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Original Article

• Roberto Rozenberg

• Lygia da Veiga Pereira
The frequency of Tay-Sachs disease
causing mutations in the Brazilian
Jewish population justifies a carrier
screening program
Laboratory of Molecular Genetics, Department of Biology/Genetics,
Institute of Biosciences, Universidade de São Paulo, São Paulo, Brazil

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ABSTRACT
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INTRODUCTION
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Following the development of prenatal di-
agnosis for Tay-Sachs disease in the early
CONTEXT: Tay-Sachs disease is an autosomal reces- Tay-Sachs disease is an autosomal reces- 1970’s,7 most couples who had had an affected
sive disease characterized by progressive
neurologic degeneration, fatal in early childhood.
sive disease of lysosome storage characterized child chose to monitor subsequent pregnan-
In the Ashkenazi Jewish population the disease by progressive neurologic degeneration.1 cies and bring to term only pregnancies of un-
incidence is about 1 in every 3,500 newborns
and the carrier frequency is 1 in every 29 indi- Children affected by classic Tay-Sachs disease affected fetuses. Other options for carrier cou-
viduals. Carrier screening programs for Tay-Sachs manifest the first symptoms at around 6 ples include adoption, sperm or egg donation,
disease have reduced disease incidence by 90%
in high-risk populations in several countries. The months and die before reaching 5 years of age. pre-implantation diagnosis, reproductive ab-
Brazilian Jewish population is estimated at 90,000 The clinical manifestations are particularly stention or simply taking their 25% risk.
individuals. Currently, there is no screening
program for Tay-Sachs disease in this population. severe including deafness, blindness, dementia, Since only couples with a previous affected
OBJECTIVE: To evaluate the importance of a Tay-Sachs
and recurrent convulsions during the terminal child could be aware of their risk, carrier screen-
disease carrier screening program in the Brazil- stage when affected children are confined to ing programs were massively initiated in the
ian Jewish population by determining the frequency
of heterozygotes and the acceptance of the pro-
bed. There is currently no treatment available. high-risk populations, aiming at detecting and
gram by the community. Tay-Sachs disease is caused by mutations informing carrier couples prior to any family
SETTING: Laboratory of Molecular Genetics – Institute in the HEXA gene, located at 15q23-q24, history of the disease. These programs were
of Biosciences – Universidade de São Paulo. which codes for the alpha subunit of the made possible due to the development of an
PARTICIPANTS: 581 senior students from selected Jew- hexosaminidase A enzyme.2, 3 In the absence enzymatic assay that allowed the detection of
ish high schools.
of the enzyme, its substrate, GM2 ganglioside, heterozygotes for Tay-Sachs disease.8, 9
PROCEDURE: Molecular analysis of Tay-Sachs disease accumulates progressively in the neurons of Up to 1992, over one million individuals
causing mutations by PCR amplification of genomic
DNA, followed by restriction enzyme digestion. the central nervous cortex leading to the clini- had been tested for Tay-Sachs disease carrier
RESULTS: Among 581 students that attended educa- cal phenotype of the disease. Late-onset Tay- status, more than 36,000 carriers had been
tional classes, 404 (70%) elected to be tested for Sachs disease (chronic form) is a rare variant detected and 1,054 carrier couples had been
Tay-Sachs disease mutations. Of these, approxi-
mately 65% were of Ashkenazi Jewish origin. Eight phenotype with appearance of first symptoms identified and informed of their risk prior to
carriers were detected corresponding to a carrier during the second or third decade of life. 4 A having an affected child. These programs led
frequency of 1 in every 33 individuals in the
Ashkenazi Jewish fraction of the sample. juvenile form is also distinguished, with an to a 90% decrease in the incidence of Tay-
CONCLUSION: The frequency of Tay-Sachs disease
intermediate presentation. The less severe phe- Sachs disease in the Ashkenazi Jewish
carriers among the Ashkenazi Jewish population notypes are due to residual enzyme activity.5 populations in the USA, Israel and Canada.10
of Brazil is similar to that of other countries where
carrier screening programs have led to a signifi-
As observed for several recessive traits, Tay- Molecular diagnosis for Tay-Sachs disease
cant decrease in disease incidence. Therefore, it Sachs disease incidence concentrates in some in specific populations has presented a com-
is justifiable to implement a Tay-Sachs disease car-
rier screening program for the Brazilian Jewish specific populations. That is the case for the plementary or even alternative way for perform-
population. Ashkenazi Jewish population (Jews of Central ing enzymatic assay in detecting carriers. Three
KEY WORDS: Tay-Sachs disease. Genetic screening. or Eastern Europe descent), in which the dis- mutations are responsible for 98% of the dis-
HEXA gene. Jewish population. Molecular diag-
nosis.
ease incidence is 1 in every 3,500 newborns: ease incidence in the Ashkenazi Jewish popula-
approximately 100 times higher than in the tion.11, 12 A 4-base pair insertion in exon 11 of
general population. Among Ashkenazi Jews, 1 the HEXA gene (InsTATC1278) is present in
in every 29 individuals is heterozygous (asymp- 80% of Tay-Sachs disease, causing alleles.13 The
tomatic) for Tay-Sachs disease causing muta- second most frequent mutation leading to Tay-
tions (here called carriers).6 Sachs disease in Ashkenazi Jews is a guanine to

Sao Paulo Med J/Rev Paul Med 2001; 119(4):146-9

22) and between the cities onset Tay-Sachs disease in the Ashkenazi Jew. 1993. “very important” or “essential” in 95% ease carriers in the Brazilian Jewish popula. Renascença (SP) 39 26 67% sub-total 111 67 60% Table 2. sify this program?”.São Paulo Medical Journal . significant when P > 0. From ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ METHODS ○○ ○ ○ ○ ○ ○ confidentially sent by mail to the students.27). (%): percentage of the total number of answers (including non-respondents). of São Paulo and Rio de Janeiro (P = 0.52). students who elected to be tested had importance of the program. we found 7 carriers among 258 par- School name Students ticipants in São Paulo and 1 carrier among Year (City) ** Attended Participated Participation Rate* 146 participants in Rio de Janeiro. described elsewhere. RJ: Rio de Janeiro. Richards et al. ** SP: São Paulo. The results are shown in designed to evaluate the need for and accept. tion of the sample. sent. This last mutation leads to late. students took home sessions were attended by 581 students. was aimed at evaluating the impact of similar Table 1 summarizes the participation rates otide of exon 7 leading to a substitution of gly. the ethnic ori. program. we asked in the consent munity to the proposal of a pilot screening sequent digestion with restriction enzymes as form about the possibility of Ashkenazi an- program for Tay-Sachs disease carriers. 15 The third and most rare mutation. Of the eight mutations detected. ing students. they were asked tion in the world. Participants’ parents’ opinions 1999 Bialik (SP) 48 36 75% on the program Peretz (SP) 43 37 86% Opinion n (%) Renascença (SP) 27 23 85% Eliezer (RJ) 35 24 69% Liessin (RJ) 36 26 72% Negative 0 0% sub-total 189 146 77% Insignificant 1 0% Not very important 5 1% 2000 Bialik (SP) 43 25 58% Important 184 28% Peretz (SP) 37 30 81% Renascença (SP) 57 40 70% Very important 274 42% Eliezer (RJ) 49 38 78% Essential 165 25% Liessin (RJ) 95 58 61% Not responded 20 3% sub-total 281 191 68% Total 649 100% TOTAL 581 404 70% n: number of parent replies. This esti- and two in the city of Rio de Janeiro (1999 Fisher’s exact test. 119(4):146-9. From 1998 to 2000. Table 2. seven were InsTATC1278 and one was tended the program at the school’s request. 20 orthodox Jewish high schools of these cities. acceptance of the program. similar to that observed in several Jewish populations (P = 0.10 Table 1. . (Gly269Ser). Chi-squared analysis cine for serine in position 269 of the alpha would serve as an indication for Tay-Sachs dis. IVS12+1 and Gly269Ser was performed by In order to estimate the Ashkenazi frac- tion and observed the reaction of the com. * Participation was defined as the student’s presence at the screening session and delivery of the completed consent form. PCR amplification of genomic DNA and sub. we evaluated the fre. where the pre-senior class at. an over- present in 2% of Tay-Sachs disease cases. All these data it was readily apparent that 26% of samples and results were identified with codes the students had no Ashkenazi Jewish ances- During the last three years. programs from other countries (whether they by year in each school. The program was rated as “impor- ance of a screening program for Tay-Sachs dis. Sao Paulo Med J/Rev Paul Med 2001.16). for the Brazilian Jewish population. This indicates a carrier frequency of 1 in every 51 students.. The dif- ference in the carrier frequency between these 1998 Bialik (SP) 41 21 51% Peretz (SP) 31 20 65% two cities was not significant (P= 0.000 individuals in 1991. Detection of mutations InsTATC1278. and is present in 16% of the a consent form with a brief explanation of the these students. For the remaining students.05. 16 About a week later and with parents’ con. Liessin (2000). guanine to adenine transition in the last nucle.Revista Paulista de Medicina 147 cytosine transvertion in the first base of intron After the presentation. were found.17 This work was swab on the inner cheek for a few seconds.71).18 of the cases. gin of the students (Ashkenazi or not) and the over the years (P = 0. Participation rates* of senior students from selected Jewish high schools When the carrier frequency was separated by state. Among the 404 participants. In order to access parents’ opinions on the Brazil has the 8th largest Jewish popula. thirteen educational IVS12+1.19. 404 came to the screening ses- alleles. three The carrier frequencies obtained were that 65% of the students’ chromosomes were in the city of São Paulo (1998. among the parents of participat- tion. All the carriers had Ashkenazi Jew- except for some participants from Colégio ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ RESULTS ○○ ○ ○ ○ ○ ish ancestry. Of 12 (IVS12+1). among consent forms for the 404 participants. tory where DNA was extracted according to tant”. These institutions are the main non. ents’ country of origin allowed us to estimate senior students at five Jewish high schools. The questionnaire all participation rate of 70%. fer significantly among the schools (P = 0. eight carriers The students were 16 years of age and over. For that purpose. the possible results of the test and a sions and delivered the consent form. counted as approximately mouth mucus collected by twirling a cotton in the consent form: “How would you clas- 90.4.14. The material was then taken to the labora. The statistical difference mate is close to others previously established and 2000). 1999 and 2000) compared to those from other studies using associated with Ashkenazi origin. the grandpar- classes on Tay-Sachs disease were presented to name and test result could not be made. quency of carriers in a sample of this popula. ish population. is a questionnaire for the parents. showed that the participation rates did not dif- subunit of the hexosaminidase A enzyme ease testing among Brazilians).11 cestry and the country of origin of the stu- The results and their interpretation were dent’s grandparents (data not shown). between two samples was considered non. educational so that a direct connection between student try.

27 Before we directed it towards high than in the population at risk. The the participant’s parents’ rating of the program mail. Such was the case in Canada. high schools between the years 1998 and 2000 were the participants’ easy access to screening cated that the success of screening programs was 70%. The Canadian Tay-Sachs disease program the tests to be performed on mouth mucus has been operating for over 20 years. plausible approach to screening were the non. orthodox Jewish high schools. For instance. maximum confidentiality of test results. diagnosis to detect Tay-Sachs disease carriers. tions causing Tay-Sachs disease in senior stu- community.28 ish individuals herein studied is similar to that Besides the targeting of the screening. three carriers contacted community institutions in order to reach par. served as a model for the research presented rier couple.24 A follow. In particular. the incidence of Tay-Sachs here. the princi. and the re. Screening can confirm or exclude the possi- observed in the Jewish population of several other ethical aspects were an essential part bility of both members of a couple being Tay- other countries. none of whom because of rec. The in the years following the first presentations would prefer to get a positive result by mail voluntary participation rate in a pilot screen- (Table 1). However. due to in- the need for a screening program in the though approval was obtained in some in. screening has been recommended even for In contrast. Among the factors that may have rather than by a phone call. This was also demonstrated by sults were delivered to the participants by dents of Jewish high schools was 1/51. sample was 1/33. the estimated mobilization has been obtained by some pro. tion for prevention until an effective treatment dicates the need of a screening program for ing on delivering precise and comprehen. an ideal outcome from this research similar populations from different countries and that both carriers and non-carriers con. identification of carriers. locations. which comprised 65% of rier screening. a similar program should nome Project has had in recent years. This procedure prevented the personal corrected carrier frequency of Tay-Sachs dis- as “important”. in other countries. avoided stigmatization of carriers by focus. Sao Paulo Med J/Rev Paul Med 2001. ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ DISCUSSION ○ ○ ○ ○ ○ ○ ○ ○ ing senior high schools students and obtain.6 where researchers decided to move into the performance of the DNA test in a small center During the study. similar to that observed in other same success.23 Initially.87). say”. ease in the Ashkenazi Jewish fraction of the tial” in 95% of the cases.28 for a recessive genetic disease is a high carrier versy of testing single teenagers. parents had already been tested for Tay. mend testing for Tay-Sachs disease mutations ease and served as a prototype for other pre. In addition. the only institutions that presented a try.26. The mother of a carrier was also tion to screening centers. significantly (USA) is lower than that observed among schools. and finally. termarriage and declining awareness of ances- former.21 stances. others have not readily reached the It has corroborated the prediction that “the 33 (8/263). Although notable community search in that it exclusively used molecular the 404 students’ chromosomes. In addition to the continuity of this frequency in the target population. becomes available for this disease. and is the best indica- found in the Brazilian Jewish population in. its ap. for individuals of Ashkenazi Jewish ancestry ventive programs. It is also up study of the program showed that most screening program for Tay-Sachs disease car- important to confirm the carrier frequency in students had positive attitudes after screening riers. we Sachs disease carriers. Additionally. The carrier frequency of the main muta- acceptance of the screening program by the samples and results were coded. propriate for the general population since dif- establishment of a carrier screening program proach to screening faced the ethical contro. collection instead of requiring blood testing. es- The 70% participation rate shows good pecially important in small communities. Only 15% of grams for Tay-Sachs disease in alerting carrier knowledge of genetics in general due to the students’ parents affirmed they had relatives couples and decreasing the disease incidence exposure in the media that the Human Ge.23 Currently. unless they contacted the laboratory.11 The molecular diagnosis also permits identified as a carrier. disease among non-Jews. the carrier frequency of Tay. couples for whom only one member is thought Sachs disease mutations in the Brazilian Jew. over 50 centers ommendation by foreign relatives. the enzyme assay is more ap- One of the necessary prerequisites for the one in this study (70%). Israel or Canada. since two previous attempts to establish carrier frequency of Tay-Sachs disease among disease among individuals of French-Canadian preventive programs in Brazil were discontin. to have ancestry in a high-risk population. but different carrier frequen. Al. at reproductive age. screen. while DNA test is adequate for ing a similar participation rate (67%) to the Ashkenazi Jews. Only 2% (11/651) of the lation.Revista Paulista de Medicina When corrected for the Ashkenazi frac. a higher need for a program in Brazil. 148 São Paulo Medical Journal . ing program of Tay-Sachs disease in Jewish led to the high participation rate in our study Data from the consent form also indi. the offer of a screening program was diminishing but not eliminating Tay-Sachs those living in Quebec (Canada). quality control required for the enzyme as- counseling. even by research. Finally. would be to bring it to the attention of physi- since different migration patterns or different sidered the test during high school as not be. the general population is about 10 times lower heritage living in northern New England ued. cians assisting Brazilian Jewish couples that admixture rates could lead to populations with ing premature. a collection method that did not in other countries does not diminish the Based on the efficiency of screening pro- involve blood extraction. Sachs disease. 25 The Canadian program they may be attending a Tay-Sachs disease car- similar origin. physicians should recom- was the first to be performed for a genetic dis. It is important to note that the cies. carrier frequency for Tay-Sachs disease is 1 in grams. The high carrier frequency of this pilot program. downplaying made to different Jewish institutions. development of molecular diagnosis allows the Ashkenazi Jewish populations (P = 0. and the absence of a ers. pal countries in which preventive programs be implemented for the Brazilian Jewish popu- The Tay-Sachs disease screening program are conducted. in order to maintain ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ CONCLUSION ○ ○ ○ ○ ○ ○ ○ ○ ○ over 30 years. this was a pioneering piece of re- tion of the sample. “very important” or “essen. similar to that in Ashkenazi significant decrease in the participation rates Most students (91%) affirmed that they Jewish populations of other countries. 119(4):146-9 . ferent mutations may be present. in the world promote Tay-Sachs disease car. living in USA. Recently. without the need to maintain the rigorous the lab for re-testing and additional ticipants instead of waiting for self-mobiliza. Tay-Sachs disease in Brazil like those effectively sive information about Tay-Sachs disease to developed in other Jewish communities for students.

Revista Paulista de Medicina 149 ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ REFERENCES ○ ○ ○ ○ ○ ○ ○ ○ 1. Nature ethics of genetic screening within the Jewish community: chal- Hum Genet 1983. Okada S. Universidade de São Paulo. Kaplan F. Schmidt JS. Ge- 2. O’Brien JS. 1992. among Ashkenazi Jews. b-Thalassemia disease carriers in high schools. Fillerup DL. é similar àquela de programa de triagem de portadores da doença outros países nos quais programas de triagem Accepted: 20 April 2001 de Tay-Sachs na população judaica brasileira. Instituto de Biociências. Tay-Sachs disease: Jewish origin: substitution of serine for glycine at position 269 Brasil Genet VI 1983. The authors wish to thank L. População PARTICIPANTES: 581 alunos do 3o. Goodman RM. 1970 19. A splicing defect due to an exon-intron 25.12:463-80. Okada S. A private view of ease gene in North American Jewish populations: geographic junctional mutation results in abnormal beta-hexosaminidase heterozigozity: eight-year follow-up study of the Tay-Sachs gene variations and origins. Oito portadores foram Institute of Biosciences. Multiplex PCR am. et al. Clow CL. Clarke JT.18:769-78. Am J Med Genet 7. Clow C. et al. comparison of DNA-based and enzyme-based tests. Proc Nat Acad 27. M. Zeiger K. 17. COPYRIGHT©2001. Genetic Epidemiology 1992. Am J Med Genet 1995. Kaplan F. Adornato BT. Department of Genetics. J Biol Chem 1988. alpha chain mRNAs in Ashkenazi Jewish patients with Tay-Sachs detected by high school screening in Montreal. Beaudet AL. In: Goodman RM. vention of genetic disease. fibroblasts of late-infantile and adult GM2 gangliosidosis patients 14. do Brasil. Levy N. Myerowitz R. Veath ML. Tay-Sachs disease – carrier screening. doença autossômica recessiva caracterizada PROCEDIMENTOS: Análise molecular de R. 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Sources of funding: CNPq and FAPESP no 98/02435-2 não há programa de triagem populacional CONCLUSÕES: A freqüência de portadores da Conflict of interest: Not declared da doença de Tay-Sachs nessa população. 277/350 Instituto de Biociências. Screening Jews and Genes: A consideration of the and of healthy probands with low hexosaminidase level. Assim. Kornreich and C. Clin Lab Med 1992. e a freqüência de portadores é palestras informativas.3:207-213. é justificável a Lygia da Veiga Pereira portadores e da aceitação desse programa pela implementação de um programa de triagem Departamento de Biologia. Valle DV. Universidade de São Paulo. Tay-Sachs 3. 26.35:900-13. et al. disease. et al. aproximadamente 65% tinham origem Lygia da Veiga Pereira. Motulsky AG. Sachs reduziram a incidência da doença em judaica Ashkenazita. São Paulo: Ática. ano do judaica. Kaback MM. Fillerup DL. Desses. Dabholkar D. prenatal diag. Proia RL. Censo demográfico metabolismo en San Pablo. Wajner M. Pelleg CONTEXTO: A doença de Tay-Sachs é uma ensino médio de escolas judaicas selecionadas.333:85-6. 270:2307-15. Molecular basis of adult. GM2 gangliosidosis. lenges and responses. 35:1258-69.243:1471-4. of inherited disease. Zeesman S. Paw BH.323:6-12. Costigan FC. Gravel RA. Triggs-Raine B. and the molecular era – an international perspective. Cantor RM. Lim-Steele J. Kamei ME. Ohno K. Maler T. Desnick. Skoletsky J. 1977:191. New York: Raven Press. 7 th ed. Wannmacher CMD. Brasil. Conzelmann E. Assignment of Specificity and sensitivity of hexosaminidase assays and DNA disease in persons of French-Canadian heritage in northern New beta-hexosaminidase A alpha-subunit to human chromosomal analysis for the detection of Tay-Sachs disease gene carriers England. Natowicz MR.br Paulo.59:793-98. Valenti C.. Navon R. Department of Biology. Am J Hum Genet G M2 N-acetyl-beta-D-hexosaminidase activity in cultured 9. Navon R. 22. doença de Tay-Sachs. In: Scriver CR.1:582-3. levaram a uma redução significativa na Address for correspondence através do estabelecimento da freqüência de incidência da doença. Rio de Janeiro: IBGE. Genetic Testing. 9:169. Palomaki GE. Petersen GM. Sandhoff K. Paulo. Med 1990. comunidade.000 indivíduos. screening inborn errors.172:61-4. Brazil. cal brushes/swabs. Nowak NJ. Byers MG. A população judaica brasileira é de portadores de um em cada 33 indivíduos na estimada em 90.São Paulo Medical Journal . Na através de amplificação de DNA genômico and FAPESP for financial support. plification from the CFTR gene using DNA prepared from buc. população judaica brasileira. 28. Richards B.283:15-20. na população judaica Last received: 20 February 2001 OBJETIVO: Avaliar a importância de um Ashkenazita brasileira. Kytzia H-J. Natowicz MR. Instituto Brasileiro de Geografia e Estatística. Sci 1989. region 15q23-q24.38:217-29. Tay-Sachs disease: prenatal diagnosis. Hum Mol Genet 1993. Cytogenet Cell Genet 1991. detection of heterozygotes and homozygotes by serum of the alpha-subunit of beta-hexosaminidase.500 RESULTADOS: Entre 581 alunos que assistiram Roberto Rozenberg. Neufeld EF. Twenty-year out- ence 1989. The metabolic and molecular bases to 1993. come analysis of genetic screening programs for Tay-Sachs and 5. Nakai H. Krynski S. Mahuran D. 1984. Science 1971. Kaback MM. MM. The Tay-Sachs dis. Feingenbaum ASJ. 18. The mutations in Ashkenazi Jews with adult 75.2:159-63. 11. onset and chronic GM2 gangliosidoses in patients of Ashkenazi ease: screening and prevention program in Porto Alegre. Screen. We also wish to por uma degeneração neurológica mutações causadoras da doença de Tay-Sachs thank the boards of the participating schools and CNPq progressiva. de triagem de portadores da doença de Tay.153:463-9. Am J Hum Genet 1983. et al. Williams J. Scriver CR. Paulo. 1981. Suzuki K. Adachi M. Dumbrille-Ross A.