Isabel Silveira

Bio: Isabel Silveira is an academic researcher from University of Porto. The author has contributed to research in topics: Spinocerebellar ataxia & Machado–Joseph disease. The author has an hindex of 31, co-authored 59 publications receiving 2599 citations. Previous affiliations of Isabel Silveira include Instituto de Biologia Molecular e Celular & McGill University.

Correlation between CAG repeat length and clinical features in Machado-Joseph disease

Abstract: Machado-Joseph disease (MJD) is associated with the expansion of a CAG trinucleotide repeat in a novel gene on 14q32.1. We confirmed the presence of this expansion in 156 MJD patients from 33 families of different geographic origins: 15 Portuguese Azorean, 2 Brazilian, and 16 North American of Portuguese Azorean descent. Normal chromosomes contain between 12 and 37 CAG repeats in the MJD gene, whereas MJD gene carriers have alleles within the expanded range of 62-84 CAG units. The distribution of expanded alleles and the gap between normal and expanded allele sizes is either inconsistent with a premutation hypothesis or most (if not all) of the alleles we studied descend from a common ancestor. There is a strong correlation between the expanded repeat size and the age at onset of the disease as well as the clinical presentation. There is mild instability of the CAG tract length with transmission of the expanded alleles; both increase and decrease in size between parents and progeny occur, with larger variations in male than in female transmissions. Together, these effects can partly explain the variability of age at onset and of phenotypic features in MJD; however, other modifying factors must exist.

Trinucleotide Repeats in 202 Families With Ataxia: A Small Expanded (CAG)n Allele at the SCA17 Locus

Abstract: nantly transmitted cases had (CAG)n expansions at the Machado-Joseph disease gene (MJD1) (63%), at SCA2 (3%), the gene for dentatorubropallidoluysian atrophy (DRPLA) (2%), SCA6 (1%), or SCA7 (1%) loci, or (CTG)n expansions at the SCA8 (2%) gene, whereas (GAA)n expansions in the Freidreich ataxia gene (FRDA) were found in 64% of families with recessive ataxia. Isolated patients also had TNR expansions at the MJD1 (6%), SCA8 (6%), or FRDA (8%) genes; in addition, an expanded allele at the TATA-binding protein gene (TBP), with 43 CAGs, was present in a patient with ataxia and mental deterioration. Associations between frequencies of SCA2 and SCA6 and a frequency of large normal alleles were found in Portuguese and Brazilian individuals, respectively. Interestingly, no association between the frequencies of DRPLA and large normal alleles was found in the Portuguese group. Conclusions: Our results show that (1) a significant number of isolated cases of ataxia are due to TNR expansions; (2) expanded DRPLA alleles in Portuguese families may have evolved from an ancestral haplotype; and (3) small (CAG)n expansions at the TBP gene may cause SCA17. Arch Neurol. 2002;59:623-629

Neurologic findings in Machado-Joseph disease : Relation with disease duration, subtypes, and (CAG)n

Abstract: Context: Machado-Joseph disease (MJD), an autoso- mal dominant spinocerebellar degeneration caused by an expanded CAG repeat on chromosome 14q32.1, is a het- erogeneous disorder for clinical manifestations. The rea- sons for the wide range of neurologic findings in this dis- ease are poorly understood. Objective: To explain part of this heterogeneity through the association of the neurologic findings with sex, dis- ease duration, age of onset, clinical type, and size of CAG repeat expansion. Design: A case-control study. Setting: Ambulatory care. and ophthalmoplegia (P,.02). The most severe forms of nuclear ophthalmoplegia were associated with type 1 MJD, whereas those of supranuclear ophthalmoplegia were as- sociated with type 3 MJD (P,.001). It was also found that higher mean (CAG)n lengths were associated with worse degrees of the pyramidal syndrome and dystonia (P,.001). The presence and severity of nystagmus, eye- lid retraction, rigidity and/or bradykinesia, and optic at- rophy were not clearly associated with any of the pre- dictive variables under study. Conclusions: Disease duration can explain part of the heterogeneity of ataxia, dysarthria, dysphagia, fascicu- lations, pyramidal syndrome, and ophthalmoplegia, in MJD. Type 1 MJD was positively associated with nuclear ophthalmoplegia; type 3 MJD was positively associated with supranuclear ophthalmoplegia. Higher mean CAG lengths were found to correlate with the pyramidal syn- drome and dystonia. Nystagmus, eyelid retraction, ri- gidity and/or bradykinesia, and optic atrophy were hardly attributable to any known reason or variable. Arch Neurol. 2001;58:899-904

Ancestral Origins of the Machado-Joseph Disease Mutation: A Worldwide Haplotype Study

Abstract: Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder originally described in families of Portuguese-Azorean ancestry. The cloning of the MJD1 gene allowed identification of the disease in many other populations, and MJD is now known to be the most common cause of dominant spinocerebellar ataxia. The hypothesis that its present world distribution could result from the spread of an original founder mutation has been raised, both at historical and molecular levels. In the present study, we tested this hypothesis by linkage-disequilibrium analysis of tightly linked polymorphisms and by haplotype comparison, in 249 families from different countries. We typed five microsatellite markers surrounding the MJD1 locus (D14S1015, D14S995, D14S973, D14S1016, and D14S977), and three intragenic single–base-pair polymorphisms (A669TG/G669TG, C987GG/G987GG, and TAA1118/TAC1118). The results show two different haplotypes, specific to the island of origin, in families of Azorean extraction. In families from mainland Portugal, both Azorean haplotypes can be found. The majority of the non-Portuguese families also share the same intragenic haplotype seen in the families coming from the island of Flores, but at least three other haplotypes were seen. These findings suggest two introductions of the mutation into the Portuguese population. Worldwide, the sharing of one intragenic haplotype by the majority of the families studied implies a founder mutation in MJD.

Hereditary Ataxia and Spastic Paraplegia in Portugal: A Population-Based Prevalence Study

Abstract: Importance Epidemiological data on hereditary cerebellar ataxia (HCA) and hereditary spastic paraplegia (HSP) are scarce. Objective To present the prevalence and distribution of HCA and HSP in Portugal. Design and Setting Population-based, nationwide, systematic survey, from January 1, 1994, through April 15, 2004, in Portugal. Participants Multiple sources of information were used (review of clinical files, active collaboration of neurologists and geneticists, and investigation of affected families), but the main source was active collaboration of general practitioners. Patients were examined by the same team of neurologists, using homogeneous inclusion criteria. The clinical data were registered, and all families were genetically tested. Results Overall, 1336 patients from a population of 10 322 million were diagnosed as having HCA or HSP, a prevalence of 12.9 per 100 000 population. Hereditary cerebellar ataxia was more prevalent (prevalence, 8.9 per 100 000 population; 5.6 for dominant and 3.3 for recessive ataxias) than HSP (prevalence, 4.1 per 100 000 population; 2.4 for dominant and 1.6 for recessive). Machado-Joseph disease (spinocerebellar ataxia type 3) (prevalence, 3.1 per 100 000 population), Friedreich ataxia (prevalence, 1.0 per 100 000 population), and ataxia with oculomotor apraxia (prevalence, 0.4 per 100 000 population) were the most frequent HCAs. Spastic paraplegia types 4 (prevalence, 0.91 per 100 000 population), 3 (prevalence, 0.14 per 100 000 population), and 11 (prevalence, 0.26 per 100 000 population) were the most prevalent HSPs. Conclusions and Relevance This population-based survey covered all the Portuguese territory and mobilized most general practitioners and health centers. To our best knowledge, this survey was the largest ever performed for HCA and HSP. Prevalence of autosomal dominant ataxias was high, particularly for Machado-Joseph disease (spinocerebellar ataxia type 3). The genetic cause has not been identified in 39.7% of the patients studied.

Glutamine Repeats and Neurodegeneration

Abstract: A growing number of neurodegenerative diseases have been found to result from the expansion of an unstable trinucleotide repeat. Over the past 6 years, researchers have focused on identifying the mechanism by which the expanded polyglutamine tract renders a protein toxic to a subset of vulnerable neurons. In this review, we summarize the clinicopathologic features of these disorders (spinobulbar muscular atrophy, Huntington disease, and the spinocerebellar ataxias, including dentatorubropallidoluysian atrophy), describe the genes involved and what is known about their products, and discuss the model systems that have lent insight into pathogenesis. The review concludes with a model for pathogenesis that illuminates the unifying features of these polyglutamine disorders. This model may prove relevant to other neurodegenerative disorders as well.

Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis.

Abstract: Summary Autosomal dominant cerebellar ataxias are hereditary neurodegenerative disorders that are known as spinocerebellar ataxias (SCA) in genetic nomenclature. In the pregenomic era, ataxias were some of the most poorly understood neurological disorders; the unravelling of their molecular basis enabled precise diagnosis in vivo and explained many clinical phenomena such as anticipation and variable phenotypes even within one family. However, the discovery of many ataxia genes and loci in the past decade threatens to cause more confusion than optimism among clinicians. Therefore, the provision of guidance for genetic testing according to clinical findings and frequencies of SCA subtypes in different ethnic groups is a major challenge. The identification of ataxia genes raises hope that essential pathogenetic mechanisms causing SCA will become more and more apparent. Elucidation of the pathogenesis of SCA hopefully will enable the development of rational therapies for this group of disorders, which currently can only be treated symptomatically.

Repeat instability: mechanisms of dynamic mutations

Abstract: Disease-causing repeat instability is an important and unique form of mutation that is linked to more than 40 neurological, neurodegenerative and neuromuscular disorders. DNA repeat expansion mutations are dynamic and ongoing within tissues and across generations. The patterns of inherited and tissue-specific instability are determined by both gene-specific cis-elements and trans-acting DNA metabolic proteins. Repeat instability probably involves the formation of unusual DNA structures during DNA replication, repair and recombination. Experimental advances towards explaining the mechanisms of repeat instability have broadened our understanding of this mutational process. They have revealed surprising ways in which metabolic pathways can drive or protect from repeat instability.

An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8)

Abstract: Myotonic dystrophy (DM) is the only disease reported to be caused by a CTG expansion. We now report that a non-coding CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). This expansion, located on chromosome 13q21, was isolated directly from the genomic DNA of an ataxia patient by RAPID cloning. SCA8 patients have expansions similar in size (107-127 CTG repeats) to those found among adult-onset DM patients. SCA8 is the first example of a dominant SCA not caused by a CAG expansion translated as a polyglutamine tract.