Lipoplexes and polyplexes as nucleic acids delivery nanosystems: The current state and future considerations.

INTRODUCTION: Designing safe and effective nucleic acid delivery nanosystems presents a challenge that requires a good understanding of various biological barriers, whose impact is frequently neglected during in vitro assessments. Hence, the development of nanosizing non-viral vectors would benefit from a more thorough physicochemical characterization to establish structure-activity relationships and increase the preclinical data relevance. AREAS COVERED: This review focused on major barriers of lipoplexes and polyplexes by systemic delivery such as blood and immune cells and is aimed to serve as a prescreening tool for the fast and safe development of both non-viral vectors in vivo. An outline of the preclinical assays to be performed under physiological representative conditions, to better account for or even predict the highly dynamic interactions in humans is also given. EXPERT OPINION: The rational design of non-viral vectors has shown promising intracellular uptake results in vitro. Translating in vitro success into clinics has gone with progress, but it is still a difficult task to achieve, and more closely mimicking biological environment in vitro assays of lipoplexes and polyplexes may provide more correlated results to in vivo experiments. Clinical practice would benefit from safer non-viral vectors, particularly when avoiding patients' immune responses and toxicity, which is of major concern.

La formación del operario en vigilancia y lucha antivectorial. Matanzas, 2019

RESUMEN Introducción: para la formación de operarios integrales en vigilancia y lucha antivectorial, está diseñado un curso de habilitación. El claustro de profesores de la provincia de Matanzas ha encontrado algunas dificultades en la adquisición de conocimientos por parte de los estudiantes. Objetivo: caracterizar la fuerza laboral de vigilancia y lucha antivectorial de la provincia de Matanzas, para diseñar un conjunto de indicaciones que complementen los contenidos del curso de habilitación de operarios, de forma que los estudiantes se sientan motivados y entiendan mejor los contenidos ya incluidos. Materiales y métodos: se realizó una investigación descriptiva, retrospectiva y longitudinal, de enero a diciembre de 2019. Resultados: el grupo de trabajadores de los operarios es el más numeroso. El nivel educacional que predominó fue el de secundaria básica. En 2019 se realizaron 17 cursos de formación, en cuyas evaluaciones el claustro de profesores encontró dificultades en las respuestas a las preguntas de tres de los temas del curso, al igual que en el uso de la lengua materna. Conclusiones: se propuso introducir contenidos en cada tema del curso de formación, que se impartirán de acuerdo a las formas de enseñanza y aprendizaje ya definidas en el programa. El profesor responsable del tema lo dará en el momento en que la situación docente lo requiera, para que el futuro trabajador logre una mejor comprensión de los contenidos.

ABSTRACT Introduction: there is an enabling course designed for the training of comprehensive operators in surveillance and vector control. The teacher staff of Matanzas province has found some difficulties in the acquisition of knowledge by students. Objective: to characterize the surveillance and anti-vector labor force of the province of Matanzas, in order to design a set of indications that complement the contents of the course of enabling operators, so that students feel motivated and better understand the contents already included. Materials and methods: a descriptive, retrospective and longitudinal investigation was carried out from January to December 2019. Results: the group of operators is the most numerous. The educational level that prevailed was that of secondary school. In 2019, 17 training courses were conducted, in whose evaluations the teacher staff found difficulties in answering the questions of three of the course subjects, as well as in the use of the mother tongue. Conclusions: it was proposed to introduce new contents in each topic of the training course, which will be taught according to the forms of teaching and learning already defined in the programme. The teacher responsible for the subject will teach it at the moment when the teaching situation requires it, in order for the future worker to achieve a better understanding of the contents.

Efectividad del temefos 1 % en larvas de Culex quinquefasciatus. Matanzas, 2019

RESUMEN Introducción: el temefos es el producto más utilizado para el tratamiento focal. Existe en diferentes formulaciones y se aplica para los depósitos de agua potable, en forma de gránulos de arena a una concentración del 1 %. Objetivo: determinar la duración de la efectividad del temefos, en su formulación costarricense Biolarv G1, en una población matancera de Culex quinquefasciatus. Materiales y métodos: se realizó un bioensayo de laboratorio, utilizando la F1 de una cepa matancera de Culex quinquefasciatus, la que se sometió a los efectos del Biolarv G1, lote 1180829. Se utilizaron tres variantes de recambio de agua potable. Resultados: la efectividad fue del 100 % de mortalidad larvaria hasta el 7º día en el recambio del 100 % de agua. Para el recambio del 50 % de agua, la mortalidad promedio del 1º al 17º día fue del 97,5 %. En el caso del recambio del 30 % de agua, la mortalidad fue del 100 % hasta el 27º día. Conclusiones: se demostró que el temefos, en su formulación Biolarv G1, puede tener mayor efectividad en recambios del 30 % de agua, con una durabilidad de alrededor de 30 días, lo que propicia la protección de los depósitos durante los ciclos de trabajo diseñados para la vigilancia y lucha antivectorial en Cuba.

ABSTRACT Introduction: temefos is the most widely used product for focal treatment. It exists in different formulations and is applied for drinking water tanks, in the form of sand-like granules at a concentration of 1 %. Objective: to determine the duration of temefos effectiveness, in its Costa Rican formulation Biolarv G1, in a Matanzas population of Culex quinquefasciatus. Materials and methods: a laboratory bioassay was performed, using the F1 of a Matanzas strain of Culex quinquefasciatus, which was subjected to the effects of Biolarv G1, lot 1180829. Three variants of drinking water replacement were used. Results: the effectiveness was 100% of larval mortality until the 7th day when 100 % of wáter was replaced. For the replacement of 50 % of water, average mortality was 97.5 % from the 1st to the 17th day. In the case of 30 % water replacement, mortality was 100 % up to the 27th day. Conclusions: it was shown that temefos, in its formulation Biolarv G1, can be more effective in replacements of 30 % of water, with a durability of about 30 days, which facilitates the protection of reservoirs during work cycles designed for surveillance and anti-vector control in Cuba.

Antisense Transcription across Nucleotide Repeat Expansions in Neurodegenerative and Neuromuscular Diseases: Progress and Mysteries.

Unstable repeat expansions and insertions cause more than 30 neurodegenerative and neuromuscular diseases. Remarkably, bidirectional transcription of repeat expansions has been identified in at least 14 of these diseases. More remarkably, a growing number of studies has been showing that both sense and antisense repeat RNAs are able to dysregulate important cellular pathways, contributing together to the observed clinical phenotype. Notably, antisense repeat RNAs from spinocerebellar ataxia type 7, myotonic dystrophy type 1, Huntington's disease and frontotemporal dementia/amyotrophic lateral sclerosis associated genes have been implicated in transcriptional regulation of sense gene expression, acting either at a transcriptional or posttranscriptional level. The recent evidence that antisense repeat RNAs could modulate gene expression broadens our understanding of the pathogenic pathways and adds more complexity to the development of therapeutic strategies for these disorders. In this review, we cover the amazing progress made in the understanding of the pathogenic mechanisms associated with repeat expansion neurodegenerative and neuromuscular diseases with a focus on the impact of antisense repeat transcription in the development of efficient therapies.

Mutational mechanism for DAB1 (ATTTC)n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution.

Dynamic mutations by microsatellite instability are the molecular basis of a growing number of neuromuscular and neurodegenerative diseases. Repetitive stretches in the human genome may drive pathogenicity, either by expansion above a given threshold, or by insertion of abnormal tracts in nonpathogenic polymorphic repetitive regions, as is the case in spinocerebellar ataxia type 37 (SCA37). We have recently established that this neurodegenerative disease is caused by an (ATTTC)n insertion within an (ATTTT)n in a noncoding region of DAB1. We now investigated the mutational mechanism that originated the (ATTTC)n insertion within an ancestral (ATTTT)n . Approximately 3% of nonpathogenic (ATTTT)n alleles are interspersed by AT-rich motifs, contrarily to mutant alleles that are composed of pure (ATTTT)n and (ATTTC)n stretches. Haplotype studies in unaffected chromosomes suggested that the primary mutational mechanism, leading to the (ATTTC)n insertion, was likely one or more T>C substitutions in an (ATTTT)n pure allele of approximately 200 repeats. Then, the (ATTTC)n expanded in size, originating a deleterious allele in DAB1 that leads to SCA37. This is likely the mutational mechanism in three similar (TTTCA)n insertions responsible for familial myoclonic epilepsy. Because (ATTTT)n tracts are frequent in the human genome, many loci could be at risk for this mutational process.

Vigilancia entomológica de culícidos en la provincia de Matanzas durante el año 2015 / Entomological surveillance of culicids in the province of Matanzas during 2015

Introducción: la vigilancia entomológica es la recolección de información sobre los vectores de enfermedades y su entorno. Es un componente de la vigilancia epidemiológica, que consiste en una actividad del control de los vectores que se realiza durante todo el año, para conocer la presencia de estos en un área geográfica, la densidad de sus poblaciones, así como identificar los principales criaderos y los más productivos. Objetivo: identificación de las especies de culícidos que circularon en la provincia de Matanzas, durante el año 2015, así como la definición de la especie que predominó y tipificación de los depósitos más colonizados por estos en su fase de vida inmadura. Materiales y Métodos: se realizó un análisis de las estadísticas de la vigilancia entomológica durante el año 2015. Según la metodología descrita en el Programa Nacional de Vigilancia y Lucha Antivectorial se clasificó los depósitos, se colectaron y diagnosticaron las muestras. Resultados: las muestras larvarias aportaron la mayor cantidad de datos. Los depósitos de agua situados en el exterior de las viviendas, y dentro de estos las larvitrampas fueron los más utilizados por los mosquitos. La especie predominante en fase inmadura fue Aedes albopictus, mientras que en fase adulta Culex quinquefasciatus. Conclusiones: se identificaron 5 géneros con 25 especies de culícidos, el 36,8 % de la fauna cubana. Como especie predominante se define al A. albopictus. Los depósitos más explotados por estos organismos según su ubicación, fueron los del exterior, y según su tipo, fueron las larvitrampas (grupo E) (AU).

Introduction: the entomological surveillance is the recollection of information on diseases´ vectors and their environment. It is part of the epidemiologic surveillance, and it is an activity of vectors controlling carried out around the year to determine their presence in a geographical area, the density of their populations, and to identify their main breeding places and the most productive ones. Objectives: to identify the culicids species living in the province of Matanzas during 2015, and also to define the predominating specie and to typify the deposits more colonized by them in the in-mature life stage. Materials and Methods: it was carried out an analysis of the entomological surveillance statistics during 2015. The reservoirs were classified, and the samples were collected and diagnosed according to the methodology described in the National Program of Antivectorial Surveillance and Struggle. Results: the larval samples gave the biggest quantity of data. The water reservoirs located outside the living accommodations, and among them the larval traps were the most used by mosquitoes. The predominant specie found in in-mature stage was Aedes albopictus, while Culex quinquefasciatus predominated in adult stage. Conclusions: 5 genus with 25 species of culicids were found, 36.8 of them part of the Cuban fauna. The Aedes albopictus was defined as the predominant specie. The reservoirs most used by these organisms were, according to their location, those located outside, and according to their type, the larval traps (group E) (AU).

A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia.

Advances in human genetics in recent years have largely been driven by next-generation sequencing (NGS); however, the discovery of disease-related gene mutations has been biased toward the exome because the large and very repetitive regions that characterize the non-coding genome remain difficult to reach by that technology. For autosomal-dominant spinocerebellar ataxias (SCAs), 28 genes have been identified, but only five SCAs originate from non-coding mutations. Over half of SCA-affected families, however, remain without a genetic diagnosis. We used genome-wide linkage analysis, NGS, and repeat analysis to identify an (ATTTC)n insertion in a polymorphic ATTTT repeat in DAB1 in chromosomal region 1p32.2 as the cause of autosomal-dominant SCA; this region has been previously linked to SCA37. The non-pathogenic and pathogenic alleles have the configurations [(ATTTT)7-400] and [(ATTTT)60-79(ATTTC)31-75(ATTTT)58-90], respectively. (ATTTC)n insertions are present on a distinct haplotype and show an inverse correlation between size and age of onset. In the DAB1-oriented strand, (ATTTC)n is located in 5' UTR introns of cerebellar-specific transcripts arising mostly during human fetal brain development from the usage of alternative promoters, but it is maintained in the adult cerebellum. Overexpression of the transfected (ATTTC)58 insertion, but not (ATTTT)n, leads to abnormal nuclear RNA accumulation. Zebrafish embryos injected with RNA of the (AUUUC)58 insertion, but not (AUUUU)n, showed lethal developmental malformations. Together, these results establish an unstable repeat insertion in DAB1 as a cause of cerebellar degeneration; on the basis of the genetic and phenotypic evidence, we propose this mutation as the molecular basis for SCA37.

Recent Advances in Nucleic Acid-Based Delivery: From Bench to Clinical Trials in Genetic Diseases.

Delivery of nucleic acids is the most promising therapy for many diseases that remain untreatable. Therefore, many research efforts have been put on finding a safe and efficient delivery system able to provide a sustained response. Viral vectors have proved to be the most efficient for delivery of nucleic acids and, thus, stand as the foremost vector used in current clinical trials. However, safety issues arise as a main concern and mitigate their use, impelling the improvement of non-viral alternatives. This review focuses on the recent advances in pre-clinical development of non-viral polyplexes and lipoplexes for nucleic acid-based delivery, in contrast with vectors being used in present clinical trials. Nucleic acid vectors for neurodegenerative ataxias, Parkinson's disease, retinitis pigmentosa, cystic fibrosis, hemophilia, pancreatic and lung cancer, and rheumatoid arthritis are discussed to illustrate current state of pre-clinical and clinical studies. Thereby, denoting the prospects for treatment of genetic diseases and elucidating the trend in non-viral vector development and improvement which is expected to significantly increase disease rescue exceeding the modest clinical successes observed so far.

Recent advances in characterization of nonviral vectors for delivery of nucleic acids: impact on their biological performance.

INTRODUCTION: Nucleic acid delivery is a complex process that requires transport across numerous extracellular and intracellular barriers, whose impact is often neglected during optimization studies. As such, the development of nonviral vectors for efficient delivery would benefit from an understanding of how these barriers relate to the physicochemical properties of lipoplexes and polyplexes. AREAS COVERED: This review focuses on the evaluation of parameters associated with barriers to delivery such as blood and immune cells compatibility which, as a collective, may serve as a useful prescreening tool for the advancement of nonviral vectors in vivo. An outline of the most relevant rationally developed polyplexes and lipoplexes for clinical application is also given. EXPERT OPINION: The evaluation of scientifically recognized parameters enabled the identification of systemic delivered nonviral vectors' behavior while in blood as one of the key determinants of vectors function and activity both in vitro and in vivo. This multiparametric approach complements the use of in vitro efficacy results alone for prescreening and improves in vitro-in vivo translation by minimizing false negatives. Further, it can aid in the identification of meaningful structure-function-activity relationships, improve the in vitro screening process of nonviral vectors before in vivo use and facilitate the future development of potent and safe nonviral vectors.

Entre o Instituto e as cidades: percorrendo quilômetros em direção à formação psicanalítica / Between the institute and the cities: traveling miles toward psychoanalytic training / Entre el Instituto y las ciudades: recorriendo kilómetros rumbo a la formación psicoanalítica

A formação psicanalítica nos institutos da IPA é, de modo geral, um processo longo, difícil, intenso e gerador de profundas mudanças na vida daqueles que a realizam. O Instituto "Durval Marcondes", sediado na cidade de São Paulo, tem atualmente 328 membros filiados, sendo que 36% destes não residem na capital. Este artigo objetiva refletir sobre a formação, considerando algumas das especificidades dessa condição de membro filiado que precisa viajar até o Instituto para fazer a sua formação...

Psychoanalytic training at IPA Institutes is generally a long and difficult process, one which generates intense and profound changes in the lives of those who do it. The Durval Marcondes Institute, situated in São Paulo, currently has 328 affiliated members, 36% of which do not live in the city. This paper aims to discuss the training, considering some of the specific implications of these members' needs, including the distance they must travel to get and complete their training...

La formación psicoanalítica en los institutos de la IPA es generalmente un largo, difícil e intenso proceso que genera profundos cambios en la vida de aquellos que la realizan. El Instituto de Psicoanálisis Durval Marcondes, con sede en la ciudad de San Pablo, cuenta actualmente con 328 miembros afiliados, siendo que el 36% de ellos no reside en la capital paulista. Este artículo tiene como objetivo reflexionar sobre la formación psicoanalítica teniendo en cuenta algunos aspectos específicos de la condición del analista en formación que precisa viajar hasta el Instituto para realizarla...

Autosomal dominant spastic paraplegias: a review of 89 families resulting from a portuguese survey.

IMPORTANCE: Hereditary spastic paraplegias (HSPs) are a group of diseases caused by corticospinal tract degeneration. Mutations in 3 genes (SPG4, SPG3, and SPG31) are said to be the cause in half of the autosomal dominant HSPs (AD-HSPs). This study is a systematic review of families with HSP resulting from a population-based survey. Novel genotype-phenotype correlations were established. OBJECTIVE: To describe the clinical, genetic, and epidemiological features of Portuguese AD-HSP families. DESIGN: Retrospective medical record review. SETTING: A population-based systematic survey of hereditary ataxias and spastic paraplegias conducted in Portugal from 1993 to 2004. PARTICIPANTS: Families with AD-HSP. MAIN OUTCOME MEASURE: Mutation detection in the most prevalent genes. RESULTS: We identified 239 patients belonging to 89 AD-HSP families. The prevalence was 2.4 in 100 000. Thirty-one distinct mutations (26 in SPG4, 4 in SPG3, and 1 in SPG31) segregated in 41% of the families (33.7%, 6.2%, and 1.2% had SPG4, SPG3 and SPG31 mutations, respectively). Seven of the SPG4 mutations were novel, and 7% of all SPG4 mutations were deletions. When disease onset was before the first decade, 31% had SPG4 mutations and 27% had SPG3 mutations. In patients with SPG4 mutations, those with large deletions had the earliest disease onset, followed by those with missense, frameshift, nonsense, and alternative-splicing mutations. Rate of disease progression was not significantly different among patients with SPG3 and SPG4 mutations in a multivariate analysis. For patients with SPG4 mutations, disease progression was worst in patients with later-onset disease. CONCLUSIONS AND RELEVANCE: The prevalence of AD-HSP and frequency of SPG3 and SPG4 mutations in the current study were similar to what has been described in other studies except that the frequency of SPG4 deletions was lower. In contrast, the frequency of SPG31 mutations in the current study was rare compared with other studies. The most interesting aspects of this study are that even in patients with early-onset disease the probability of finding a SPG4 mutation was higher than for patients with SPG3 mutations; there was no difference in disease progression with genotype but an association with the age at onset; 7 new SPG4 mutations were identified; and for the first time, to our knowledge, the nature of the SPG4 mutations was found to predict the age at onset.

Suicide prevention training for professionals in the public health network in a large Brazilian city.

The objective of this study was to improve health professionals' knowledge and attitudes toward suicide prevention. A suicide prevention training of 18 hours duration was conducted with 270 health professionals, mainly primary care workers, who were routinely involved with patients at high risk for suicide. Questionnaires were used to assess changes in attitudes and knowledge. The score in the knowledge questionnaire, with 21 points as maximum value, increased from 8.9 to 13 points (p < .001, significance level of 95%). Of the 25 questionnaire items representing attitudes, 18 showed significant change after the training. This training model has enhanced knowledge and attitudes toward suicide prevention in healthcare workers.

Calidad del hibitane como desinfectante químico en la prevención y control de la contaminación microbiana / Quality of the hibitane as a chemical disinfectant in the prevention and control of the microbial contamination

El empleo de disoluciones químicas desinfectantes en la prevención de las infecciones intrahospitalarias representa una problemática compleja, por diversas causas, estas no cumplen los requisitos de calidad físico-químicos establecidos para su manejo efectivo, lo que origina contaminación microbiológica por gérmenes perjudiciales a la salud y al medio ambiente, el objetivo de este trabajo es hacer un estudio descriptivo sobre el control de la calidad del hibitane como principal solución desinfectante utilizada en el Hospital Clínico-Quirúrgico Universitario Comandante Faustino Pérez, en el período que abarca desde enero de 1997 hasta diciembre de 2006. En esta etapa se chequeó la calidad de esta disolución, según la normativa de la vigilancia higiénico-epidemiológica, y se pudo comprobar que la misma no cumple los parámetros establecidos para tales efectos, con vista a minimizar los impactos negativos que ejerce la contaminación microbiológica sobre la salud humana y el medio ambiente

The usage of chemical disinfectant dissolutions in the prevention of the in-hospital infections is a complex problem because of different causes; they do not fulfil the established physical-chemical requirements of quality for its effective handling, what originates microbiologic contamination for germs that are harmful to the health and the environment: The objective of this work was making a descriptive study on the quality control of the hibitane like a main disinfectant solution used in the University Clinic-surgical Hospital Comandante Faustino Pérez, in the period from January 1997 to December 2006. In this period we checked the quality of this dissolution, according to the normative of the hygiene-epidemiologic surveillance, and we stated that it does not fulfil the established parameters, with the objective of minimizing the negative impacts exerted by the microbiologic contamination on the human health and the environment

Common origin of pure and interrupted repeat expansions in spinocerebellar ataxia type 2 (SCA2).

The spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease characterized by gait and limb ataxia. This disease is caused by the expansion of a (CAG)(n) located in the ATXN2, that encodes a polyglutamine tract of more than 34 repeats. Lately, alleles with 32-33 CAGs have been associated to late-onset disease cases. Repeat interruptions by CAA triplets are common in normal alleles, while expanded alleles usually contain a pure repeat tract. To investigate the mutational origin and the instability associated to the ATXN2 repeat, we performed an extensive haplotype study and sequencing of the CAG/CAA repeat, in a cohort of families of different geographic origins and phenotypes. Our results showed (1) CAA interruptions also in expanded ATXN2 alleles; (2) that pathological CAA interrupted alleles shared an ancestral haplotype with pure expanded alleles; and (3) higher genetic diversity in European SCA2 families, suggesting an older European ancestry of SCA2. In conclusion, we found instability towards expansion in interrupted ATXN2 alleles and a shared ancestral ATXN2 haplotype for pure and interrupted expanded alleles; this finding has strong implications in mutation diagnosis and counseling. Our results indicate that interrupted alleles, below the pathological threshold, may be a reservoir of mutable alleles, prone to expansion in subsequent generations, leading to full disease mutation.

Phenotypes of spinocerebellar ataxia type 6 and familial hemiplegic migraine caused by a unique CACNA1A missense mutation in patients from a large family.

BACKGROUND: Different mutations in the alpha 1A-subunit of the brain P/Q-type calcium channel gene (CACNA1A) are responsible for familial hemiplegic migraine (FHM), episodic ataxia type 2, and spinocerebellar ataxia type 6 (SCA6). Missense and splice site mutations have been found in FHM and episodic ataxia type 2, respectively, whereas a CAG repeat in the CACNA1A gene was found expanded in patients with SCA6. OBJECTIVE: To identify the disease causing mutation in a large family of patients with phenotypes of hemiplegic migraine with or without cerebellar signs or permanent cerebellar ataxia without migraine inherited in a dominant manner. PATIENTS AND METHODS: We examined 15 patients from a large family identified through a systematic survey of hereditary ataxias being conducted in Portugal. Linkage analysis was performed with CACNA1A gene markers, and mutation analysis was performed by single strand conformational polymorphism analysis and sequencing. RESULTS: Genetic linkage analysis with CACNA1A intragenic markers showed positive LOD scores. The maximal LOD score was obtained with the polymorphic CAG repeat (Zmax = 4.47, theta = 0). By single-strand conformational polymorphism analysis, a shift in exon 13 of the CACNA1A gene was detected in all patients. A G-to-A substitution was then identified, resulting in an arginine-to-glutamine change at codon 583 of this calcium channel alpha 1A-subunit. CONCLUSIONS: The disease-causing mutation in this family was identified, showing that a unique mutation in the CACNA1A gene causes several phenotypes, including those of SCA6 and FHM, thus suggesting that SCA6 and FHM are not only allelic diseases but are the same disorder with a large phenotypic variability.

Frequency of the different mutations causing spinocerebellar ataxia (SCA1, SCA2, MJD/SCA3 and DRPLA) in a large group of Brazilian patients

Spinocerebellar ataxia type 1 (SCA1), spinocerebellar ataxia type 2 (SCA2) and Machado-Joseph disease or spinocerebellar ataxia type 3 (MJD/SCA3) are three distinctive forms of autosomal dominant spinocerebellar ataxia (SCA) caused by expansions of an unstable CAG repeat localized in the coding region of the causative genes. Another related disease, dentatorubropallidoluysian atrophy (DRPLA) is also caused by an unstable triplet repeat and can present as SCA in late onset patients. We investigated the frequency of the SCA1, SCA2, MJD/SCA3 and DRPLA mutations in 328 Brazilian patients with SCA, belonging to 90 unrelated families with various patterns of inheritance and originating in different geographic regions of Brazil. We found mutations in 35 families (39 percent), 32 of them with a clear autosomal dominant inheritance. The frequency of the SCA1 mutation was 3 percent of all patients; and 6 percent in the dominantly inherited SCAs. We identified the SCA2 mutation in 6 percent of all families and in 9 percent of the families with autosomal dominant inheritance. The MJD/SCA3 mutation was detected in 30 percent of all patients; and in the 44 percent of the dominantly inherited cases. We found no DRPLA mutation. In addition, we observed variability in the frequency of the different mutations according to geographic origin of the patients, which is probably related to the distinct colonization of different parts of Brazil. These results suggest that SCA may be occasionally caused by the SCA1 and SCA2 mutations in the Brazilian population, and that the MJD/SCA3 mutation is the most common cause of dominantly inherited SCA in Brazil.

Clinical and molecular characteristics of a brazilian family with spinocerebellar ataxia type 1

The spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of late onset neurodegenerative disorders. To date, seven different genes causing autosomal dominant SCA have been mapped:SCA1,SCA2, Machado-Joseph disease(MJD)/SCA3,SCA4,SCA5,SCA7 and dentatorubropallidoluysian atrophy (DRPLA). Expansions of an unstable trinucleotide CAG repeat cause three of these disorders: SCA1, MJD/SCA3 and DRPLA. We studied one Brazilian family segregating an autosomal dominant type of SCA. A total of ten individuals were examined and tested for the presence of the SCA1, MJD and DRPLA mutations. Three individuals, one male and two females, were considered affected based on neurological examination; ages at onset were: 32, 36 and 41 years. The first complaint in all three patients was gait ataxia which progressed slowly over the years. Six individuals showed one allele containing an expanded CAG repeat in the SCA1 gene. The mean size of the expanded allele was 48.2 CAG units. Instability of the expanded CAG tract was seen in the two transmissions that were observed in this family. In both occasions there was a contraction of the CAG tract. Our study demonstrates that SCA1 occurs in the Brazilian population. In addition, our results stress the importance of molecular studies in the confirmation of diagnosis and for pre-symptomatic testing in SCAs.