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Torsion Dystonia in Israel

Amos D. Korczyn, MD, MSc, Esther Kahana, MD, Nelly Zilber, D es Sc, Max Streifler, MD, Raphael Carasso, MD, and Milton Alter, MD
torsion dystonia (lTD) in Israel between 1969 and 1975 revealed 42 patients (4lJewish and I Druze Arab). Prevalence of lTD per million population, age-adjusted to the United States population 1970,was lO.8 in the total Jewish population (22.0 among Jews of European extraction contrasted with 1.5 in among Jews with Afro-Asian forebears). Among Europeans, the highest prevalence was among Jews from Eastern Europe. Theaverage age-adjusted annual incidence rates per million population were 0.43 in the total Jewish population, 0.98 in the Europeans, and 0.11 in the Afro-Asians. Among the 40 patients for whom familial data were available, themajority of cases (26) were sporadic. The other 14 belonged to four unrelated European families, all of Russian-Polishrigin. The pattern of inheritance o in these four families fits an autosomal dominant model with incomplete penetrance. Korczyn AD, Kahana E, Zilber N, et al: Torsion dystonia in Israel. Ann Neurol 8:387-391, 1980

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Idiopathic torsion dystonia (lTD) is a movement disorder haracterized by irregular, sustained involunc tary movements, often resulting in abnormal poslUres The onset of symptoms is preceded by a [9]. periodf normal neurological and intellectual develo opment. The disorder is not accompanied by other organ system disease. Although there is still no general agreement as to the nosology, pathology, or [2], some evidence exists that disturbance of brain catecholamine function may be the pathophysiological basis of dystonia [10]. Thepossibility that lTD might be an inherited disorder wasconsidered in the earliest reports, and the likelihood the Jewish ethnic group might have a that frequency of the disorder than other groups wasupported by observations of familial aggregates s lTD in Jews [2, 3]. Recently, extensive family studies Eldridge et al [4, 5] have provided a larger by clinical material, from which they conclude that there might two genetic forms of lTD. About one-third be ofthefamilies with typical dystonia studied by Eldridget al were Jewish, and a recessive pattern of e inheritance thought to be more common in this was group. Onset occurred between 4 and 16 years of age, limbswere involved earlier and more severely than axial musculature, and clinical deterioration the wasapidin the early stages of the disease. However, r after dolescence, symptoms often tended to staa bilize. was suggested that the recessive form of It

lTD might be due to a gene occurring with unusual frequency in Jews who have immigrated to America from Eastern Europe. In the series of Eldridge et al[3-5J, the autosomal dominant form of lTD was thought to occur mostly in non-Jewish families. In this form of dystonia, age at onset was more variable but onset usually occurred in adulthood, there was earlier involvement of the axial musculature, torticollis was frequently the presenting complaint, and the clinical course was slowly progressive. The gene postulated to cause the dominant form of lTD appeared to have no geographical selectivity. The disease was rare in some ethnic groups, such as blacks in the United States [7]. Previously we reported the results of a nationwide survey of hospital records for lTD in Israel [IJ and measured the levels of dopamine ,a-hydroxylase [ 11, 12]. In the present study, we were able to extend and enlarge the clinical material available for analysis. By studying a well-defined population, we minimized bias in case selection and were able to present a more complete epidemiological analysis of lTD among Jews. Methods
In the present study, the National Registry of Neurological Diseases, maintained by the Uri Leibowitz Neuroepidemiology Unit of Hadassah University Hospital, Jerusalem, served as a major source for case finding. The

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From the Sackler School of Medicine, Tel Aviv University, and Beilinson Hospital, Petah Tikva, Hadassah University Hospital, ~rusalem, arzilai Hospital, B Ashkelon, Ichilov Hospital, Tel Aviv, Israel,and Temple University Hospital, Philadelphia, P A.

Received Nov 19, 1979, and in revised cepted for publication Feb 10, 1980.

form Feb 7, 1980. Ac-

Address reprint requests to A. D. Korczyn, MD, Department of Physiology and Pharmacology, Tel Aviv University Medical School, Ramat Aviv, Israel.

7146/80

0364-5134/80/100387-05$01.25

1979

by Amos D. Korczyn

387

registry receives data on every patient with a neurological disorder discharged from any hospital in Israel. Demographic data about the general population of Israel are available from detailed reports published annually by the Central Bureau of Statistics [13J. The population is ethnically diverse, consisting of native-born Jews and Arabs as well as immigrants from Europe, Africa, Asia, and America [8J. In publications of the Central Bureau of Statistics, ethnic origin is based on the individual's place of birth or, if born in Israel, on the father's place of birth [13]. Hence we accepted this convention as well. In the present study we retrieved from the registry names of patients hospitalized during the period 1969 through 1975 and suspected of having lTD. All cases covered in the previous study of lTD in Israel [1] were included in the present study, and additional names were obtained through notification by other neurologists as well as through data gathered from patients about affected relatives. All suspected cases of lTD, spasmodic torticollis, blepharospasm, and graphospasm were identified. These patients were visited by a trained field worker. Patients who had not recently been hospitalized in a neurological department were reexamined by one of us (A. D. K. or E. K.). Information pertaining to ethnic origin and fame ily pedigree was systematically collected on a specially designed form. Family data were obtained for all but 1 patient. Only patients who satisfied all five of the following clinical criteria were accepted as having lTD: (1) dystonic posture or movement; (2) a progressive clinical course at some time; (3) normal perinatal history and no other abnormal neurological signs (intellectual, sensory, pyramidal, or cerebellar); (4) no history of encephalitis or brain trauma; and (5) no metabolic disorder (e.g., Wilson disease or abnormal calcium levels) that could account for the condition.

lTD; 19 had only focal abnormalities such as torticollis; and 25 could not be located despite intensive efforts (2 of these are known to have died and 3 were living abroad). Forty-two patients were accepted as having lTD. There were 25 males and 17 females, a nonsignificant difference. One subject was an Arab of die Druze sect; the others 1977,

T able 2.

Age-sjJe(

Ethnic G rou ps i, Millio/l POjJII/elli

Group Total populatio Non-Jewish Jewish Europcan East Europ Central Eu Other Afro-Asian
a Age

42 patients,

35 were known

on December 31, prevalence day. Prevalence data

were Jewish. Of the to be alive and in Israel which was designated the in Table

are summarized

l. The

crude point-prevalence rate of lTD in Israel on that day was 9.6 per million population. In the Jewish population it was 11.1 per million. The prevalence of lTD in European Jews was 23.8 per million, compared with only l.1 per million in Afro-Asian Jews. The highest prevalence among Europeans (27.0) was observed in East Europeans, compared with Central Europeans and Jews from elsewhere in Europe (21.2 and 13.5, respectively). The prevalence among nonJews was 1.7 per million population, which was similar to that of Afro-Asian Jews but was based on a single Arab case. Populations of different origins living in Israel vary considerably in age distribution. Therefore, prevalence rates were adjusted to a standard population

groupings 1 year period s II) I

Table 3. Al'erag 0/ lTD in !.rrae.

Age Group 0-9 10-19 20-29 30-39 40-49 50-'59

(U nited States population in 1970 [6]). However, even after standardization for age differences, European Jews-in particular those of Eastern European origin-had the highest prevalence of lTD (see Table 1). The age-specific prevalence rates among various ethnic groups are shown in Table 2. No patient was
younger than 15 years of age. The prevalence rate was significantly higher for younger individuals among people of Eastern European origin than among other ethnic groups (p < 0.001). The average annual incidence rate of lTD was calculated for the period January 1, 1969, through De-

60+
Total Crude Age-adjustc

Results A total of 137 names were collected of patients tentatively considered to have lTD. Of these, 95 were excluded for various reasons: 51 had other disorders such as cerebral palsy or signs incompatible with Table 1. Prevalence Rates

"To United Stat,

N = number dence rate. ol

0/ lTD

among Ethnic Groups in Israel on December 31, 1977, per Million Population No. of Patients 35 1 34 31 24 4 3 2 Population (x 103) 3,653 576 3,077 1,300 889 189 222 1,777 Prevalence Crude 9.6 1.7 11.1 23.8 27.0 21.2 13.5 1.1 Age-adjusted' 9.8 2.2 10.8 22.0 25.8 17.9 14.5 1.5

cember 31, cases occurre age annual a population w 0.98 for (he Afro-Asian r cases, onset years of age.

Group Total in Israel" Non-Jcwish Jewish European East European" Central European" Other Afro-Asian Uncerrain

dence rates 0 3.38, and 0.'1 pean Jews, a: 3). Thcre was disorder in : famil y data ; of these 25 \ the patient' blepharospa:

"United States population in 1970. "Seven patients were deceased Of not living in Israel on prevalence "Latvia, Lithuania, Russia, Poland, and Rumania. "Germany, Austria, Czechoslovakia, and Hungary.

day (12/31/77).

before she (; with lTD we

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Tahle 2. Age-specific Preralence Rates oj ITO among Ethnic G ronps in Israel on December 31, 1977, per lVlil/ioli Popalat itm Age Group" Group Total population Non-Jewish Jewish European East European Central European Other Afro-Asian
Age groupings by country year periods l13J.
a

0-14 0 0 0 0 0 0 0 0

15-29 14.5 0 17.1 41.8 55.0 19.7 19.7 2.0

30-44 19.0 13.0 21.9 43.5 51.6 31.8 24.8 0

45+ 10.1 0 11.2 14.9 12.4 25.6 18.3 3.5

to four apparently unrelated families (Figure). Thirteen of these patients were born in Russia or Poland, and the family of the fourteenth proband, who was born in Germany, originated in Poland. In contrast, only 9 of the 25 patients for whom family history was negative for dystonic phenomena were born in Eastern Europe. Thus, there was a significant (P < 0.001) clustering of familial cases of ITO in Jews from Eastern Europe. If the family in which the mother had only blepharospasm were included among the familial cases, the clustering would have been still greater, since that family originated in Poland. Discussion The intensive search for ITO in Israel disclosed 42 cases, almost doubling the number available from our previous study [1]. All 42 patients accepted in the present study satisfied rigid diagnostic criteria. There were 25 patients whom we were not able to trace. However, 23 of these were hospitalized prior to 1969; i.e., failure to include these subjects relates to the long retrospective period. Thus, practically, it does not interfere with the incidence rates calculated for the period 1969 through 1975. Moreover, most of these cases (18 out of 23) were diagnosed as having focal troubles (graphospasm or torticollis). In the traced cases, out of 19 patients first diagnosed as suffering from these focal signs, only 3 were accepted as having ITO. If the same proportion of accepted cases held among the nontraced patients, one should expect 2 or 3 ITO cases; the same type of calculation for the 5 remaining patients first diagnosed as having ITO leads to an expected number of 2 ITO cases among them, i.e., one could expect to have lost 4 to 5 cases total. The number is certainly smaller for two reasons. First, 78% of the nontraced patients and only 17% of those traced were first diagnosed as having focal abnormalities; the most probable reason for this difference in percentages is that most of those who could not be traced had no evolution of the focal trouble and no further hospitalization, i.e., probably were not ITO patients. Second, of the 42 accepted cases, 7 were deceased or were not living in Israel on prevalence day (December 31, 1977). In view of the earlier date of ITO onset of the nonlocated cases, we could expect that several of them would not have been included in the prevalence data. Thus, no more than 2 or 3 cases should have been missed, and it seems unlikely that their inclusion could have altered our conclusions appreciably. It is widely accepted that the ITO gene has a high frequency among Ashkenazic Jews [2J. * However,
'In the present study we have based our analysis on statistical data which refer to the country of birth. Thus we have used the terms "European" and "non-European" Jews. Jews originating in Europe are mostly Ashkenazic.

of origin were available

only for 15-

Table 3. Average Annual /vge-specific Incidence Rates 0/ ITO in Israel (1969-1975) per Million Population Total Jewish Age Group 0-9 10-19 20-29 30-39 40-49 50-59 60+ Total Crude Age-ad j usted"
"To United N = number dence rate.

European N 0 4 1 1 0 1 0 7 IR 0 3.38 0.67 1.19 0 0.85 0 0.85 0.98 N 0 0 0 0 0 0

A froAsian IR 0 0.48 0 0 0 0 0 0.11 0.11

N 0 5

IR 0 1.38 0.31 0.49 0 0.56 0 0.42 0.43

in 1970.

0 0 8

States population

of cases diagnosed

during

1969-1975;

lR = inci-

cember 31, 1975. During these seven years, 8 new cases occurred, 1 of which was Afro-Asian. The average annual age-adjusted incidence rate per million population was 0.43 for the total Jewish population, 0.98 for the European population, and 0.11 for the Afro-Asian population (Table 3). In 5 of the 8 new cases, onset of ITO occurred between 10 and 19 years of age. For this age group, the age-specific incidence rates of ITO per million population were 1.38, 3.38, and 0.48 for the total Jewish population, European Jews, and Afro-Asian Jews, respectively (Table
3).

There was no family history of ITO or a related disorder in 25 of the 40 Jewish patients for whom family data were available. However, the parents of 1 of these 25 were first cousins. In a twenty-sixth case, the patient's mother was described as having blepharospasm and a neurotic personality. She died before she could be examined. The other 14 patients with ITO were in familial aggregates. They belonged

Korczyn

er al: Torsion

Dystonia

m Israel

389

A
Lithuania

KEY

8 <V

Mal. Female 3 sibs

o ~
,0 0
[J==()

Af tec te d Consanguinous Dead Marr1cgg

1951

1953 "

1958 16

12

B
Poland

1923 10

1940 12

1950

10

c
Poland

1943 20

1944

1947

25

1948
10

1950
13

Simplified famiiy trees 0/ the familial raw. For each family the cotrnt ry of origi n is indicated. The year 0/ birth and age 0/ onset (in yean) appear for each affected penon. In Family A, d-12 = dead when 12 years old and d-l u: = dead when 1 ueee old: in Family B. S = subject saffered from stammering: in Family C. T = subirct SII//ered/rom tremor.

previous studies of I in populations with The present count: non-European Jews segment of the POI Jews had a much hi) lTD than non-Euro the population in Is care, including host: not explain this diJ confirmed that the ( Jews of Eastern Eur Eldridge et al e among Jews in the population initially I These rates are bast assumed number ( States. Our estirnan European Jews in prevalence rate, ag population in 1970 whichis the corresj on prevalence d2 190,544 Jewish liv from mothers of (i.e., mothers born rae! from parents ( our Jewish lTD pa this period, giving births, a figure closi [3], Our results, base available in Israel n but for different etl time to give accura In general, these sumption that ITI kenazic Jews, part. ern Europe (see T, Eldridge and Go Jews is usually inl disorder may be q sults of our Israeli ~ than one member more than one g dominant transmis (see the Figure). I tively rare disorde quent parental con curred only once general population would be expecte. familial cases sibli parent was also af A first approxirr

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..

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previous studies of lTD among Jews were performed in populations with very few non-Ashkenazic Jews. The present country-wide survey in Israel, where non-European Jews comprise a large and well-defined segment of the population, showed that European Jews had a much higher prevalence and incidence of lTD than non-European Jews. Since all segments of the population in Israel have ready access to medical care, including hospitalization, selection artifact cannot explain this difference. In addition, our study confirmed that the disease is particularly common in Jews of Eastern European ancestry (see Table 1). Eldridge et al estimated the frequency of lTD among Jews in the United States as 25 per million population initially [5], and later [3] as 59 per million. These rates are based on a denominator which is the assumed number of Jewish births in the United States. Our estimate of 22 per million population for European Jews in Israel is, however, the pointprevalence rate, age-ad j usred to the United States population in 1970, i.e., it is based on a denominator which is the corresponding population living in Israel on prevalence day. Between 1949 and 1959, 190,544 Jewish live births were recorded in Israel from mothers of European or American origin (i.e., mothers born in these continents or born in Israel from parents of Euro-American origin). Ten of our Jewish lTD patients were born in Israel during this period, giving a rate of 52.5 per million live births, a figure closer to that of Eldridge and Gottlieb

cessive inheritance can be based on the number of lTD patients who are offspring from rnarings of nonaffected parents as compared to rnatings in which one of the parents also suffered from lTD. Assuming recessive inheritance, the expected number of affected individuals from normal parents should be much smaller. In the four lTD families, 7 patients were products of phenotypically normal parents, and in each of 6 cases one parent was affected. In addition, it should be noted that the patients with sporadic lTD had 57 nonaffected siblings, an unlikely occurrence for a recessive mode of transmission. Thus the results of our survey make it more likely that in Jews, as in non-Jews, transmission of lTD is dominant, although the penetrance rate is low.

Supporred

in part by a grant from the Israel-United

States Bina-

tional Science Foundation. N. Zilber, on leave from the Laboraroire de Neurobiologie Cellulaire, 91190-Gif-sur-Yvette, France, received support from the Centre National de la Recherche Scientinque, France.

References
1. Alter M, Kahana E, Feldman S: Differences in torsion dystonia among Israeli ethnic groups. Adv Neurol 14: 115-120, 1975 2. Eldridge R: The torsion dysronias: literature review and genetic and clinical studies. Neurology (Minneap) 20:1-78, 1970 3. Eldridge 4. R, Gottlieb R: The primary hereditary dystonias.

[3J.
Our results, based on the exact demographic data available in Israel not only for the general population but for different ethnic groups, enable us for the first time to give accurate prevalence and incidence rates. In general, these figures confirm the previous assumption that lTD is more common among Ashkenazic Jews, particularly those originating in Eastern Europe (see Tables 1-3). Eldridge and Gottlieb's [3] conclusion that lTD in Jews is usually inherited as an autosomal recessive disorder may be questioned on the basis of the results of our Israeli study. In all families in which more than one member was affected, lTD appeared in more than one generation, suggesting autosomal dominant transmission with incomplete penetrance (see the Figure). In recessive inheritance of a relatively rare disorder, one would expect to find frequem parental consanguinity. In our material this occurred only once, not exceeding the rate in the general population [8]. In addition, contrary to what would be expected for recessive inheritance, in the familial cases siblings were never affected unless a parent was also affected. A first approximation to test the hypothesis of re-

5. 6.

7.

Adv Neurol 14:457-474, 1976 Eldridge R, Harlan A, Cooper IS, Riklan M: The hereditary torsion dysronias (dystonia musculorum deformans): geographical distribution and IQ in dominant and recessive forms. Trans Am Neurol Assoc 94:248-250, 1969 Eldridge R, Koerber T: The torsion dystonias: some genetic and psychiatric implications. Psychiatr Forum 3:27-33, 1971 General Population Characteristics, U.S. Summary, U.S. Department of Commerce, Bureau of the Census. Washington, DC, Government Printing Office, 1970 Golden GS: Dystonia in the Black and Puerto Rican popula-

tion. Adv Neurol 14:121-124, 1976 8. Goodman RM: Various genetic traits and diseases among the Jewish ethnic groups. Birth Defects 1O:205-2l9, 1974 9. Hertz E: Dystonia I. Historical review; analysis of dystonic symptoms and physiologic mechanisms involved. Arch Neurol Psychiatry 51:305-355, 1944 10. Korczyn AD: The pathophysiology of dystonia.

Neural

Transm 42:245-250, 1978 11. Korczyn AD, Kahana E, Alter M, et al: Dopamine-betahydroxylase and pupillary sympathetic activity in idiopathic torsion dystonia. In Usdin E, Kopin 1], Barchas I (eds): Carecholamines: Basic and Clinical Frontiers. New York, Pergamon, 1979, pp 1631-1633 12. Rabinowitz R, Korczyn AD, Kahana E, et al: Serum levels of dopamine-beta-hydroxylase in dystonia. Isr J Med Sci 15 :290, 1979 13. Statistical Abstract of Israel, nos. 20-29, Central Bureau of Statistics. Jerusalem, Israel, The Government Printer, 19691975

Korczyn

et al: Torsion

Dystonia

in Israel

391