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The frequency of Tay-Sachs disease causing mutations in the Brazilian Jewish population justifies a carrier screening program


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Tay-Sachs disease is an autosomal recessive disease characterized by progressive neurologic degeneration, fatal in early childhood. In the Ashkenazi Jewish population the disease incidence is about 1 in every 3,500 newborns and the carrier frequency is 1 in every 29 individuals. Carrier screening programs for Tay-Sachs disease have reduced disease incidence by 90% in high-risk populations in several countries. The Brazilian Jewish population is estimated at 90,000 individuals. Currently, there is no screening program for Tay-Sachs disease in this population. To evaluate the importance of a Tay-Sachs disease carrier screening program in the Brazilian Jewish population by determining the frequency of heterozygotes and the acceptance of the program by the community. Laboratory of Molecular Genetics--Institute of Biosciences--Universidade de São Paulo. 581 senior students from selected Jewish high schools. Molecular analysis of Tay-Sachs disease causing mutations by PCR amplification of genomic DNA, followed by restriction enzyme digestion. Among 581 students that attended educational classes, 404 (70%) elected to be tested for Tay-Sachs disease mutations. Of these, approximately 65% were of Ashkenazi Jewish origin. Eight carriers were detected corresponding to a carrier frequency of 1 in every 33 individuals in the Ashkenazi Jewish fraction of the sample. The frequency of Tay-Sachs disease carriers among the Ashkenazi Jewish population of Brazil is similar to that of other countries where carrier screening programs have led to a significant decrease in disease incidence. Therefore, it is justifiable to implement a Tay-Sachs disease carrier screening program for the Brazilian Jewish population.
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Tay-Sachs disease is an autosomal reces-
sive disease of lysosome storage characterized
by progressive neurologic degeneration.
Children affected by classic Tay-Sachs disease
manifest the first symptoms at around 6
months and die before reaching 5 years of age.
The clinical manifestations are particularly
severe including deafness, blindness, dementia,
and recurrent convulsions during the terminal
stage when affected children are confined to
bed. There is currently no treatment available.
Tay-Sachs disease is caused by mutations
in the HEXA gene, located at 15q23-q24,
which codes for the alpha subunit of the
hexosaminidase A enzyme.
2, 3
In the absence
of the enzyme, its substrate, G
accumulates progressively in the neurons of
the central nervous cortex leading to the clini-
cal phenotype of the disease. Late-onset Tay-
Sachs disease (chronic form) is a rare variant
phenotype with appearance of first symptoms
during the second or third decade of life.
juvenile form is also distinguished, with an
intermediate presentation. The less severe phe-
notypes are due to residual enzyme activity.
As observed for several recessive traits, Tay-
Sachs disease incidence concentrates in some
specific populations. That is the case for the
Ashkenazi Jewish population (Jews of Central
or Eastern Europe descent), in which the dis-
ease incidence is 1 in every 3,500 newborns:
approximately 100 times higher than in the
general population. Among Ashkenazi Jews, 1
in every 29 individuals is heterozygous (asymp-
tomatic) for Tay-Sachs disease causing muta-
tions (here called carriers).
Following the development of prenatal di-
agnosis for Tay-Sachs disease in the early
most couples who had had an affected
child chose to monitor subsequent pregnan-
cies and bring to term only pregnancies of un-
affected fetuses. Other options for carrier cou-
ples include adoption, sperm or egg donation,
pre-implantation diagnosis, reproductive ab-
stention or simply taking their 25% risk.
Since only couples with a previous affected
child could be aware of their risk, carrier screen-
ing programs were massively initiated in the
high-risk populations, aiming at detecting and
informing carrier couples prior to any family
history of the disease. These programs were
made possible due to the development of an
enzymatic assay that allowed the detection of
heterozygotes for Tay-Sachs disease.
8, 9
Up to 1992, over one million individuals
had been tested for Tay-Sachs disease carrier
status, more than 36,000 carriers had been
detected and 1,054 carrier couples had been
identified and informed of their risk prior to
having an affected child. These programs led
to a 90% decrease in the incidence of Tay-
Sachs disease in the Ashkenazi Jewish
populations in the USA, Israel and Canada.
Molecular diagnosis for Tay-Sachs disease
in specific populations has presented a com-
plementary or even alternative way for perform-
ing enzymatic assay in detecting carriers. Three
mutations are responsible for 98% of the dis-
ease incidence in the Ashkenazi Jewish popula-
11, 12
A 4-base pair insertion in exon 11 of
the HEXA gene (InsTATC1278) is present in
80% of Tay-Sachs disease, causing alleles.
second most frequent mutation leading to Tay-
Sachs disease in Ashkenazi Jews is a guanine to
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
CONTEXT: Tay-Sachs disease is an autosomal reces-
sive disease characterized by progressive
neurologic degeneration, fatal in early childhood.
In the Ashkenazi Jewish population the disease
incidence is about 1 in every 3,500 newborns
and the carrier frequency is 1 in every 29 indi-
viduals. Carrier screening programs for Tay-Sachs
disease have reduced disease incidence by 90%
in high-risk populations in several countries. The
Brazilian Jewish population is estimated at 90,000
individuals. Currently, there is no screening
program for Tay-Sachs disease in this population.
OBJECTIVE: To evaluate the importance of a Tay-Sachs
disease carrier screening program in the Brazil-
ian Jewish population by determining the frequency
of heterozygotes and the acceptance of the pro-
gram by the community.
SETTING: Laboratory of Molecular Genetics – Institute
of Biosciences – Universidade de São Paulo.
PARTICIPANTS: 581 senior students from selected Jew-
ish high schools.
PROCEDURE: Molecular analysis of Tay-Sachs disease
causing mutations by PCR amplification of genomic
DNA, followed by restriction enzyme digestion.
RESULTS: Among 581 students that attended educa-
tional classes, 404 (70%) elected to be tested for
Tay-Sachs disease mutations. Of these, approxi-
mately 65% were of Ashkenazi Jewish origin. Eight
carriers were detected corresponding to a carrier
frequency of 1 in every 33 individuals in the
Ashkenazi Jewish fraction of the sample.
CONCLUSION: The frequency of Tay-Sachs disease
carriers among the Ashkenazi Jewish population
of Brazil is similar to that of other countries where
carrier screening programs have led to a signifi-
cant decrease in disease incidence. Therefore, it
is justifiable to implement a Tay-Sachs disease car-
rier screening program for the Brazilian Jewish
KEY WORDS: Tay-Sachs disease. Genetic screening.
HEXA gene. Jewish population. Molecular diag-
Sao Paulo Med J/Rev Paul Med 2001; 119(4):146-9
São Paulo Medical Journal - Revista Paulista de Medicina
Table 2. Participants’ parents’ opinions
on the program
Opinion n (%)
Negative 0 0%
Insignificant 1 0%
Not very important 5 1%
Important 184 28%
Very important 274 42%
Essential 165 25%
Not responded 20 3%
Total 649 100%
n: number of parent replies, among consent forms for the 404 participants;
(%): percentage of the total number of answers (including non-respondents).
cytosine transvertion in the first base of intron
12 (IVS12+1), and is present in 16% of the
14, 15
The third and most rare mutation,
present in 2% of Tay-Sachs disease cases, is a
guanine to adenine transition in the last nucle-
otide of exon 7 leading to a substitution of gly-
cine for serine in position 269 of the alpha
subunit of the hexosaminidase A enzyme
(Gly269Ser). This last mutation leads to late-
onset Tay-Sachs disease in the Ashkenazi Jew-
ish population.
4, 16
Brazil has the 8
largest Jewish popula-
tion in the world, counted as approximately
90,000 individuals in 1991.
This work was
designed to evaluate the need for and accept-
ance of a screening program for Tay-Sachs dis-
ease carriers in the Brazilian Jewish popula-
tion. For that purpose, we evaluated the fre-
quency of carriers in a sample of this popula-
tion and observed the reaction of the com-
munity to the proposal of a pilot screening
program for Tay-Sachs disease carriers.
During the last three years, educational
classes on Tay-Sachs disease were presented to
senior students at five Jewish high schools, three
in the city of São Paulo (1998, 1999 and 2000)
and two in the city of Rio de Janeiro (1999
and 2000). These institutions are the main non-
orthodox Jewish high schools of these cities.
The students were 16 years of age and over,
except for some participants from Colégio
Liessin (2000), where the pre-senior class at-
tended the program at the school’s request.
After the presentation, students took home
a consent form with a brief explanation of the
program, the possible results of the test and a
questionnaire for the parents. The questionnaire
was aimed at evaluating the impact of similar
programs from other countries (whether they
would serve as an indication for Tay-Sachs dis-
ease testing among Brazilians), the ethnic ori-
gin of the students (Ashkenazi or not) and the
acceptance of the program.
About a week later and with parents’ con-
sent, students who elected to be tested had
mouth mucus collected by twirling a cotton
swab on the inner cheek for a few seconds.
The material was then taken to the labora-
tory where DNA was extracted according to
Richards et al., 1993.
Detection of mutations InsTATC1278,
IVS12+1 and Gly269Ser was performed by
PCR amplification of genomic DNA and sub-
sequent digestion with restriction enzymes as
described elsewhere.
The results and their interpretation were
confidentially sent by mail to the students. All
samples and results were identified with codes
so that a direct connection between student
name and test result could not be made.
The carrier frequencies obtained were
compared to those from other studies using
Fisher’s exact test. The statistical difference
between two samples was considered non-
significant when P > 0.05.
From 1998 to 2000, thirteen educational
sessions were attended by 581 students. Of
these students, 404 came to the screening ses-
sions and delivered the consent form, an over-
all participation rate of 70%.
Table 1 summarizes the participation rates
by year in each school. Chi-squared analysis
showed that the participation rates did not dif-
fer significantly among the schools (P = 0.52),
over the years (P = 0.22) and between the cities
of São Paulo and Rio de Janeiro (P = 0.71).
In order to access parents’ opinions on the
importance of the program, they were asked
in the consent form: “How would you clas-
sify this program?”. The results are shown in
Table 2. The program was rated as “impor-
tant”, “very important” or “essential” in 95%
of the cases, among the parents of participat-
ing students.
In order to estimate the Ashkenazi frac-
tion of the sample, we asked in the consent
form about the possibility of Ashkenazi an-
cestry and the country of origin of the stu-
dent’s grandparents (data not shown). From
these data it was readily apparent that 26% of
the students had no Ashkenazi Jewish ances-
try. For the remaining students, the grandpar-
ents’ country of origin allowed us to estimate
that 65% of the students’ chromosomes were
associated with Ashkenazi origin. This esti-
mate is close to others previously established
for the Brazilian Jewish population.
19, 20
Among the 404 participants, eight carriers
were found. All the carriers had Ashkenazi Jew-
ish ancestry. Of the eight mutations detected,
seven were InsTATC1278 and one was
IVS12+1. This indicates a carrier frequency of
1 in every 51 students, similar to that observed
in several Jewish populations (P = 0.16).
When the carrier frequency was separated
by state, we found 7 carriers among 258 par-
ticipants in São Paulo and 1 carrier among
146 participants in Rio de Janeiro. The dif-
ference in the carrier frequency between these
two cities was not significant (P= 0.27).
Table 1. Participation rates* of senior students from selected Jewish high schools
School name Students
Year (City) ** Attended Participated Participation Rate*
1998 Bialik (SP) 41 21 51%
Peretz (SP) 31 20 65%
Renascença (SP) 39 26 67%
111 67 60%
1999 Bialik (SP) 48 36 75%
Peretz (SP) 43 37 86%
Renascença (SP) 27 23 85%
Eliezer (RJ) 35 24 69%
Liessin (RJ) 36 26 72%
189 146 77%
2000 Bialik (SP) 43 25 58%
Peretz (SP) 37 30 81%
Renascença (SP) 57 40 70%
Eliezer (RJ) 49 38 78%
Liessin (RJ) 95 58 61%
281 191 68%
TOTAL 581 404 70%
* Participation was defined as the student’s presence at the screening session and delivery of the completed consent form. ** SP: São Paulo, RJ: Rio de Janeiro.
Sao Paulo Med J/Rev Paul Med 2001; 119(4):146-9.
São Paulo Medical Journal - Revista Paulista de Medicina
When corrected for the Ashkenazi frac-
tion of the sample, which comprised 65% of
the 404 students’ chromosomes, the estimated
carrier frequency for Tay-Sachs disease is 1 in
33 (8/263), similar to that observed in other
Ashkenazi Jewish populations (P = 0.87).
During the study, three carriers contacted
the lab for re-testing and additional
counseling. The mother of a carrier was also
identified as a carrier.
One of the necessary prerequisites for the
establishment of a carrier screening program
for a recessive genetic disease is a high carrier
frequency in the target population. It is also
important to confirm the carrier frequency in
similar populations from different countries
since different migration patterns or different
admixture rates could lead to populations with
similar origin, but different carrier frequen-
cies. For instance, the incidence of Tay-Sachs
disease among individuals of French-Canadian
heritage living in northern New England
(USA) is lower than that observed among
those living in Quebec (Canada), downplaying
the need for a screening program in the
In contrast, the carrier frequency of Tay-
Sachs disease mutations in the Brazilian Jew-
ish individuals herein studied is similar to that
observed in the Jewish population of several
other countries. The high carrier frequency
found in the Brazilian Jewish population in-
dicates the need of a screening program for
Tay-Sachs disease in Brazil like those effectively
developed in other Jewish communities for
over 30 years.
The 70% participation rate shows good
acceptance of the screening program by the
community. This was also demonstrated by
the participant’s parents’ rating of the program
as “important”, “very important” or “essen-
tial” in 95% of the cases, and the absence of a
significant decrease in the participation rates
in the years following the first presentations
(Table 1). Among the factors that may have
led to the high participation rate in our study
were the participants’ easy access to screening
locations; a collection method that did not
involve blood extraction; and finally, a higher
knowledge of genetics in general due to the
exposure in the media that the Human Ge-
nome Project has had in recent years.
The Tay-Sachs disease screening program
was the first to be performed for a genetic dis-
ease and served as a prototype for other pre-
ventive programs.
Currently, over 50 centers
in the world promote Tay-Sachs disease car-
rier screening. Although notable community
mobilization has been obtained by some pro-
grams, others have not readily reached the
same success. Such was the case in Canada,
where researchers decided to move into the
community institutions in order to reach par-
ticipants instead of waiting for self-mobiliza-
tion to screening centers.
The Canadian Tay-Sachs disease program
has been operating for over 20 years, screen-
ing senior high schools students and obtain-
ing a similar participation rate (67%) to the
one in this study (70%).
Initially, its ap-
proach to screening faced the ethical contro-
versy of testing single teenagers.
A follow-
up study of the program showed that most
students had positive attitudes after screening
and that both carriers and non-carriers con-
sidered the test during high school as not be-
ing premature.
The Canadian program
served as a model for the research presented
here, since two previous attempts to establish
preventive programs in Brazil were discontin-
26, 27
Before we directed it towards high
schools, the offer of a screening program was
made to different Jewish institutions. Al-
though approval was obtained in some in-
stances, the only institutions that presented a
plausible approach to screening were the non-
orthodox Jewish high schools.
Besides the targeting of the screening,
other ethical aspects were an essential part
of this pilot program. In particular, we
avoided stigmatization of carriers by focus-
ing on delivering precise and comprehen-
sive information about Tay-Sachs disease to
students. Additionally, in order to maintain
maximum confidentiality of test results, es-
pecially important in small communities,
samples and results were coded, and the re-
sults were delivered to the participants by
mail. This procedure prevented the personal
identification of carriers, even by research-
ers, unless they contacted the laboratory.
Most students (91%) affirmed that they
would prefer to get a positive result by mail
rather than by a phone call.
Data from the consent form also indi-
cated that the success of screening programs
in other countries does not diminish the
need for a program in Brazil. Only 15% of
students’ parents affirmed they had relatives
living in USA, Israel or Canada, the princi-
pal countries in which preventive programs
are conducted. Only 2% (11/651) of the
parents had already been tested for Tay-
Sachs disease, none of whom because of rec-
ommendation by foreign relatives.
Finally, this was a pioneering piece of re-
search in that it exclusively used molecular
diagnosis to detect Tay-Sachs disease carriers.
It has corroborated the prediction that “the
development of molecular diagnosis allows the
performance of the DNA test in a small center
without the need to maintain the rigorous
quality control required for the enzyme as-
The molecular diagnosis also permits
the tests to be performed on mouth mucus
collection instead of requiring blood testing.
However, while DNA test is adequate for
Ashkenazi Jews, the enzyme assay is more ap-
propriate for the general population since dif-
ferent mutations may be present.
In addition to the continuity of this
screening program for Tay-Sachs disease car-
riers, an ideal outcome from this research
would be to bring it to the attention of physi-
cians assisting Brazilian Jewish couples that
they may be attending a Tay-Sachs disease car-
rier couple. It is important to note that the
carrier frequency of Tay-Sachs disease among
the general population is about 10 times lower
than in the population at risk, significantly
diminishing but not eliminating Tay-Sachs
disease among non-Jews. Recently, due to in-
termarriage and declining awareness of ances-
try, screening has been recommended even for
couples for whom only one member is thought
to have ancestry in a high-risk population.
Screening can confirm or exclude the possi-
bility of both members of a couple being Tay-
Sachs disease carriers, and is the best indica-
tion for prevention until an effective treatment
becomes available for this disease.
The carrier frequency of the main muta-
tions causing Tay-Sachs disease in senior stu-
dents of Jewish high schools was 1/51. The
corrected carrier frequency of Tay-Sachs dis-
ease in the Ashkenazi Jewish fraction of the
sample was 1/33, similar to that in Ashkenazi
Jewish populations of other countries. The
voluntary participation rate in a pilot screen-
ing program of Tay-Sachs disease in Jewish
high schools between the years 1998 and 2000
was 70%.
Based on the efficiency of screening pro-
grams for Tay-Sachs disease in alerting carrier
couples and decreasing the disease incidence
in other countries, a similar program should
be implemented for the Brazilian Jewish popu-
lation. In addition, physicians should recom-
mend testing for Tay-Sachs disease mutations
for individuals of Ashkenazi Jewish ancestry
at reproductive age.
Sao Paulo Med J/Rev Paul Med 2001; 119(4):146-9
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CONTEXTO: A doença de Tay-Sachs é uma
doença autossômica recessiva caracterizada
por uma degeneração neurológica
progressiva, fatal na primeira infância. Na
população judaica Ashkenazita a incidência
da doença é de um para cada 3.500
nascimentos, e a freqüência de portadores é
de um para cada 29 indivíduos. Programas
de triagem de portadores da doença de Tay-
Sachs reduziram a incidência da doença em
90% nas populações em risco de diversos
países. A população judaica brasileira é
estimada em 90.000 indivíduos. Atualmente
não há programa de triagem populacional
da doença de Tay-Sachs nessa população.
OBJETIVO: Avaliar a importância de um
programa de triagem de portadores da doença
de Tay-Sachs na população judaica brasileira,
através do estabelecimento da freqüência de
portadores e da aceitação desse programa pela
LOCAL: Laboratório de genética molecular,
Instituto de Biociências, Universidade de São
PARTICIPANTES: 581 alunos do 3
. ano do
ensino médio de escolas judaicas selecionadas.
PROCEDIMENTOS: Análise molecular de
mutações causadoras da doença de Tay-Sachs
através de amplificação de DNA genômico
por PCR e digestão por enzimas de restrição.
RESULTADOS: Entre 581 alunos que assistiram
palestras informativas, 404 (70%) decidiram
realizar o teste para detecção de portadores.
Desses, aproximadamente 65% tinham origem
judaica Ashkenazita. Oito portadores foram
identificados correspondendo a uma freqüência
de portadores de um em cada 33 indivíduos na
fração judaica Ashkenazita da amostra.
CONCLUSÕES: A freqüência de portadores da
doença de Tay-Sachs, na população judaica
Ashkenazita brasileira, é similar àquela de
outros países nos quais programas de triagem
levaram a uma redução significativa na
incidência da doença. Assim, é justificável a
implementação de um programa de triagem
de portadores da doença de Tay-Sachs na
população judaica brasileira.
PALAVRAS-CHAVE: Doença de Tay-Sachs.
Triagem genética. Gene HEXA. População
judaica. Diagnóstico molecular.
Acknowledgments. The authors wish to thank L. Pelleg
from the Israeli Tay-Sachs disease test center and R. Desnick,
R. Kornreich and C. Eng from Mount Sinai Hospital (NY)
for the positive control samples obtained. We also wish to
thank the boards of the participating schools and CNPq
and FAPESP for financial support.
Roberto Rozenberg, MSc. Department of Genetics,
Institute of Biosciences, Universidade de São Paulo, São
Paulo, Brazil.
Lygia da Veiga Pereira, PhD. Department of Biology,
Institute of Biosciences, Universidade de São Paulo, São
Paulo, Brazil.
Sources of funding: CNPq and FAPESP n
Conflict of interest: Not declared
Last received: 20 February 2001
Accepted: 20 April 2001
Address for correspondence
Lygia da Veiga Pereira
Departamento de Biologia, Instituto de Biociências,
Universidade de São Paulo
Rua do Matão, 277/350
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Sao Paulo Med J/Rev Paul Med 2001; 119(4):146-9.
... Lethal recessive alleles are gene alleles, which either are lethal for a homozygote, or were so in past centuries. They cause rare serious diseases including Cystic Fibrosis (carrier frequency 1/24 in Northern Europeans, see [1]), Tay-Sachs disease (1/29 Ashkenazi Jews [2]), Gaucher disease (1/18 in Ashkenazi Jews [3]), α-Thalessemia (1/25 Chinese and SE Asians [4]), β-Thalessemia (1/30 Greeks and Italians [5]). Most of these diseases can be caused by several different mutations, but the disease is expressed by a homozygote of a single mutated allele. ...
... x − . Thus the probability of two alleles a is 2 x and it is the probability of a homozygote aa. In a similar way the probability of a homozygote AA is (1) ...
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The article derives the probability for lethal recessive alleles in the case of recessive disadvantage or advantage. It is shown that the recessive advantage of a lethal gene can be detected by the ratio of heterozygotes and homozygotes. This demonstrates that the higher IQ of certain ethnic groups cannot be explained by the recessive advantage of lethal genes. The article shows that lethal genes can survive in the population if some lineages of families have much more children than the average.
... In the literature, 42 single case reports of LOTS presented a prominent motoneuronal phenotype [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] (Table 2). Similarly to our cases, the age of onset was mostly in the second decade, except for few exceptions [21,[23][24][25]. ...
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Background: Late-Onset Tay-Sachs (LOTS) disease is a rare, progressive neurological condition that can dramatically affect the life of these patients. The diagnosis of LOTS is easily missed because of the multifaced presentation of these patients, who can initially be assessed by neuromuscular or movement disorder specialists, or psychiatrists. Clinical trials are now becoming available for LOTS. Therefore, early diagnosis can be detrimental for these patients and for insuring informative research outcomes. Methods: We characterized a cohort of nine patients with LOTS through a detailed clinical and video description. We then reviewed the available literature regarding the clinical description of patients with LOTS. Our findings were summarized based on the predominant phenotype of presentation to highlight diagnostic clues to guide the diagnosis of LOTS for different neurology specialists (neuromuscular, movement disorders) and psychiatrist. Results: We described a cohort of 9 new patients with LOTS seen at our clinic. Our literature review identified 76 patients mainly presenting with a neuromuscular, cerebellar, psychiatric, stuttering, or movement disorder phenotype. Diagnostic tips, such as the triceps sign, distinct speech patterns, early psychiatric presentation and impulsivity, as well as neurological symptoms (cerebellar or neuromuscular) in patients with a prominent psychiatric presentation, are described. Discussion: Specific diagnostics clues can help neurologists and psychiatrists in the early diagnosis of LOTS disease. Our work also represent the first video presentation of a cohort of patients with LOTS that can help different specialists to familiarize with these features and improve diagnostic outcomes. Highlights: Late-Onset Tay-Sachs (LOTS) disease, a severe progressive neurological condition, has multifaced presentations causing diagnostic delays that can significantly affect research outcomes now that clinical trials are available. We highlight useful diagnostic clues from our cohort (including the first video representation of a LOTS cohort) and comprehensive literature review.
... Частота встречаемости GM2-ганглиозидоза, тип I варьирует от 1:3000 новорожденных среди евреев-ашкенази до 1:320 000 новорожденных в США [4][5][6][7]. Во франко-канадской популяции Квебека частота болезни Тея -Сакса составляет 1:218 144 живых новорожденных [6]. В 2013 г. ...
Background. GM2-gangliosidosis, type I (Tay-Sachs disease) is rare hereditary disease caused by mutations in the HEXA gene encoding the alpha subunit of lysosomal hexosaminidase A. It leads to accumulation of GM2-ganglioside in lysosomes and cell death. The major clinical signs of this disease are regression of motor and psychoverbal skills, progressive macrocephaly, diffuse muscle hypotension, convulsive disorder. Almost all patients with this disease have the “cherry red spot” symptom on the fundus of the eye. Clinical case description. We show clinical description of the patient with disease manifested with the lesion of visual analyzer. The child was sent for geneticist’s consultation due to revealed ophthalmic picture of the “cherry red spot” symptom on the fundus of the eye. Molecular genetic testing has revealed in the patient c.1274_1278 dupTATC (CI 880091) mutation in homozygous state in HEXA gene. Concllusion. Differential diagnosis of this disease should be performed with other diseases from the group of inherited metabolic diseases associated with early regression of psychomotor skills, progressive vision loss, “cherry red spot” symptom on the fundus of the eye and convulsive disorder
... Accumulation of this substrate results in progressive neurodegeneration [2,3] . TSD most commonly affects the Ashkenazi Jewish population, with a rate of 1 in 30 individuals being carriers of the mutation causing a guanine to cytosine transversion in the first base of intron 12 (IVS12+1) [4,5] . There are currently no effective treatments nor cure for TSD, however, gene therapy offers a promising venue [1] . ...
Research Proposal
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Application of Crispr Cas 9 to correct the second most prevalent genetic mutation that causes Tay Sachs Disease (TSD); a guanine to cytosine trans version mutation present on the HEXA gene.
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A legalização do aborto gera diversas discussões, especialmente com relação a aspectos deontológicos e/ou técnicos do campo da ginecologia e obstetrícia. O objetivo do estudo foi analisar concepções bioéticas dos estudantes sobre a moralidade do aborto e saber o que pensam sobre os direitos do feto. O estudo é quantitativo, transversal, realizado mediante aplicação de questionário aos alunos do 6º e 7º períodos de medicina. Um total de 132 alunos participou do estudo, sendo a maioria, (63,6%) do 7º período e o restante, do 6º período do curso médico (36,4%). Os participantes da pesquisa tinham em média 25 anos de idade; eram, em sua maioria, do sexo feminino (73,5%) e tinham orientação religiosa, predominantemente, católica (63%). A maior parte dos entrevistados informou ser a favor do aborto, porém 74% condicionaram a sua resposta a “depende”. Para os entrevistados o aborto deveria ser realizado quando fossem causados por: estupro em 44% dos casos, seguida pelo risco de morte à gestante com 22%, e, por último, a anencefalia com 18% dos casos; 16%, não citaram qual era o condicionante e apenas associaram à necessidade de se analisar cada situação para tomar uma decisão. Apenas 21% dos alunos disseram ser contra. A maioria reconhece o embrião como indivíduo, o que demonstra uma divergência na opinião em determinadas condições. Concluímos que há necessidade de discussão mais ampla e curricular do assunto, procurando fundamentar melhor o tema entre os estudantes, enfatizando os direitos do nascituro, valorizando, o imperativo da vida.
Conference Paper
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Projection-iterative modifications of the variational-grid methods for problems of nonlinear solid mechanics and strength of inhomogeneous structural members // Scientific Research in XXI Century: Proceedings of the VIII International Scientific and Practical Conference (March 6-8, 2021). – Ottawa, Canada: Methuen Publishing House. – Р. 691–692. Available from:
Tay–Sachs disease is a genetic disorder that results in the destruction of nerve cells in the brain and spinal cord..also known as GM2 gangliosidosis or Hexosaminidase A deficiency) is an autosomal recessive genetic disorder. In its most common variant known as infantile Tay-Sachs disease it presents with a relentless deterioration of mental and physical abilities which commences at 6 months of age and usually results in death by the age of four.It is caused by a genetic defect in a single gene with one defective copy of that gene inherited from each parent. The disease occurs when harmful quantities of gangliosides accumulate in the nerve cells of the brain, eventually leading to the premature death of those cells. There is currently no cure or treatment. Tay- Sachs disease is a rare disease. Other autosomal disorders such as cystic fibrosis and sickle cell anemia are far more common. TSD is an autosomal recessive genetic disorder, meaning that when both parents are carriers, there is a 25% risk of giving birth to an affected child.
Purpose The Mexican Jewish community (MJC) is a previously uncharacterized genetically isolated group composed of Ashkenazi (AJ) and Sephardi-Mizrahi (SMJ) Jews that migrated in the early 1900s. We aimed to determine the heterozygote frequency of disease-causing variants in 302 genes in this population. Methods We conducted a cross-sectional study of the MJC involving individuals representing AJ, SMJ, or mixed-ancestry (MA) origin. We offered saliva-based preconception pan-ethnic expanded carrier screening that examined 302 genes. We analyzed heterozygote frequencies of pathogenic/likely pathogenic (P/LP) variants and compared them with gnomAD. Results We recruited 208 participants. The carrier screening results showed that 72.1% were heterozygous for at least one severe disease-causing variant in one of the genes analyzed. The most common genes with severe disease-causing variants were CFTR (16.8% of participants), MEFV (11.5%), WNT10A (6.7%) and GBA (6.7%). The allele frequencies were compared with gnomAD; 85% of variants were statistically different to gnomAD frequencies (p<0.05). Finally, 6% of couples were at-risk of having a child with a severe disorder. Conclusions The heterozygote frequency of at least one severe disease-causing variant in the MJC was 72.1%. The use of carrier screening in the MJC, and other understudied populations could help parents make more informed decisions.
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Tay-Sachs disease results from a mutation in the α subunit of β-hexosaminidase. Using a cDNA clone, we have mapped the gene to 15q23→q24 by in situ hybridization.Copyright © 1991 S. Karger AG, Basel
Objectives.-To provide an update of the international experience with carrier screening and prenatal diagnosis for Tay-Sachs disease (TSD), to assess the impact of these efforts, and to review the recent developments in DNA technology with application to TSD carrier detection and screening. Design.-Through the International TSD Testing, Quality Control, and Data Collection Center, all testing centers in the world were surveyed annually to assess overall experience with carrier testing and prenatal diagnosis. Quality control and laboratory surveillance of testing centers were performed through an annual assessment, using samples provided by the center. Setting.-Tay-Sachs disease testing centers around the world. Participants.-Nearly 1 million young adults from both Jewish and non-Jewish populations. Intervention.-Gene product screening (enzyme testing) and DNA-based mutation analysis (in some populations). Main Outcome Measure.-Impact of screening program on disease incidence. Results.-Data from all centers in the international TSD network on experience with TSD carrier testing and prenatal diagnosis since 1974 indicated that more than 36 000 heterozygotes were identified and 1056 couples found to be at risk for TSD in their offspring. A total of 2416 pregnancies at increased risk for TSD were monitored by amniocentesis or chorionic villus sampling. A dramatic decrease in the incidence of TSD in the Jewish populations was demonstrated. With both serum and leukocyte proficiency testing, there have been only 16 instances (of 845 cumulative laboratory evaluations) of one or more errors reported by a laboratory since 1983 resulting in nonaccreditation. Conclusions.-This analysis represents a prototypic effort in coordinating adult education, carrier testing, and genetic counseling directed toward prospective prevention of a uniformly fatal childhood disease and demonstrates that such an effort can dramatically affect disease incidence.
Tay-Sachs disease is an autosomal recessive genetic disorder resulting from mutation of the HEXA gene encoding the α-subunit of the lysosomal enzyme, β-N-acerylhexosaminidase A (ref. 1). A relatively high frequency of carriers (1/27) of a lethal, infantile form of the disease is found in the Ashkenazi Jewish population, but it is not yet evident whether this has resulted from a founder effect and random genetic drift or from a selective advantage of heterozygotes2. We have identified a single-base mutation in a cloned fragment of the HEXA gene from an Ashkenazi Jewish patient. This change, the substitution of a C for G in the first nucleotide of intron 12 is expected to result in defective splicing of the messenger RNA3. A test for the mutant allele based on amplification of DNA by the 'polymerase chain rection'4 and cleavage of a DdeI restriction site generated by the mutation revealed that this case and two other cases of the Ashkenazi, infantile form of Tay-Sachs disease are heterozygous for two different mutations. The occurrence of multiple mutant alleles warrants further examination of the selective advantage hypothesis.
In the absence of treatments for most inborn errors of metabolism, the goal of both geneticists and health care providers has been the prevention of disease through identification of at-risk couples. When the enzyme deficiency responsible for a disorder is known, heterozygotes can frequently be identified by enzyme assay. The presence or absence of specific mutations in the genes coding for these enzymes may be determined directly if the gene of interest has been identified and characterized. Because the inherited metabolic disorders are rare, these approaches are useful only for individuals with a family history of a specific disease or for populations in which the gene frequency for a specific disease is increased. Tay-Sachs disease is a fatal, autosomal recessive, metabolic disease caused by deficient activity of the lysosomal enzyme Hex A. Although it is rare in the general population, in which the heterozygote frequency is approximately 1/167, it is elevated in a few populations, including the Ashkenazi Jewish community, in which the heterozygote frequency is 1/30. The ability to detect TSD heterozygotes reliably and to diagnose TSD prenatally using a simple and rapid enzyme assay has made prevention of this disorder possible through education and carrier screening. The identification of specific TSD mutations at the DNA level enables laboratories to provide more accurate screening and diagnosis in some families. The success of TSD screening in the Ashkenazi Jewish population has made it the prototype for screening among the inborn errors of metabolism. The TSD example becomes increasingly relevant as heterozygote detection becomes possible for other genetic disorders that are increased in well-defined populations. Cystic fibrosis is such a disease in the caucasian population.
Tay-Sachs disease (TSD), a neurodegenerative disorder resulting from a deficiency of the lysosomal enzyme hexosaminidase A (HexA), clusters in Ashkenazic Jews. Population-based screening programs to detect carriers of TSD genes by means of HexA assays have been active since the 1970s. The recent characterization of 3 mutations in the HEXA gene (in exon 7, exon 11, and intron 12), which account for over 90% of HEXA mutations in Ashkenazim, appeared to offer better options for screening and diagnosis. The relative frequencies of the three mutations in Montreal are similar to those reported in four other North American populations. We compared enzyme and DNA analyses to determine specificity and sensitivity of each test when the other was used as the confirmatory procedure. Neither procedure has a sensitivity of 1.0. Maximum sensitivity and specificity were achieved by using both tests together. The findings here are likely to apply to most cases where the variant screened enzyme phenotype can result from more than one mutation.
Tay-Sachs disease results from a mutation in the alpha subunit of beta-hexosaminidase. Using a cDNA clone, we have mapped the gene to 15q23----q24 by in situ hybridization.
Tay-Sachs disease results from mutation in the gene encoding beta-hexosaminidase A alpha-subunit. Although some reports have suggested the locus on 15q, we tried to determine the finer gene locus using high resolution in situ hybridization. cDNA probe, p beta H alpha-5, containing the full-length sequence for the enzyme subunit, was 3H-labeled within 1-4 x 10(7) cpm/micrograms of cDNA by nick-translation. After molecular hybridization and autoradiography, prometaphases were G-banded by Hoechst 33258, UV-exposure and Giemsa. A total of 227 silver grains on chromosomes within 115 prometaphase spreads were analyzed. The region 15q23-q24 had 27 grains, corresponding to 11.9% of the total grains and to 77.1% of the grains on chromosome 15. 20.9% of prometaphases were observed with a grain at 15q23-q24. According to several previous reports, the shortest region of overlap (SRO) of the locus has been 15q22-q25.1. Here we have assigned the gene locus to the narrower region 15q23-q24 by high-resolution in situ hybridization, which is one of the most powerful strategy for the completion of human gene map.