Manuela Lima

University of the Azores | UAc · Faculty of Sciences and Technology

Background: Disease severity in spinocerebellar ataxia type 3 (SCA3) is commonly defined by the Scale for the Assessment and Rating of Ataxia (SARA) sum score, but little is known about the contributions and progression patterns of individual items. Objectives: To investigate the temporal dynamics of SARA item scores in SCA3 patients and evaluat...

Background: Clinical trials in SCA3 will require biomarkers for use as outcome measures. Methods: To evaluate total tau (t-tau), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCHL1), and neurofilament light-chain (NfL) as fluid biomarkers in SCA3, ATXN3 mutation carriers (n=143) and controls (n=172) were clinic...

Untranslated regions are involved in the regulation of transcriptional and post-transcriptional processes. Characterization of these regions remains poorly explored for ATXN3, the causative gene of Machado-Joseph disease (MJD). Although a few genetic modifiers have been identified for MJD age at onset (AO), they only explain a small fraction of the...

Machado-Joseph disease (MJD/SCA3) is a neurodegenerative polyglutamine disorder exhibiting a wide spectrum of phenotypes. The abnormal size of the (CAG)n at ATXN3 explains ~55% of the age at onset variance, suggesting the involvement of other factors, namely genetic modifiers, whose identification remains limited. Our aim was to find novel genetic...

Background: Lifestyle could influence the course of hereditary ataxias, but representative data are missing. Objective: The objective of this study was to characterize lifestyle in spinocerebellar ataxia type 3 (SCA3) and investigate possible associations with disease parameters. Methods: In a prospective cohort study, data on smoking, alcohol...

Background: Spinocerebellar ataxia type 3 is a rare neurodegenerative disease caused by a CAG repeat expansion in the ataxin-3 gene. Although no curative therapy is yet available, preclinical gene-silencing approaches to reduce polyglutamine (polyQ) toxicity demonstrate promising results. In view of upcoming clinical trials, quantitative and easil...

Spinocerebellar ataxia type 3 is a rare neurodegenerative disease, caused by a CAG repeat expansion leading to polyglutamine elongation in the ataxin-3 protein. While no curative therapy is yet available, preclinical gene silencing approaches to reduce polyglutamine-toxicity demonstrate promising results. In view of upcoming clinical trials, quanti...

With molecular treatments coming into reach for spinocerebellar ataxia type 3 (SCA3), easily accessible, cross-species validated biomarkers for human and preclinical trials are warranted, particularly for the preataxic disease stage. We assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in ataxic and pr...

Machado-Joseph disease (MJD/SCA3) is the most common form of dominantly inherited ataxia worldwide. The disorder is caused by an expanded CAG repeat in the ATXN3 gene. Past studies have revealed that the length of the expansion partly explains the disease age at onset (AO) variability of MJD, which is confirmed in this study (Pearson's correlation...

Spinocerebellar ataxia type 3 (SCA3) is a devastating multisystemic neurodegenerative disease for which targeted molecular therapies are coming into reach (e.g. antisense oligonucleotides). To pave the way for upcoming translational trials, easily accessible biomarkers in SCA3 are needed, particularly for subjects at the preataxic stage and cross-v...

Machado-Joseph disease (MJD/SCA3) is the most common form of dominantly inherited ataxia worldwide. The disorder is caused by an expanded CAG repeat in the ATXN3 gene. Past studies have revealed that the length of the expansion partly explains the disease age at onset (AO) variability of MJD, which is confirmed in this study. Using a total of 786 M...

Alongside with the emergent clinical trials for Machado-Joseph disease/Spinocerebellar ataxia type 3 (MJD/SCA3) comes the need to identify molecular biomarkers of disease that can be tracked throughout the trial. MJD is an autosomal dominant neurodegenerative disorder caused by expansion of a CAG repeat in the coding region of the ATXN3 gene. Previ...

Molecular alterations reflecting pathophysiologic changes thought to occur many years before the clinical onset of Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3), a late-onset polyglutamine disorder, remain unidentified. The absence of molecular biomarkers hampers clinical trials, which lack sensitive measures of disease progress...

Background Mitochondrial dysfunction has been implicated in the pathogenesis of several neurodegenerative disorders, namely of Machado‐Joseph disease, an autosomal dominant late‐onset polyglutamine ataxia that results from an unstable expansion of a CAG tract in the ATXN3 gene. The size of the CAG tract only partially explains age at onset, highlig...

Hydrothermal areas are potentially hazardous to humans as volcanic gases such as radon ((222)Rn) are continuously released from soil diffuse degassing. Exposure to radon is estimated to be the second leading cause of lung cancer, but little is known about radon health-associated risks in hydrothermal regions. This cross-sectional study was designed...

Objectives Ankylosing spondylitis (AS) is the most prevalent form of spondyloarthritis, with a known genetic association with the HLA-B27 molecule. The aim of this study was to assess the contribution of the HLA-G, HLA-E and HLA-F to AS susceptibility/protection in Portuguese patients with HLA-B27 AS and HLA-B27 unaffected controls. Methods High-r...

With the “mitochondrial Eve” theory proposed by Rebecca Cann in the eighties, human mitochondrial DNA (mtDNA) has been used as a tool in studying human variation and evolution. Although the existence of recombination in human mtDNA has been previously advocated, studies dealing with human variation and evolution have assumed that human mtDNA does n...

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant disease and is caused by an abnormal number of CAG repeats in exon 10 of the ATXN3 gene, located on 14q32.1. Age at onset and severity of the disease is mainly explained by the size of the CAG motifs in the expanded allele. Normal alleles pres...

Whereas spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD) remains an untreatable disorder, disease-modifying compounds have begun being tested in the context of clinical trials; their success is dependent on the sensitivity of the methods used to measure subtle therapeutic benefits. Thus, efforts are being made to propose a battery...

Autophagy is especially important in disorders where accumulation of the mutant protein is a hallmark, such as the Machado-Joseph disease/spinocerebellar ataxia type 3 (MJD/SCA3). We analyzed the promoter of the BECN1 gene, whose overexpression has been reported to exert neuroprotective effects in MJD, with the aim of finding variants that could be...

Age at onset in spinocerebellar ataxia type 3 (SCA3/MJD) is incompletely explained by the size of the CAG tract at the ATXN3 gene, implying the existence of genetic modifiers. A role of inflammation in SCA3 has been postulated, involving altered cytokines levels; promoter variants leading to alterations in cytokines expression could influence onset...

Resumo A doença de Machado-Joseph (DMJ)/ataxia espinocerebelosa do tipo 3 (SCA3) é uma doença neurodegenerativa autossómica dominante de manifestação tardia. A presença da doença faz-se acompanhar, frequentemente, por alterações psicológicas assinaláveis, sobretudo nas fases avançadas. O presente trabalho teve como principal objetivo explorar os ní...

Introduction and Objective Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine (polyQ) disorder for which the routine molecular testing is based on PCR and automated capillary electrophoresis. When only a normal allele is detected by standard PCR, the hypothesis of a failed amplification of the expanded allele must be raised. In such cases, com...

Background Over 30 human diseases are caused by expansion of unstable microsatellite sequences. Nine of these are caused by expanded CAG tracts encoding polyglutamines in different genes. This subgroup of diseases, usually referred to as the polyglutamine diseases which include Huntington’s disease (HD), several spinocerebellar ataxias (SCAs), and...

Spinocerebellar ataxia type 3 (SCA3)/Machado - Joseph disease (MJD) is the most common form of autosomal dominant ataxias worldwide. In Portugal, the epidemiological situation of the Azores Islands, known to be a worldwide cluster for this disorder, needs to be regularly monitored. The present work aims to characterize the epidemiological situation...

OBJECTIVE: The polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not a...

Objective: The polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are amongst the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does no...

The polyglutamine spinocerebellar ataxias (SCAs) constitute a clinically and genetically heterogeneous group of rare late-onset neurodegenerative disorders, caused by CAG expansions in the coding region of the respective genes. Given their considerable clinical overlapping, differential diagnosis relies on molecular testing. Laboratory best practic...

Sir, We read with interest the paper by Tezenas du Montcel and colleagues (2014), which identified modifiers of the age at onset in spinocerebellar ataxias (SCAs). In polyglutamine (polyQ) SCAs, the size of the CAG expansion is incompletely correlated with the age at onset of the disease, suggesting the involvement of additional genetic factors. T...

The autosomal dominant (AD) forms of hereditary ataxias compose a heterogeneous group of diseases, in which cerebellar degeneration and dysfunction is consistently present. Polyglutamine (polyQ) ataxias are a subset of AD ataxias, comprising spinocerebellar ataxias (SCAs) 1, 2, 3, 6, 7 and 17, as well as dentatorubral-pallydoluysian atrophy (DRPLA)...

Machado-Joseph disease (or spinocerebellar ataxia type 3) is a late-onset polyglutamine neurodegenerative disorder caused by a mutation in the ATXN3 gene, which encodes for the ubiquitously expressed protein ataxin-3. Previous studies on cell and animal models have suggested that mutated ataxin-3 is involved in transcriptional dysregulation. Starti...

Familial hypercholesterolemia (FH) is an autosomal dominant disor-der of the cholesterol metabolism, which constitutes a risk factor for coronary arterial disease (CAD). In the Azores Islands (Portugal), where mortality from CAD doubles its rate comparatively to the rest of the country and where a high frequency of dyslipidemia has been reported, t...

Objectives. To investigate the efficacy of infliximab in the treatment of severe calcium pyrophosphate deposition diseases (CPPD). Methods. Two patients with severe CPPD and diffuse idiopathic skeletal hyperostosis- (DISH-) like phenotype are described. Both patients were resistant to therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). Both...

Background and Objectives: Autophagy, as a process of lysosomal-dependent intracellular components degradation, is especially important in disorders where accumulation of the mutant protein is a hallmark, such as Machado-Joseph disease (MJD/SCA3; OMIM 109150), a late onset progressive polyglutamine ataxia, considered the worldwide most common autos...

Mitochondrial dysfunction has been associated with late onset neurodegenerative disorders, among which is Machado-Joseph disease (MJD/SCA3). In a previous study, using a transgenic mouse model of MJD, we reported a decrease in mitochondrial DNA (mtDNA) copy number and an accumulation of the 3876-bp deletion with age and with phenotype development....

Spinocerebellar ataxias (SCAs) represent a clinically, genetically and pa-thologically heterogeneous group of rare hereditary untreatable neurode-generative disorders, which affect the cerebellum and its connections. As far as we known, there are more than 30 subtypes reported in literature. In Europe, it’s estimated that one to three per 100 000 i...

Machado-Joseph disease (MJD; MIM #109150; ORPHA98757), or spinocerebellar ataxia type 3 (SCA3) is a protein misfolding-associated disease, being the worldwide most prevalent autosomal dominant ataxia as well as the second more common polyglutamine (polyQ) disorder. Abnormal conformation of mutated ataxin-3, promotes a gain of a toxic function compr...

Background and Objectives: Autophagy, as a process of intracellular components degradation, is especially important in disorders where accumulation of the mutant protein is a hallmark, such as MJD, a late onset polyglutamine ataxia. We documented the variation in the promoter of the BECN1 gene whose overexpression has been reported to exert neuropr...

Machado-Joseph disease (MJD), also named spinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominant ataxia worldwide. Although nystagmus is one of the most frequently reported ocular alterations in MJD patients its behaviour during the course of the disease, namely in its early stages, has only recently started to be investigated. T...

A significant body of work, accumulated over the years, strongly suggests that damage in mitochondrial DNA (mtDNA) contributes to aging in humans. Contradictory results, however, are reported in the literature, with some studies failing to provide support to this hypothesis. With the purpose of further understanding the aging process, several model...

Objective: The association of non-MHC genes with AS has been recently suggested. We aimed to investigate the association of the ERAP1, IL23R and TNFSF15 regions and the susceptibility to and protection from AS in HLA-B27-positive individuals. Methods: A total of 200 unrelated AS patients and 559 healthy unrelated subjects, all HLA-B27 positive,...

Background: Autophagy is a process of intracellular components degradation, crucial for the management of insoluble aggregate-prone proteins and essential for neuronal survival. Autophagy is thus thought to be especially important in disorders where accumulation of the mutant protein is a hallmark, such as Machado–Joseph disease (MJD), an auto...

In the Azores archipelago the mortality rate for ischemic heart disease, a form of cardiovascular disease (CVD) doubles its rate comparatively to the rest of the country. One of the risk factors underlying CVD is familial hypercholesterolemia (FH), a form of dyslipidemia whose prevalence and distribution in the Azores remains unknown. FH is a...

The present study on long-term outcome of presymptomatic testing for Machado-Joseph disease (MJD) aimed to evaluate the psychological well-being and the familial satisfaction of subjects that 5 years prior received an unfavorable result in the predictive testing (PT). The study included 47 testees of Azorean origin (23 from the island of Flores and...

Hereditary ataxias comprise a clinically and genetically heterogeneous group of rare neurological disorders (prevalence of ~6/100,000). Autosomal dominant forms, known as spinocerebellar ataxias (SCAs), will be the focus of this review. SCAs are characterized by progressive degeneration of the cerebellum and spinocerebellar tracts, associated with...

Background: Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar ataxia caused by a CAG tract expansions in the ATXN3 gene. Patterns of mitochondrial damage associated with pathological findings of brain tissues could provide molecular biomarkers of this disorder. Objective: The potential of mitochondrial DNA (mtDNA) damage as a...

Alternative splicing (AS) of pre-mRNA is an important regulatory mechanism that enables one gene to produce multiple mature transcripts and, therefore, multiple protein isoforms. Besides the information content of core splicing signals, additional cis-regulatory elements (splicing enhancers and silencers) are needed to precisely define exons. AS is...

Heterozygous familial hypercholesterolemia (FH) is an autosomal dominant inherited disorder that affects approximately 1 in 500 individuals worldwide, which makes it one of the most common monogenic pathologies. FH is caused mainly by mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB) and Proprotein convertase subt...

Differences in the presence of diseases, their frequency and associated health outcomes are observed in many world populations. The knowledge relative to the genetic variants underlying diseases, namely the characterization of their distribution in the various populations, as well as the analysis of the factors which control this distribution ar...

Machado-Joseph disease (MJD) is a late-onset autosomal dominant neurodegenerative disorder, which is caused by a coding (CAG)(n) expansion in the ATXN3 gene (14q32.1). The number of CAG repeats in the expanded alleles accounts only for 50 to 75 % of onset variance, the remaining variation being dependent on other factors. Differential allelic expre...

Hereditary ataxias constitute a clinically and genetically heterogeneous group of rare neurological disorders that cannot be distinguished solely by clinical criteria, thus demanding a subtype confirmation by molecular diagnosis. Enclosed in this group are spinocerebellar ataxias (SCAs), which are autosomal dominant disorders. In several SCAs, the...

Machado-Joseph disease/spinocerebellar ataxia type 3 (MJD/SCA3) may rarely presents a parkinsonian phenotype. Considering that mutations in the glucocerebrosidase (GBA) gene have been associated with Parkinson disease, we investigated whether these would be more prevalent in MJD/SCA3 patients with parkinsonian manifestations than in those without t...

Objective: To investigate a modulating effect of the apolipoprotein E (APOE) polymorphism on age at onset of Machado-Joseph disease (MJD). Design: We collected blood samples from 192 patients with MJD and typed the APOE polymorphism. Patients: The 192 patients with MJD included 59 from the Azores, 73 from mainland Portugal, and 60 from Brazil. Sett...

To investigate a modulating effect of the apolipoprotein E (APOE) polymorphism on age at onset of Machado-Joseph disease (MJD). We collected blood samples from 192 patients with MJD and typed the APOE polymorphism. Patients The 192 patients with MJD included 59 from the Azores, 73 from mainland Portugal, and 60 from Brazil. Academic research center...