones, have no tradition of having had Jews marrying in. The Jews who have arrived in South America have spread to many countries, but still the only focus identified is in Chile. The assumption that Jewish mutation bearers have carried the codon 200 mutation from Spain to Libya, Slovakia and Chile, also disregards the fact that the mutation has not yet been identified in Spain itself, in spite of a considerable effort, testing several cases (Goldfarb and Brown, personal communication). Many spontaneous mutations occur repeatedly through history. Some regions of the human genome are more prone to mutations than others, and the number of recognized mutations of the prion protein gene is large and growing. Thus it is more likely to assume that the codon 200 mutation occurred independently in the three geographical areas mentioned, rather than in Spain. A recent description of the same mutation in Japan underlies this argument. Future discoveries of cases with the same point mutation in other ethnic groups and geographical areas may further strengthen this view.

Idiopathic

torsion

dystonia

Idiopathic torsion dystonia (ITD) is another neurological disease with a high frequency among East European Ashkenazi Jews [ 151. Clinical manifestations (table IV) should be compatible with ITD, and structural brain lesions or abnormal biochemical findings should be absent. When these criteria are adhered to, it becomes clear that many cases are familial. Since the early description of the disease, a seemingly high occurrence among Jews was noted. One of the very first families described, the Lewin family, clearly Jewish, followed an apparently dominant mode inheritance. Thus, it was believed that ITD is a genetically inherited disease and clinical observations suggested a particularly high prevalence among Jews. In a very extensive survey of ITD in the United States, Eldridge [ 151 identified 41 Jewish families and 44 non-Jewish families and concluded that the disease among Jews and non-

395 Table IV. Criteria

for the diagnosis

Inclusion

of ITD.

criteria

Insidious onset after age three Normal perinatal history Consistent clinical features Consistent clinical course

Jews was different. Eldridge suggested that differences between Jewish and non-Jewish patients were related to age of onset (younger in Jews), mode of onset (axial in non-Jews, limb in Jews) and degree of generalization (more limited in non-Jews). Moreover, Eldridge has suggested that among Jews, the genetic mode of transmission was usually recessive, thus making the Lewin family an atypical example, but putting ITD in the same category as familial dysautonomia and Tay Sachs disease, which are also common among East-European Ashkenazi Jews and have followed a recessive transmission. Another question related to the frequency of the disease among different Jewish ethnic groups, and particularly whether it was confined to Ashkenazi Jews, like other diseases with recessive inheritance (eg lipidoses). In order to answer this question, Alter et al [2] have analyzed the data of ITD patients hospitalized in Israel during the years 1969-1972. It appeared that Ashkenazi Jews were represented considerably more frequently than other ethnic groups. Again, the parallelism with other recessive diseases affecting Ashkenazi Jews was noted. This study was deficient because the patients were not personally seen by the authors, the ascertainment was incomplete, and the total number of cases was small. Therefore in 1975 we undertook a country-wide survey of the disease in Israel for the years 1969-1975. This study [36] has confirmed that the disease has a higher prevalence and incidence among Ashkenazi than among non-Ashkenazi Jews; however, it also created a query about the mode of transmission. In particular, the cases identified consisted of 32 “sporadic” cases, and 14 who belonged to four families. Vertical transmission was common, and parental consanguinity rare. Thus, we have casted doubt on the suggestion that ITD among Jews is inherited recessively [36, 371. Indeed, our data have led us to conclude that ITD

Exclusion

crirerio

Prior treatment with neuroleptics Marked diurnal fluctuations Sensory changes Oculomotor disturbances Pyramidal of cerebellar dysfunction Abnormal findings on CT or MRI Abnormal copper metabolism Abnormal ganglioside metabolism

among

Ashkenazi

Jews

is transmitted

as an au-

tosomal dominant trait with incomplete penetrance [36, 37, 541. According to our calculations, the penetrance was 51%, and this has accounted for skip generations. More recent data from the Columbia group [9] have confirmed the conclusion that, among Ashkenazi Jews, ITD is transmitted by an autosomal gene, but they have calculated a lower penetrance, ie. 30%. In order to settle the issue of genetic transmission of ITD among Ashkenazi Jews completely, we have recently re-analyzed the original data of Eldridge [15]. Because he has provided family trees of his cases, the data could be used for sophisticated genetic analysis using the Pointer computer program. This analysis of the Eldridge [15] cohort, as well as of the Israeli patients, demonstrated autosomal dominant transmission with incomplete penetrance in both groups [48, 491. Estimates of penetrance ranging from 25% in Eldridge’s series [ 15,481 and 30-32% in the Columbia series [9] to 5 1% in the Israeli series [23]. The differences could be accounted for by selection bias as well as by whether formes frustes were included or not. The mechanism responsible for the reduced penetrance if ITD has not been addressed so far may be due to modifying genes or external factors. Identification of such factors could be extremely important since they could be amenable to manipulation more easily than gene doctoring. Based on the previously reported association of dystonia with cerebral palsy [ 11, 5 11, and the reported high frequency of perinatal anoxia in ITD [15], we have examined whether perinatal anoxia could be a precipitating factor in subjects predisposed because of an abnormal gene, but found this not to be the case (Pauls and Korczyn, unpublished data). Another factor identified by us recently was the association of right handedness with onset of dystonia on the right side. Con-

396 versely, left handed patients had the onset of their dystonia on the left [34]. Thus it seems that the use of a limb may provoke, or accelerate, the development of dystonia in a genetically predisposed individual. Obviously the mechanisms involved are still unclear; more data on additional factors are needed. The issue of modifying factors is not unique to ITD, and is also true for other, perhaps most dominantly inherited diseases. A critical issue relates to the reason for the high frequency of ITD among Jews. Eldridge et al [ 161, claiming that ITD is inherited recessively among Jews, suggested that the gene also conferred superior intelligence and this beneficial effect extended to gene carriers, thus providing a positive selection bias. This hypothesis has never been confirmed, and in any case had to be modified since the demonstration of dominant inheritance of the dystonia gene among Ashkenazi Jews. One widely held explanation is of a founder effect, implying a single mutation having occurred among Jews in East Europe. While such an hypothesis may be satisfactory for diseases with a very low mutation rate, it is somewhat more difficult to accept when new mutations are relatively common, eg 1:30.000 gametes [ 18, 541, and because of the reduced fitness [ 181 the rates among Jews and non-Jews should have equalized over several generations. The question of the frequency of new mutations is therefore critical. If new mutations are uncommon, it is likely that the high frequency among Jews of ITD is due to a selective advantage of the gene, even if it is not expressed as a motor disability. Interestingly, this question has been answered. The gene responsible for ITD in most Jews and many non-Jews was located [ 17,40,47] to chromosome 9q. More importantly, an unusual marker for this gene was identified in Ashkenazi Jews. Thus, this marker is rare in the general Jewish population. It seems that the high frequency of ITD among Ashkenazi Jews is due to a founder effect. What selective advantage this affords to the carriers remains to be established.

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