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J. Inherit. Metab. Dis. 27 (2004) 109^110

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SHORT REPORT Tay^Sachs disease in Brazilian patients: Prevalence of the IVS7 þ 1g>c mutation R. Rozenberg1 , A. M. Martins2 , C. Micheletti2 , Z. Mustacchi3 and L. V. Pereira1Ã

¤ " Centro de Estudos do Genoma Humano, Depto de Genetica, Instituto de Biociencias, a Universidade de S~ o Paulo; 2Depto de Pediatria, Universidade Federal do Estado de S~ o Paulo, a ¤ Escola Paulista de Medicina; 3Depto de Genetica, Universidade Paulista, Brazil " *Correspondence: Universidade de S~ o Paulo, Instituto de Biociencias ^ Depto Biologia, a Rua do Mat~ o, 277/sala 350, CEP: 05508-900, S~ o Paulo, SP, Brazil. E-mail: [email protected] a a

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Summary: Seven Brazilian Tay^Sachs disease cases were screened for the most frequent causative mutations. They all presented at least one copy of the IVS7 þ 1g>c mutation. Three patients were homozygotes, three were compound heterozygotes, and in one case only the mother was tested and shown to carry the IVS7 þ 1g>c mutation. In the second allele the compound heterozygotes presented: R178H (the DN allele), InsTATC1278 and an unidenti¢ed mutation. The IVS7 þ 1g>c mutation has already been described in three Portuguese patients. In this study, all families were unaware of any Portuguese ancestry. Since Brazil was a Portuguese colony, the mutation most probably came from ancient common ancestry. The initial molecular analysis of Tay^Sachs disease patients in Brazil indicated a prevalence of the IVS7 þ 1g>c mutation, possibly as a result of genetic drift.

Molecular analysis of 7 Brazilian Tay^Sachs disease (TSD) patients was performed to identify frequent causative mutations. The families studied were referred to our centre after an active search in genetic services around the country. Most were from northeast Brazil. Although more than 90 mutations have been described in TSD patients, we searched for the most frequent three Jewish (InsTATC1278, IVS12 þ 1g>c and G269S) and two Portuguese (IVS7 þ 1g>c and R178H) mutations (MeKusick 272800). All TSD cases had at least one copy of the IVS7 þ 1g>c mutation. Three were homozygotes (two consanguineous), three were compound heterozygotes, and in one case the child was deceased and only the mother was available for DNA collection. She carried the IVS7 þ 1g>c mutation. The IVS7 þ 1g>c homozygotes had a classical TSD phenotype, con¢rming earlier genotype^phenotype correlation (Fernandes et al 1992). Among two compound heterozygotes, the mothers were sisters. One of these cases presented the R178H mutation (the so-called DN allele) in combination with IVS7 þ 1g>c and the phenotype was the B1 variant, late-infantile type. Disease onset was at 10 months and the patient is currently over 7 years old. Although no such genotype was found in the literature, this observation is in accordance with previous reports suggesting 109

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that the presence of at least one copy of R178H leads to a slower disease progression as a results of residual enzyme activity. The other compound heterozygote had an unidenti¢ed second mutation. In the only instance of Jewish ancestry, the patient inherited the InsTATC1278 mutation from the Jewish father. The mother, who was not Jewish, had the IVS7 þ 1g>c mutation. The phenotype was of classical TSD. In Brazil, the frequency of TSD heterozygotes in the Ashkenazi Jewish population is similar to that from other countries (Rozenberg and Pereira 2000), but since this population represents less than 0.01% of the total Brazilian population, it may be anticipated that a minority of TSD cases in Brazil have Jewish ancestry. On the other hand, the IVS7 þ 1g>c mutation has already been described in three Portuguese patients (Fernandes et al 1992; Ribeiro et al 1995). In this study, all families were unaware of any Portuguese ancestry. Since Brazil was a Portuguese colony, the mutation most probably came from ancient common ancestry. Although further studies may highlight this point, the initial molecular analysis of TSD patients in Brazil indicated a prevalence of the IVS7 þ 1g>c mutation, possibly as a result of genetic drift.

REFERENCES Fernandes M, Boulay B, Hechtman P, Kaplan F, Strasberg P (1992) Five novel HEXA mutations in non-Jewish Tay^Sachs disease (TSD) patients. Am J Hum Genet 51: Abstract 656. OMIM, Online Mendelian Inheritance in Man Johns Hopkins University, Baltimore, MD. MIM Number: 272800: 18/08/2003: World Wide Web URL:http://www.ncbi.nlm.nih. gov/omim/ Ribeiro MG, Pinto R, Miranda MCS, Suzuki K (1995). Tay^Sachs disease: intron 7 splice junction mutation in two Portuguese patients. Biochim Biophys Acta 1270: 44^51. Rozenberg R, Pereira LV (2001). The frequency of Tay^Sachs disease causing mutations in the Brazilian Jewish population justi¢es a carrier screening program. SP Med J 119: 146^149.

J. Inherit. Metab. Dis. 27 (2004)

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JIMD-4299 109..110

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