We studied the allelic profile of CAG and CCG repeats in 61 Brazilian individuals in 21 independent families affected by Huntington's disease (HD). Thirteen individuals had two normal alleles for HD, two had one mutable normal allele and no HD phenotype, and forty-six patients carried at least one expanded CAG repeat allele. Forty-five of these individuals had one expanded allele and one individual had one mutable normal allele (27 CAG repeats) and one expanded allele (48 CAG repeats). Eleven of these forty-five subjects had a mutant allele with reduced penetrance, and thirty-four patients had a mutant allele with complete penetrance. Inter-and intragenerational investigations of CAG repeats were also performed. We found a negative correlation between the number of CAG repeats and the age of disease onset (r ¼ À0.84; Po0.001) and no correlation between the number of CCG repeats and the age of disease onset (r ¼ 0.06). We found 40 different haplotypes and the analysis showed that (CCG) 10 was linked to a CAG normal allele in 19 haplotypes and to expanded alleles in two haplotypes. We found that (CCG) 7 was linked to expanded CAG repeats in 40 haplotypes (95.24%) and (CCG) 10 was linked to expanded CAG repeats in only two haplotypes (4.76%). Therefore, (CCG) 7 was the most common allele in HD chromosomes in this Brazilian sample. It was also observed that there was a significant association of (CCG) 7 with the expanded CAG alleles (v 2 ¼ 6.97, P ¼ 0.0084). Worldwide, the most common CCG alleles have 7 or 10 repeats. In Western Europe, (CCG) 7 is the most frequent allele, similarly to our findings.

ABSTRACT. Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder caused by a dynamic mutation due to the expansion of CAG repeats in the HTT gene (4p16.3). The considered normal alleles have less than 27 CAG repeats. Intermediate alleles (IAs) show 27 to 35 CAG repeats and expanded alleles have more than 35 repeats. The IAs apparently have shown a normal phenotype. However, there are some reported associations between individuals that bear an IA and clinical HD signs, such as behavioral disturbs. The association of IAs with the presence of clinical signs gives clinical relevance to these patients. We emphasized the importance of determining the frequency of IA alleles in the general population as well as in HD families. Therefore, the aim of this study was to conduct a systematic review, in order to investigate the frequency of IAs in the overall chromosomes of different ethnic groups and of families with HD history worldwide as well as the frequency of individuals who bear the intermediate alleles. We searched indexed articles from the following electronic databases: U.S. National Library of Medicine and the National Institutes of Health (PubMed), Pubmed Central (PMC) and Virtual Health Library (VHL). Therefore, 488 articles were obtained and, of these, 33 had been published in more than one database. We accepted the article of only one database and ended up with 455 articles for this review. The frequency of IAs within the chromosomes of the general population ranged from 0.45 to 8.7% and of individuals with family history of HD ranged from 0.05 to 5.1%. The higher frequency of IAs in the general population (8.7%) was found in one Brazilian cohort.

Huntington disease (HD) is a fatal neurodegenerative disorder caused by a gain-of-function mutation in HTT. Suppression of mutant HTT has emerged as a leading therapeutic strategy for HD, with allele-selective approaches targeting HTT SNPs now in clinical trials. Haplotypes associated with the HD mutation (A1, A2, A3a) represent panels of allele-specific gene silencing targets for efficient treatment of individuals with HD of Northern European and indigenous South American ancestry. Here we extend comprehensive haplotype analysis of the HD mutation to key populations of Southern European, South Asian, Middle Eastern, and admixed African ancestry. In each of these populations, the HD mutation occurs predominantly on the A2 HTT haplotype. Analysis of HD haplotypes across all affected population groups enables rational selection of candidate target SNPs for development of allele-selective gene silencing therapeutics worldwide. Targeting SNPs on the A1 and A2 haplotypes in parallel is essential to achieve treatment of the most HD-affected subjects in populations where HD is most prevalent. Current allele-specific approaches will leave a majority of individuals with HD untreated in populations where the HD mutation occurs most frequently on the A2 haplotype. We further demonstrate preclinical development of potent and selective ASOs targeting SNPs on the A2 HTT haplotype, representing an allele-specific treatment strategy for these individuals. On the basis of comprehensive haplotype analysis, we show the maximum proportion of HD-affected subjects that may be treated with three or four allele targets in different populations worldwide, informing current allele-specific HTT silencing strategies.

Background/Aims: Our aim was to investigate a geographical cluster of Huntington's disease (HD) in Ervalia, a Brazilian town of Minas Gerais state (MG). Therefore, we calculated the minimum prevalence of HD in Ervalia, known to have many HD affected families. We also determined the genetic profile of the polymorphic CAG region of the HTT gene in 32 subjects of these affected families. Methods: A descriptive cross-sectional study was performed, starting in January 2011 until June 2013. Individuals who participated in the survey were all from Ervalia town, MG. Results: The minimum prevalence rate found was 7.2/10,000 people, higher than the worldwide prevalence. Conclusion: The minimum prevalence of HD in Ervalia was at least 10.3- to 14.4-fold greater than that of the world population, although it does not represent the overall prevalence of the disease in Brazil. Certainly an expanded survey in the country will lead to a lower prevalence estimate than Ervalia's.

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Analisar o potencial genotóxico de um herbicida com flumioxazina pelo bioensaio Allium cepa. MATERIAIS E MÉTODOS: O herbicida foi testado em duas concentrações: 0,5 g/L (concentração indicada para o uso) e 1,0 g/L (dobro da concentração recomendada). Foram utilizados água destilada como controle negativo e, como controle positivo de citotoxicidade, benzoato de sódio 1%. RESULTADOS: Os resultados obtidos evidenciaram efeitos de toxicidade em ambas as concentrações do herbicida. Efeitos de citotoxicidade foram observados no herbicida com flumioxazina na concentração de 0,5 g/L, que apresentou padrão microscópico igual ao do controle positivo. Os efeitos de genotoxicidade foram observados em ambas as concentrações (0,5 g/L e 1,0 g/L) que resultaram em aberrações cromossômicas nas células, mostrando que o herbicida interfere diretamente no ciclo celular das células vegetais da cebola. CONCLUSÃO: O herbicida com flumioxazina apresentou toxicidade e genotoxicidade nas concentrações analisadas e efeitos de citotoxicidade somente na concentração recomendada para o uso.

The objective of this study was to investigate the association between the HLA alleles at the DQA1, DQB1 and DRB1 loci, the CIITA genetic polymorphisms -168A/G and +1614G/C, and susceptibility to multiple sclerosis (MS) in a sample from Rio de Janeiro State, Brazil. Furthermore, we wished to determine whether any of these associations might be more significant in women compared with men. DNA samples from 52 relapsing-remitting MS (RRMS) patients and 126 healthy controls matched for sex and age were analyzed. We identified a significant HLA-DRB1*15:01-MS association that was female-specific (Odds Ratio (OR) = 4.78; p = 0.001). Furthermore, we observed that the +1614G/C mutation in combination with the HLA-DRB1*15:01 allele increased susceptibility to MS in females (OR = 4.55; p = 0.01). Together, these findings highlight the polygenic nature of MS.

Background: Huntington disease (HD) (MIM: 143100) is a severe autosomal dominant neurodegenerative disease caused by the expansion of CAG trinucleotides (>35) in the HTT. Objective: To investigate the frequency of intermediate CAG alleles (IAs) in individuals residing in Rio de Janeiro city with no familial history of HD (general population, GP) in comparison with a sample of individuals from families presenting with HD who were previously investigated by our group (affected sample, AS).Results: The frequency of normal CAG alleles was 96.2%, while that of IAs was 3.6%, and that of reduced penetrance alleles was 0.2% in the GP (n = 470 chromosomes); 7.2% (17/235 individuals) of the GP presented an IA in heterozygosis with a normal allele. There was no statistically significant difference between the frequencies of the IAs in the GP and in the AS (p = .9). The most frequent haplotype per normal allele was (CAG)17-(CCG)7 (101/461) and per IA was (CAG)27-(CCG)7 (6/17) in the GP. These haplotypes were also the most frequent in the normal and IA chromosomes of the AS, respectively. Conclusion: The genetic profiles of the IAs obtained from GP and AS were rather similar. It is important to investigate the frequencies of the IAs because expansions arise from a step-by-step mechanism in which, during intergenerational transmission, large normal alleles can generate IAs, which are then responsible for generating de novo HD mutations. The genetic investigation of IAs in the GP was also important because it was focused on the population of Rio de Janeiro, an understudied group.CCG7 was the most frequent CCG allele in linkage disequilibrium with normal, intermediate, and expanded CAG alleles, similar to the Western Europe population.However, a more robust investigation, in conjunction with haplogroup determination (A, B, or C), will be required to elucidate the ancestral origin of the HTT mutations in Brazilians.