193 results on '"Iscia Lopes-Cendes"'
Search Results
2. Multi-omics in mesial temporal lobe epilepsy with hippocampal sclerosis: Clues into the underlying mechanisms leading to disease
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Jaqueline C Geraldis, Estela M. Bruxel, Danielle do Carmo Ferreira Bruno, Alexandre B Godoi, Mariana Martin, Amanda Morato do Canto, and Iscia Lopes-Cendes
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Adult ,Adult population ,Disease ,Severe epilepsy ,Hippocampus ,Lesion ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,medicine ,Humans ,Hippocampal sclerosis ,Sclerosis ,business.industry ,General Medicine ,medicine.disease ,Magnetic Resonance Imaging ,nervous system diseases ,Epilepsy, Temporal Lobe ,Neurology ,Multi omics ,Neurology (clinical) ,medicine.symptom ,business ,Neuroscience ,030217 neurology & neurosurgery ,Mesial temporal lobe epilepsy - Abstract
Mesial temporal lobe epilepsy (MTLE) is one of the most common types of focal epilepsy in the adult population. MTLE is frequently associated with a specific histopathological lesion in the medial temporal structures, namely hippocampal sclerosis (HS). A significant proportion of patients with MTLE+HS have severe epilepsy, which is often resistant to clinical treatment. For these patients, surgical resection of the epileptogenic lesion can be performed. Our understanding of the underlying mechanisms leading to MTLE+HS has improved significantly over the past few decades. In this review, we aim to present and discuss the most recent findings regarding the genetic determinants of MTLE+HS. Furthermore, we will address studies about transcriptomics, proteomics, metabolomics, and epigenomic signatures of the tissue that is surgically removed from patients with refractory MTLE+HS and animal models of the disorder. We expect to provide an overview and a critical discussion of the findings, limitations, new approaches, and future directions for multi-omics studies in MTLE+HS.
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- 2021
3. Slowly progressive behavioral frontotemporal dementia syndrome in a family co‐segregating the C9orf 72 expansion and a Synaptophysin mutation
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Joana Prota, Rodrigo Secolin, Paulo Caramelli, Luciana Cardoso Bonadia, Leonardo Cruz de Souza, Iscia Lopes-Cendes, Liara Rizzi, and Marcio Luiz Figueredo Balthazar
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Epidemiology ,Synaptophysin ,medicine.disease_cause ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,C9orf72 ,Intellectual disability ,medicine ,Humans ,Dementia ,Exome sequencing ,Genetics ,Mutation ,DNA Repeat Expansion ,C9orf72 Protein ,biology ,Health Policy ,Amyotrophic Lateral Sclerosis ,Proteins ,medicine.disease ,Psychiatry and Mental health ,Frontotemporal Dementia ,biology.protein ,Neurology (clinical) ,Geriatrics and Gerontology ,Trinucleotide repeat expansion ,Frontotemporal dementia - Abstract
Introduction Synaptophysin, already related to X-linked intellectual disability, is expressed mainly in the central nervous system. Studies in humans indicate that the downregulation of synaptophysin could be involved in the development of dementia. Our study presents the first familial case of behavioral variant frontotemporal dementia associated with the co-occurrence of the repeat expansion in C9orf72 and a pathogenic variant in the SYP gene. Methods Exome sequencing and repeat-primed PCR for C9orf72 were performed for two siblings with clinical and imaging findings suggestive of slowly progressive behavioral frontotemporal dementia. Results We found that both siblings have the hexanucleotide expansion in C9orf72 and a null variant in the SYP gene. The most affected sibling presents the putative variant in a hemizygous state. With milder symptoms, his sister has the same pathogenic variant in heterozygosis, compatible with X-linked inheritance. Discussion Our results strengthened previous suggestive evidence that the phenotypes associated with C9orf72 repeat expansion are variable and probably influenced by additional genetic modifiers. We hypothesized that the pathogenic variant in the SYP gene might have modified the typical phenotype associated with the C9orf72 mutation.
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- 2021
4. Multi‐omics analysis suggests enhanced epileptogenesis in the Cornu Ammonis 3 of the pilocarpine model of mesial temporal lobe epilepsy
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Amanda M Canto, André Schwambach Vieira, Alexandre Hilário Berenguer de Matos, Benilton S. Carvalho, Rovilson Gilioli, Diogo F.T. Veiga, Vinicius D'Ávila Bitencourt Pascoal, Barbara Henning, Alexandre B Godoi, Cristiane S. Rocha, Iscia Lopes-Cendes, Fernando Cendes, and Beatriz Bertelli Aoyama
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Proteomics ,Cognitive Neuroscience ,Hippocampus ,Hippocampal formation ,Biology ,Epileptogenesis ,050105 experimental psychology ,Temporal lobe ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,0501 psychology and cognitive sciences ,Rats, Wistar ,CAMK ,Hippocampal sclerosis ,Dentate gyrus ,05 social sciences ,Pilocarpine ,medicine.disease ,Rats ,Epilepsy, Temporal Lobe ,nervous system ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Mesial temporal lobe epilepsy (MTLE) is a chronic neurological disorder characterized by the occurrence of seizures, and histopathological abnormalities in the mesial temporal lobe structures, mainly hippocampal sclerosis (HS). We used a multi-omics approach to determine the profile of transcript and protein expression in the dorsal and ventral hippocampal dentate gyrus (DG) and Cornu Ammonis 3 (CA3) in an animal model of MTLE induced by pilocarpine. We performed label-free proteomics and RNAseq from laser-microdissected tissue isolated from pilocarpine-induced Wistar rats. We divided the DG and CA3 into dorsal and ventral areas and analyzed them separately. We performed a data integration analysis and evaluated enriched signaling pathways, as well as the integrated networks generated based on the gene ontology processes. Our results indicate differences in the transcriptomic and proteomic profiles among the DG and the CA3 subfields of the hippocampus. Moreover, our data suggest that epileptogenesis is enhanced in the CA3 region when compared to the DG, with most abnormalities in transcript and protein levels occurring in the CA3. Furthermore, our results show that the epileptogenesis in the pilocarpine model involves predominantly abnormal regulation of excitatory neuronal mechanisms mediated by N-methyl D-aspartate (NMDA) receptors, changes in the serotonin signaling, and neuronal activity controlled by calcium/calmodulin-dependent protein kinase (CaMK) regulation and leucine-rich repeat kinase 2 (LRRK2)/WNT signaling pathways.
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- 2020
5. Transcriptomic analysis of dorsal and ventral subiculum after induction of acute seizures by electric stimulation of the perforant pathway in rats
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Schwambach Vieira A, Elayne Vieira Dias, Gabriel Gerardini Zanetti, Beatriz Bertelli Aoyama, Maria Carolina Pedro Athie, and Iscia Lopes-Cendes
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Hippocampal sclerosis ,Perforant Pathway ,Cognitive Neuroscience ,Subiculum ,Hippocampus ,Stimulation ,Status epilepticus ,Hippocampal formation ,Biology ,medicine.disease ,Electric Stimulation ,Astrogliosis ,Rats ,Seizures ,medicine ,Animals ,medicine.symptom ,Transcriptome ,Neuroscience - Abstract
Preconditioning is a mechanism in which injuries induced by non-lethal hypoxia or seizures trigger cellular resistance to subsequent events. Norwood et al., in a 2010 study, showed that an 8-hour-long period of electrical stimulation of the perforant pathway in rats is required for the induction of hippocampal sclerosis. However, in order to avoid generalized seizures, status epilepticus (SE), and death, a state of resistance to seizures must be induced in the hippocampus by a preconditioning paradigm consisting of 2 daily 30-minute stimulation periods. Due to the importance of the subiculum in the hippocampal formation, this study aims to investigate differential gene expression patterns in the dorsal and ventral subiculum using RNA-sequencing, after induction of a preconditioning protocol by electrical stimulation of the perforant pathway. The dorsal (dSub) and ventral (vSub) subiculum regions were collected by laser-microdissection 24 hours after preconditioning protocol induction in rats. RNA sequencing was performed in a Hiseq 4000 platform, reads were aligned using the STAR and DESEq2 statistics package was used to estimate gene expression. We identified 1176 differentially expressed genes comparing control to preconditioned subiculum regions, 204 genes were differentially expressed in dSub and 972 in vSub. The gene ontology enrichment analysis showed that the most significant common enrichment pathway considering up-regulated genes in dSub and vSub was Cholesterol Biosynthesis. In contrast, the most significant enrichment pathway considering down-regulated genes in vSub was Axon guidance. Our results indicate that preconditioning induces synaptic reorganization, increased cholesterol metabolism, and astrogliosis in both dSub and vSub. Both regions also presented a decrease in glutamatergic transmission, an increase in complement system activation, and increased in GABAergic transmission. The down-regulation of proapoptotic and axon guidance genes in the ventral subiculum suggests that preconditioning induces a neuroprotective environment in this region.
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- 2022
6. The Machado–Joseph disease‐associated form of ataxin‐3 impacts dynamics of clathrin‐coated pits
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Luciana K. Rosselli-Murai, Allen P. Liu, Iscia Lopes-Cendes, Marcelo J. Murai, and Jophin G. Joseph
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0301 basic medicine ,media_common.quotation_subject ,Protein aggregation ,Endocytosis ,Protein Aggregation, Pathological ,Clathrin ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Ataxin-3 ,Internalization ,Receptor ,media_common ,biology ,Chemistry ,Neurodegeneration ,Coated Pits, Cell-Membrane ,Machado-Joseph Disease ,Cell Biology ,General Medicine ,medicine.disease ,Cell biology ,Repressor Proteins ,030104 developmental biology ,030220 oncology & carcinogenesis ,Ataxin ,biology.protein ,Peptides ,Machado–Joseph disease - Abstract
Expansion above a certain threshold in the polyglutamine (polyQ) tract of ataxin-3 is the main cause of neurodegeneration in Machado-Joseph disease. Ataxin-3 contains an N-terminal catalytic domain, called Josephin domain, and a highly aggregation-prone C-terminal domain containing the polyQ tract. Recent work has shown that protein aggregation inhibits clathrin-mediated endocytosis (CME). However, the effects of polyQ expansion in ataxin-3 on CME have not been investigated. We hypothesize that the expansion of the polyQ tract in ataxin-3 could impact CME. Here, we report that both the wild-type and the expanded ataxin-3 reduce transferrin internalization and expanded ataxin-3 impacts dynamics of clathrin-coated pits (CCPs) by reducing CCP nucleation and increasing short-lived abortive CCPs. Since endocytosis plays a central role in regulating receptor uptake and cargo release, our work highlights a potential mechanism linking protein aggregation to cellular dysregulation.
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- 2020
7. Epigenetics explained: a topic 'primer' for the epilepsy community by the ILAE Genetics/Epigenetics Task Force
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Albert J. Becker, Alica M. Goldman, Erwin A. van Vliet, Annapurna Poduri, Gemma L. Carvill, Iscia Lopes-Cendes, Shinichi Hirose, Marvin Johnson, Christopher A. Reid, Hela Mrabet Khiari, David C. Henshall, Katja Kobow, Cellular and Computational Neuroscience (SILS, FNWI), Pathology, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, APH - Aging & Later Life, and APH - Mental Health
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Glossary ,non-coding RNA ,chromatin remodelling ,Chromatin remodelling ,Epigenesis, Genetic ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,medicine ,Humans ,Epigenetics ,Genetics ,DNA methylation ,histone modifications ,Task force ,Disease mechanisms ,General Medicine ,medicine.disease ,Neurology ,epileptogenesis ,Neurology (clinical) ,Societies ,Psychology ,International league against epilepsy ,030217 neurology & neurosurgery - Abstract
Epigenetics refers broadly to processes that influence medium to long-term gene expression by changing the readability and accessibility of the genetic code. The Neurobiology Commission of the International League Against Epilepsy (ILAE) recently convened a Task Force to explore and disseminate advances in epigenetics to better understand their role and intersection with genetics and the neurobiology of epilepsies and their co-morbidities, and to accelerate translation of these findings into the development of better therapies. Here, we provide a topic primer on epigenetics, explaining the key processes and findings to date in experimental and human epilepsy. We review the growing list of genes with epigenetic functions that have been linked with epilepsy in humans. We consider potential practical applications, including using epigenetic signals as biomarkers for tissue- and biofluid-based diagnostics and the prospects for developing epigenetic-based treatments for epilepsy. We include a glossary of terms, FAQs and other supports to facilitate a broad understanding of the topic for the non-expert. Last, we review the limitations, research gaps and the next challenges. In summary, epigenetic processes represent important mechanisms controlling the activity of genes, providing opportunities for insight into disease mechanisms, biomarkers and novel therapies for epilepsy.
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- 2020
8. Genome-wide association study identifies genetic factors that modify age at onset in Machado-Joseph disease
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Patrick A. Dion, Marcondes C. França, Sandra Martins, Laura Bannach Jardim, Fulya Akçimen, Mafalda Raposo, Cynthia V. Bourassa, Hélène Catoire, Guy A. Rouleau, Olaf Riess, Iscia Lopes-Cendes, Jorge Sequeiros, Maria Luiza Saraiva-Pereira, Garth A. Nicholson, João Vasconcelos, Calwing Liao, Manuela Lima, and Instituto de Investigação e Inovação em Saúde
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Adult ,Male ,0301 basic medicine ,Cag expansion ,congenital, hereditary, and neonatal diseases and abnormalities ,Aging ,Ataxia ,DNA repair ,Machado-Joseph disease ,Genome-wide association study ,Repressor Proteins / genetics ,Disease ,Biology ,Polymorphism, Single Nucleotide ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,medicine ,GWAS ,Humans ,Age of Onset ,Ataxin-3 ,Gene ,Genetics ,modifier ,Machado-Joseph Disease / epidemiology ,ATXN3 ,Cell Biology ,Machado-Joseph Disease / genetics ,medicine.disease ,Repressor Proteins ,030104 developmental biology ,Ataxin-3 / genetics ,Female ,medicine.symptom ,age at onset ,Machado–Joseph disease ,030217 neurology & neurosurgery ,Research Paper ,Genome-Wide Association Study - Abstract
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 coefficient R2 = 0.62). Using a total of 786 MJD patients from five different geographical origins, a genome-wide association study (GWAS) was conducted to identify additional AO modifying factors that could explain some of the residual AO variability. We identified nine suggestively associated loci (P < 1 × 10-5). These loci were enriched for genes involved in vesicle transport, olfactory signaling, and synaptic pathways. Furthermore, associations between AO and the TRIM29 and RAG genes suggests that DNA repair mechanisms might be implicated in MJD pathogenesis. Our study demonstrates the existence of several additional genetic factors, along with CAG expansion, that may lead to a better understanding of the genotype-phenotype correlation in MJD. FA and CL were funded by the Fonds de Recherche du Québec–Santé. SM is funded by FCT (CEECIND/00684/2017) and by NORTE-01-0145- FEDER-000008, supported by Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). FM and LI are funded by Fundaçao de Amparo a Pesquisa do Estado de São Paulo (FAPESP, 2013/07559-3). MLSP and LBJ were funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil (CNPq) and by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). GAR holds a Canada Research Chair in Genetics of the Nervous System and the Wilder Penfield Chair in Neurosciences.
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- 2020
9. Multi-omic strategies applied to the study of pharmacoresistance in mesial temporal lobe epilepsy
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Iscia Lopes-Cendes, Amanda Morato do Canto, Danielle do Carmo Ferreira Bruno, Jaqueline C Geraldis, and Estela M. Bruxel
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Adult ,Hippocampal sclerosis ,Epilepsy ,Sclerosis ,business.industry ,Mental Disorders ,Disease ,medicine.disease ,Omics ,Response to treatment ,Hippocampus ,nervous system diseases ,Neurology ,Epilepsy, Temporal Lobe ,Pharmacogenomics ,Medicine ,Multifactorial Inheritance ,Humans ,Neurology (clinical) ,business ,Neuroscience ,Mesial temporal lobe epilepsy - Abstract
Mesial temporal lobe epilepsy (MTLE) is the most common type of focal epilepsy in adults, and hippocampal sclerosis (HS) is a frequent histopathological feature in patients with MTLE. Pharmacoresistance is present in at least one third of patients with MTLE with HS (MTLE+HS). Several hypotheses have been proposed to explain the mechanisms of pharmacoresistance in epilepsy, including the effect of genetic and molecular factors. In recent years, the increased knowledge generated by high-throughput omic technologies has significantly improved the power of molecular genetic studies to discover new mechanisms leading to disease and response to treatment. In this review, we present and discuss the contribution of different omic modalities to understand the basic mechanisms determining pharmacoresistance in patients with MTLE+HS. We provide an overview and a critical discussion of the findings, limitations, new approaches, and future directions of these studies to improve the understanding of pharmacoresistance in MTLE+HS. However, it is important to point out that, as with other complex traits, pharmacoresistance to anti-seizure medications is likely a multifactorial condition in which gene-gene and gene-environment interactions play an important role. Thus, studies using multidimensional approaches are more likely to unravel these intricate biological processes.
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- 2021
10. Multidimensional Approach Assessing the Role of Interleukin 1 Beta in Mesial Temporal Lobe Epilepsy
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Renato O. Santos, Rodrigo Secolin, Patrícia G. Barbalho, Mariana S. Silva-Alves, Marina K. M. Alvim, Clarissa L. Yasuda, Fábio Rogerio, Tonicarlo R. Velasco, Americo C. Sakamoto, Antonio L. Teixeira, Fernando Cendes, Claudia V. Maurer-Morelli, and Iscia Lopes-Cendes
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,mesial temporal sclerosis ,Autopsy ,Single-nucleotide polymorphism ,Hippocampal formation ,association study ,neuroinflammation ,03 medical and health sciences ,0302 clinical medicine ,hippocampal atrophy ,Gene expression ,medicine ,RC346-429 ,Beta (finance) ,Neuroinflammation ,Genetic association ,Original Research ,Hippocampal sclerosis ,business.industry ,medicine.disease ,nervous system diseases ,030104 developmental biology ,Neurology ,gene expression ,Neurology. Diseases of the nervous system ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
We aimed to investigate the role of interleukin-1 beta (IL-1β) in the mechanisms underlying mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE+HS). We assessed a cohort of 194 patients with MTLE+HS and 199 healthy controls. Patients were divided into those with positive and negative antecedent febrile seizures (FS). We used a multidimensional approach, including (i) genetic association with single nucleotide polymorphisms (SNPs) in the IL1B gene; (ii) quantification of the IL1B transcript in the hippocampal tissue of patients with refractory seizures; and (iii) quantification of the IL-1β protein in the plasma. We found a genetic association signal for two SNPs, rs2708928 and rs3730364*C in the IL1B gene, regardless of the presence of FS (adjusted p = 9.62e–11 and 5.14e–07, respectively). We found no difference between IL1B transcript levels when comparing sclerotic hippocampal tissue from patients with MTLE+HS, without FS, and hippocampi from autopsy controls (p > 0.05). Nevertheless, we found increased IL-1β in the plasma of patients with MTLE+HS with FS compared with controls (p = 0.0195). Our results support the hypothesis of a genetic association between MTLE+HS and the IL1B gene
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- 2021
11. Association Analysis of Candidate Variants in Admixed Brazilian Patients With Genetic Generalized Epilepsies
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Felipe S. Kaibara, Tânia K. de Araujo, Patricia A. O. R. A. Araujo, Marina K. M. Alvim, Clarissa L. Yasuda, Fernando Cendes, Iscia Lopes-Cendes, and Rodrigo Secolin
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0301 basic medicine ,admixed population ,population genomics ,QH426-470 ,Biology ,Juvenile Absence Epilepsy ,03 medical and health sciences ,0302 clinical medicine ,Childhood absence epilepsy ,Genetics ,medicine ,genetic generalized epilepsies ,Genetics (clinical) ,Original Research ,Genetic association ,neurology ,Jeavons syndrome ,medicine.disease ,Minor allele frequency ,030104 developmental biology ,association studies ,Epilepsy syndromes ,Molecular Medicine ,Juvenile myoclonic epilepsy ,030217 neurology & neurosurgery ,SNP array - Abstract
Genetic generalized epilepsies (GGEs) include well-established epilepsy syndromes with generalized onset seizures: childhood absence epilepsy, juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), myoclonic absence epilepsy, epilepsy with eyelid myoclonia (Jeavons syndrome), generalized tonic–clonic seizures, and generalized tonic–clonic seizures alone. Genome-wide association studies (GWASs) and exome sequencing have identified 48 single-nucleotide polymorphisms (SNPs) associated with GGE. However, these studies were mainly based on non-admixed, European, and Asian populations. Thus, it remains unclear whether these results apply to patients of other origins. This study aims to evaluate whether these previous results could be replicated in a cohort of admixed Brazilian patients with GGE. We obtained SNP-array data from 87 patients with GGE, compared with 340 controls from the BIPMed public dataset. We could directly access genotypes of 17 candidate SNPs, available in the SNP array, and the remaining 31 SNPs were imputed using the BEAGLE v5.1 software. We performed an association test by logistic regression analysis, including the first five principal components as covariates. Furthermore, to expand the analysis of the candidate regions, we also interrogated 14,047 SNPs that flank the candidate SNPs (1 Mb). The statistical power was evaluated in terms of odds ratio and minor allele frequency (MAF) by the genpwr package. Differences in SNP frequencies between Brazilian and Europeans, sub-Saharan African, and Native Americans were evaluated by a two-proportion Z-test. We identified nine flanking SNPs, located on eight candidate regions, which presented association signals that passed the Bonferroni correction (rs12726617; rs9428842; rs1915992; rs1464634; rs6459526; rs2510087; rs9551042; rs9888879; and rs8133217; p-values –06). In addition, the two-proportion Z-test indicates that the lack of association of the remaining candidate SNPs could be due to different genomic backgrounds observed in admixed Brazilians. This is the first time that candidate SNPs for GGE are analyzed in an admixed Brazilian population, and we could successfully replicate the association signals in eight candidate regions. In addition, our results provide new insights on how we can account for population structure to improve risk stratification estimation in admixed individuals.
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- 2021
12. Inflammatory and neurotrophic factor plasma levels are related to epilepsy independently of etiology
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Mateus Henrique Nogueira, Luciana Ramalho Pimentel-Silva, Natalia Pessoa Rocha, Fernando Cendes, Marina K. M. Alvim, Érica Leandro Marciano Vieira, Iscia Lopes-Cendes, Marcia Morita-Sherman, Antônio Lúcio Teixeira, Renata Barbosa, Ana Carolina Coan, Clarissa L. Yasuda, and Nancy Watanabe
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medicine.medical_specialty ,Inflammation ,Ciliary neurotrophic factor ,Epileptogenesis ,Epilepsy ,Interferon-gamma ,Neurotrophic factors ,Seizures ,Internal medicine ,Nerve Growth Factor ,medicine ,Glial cell line-derived neurotrophic factor ,Humans ,Ciliary Neurotrophic Factor ,Glial Cell Line-Derived Neurotrophic Factor ,biology ,business.industry ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Brain-Derived Neurotrophic Factor ,Interleukin-17 ,medicine.disease ,Interleukin-10 ,Endocrinology ,Nerve growth factor ,Neurology ,biology.protein ,Cytokines ,Interleukin-2 ,Neurology (clinical) ,Interleukin-4 ,medicine.symptom ,business ,Neurotrophin - Abstract
OBJECTIVE Inflammation plays an essential role in epilepsy. Studies indicate that cytokines and neurotrophic factors can act in neuroexcitability and epileptogenesis. We aimed to investigate the association between plasma inflammatory and neurotrophic markers, seizure frequency, and chronic epilepsy subtypes. METHODS We studied 446 patients with epilepsy and 166 healthy controls. We classified patients according to etiology and seizure frequency. We measured plasma levels of interleukin-1 (IL-1), IL-2, IL-4, IL-6, IL-10, IL-17, interferon-γ (IFNγ), tumor necrosis factor α (TNFα), soluble TNF receptor 1 (sTNFr1), sTNFr2, brain-derived neurotrophic factor (BDNF), neurotrophic factor 3 (NT3), NT4/5, ciliary neurotrophic factor (CNTF), nerve growth factor (NGF), and glial cell line-derived neurotrophic factor (GDNF) by enzyme-linked immunosorbent assay or cytometric bead array. RESULTS The plasma levels of BDNF, NT3, NGF, and sTNFr2 were higher, whereas IL-2, IL-4, IL-6, IL-10, IL-17, IFNγ, TNFα, CNTF, and sTNFr1 were lower in patients than controls. IL1, GDNF, and NT4/5 were similar between groups. These markers did not correlate with age, sex, and epilepsy duration. The molecule sTNFr2 was the best marker to discriminate patients from controls (area under the curve = .857), also differing between patients with frequent and infrequent seizures. SIGNIFICANCE This large cohort confirmed that patients with epilepsy have abnormal levels of plasma inflammatory and neurotrophic markers independent of the underlying etiology. Plasma level of sTNFr2 was related to seizure frequency and discriminated people with or without epilepsy with good accuracy, making it a potential biomarker for epilepsy and seizure burden.
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- 2021
13. Whole-exome sequencing indicates FLG2 variant associated with leg ulcers in Brazilian sickle cell anemia patients
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Fernando Ferreira Costa, Aderson S Araujo, Sara Teresinha Olalla Saad, Igor de Farias Domingos, Mônica Barbosa de Melo, Iscia Lopes-Cendes, Diego Arruda Falcão, Mirta Tomie Ito, Bruno Batista de Souza, Marcos André Cavalcanti Bezerra, Murilo Guimarães Borges, Sueli Matilde da Silva-Costa, Galina Ananina, Gabriela Queila de Carvalho-Siqueira, Marilda Souza Goncalves, and Antonio R. Lucena-Araujo
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0301 basic medicine ,medicine.medical_specialty ,Bioinformatics analysis ,business.industry ,Disease ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,Sickle cell anemia ,Pathogenesis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Quality of life ,030220 oncology & carcinogenesis ,Internal medicine ,Cohort ,medicine ,Complication ,business ,Exome sequencing - Abstract
Although sickle cell anemia results from homozygosity for a single mutation at position 7 of the β-globin chain, the clinical aspects of this condition are very heterogeneous. Complications include leg ulcers, which have a negative impact on patients’ quality of life and are related to the severity of the disease. Nevertheless, the complex pathogenesis of this complication has yet to be elucidated. To identify novel genes associated with leg ulcers in sickle cell anemia, we performed whole-exome sequencing of extreme phenotypes in a sample of Brazilian sickle cell anemia patients and validated our findings in another sample. Our discovery cohort consisted of 40 unrelated sickle cell anemia patients selected based on extreme phenotypes: 20 patients without leg ulcers, aged from 40 to 61 years, and 20 with chronic leg ulcers. DNA was extracted from peripheral blood leukocytes and used for whole-exome sequencing. After the bioinformatics analysis, eight variants were selected for validation by Sanger sequencing and TaqMan® genotyping in 293 sickle cell anemia patients (153 without leg ulcers) from two different locations in Brazil. After the validation, Fisher’s exact test revealed a statistically significant difference in a stop codon variant (rs12568784 G/T) in the FLG2 gene between the GT and GG genotypes ( P = 0.035). We highlight the importance of rs12568784 in leg ulcer development as this variant of the FLG2 gene results in impairment of the skin barrier, predisposing the individual to inflammation and infection. Additionally, we suggest that the remaining seven variants and the genes in which they occur could be strong candidates for leg ulcers in sickle cell anemia. Impact statement To our knowledge, the present study is the first to use whole-exome sequencing based on extreme phenotypes to identify new candidate genes associated with leg ulcers in sickle cell anemia patients. There are few studies about this complication; the pathogenesis remains complex and has yet to be fully elucidated. We identified interesting associations in genes never related with this complication to our knowledge, especially the variant in the FLG2 gene. The knowledge of variants related with leg ulcer in sickle cell anemia may lead to a better comprehension of the disease’s etiology, allowing prevention and early treatment options in risk genotypes while improving quality of life for these patients.
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- 2019
14. ATP Synthase Subunit Beta Immunostaining is Reduced in the Sclerotic Hippocampus of Epilepsy Patients
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Amanda Morato do Canto, André Schwambach Vieira, Bruna Cunha Zaidan, Enrico Ghizoni, Marcelo Vilas Boas Mota, Fernando Cendes, Marina K. M. Alvim, Helder Tedeschi, Fabio Rogerio, André Almeida Schenka, Iscia Lopes-Cendes, and Luciano de Souza Queiroz
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Adult ,Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Adolescent ,ATP5B ,Cell Count ,Hippocampal formation ,Hippocampus ,Temporal lobe ,Young Adult ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Epilepsy ,0302 clinical medicine ,medicine ,Humans ,Neurons ,Hippocampal sclerosis ,Sclerosis ,biology ,business.industry ,Dentate gyrus ,Cell Biology ,General Medicine ,Middle Aged ,Mitochondrial Proton-Translocating ATPases ,medicine.disease ,Immunohistochemistry ,030104 developmental biology ,nervous system ,Dentate Gyrus ,biology.protein ,Female ,Sodium-Potassium-Exchanging ATPase ,business ,030217 neurology & neurosurgery ,Immunostaining ,ATP synthase alpha/beta subunits - Abstract
Epilepsy is a common disease presenting with recurrent seizures. Hippocampal sclerosis (HS) is the commonest histopathological alteration in patients with temporal lobe epilepsy (TLE) undergoing surgery. HS physiopathogenesis is debatable. We have recently studied, by using mass spectrometry-based proteomics, an experimental model of TLE induced by electrical stimulation. Specifically, protein expressions of both the beta subunit of mitochondrial ATP synthase (ATP5B) and of membrane ATPases were found to be reduced. Here, we investigated tissue distribution of ATP5B and sodium/potassium-transporting ATPase subunit alpha-3 (NKAα3), a protein associated with neuromuscular excitability disorders, in human hippocampi resected "en bloc" for HS treatment (n = 15). We used immunohistochemistry and the stained area was digitally evaluated (increase in binary contrast of microscopic fields) in the hippocampal sectors (CA1-CA4) and dentate gyrus. All HS samples were classified as Type 1, according to the International League Against Epilepsy (ILAE) 2013 Classification (predominant cell loss in CA1 and CA4). ATP5B was significantly decreased in all sectors and dentate gyrus of HS patients compared with individuals submitted to necropsy and without history of neurological alterations (n = 10). NKAα3 expression showed no difference. Moreover, we identified a negative correlation between frequency of pre-operative seizures and number of neurons in CA1. In conclusion, our data showed similarity between changes in protein expression in a model of TLE and individuals with HS. ATP5B reduction would be at least in part due to neuronal loss. Future investigations on ATP5B activity could provide insights into the process of such cell loss.
- Published
- 2018
15. The Machado-Joseph disease-associated expanded form of ataxin-3: Overexpression, purification, and preliminary biophysical and structural characterization
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Iris L. Torriani, Maria Cimelia Garcia, Luciana K. Rosselli-Murai, Cristiano L. P. Oliveira, Miriam G.G. Contessotto, Iscia Lopes-Cendes, and Marcelo J. Murai
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Models, Molecular ,0301 basic medicine ,Protein Folding ,Thermal shift assay ,Melting temperature ,Genetic Vectors ,Size-exclusion chromatography ,Gene Expression ,Protein Structure, Secondary ,Deubiquitinating enzyme ,03 medical and health sciences ,0302 clinical medicine ,Protein Domains ,X-Ray Diffraction ,Scattering, Small Angle ,Escherichia coli ,medicine ,Humans ,Cloning, Molecular ,Ataxin-3 ,biology ,Small-angle X-ray scattering ,Chemistry ,Machado-Joseph Disease ,medicine.disease ,Recombinant Proteins ,Cell biology ,Repressor Proteins ,030104 developmental biology ,Ataxin ,Chromatography, Gel ,Leukocytes, Mononuclear ,biology.protein ,Peptides ,Machado–Joseph disease ,030217 neurology & neurosurgery ,Biotechnology - Abstract
An expansion of the polyglutamine (polyQ) tract within the deubiquitinase ataxin-3 protein is believed to play a role in a neurodegenerative disorder. Ataxin-3 contains a Josephin catalytic domain and a polyQ tract that renders it intrinsically prone to aggregate, and thus full-length protein is difficult to characterize structurally by high-resolution methods. We established a robust protocol for expression and purification of wild-type and expanded ataxin-3, presenting 19Q and 74Q, respectively. Both proteins are monodisperse as assessed by analytical size exclusion chromatography. Initial biophysical characterization was performed, with apparent transition melting temperature of expanded ataxin-3 lower than the wild-type counterpart. We further characterize the molecular envelope of wild-type and expanded polyQ tract in ataxin-3 using small angle X-ray scattering (SAXS). Characterization of protein-protein interactions between ataxin-3 and newly identified binding partners will benefit from our protocol.
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- 2018
16. SPG11-related parkinsonism: Clinical profile, molecular imaging and <scp>l</scp> -dopa response
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Celso Dario Ramos, Ingrid Faber, Joseph H. Friedman, Charles Marques Lourenço, Juliana Pasquotto Souza, Wilson Marques, Orlando Graziani Povoas Barsottini, Celeste Montecchiani, Bárbara Juarez Amorim, Carlos Roberto Martins, José Luiz Pedroso, Marcondes C. França, Maidane Luise Maia, Iscia Lopes-Cendes, Alberto R. M. Martinez, and Antonio Orlacchio
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0301 basic medicine ,medicine.medical_specialty ,Hereditary spastic paraplegia ,Degeneration (medical) ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Postsynaptic potential ,Internal medicine ,medicine ,Dopamine transporter ,medicine.diagnostic_test ,biology ,business.industry ,Parkinsonism ,Dopaminergic ,medicine.disease ,nervous system diseases ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,Dopaminergic pathways ,biology.protein ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Emission computed tomography - Abstract
Background Molecular imaging has proven to be a powerful tool to elucidate degenerated paths in a wide variety of neurological diseases and has not been systematically studied in hereditary spastic paraplegias. Objectives To investigate dopaminergic degeneration in a cohort of 22 patients with hereditary spastic paraplegia attributed to SPG11 mutations and evaluate treatment response to l-dopa. Methods Patients and controls underwent single-photon emission computed tomography imaging utilizing 99m Tc-TRODAT-1 tracer. A single-blind trial with 600 mg of l-dopa was performed comparing UPDRS scores. Results Reduced dopamine transporter density was universal among patients. Nigral degeneration was symmetrical and correlated with disease duration and motor and cognitive handicap. No statistically significant benefit could be demonstrated with l-dopa intake during the trial. Conclusion Disruption of presynaptic dopaminergic pathways is a widespread phenomenon in patients with SPG11 mutations, even in the absence of parkinsonism. Unresponsiveness to treatment could be related to postsynaptic damage that needs to be further investigated.
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- 2018
17. Neuroproteomics in Epilepsy: What Do We Know so Far?
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Amanda M. do Canto, Amanda Donatti, Jaqueline C. Geraldis, Alexandre B. Godoi, Douglas C. da Rosa, and Iscia Lopes-Cendes
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0301 basic medicine ,mesial temporal lobe epilepsy ,Clinical manifestation ,Review ,Affect (psychology) ,Epileptogenesis ,Social burden ,lcsh:RC321-571 ,03 medical and health sciences ,Epilepsy ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,proteomics ,medicine ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Molecular Biology ,seizures ,Hippocampal sclerosis ,business.industry ,malformations of cortical development ,medicine.disease ,Brain region ,030104 developmental biology ,Neuroproteomics ,hippocampal sclerosis ,epileptogenesis ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Epilepsies are chronic neurological diseases that affect approximately 2% of the world population. In addition to being one of the most frequent neurological disorders, treatment for patients with epilepsy remains a challenge, because a proportion of patients do not respond to the antiseizure medications that are currently available. This results in a severe economic and social burden for patients, families, and the healthcare system. A characteristic common to all forms of epilepsy is the occurrence of epileptic seizures that are caused by abnormal neuronal discharges, leading to a clinical manifestation that is dependent on the affected brain region. It is generally accepted that an imbalance between neuronal excitation and inhibition generates the synchronic electrical activity leading to seizures. However, it is still unclear how a normal neural circuit becomes susceptible to the generation of seizures or how epileptogenesis is induced. Herein, we review the results of recent proteomic studies applied to investigate the underlying mechanisms leading to epilepsies and how these findings may impact research and treatment for these disorders.
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- 2021
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18. Is Ataxia an Underestimated Symptom of Huntingtons Disease?
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Francisco M.B. Germiniani, A. C. Oliveira, Orlando Graziani Povoas Barsottini, Pedro Manzke de Carvalho, Marcondes C. França, Fernanda Aparecida Maggi, Carlos Henrique Ferreira Camargo, Luiza Piovesana, Rachel Guimaraes, Paula Azevedo, Hélio A.G. Teive, Iscia Lopes-Cendes, Barbara Braga, Salmo Raskin, Alex Tiburtino Meira, José Luiz Pedroso, Nayra S. C. Lima, Gustavo L. Franklin, Laura Cristina Souza, Vitor Tumas, Alberto R. M. Martinez, Giovana Memari Pavanelli, and Sibele Sauzem Milano
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0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Cerebellum ,Pediatrics ,medicine.medical_specialty ,Ataxia ,cerebellum ,Huntington (disease) ,Disease ,polyglutamine (polyQ) diseases ,lcsh:RC346-429 ,03 medical and health sciences ,0302 clinical medicine ,Huntington's disease ,Severity of illness ,medicine ,chorea ,lcsh:Neurology. Diseases of the nervous system ,Cognitive deficit ,Cerebellar ataxia ,business.industry ,ataxia ,Chorea ,Brief Research Report ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Background: Huntington's disease (HD) is a progressive disorder characterized by motor, cognitive and psychiatric features. Cerebellar ataxia is classically considered as uncommon in HD clinical spectrum. Objective: To determine the prevalence of cerebellar ataxia in patients with HD, both in the early and in the late stages of HD. Methods: Seventy-two individuals considered eligible were assessed by two trained doctors, applying the Scale for Assessment and Rating of Ataxia (SARA) and Brief Ataxia Rating Scale (BARS) for ataxia, the Unified Huntington's Disease Rating Scale (UHDRS) and also, Barthel Index (BI), in order to evaluate functional capacity. Results: Fifty-one patients (70.8%) presented with clinical ataxia at the time of examination (mean time of disease was 9.1 years). Six (8.33%) patients presented with cerebellar ataxia as first symptom. When stratified according to time of disease, a decline in the presence of chorea (p = 0.032) and an increase in cognitive deficit (p = 0.023) were observed in the patients as the disease progressed. The presence of ataxia was associated with longer duration of illness and severity of illness (UHDRS) (p < 0.0001), and shorter Barthel (less functionality) (p = 0.001). Conclusions: Cerebellar involvement may play an important role in natural history of brain degeneration in HD. The presence of cerebellar ataxia in HD is relevant and it may occur even in early stages, and should be included as part of the motor features of the disease.
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- 2020
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19. Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy
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Schijven, D., Stevelink, R., Mccormack, M., van Rheenen, W., Luykx, J. J., Koeleman, B. P. C., Veldink, J. H., Aleksey, Shatunov, Mclaughlin, Russell L., van der Spek, Rick A. A., Alfredo, Iacoangeli, Kenna, Kevin P., van Eijk, Kristel R., Nicola, Ticozzi, Boris, Rogelj, Katarina, Vrabec, Metka, Ravnik-Glavač, Blaž, Koritnik, Janez, Zidar, Lea, Leonardis, Leja Dolenc Grošelj, Stéphanie, Millecamps, François, Salachas, Vincent, Meininger, Mamede de Carvalho, Susana, Pinto, Marta, Gromicho, Ana, Pronto-Laborinho, Mora, Jesus S., Ricardo, Rojas-García, Meraida, Polak, Siddharthan, Chandran, Shuna, Colville, Robert, Swingler, Morrison, Karen E., Shaw, Pamela J., John, Hardy, Orrell, Richard W., Alan, Pittman, Katie, Sidle, Pietro, Fratta, Andrea, Malaspina, Simon, Topp, Susanne, Petri, Susanna, Abdulla, Carsten, Drepper, Michael, Sendtner, Thomas, Meyer, Ophoff, Roel A., Staats, Kim A., Martina, Wiedau-Pazos, Catherine, Lomen-Hoerth, Van Deerlin, Vivianna M., Trojanowski, John Q., Lauren, Elman, Leo, Mccluskey, Nazli Basak, A., Thomas, Meitinger, Peter, Lichtner, Milena, Blagojevic-Radivojkov, Andres, Christian R., Gilbert, Bensimon, Bernhard, Landwehrmeyer, Alexis, Brice, Payan, Christine A. M., Safaa, Saker-Delye, Alexandra, Dürr, Wood, Nicholas W., Lukas, Tittmann, Wolfgang, Lieb, Andre, Franke, Marcella, Rietschel, Sven, Cichon, Nöthen, Markus M., Philippe, Amouyel, Christophe, Tzourio, Jean-François, Dartigues, Uitterlinden, Andre G., Fernando, Rivadeneira, Karol, Estrada, Albert, Hofman, Charles, Curtis, van der Kooi, Anneke J., Markus, Weber, Shaw, Christopher E., Smith, Bradley N., Daisy, Sproviero, Cristina, Cereda, Mauro, Ceroni, Luca, Diamanti, Roberto Del Bo, Stefania, Corti, Comi, Giacomo P., Sandra, D'Alfonso, Lucia, Corrado, Bertolin, Cinzia, Soraru', Gianni, Letizia, Mazzini, Viviana, Pensato, Cinzia, Gellera, Cinzia, Tiloca, Antonia, Ratti, Andrea, Calvo, Cristina, Moglia, Maura, Brunetti, Simona, Arcuti, Rosa, Capozzo, Chiara, Zecca, Christian, Lunetta, Silvana, Penco, Nilo, Riva, Alessandro, Padovani, Massimiliano, Filosto, Ian, Blair, Nicholson, Garth A., Rowe, Dominic B., Roger, Pamphlett, Kiernan, Matthew C., Julian, Grosskreutz, Witte, Otto W., Robert, Steinbach, Tino, Prell, Beatrice, Stubendorff, Ingo, Kurth, Hübner, Christian A., Nigel Leigh, P., Federico, Casale, Adriano, Chio, Ettore, Beghi, Elisabetta, Pupillo, Rosanna, Tortelli, Giancarlo, Logroscino, John, Powell, Ludolph, Albert C., Weishaupt, Jochen H., Wim, Robberecht, Philip Van Damme, Brown, Robert H., Glass, Jonathan D., Landers, John E., Orla, Hardiman, Andersen, Peter M., Philippe, Corcia, Patrick, Vourc'H, Vincenzo, Silani, van Es, Michael A., Jeroen Pasterkamp, R., Lewis, Cathryn M., Gerome, Breen, Ammar, Al-Chalabi, van den Berg, Leonard H., Veldink, Jan H., Daniela, Calini, Isabella, Fogh, Barbara, Castellotti, Franco, Taroni, Stella, Gagliardi, Giacomo, Comi, Sandra, D’Alfonso, Pegoraro, Elena, Giorgia, Querin, Francesca, Gerardi, Fabrizio, Rinaldi, Maria Sofia Cotelli, Luca, Chiveri, Maria Cristina Guaita, Patrizia, Perrone, Giancarlo, Comi, Carlo, Ferrarese, Lucio, Tremolizzo, Marialuisa, Delodovici, Giorgio, Bono, Stefania, Cammarosano, Antonio, Canosa, Dario, Cocito, Leonardo, Lopiano, Luca, Durelli, Bruno, Ferrero, Antonio, Bertolotto, Alessandro, Mauro, Luca, Pradotto, Roberto, Cantello, Enrica, Bersano, Dario, Giobbe, Maurizio, Gionco, Daniela, Leotta, Lucia, Appendino, Cavallo, Cavallo, Enrico, Odddenino, Claudio, Geda, Fabio, Poglio, Paola, Santimaria, Umberto, Massazza, Antonio, Villani, Roberto, Conti, Fabrizio, Pisano, Mario, Palermo, Franco, Vergnano, Paolo, Provera, Maria Teresa Penza, Marco, Aguggia, Nicoletta Di Vito, Piero, Meineri, Ilaria, Pastore, Paolo, Ghiglione, Danilo, Seliak, Nicola, Launaro, Giovanni, Astegiano, Bottacchi, Edo, Isabella Laura Simone, Stefano, Zoccolella, Michele, Zarrelli, Franco, Apollo, William, Camu, Jean Sebastien Hulot, Francois, Viallet, Philippe, Couratier, David, Maltete, Christine, Tranchant, Marie, Vidailhet, Bassel, Abou-Khalil, Pauls, Auce, Andreja, Avbersek, Melanie, Bahlo, David, J Balding, Thomas, Bast, Larry, Baum, Albert, J Becker, Felicitas, Becker, Bianca, Berghuis, Samuel, F Berkovic, Katja, E Boysen, Jonathan, P Bradfield, Lawrence, C Brody, Russell, J Buono, Ellen, Campbell, Gregory, D Cascino, Claudia, B Catarino, Gianpiero, L Cavalleri, Stacey, S Cherny, Krishna, Chinthapalli, Alison, J Coffey, Alastair, Compston, Antonietta, Coppola, Patrick, Cossette, John, J Craig, Gerrit-Jan de Haan, Peter De Jonghe, Carolien G, F de Kovel, Norman, Delanty, Chantal, Depondt, Orrin, Devinsky, Dennis, J Dlugos, Colin, P Doherty, Christian, E Elger, Johan, G Eriksson, Thomas, N Ferraro, Martha, Feucht, Ben, Francis, Jacqueline, A French, Saskia, Freytag, Verena, Gaus, Eric, B Geller, Christian, Gieger, Tracy, Glauser, Simon, Glynn, David, B Goldstein, Hongsheng, Gui, Youling, Guo, Kevin, F Haas, Hakon, Hakonarson, Kerstin, Hallmann, Sheryl, Haut, Erin, L Heinzen, Ingo, Helbig, Christian, Hengsbach, Helle, Hjalgrim, Michele, Iacomino, Andrés, Ingason, Michael, R Johnson, Reetta, Kälviäinen, Anne-Mari, Kantanen, Dalia, Kasperavičiūte, Dorothee Kasteleijn-Nolst Trenite, Heidi, E Kirsch, Robert, C Knowlton, Bobby P, C Koeleman, Roland, Krause, Martin, Krenn, Wolfram, S Kunz, Ruben, Kuzniecky, Patrick, Kwan, Dennis, Lal, Yu-Lung, Lau, Anna-Elina, Lehesjoki, Holger, Lerche, Costin, Leu, Dick, Lindhout, Warren, D Lo, Iscia, Lopes-Cendes, Daniel, H Lowenstein, Alberto, Malovini, Anthony, G Marson, Thomas, Mayer, Mark, Mccormack, James, L Mills, Nasir, Mirza, Martina, Moerzinger, Rikke, S Møller, Anne, M Molloy, Hiltrud, Muhle, Mark, Newton, Ping-Wing, Ng, Markus, M Nöthen, Peter, Nürnberg, Terence, J O’Brien, Karen, L Oliver, Aarno, Palotie, Faith, Pangilinan, Sarah, Peter, Slavé, Petrovski, Annapurna, Poduri, Michael, Privitera, Rodney, Radtke, Sarah, Rau, Philipp, S Reif, Eva, M Reinthaler, Felix, Rosenow, Josemir, W Sander, Thomas, Sander, Theresa, Scattergood, Steven, C Schachter, Christoph, J Schankin, Ingrid, E Scheffer, Bettina, Schmitz, Susanne, Schoch, Pak, C Sham, Jerry, J Shih, Graeme, J Sills, Sanjay, M Sisodiya, Lisa, Slattery, Alexander, Smith, David, F Smith, Michael, C Smith, Philip, E Smith, Anja C, M Sonsma, Doug, Speed, Michael, R Sperling, Bernhard, J Steinhoff, Ulrich, Stephani, Remi, Stevelink, Konstantin, Strauch, Pasquale, Striano, Hans, Stroink, Rainer, Surges, K Meng Tan, Liu Lin Thio, G Neil Thomas, Marian, Todaro, Rossana, Tozzi, Maria, S Vari, Eileen P, G Vining, Frank, Visscher, Sarah von Spiczak, Nicole, M Walley, Yvonne, G Weber, Zhi, Wei, Judith, Weisenberg, Christopher, D Whelan, Peter, Widdess-Walsh, Markus, Wolff, Stefan, Wolking, Wanling, Yang, Federico, Zara, Fritz, Zimprich, Project MinE ALS GWAS Consortium, International League Against Epilepsy Consortium on Complex Epilepsies, Department of Medical and Clinical Genetics, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, and HUS Helsinki and Uusimaa Hospital District
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Risk ,0301 basic medicine ,Aging ,Genetic correlation ,Geriatrics & Gerontology ,education ,Genome-wide association study ,Biology ,ALS ,Epilepsy ,Amyotrophic Lateral Sclerosis ,Gene Frequency ,Humans ,Genetic Variation ,Genome-Wide Association Study ,Negative Results ,Article ,3124 Neurology and psychiatry ,03 medical and health sciences ,0302 clinical medicine ,Genetic variation ,medicine ,Amyotrophic lateral sclerosis ,Allele frequency ,Genetics ,Science & Technology ,Mechanism (biology) ,General Neuroscience ,3112 Neurosciences ,Neurosciences ,medicine.disease ,3. Good health ,Minor allele frequency ,030104 developmental biology ,Neurology (clinical) ,Neurosciences & Neurology ,Geriatrics and Gerontology ,Life Sciences & Biomedicine ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins. ispartof: NEUROBIOLOGY OF AGING vol:92 ispartof: location:United States status: published
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- 2020
20. Structural signature of SCA3: From presymptomatic to late disease stages
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Thiago Junqueira Ribeiro de Rezende, Fernando Cendes, José Luiz Pedroso, Marcondes C. França, Jean Levi Ribeiro de Paiva, Orlando Graziani Povoas Barsottini, Iscia Lopes-Cendes, and Alberto R. M. Martinez
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congenital, hereditary, and neonatal diseases and abnormalities ,Pathology ,medicine.medical_specialty ,Ataxia ,business.industry ,Central nervous system ,medicine.disease ,Spinal cord ,030218 nuclear medicine & medical imaging ,White matter ,Midbrain ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Neurology ,Cerebral cortex ,Basal ganglia ,Spinocerebellar ataxia ,medicine ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Objective Machado-Joseph disease (SCA3/MJD) is the most frequent spinocerebellar ataxia worldwide and characterized by brainstem, basal ganglia, and cerebellar damage. However, little is known about the natural history of the disease. This motivated us to determine the extension and progression of central nervous system involvement in SCA3/MJD using multimodal magnetic resonance imaging (MRI)-based analyses in a large cohort of patients (n = 79) and presymptomatic subjects (n = 12). Methods All subjects underwent MRI in a 3T device to assess gray and white matter. To evaluate the cerebral and cerebellar cortices, we used measures from FreeSurfer and SUIT. T1-multiatlas assessed deep gray matter. Diffusion tensor imaging multiatlas was used to investigate cerebral white matter (WM) and SpineSeg to assess the cervical spinal cord. Results There was widespread WM and cerebellar damage, in contrast to the restricted motor cortex involvement when all patients are compared to age- and sex-matched controls. Presymtomatic patients showed WM microstructural abnormalities mainly in the cerebellar and cerebral peduncles and volumetric reduction of midbrain, spinal cord, and substantia nigra. To assess the disease progression, we divided patients into four subgroups defined by time from ataxia onset. There was a clear pattern of evolving structural compromise, starting in infratentorial structures and progressing up to the cerebral cortex. Conclusion Structural damage in SCA3/MJD begins in the spinal cord, cerebellar peduncles, as well as substantia nigra and progresses to cerebral areas in the long term. These structural differences reveal some insights into the pathogenesis of SCA3/MJD and suggest a staging scheme to map the progression of the disease. Ann Neurol 2018;84:401-408.
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- 2018
21. CAG repeats ≥ 34 in Ataxin-1 gene are associated with amyotrophic lateral sclerosis in a Brazilian cohort
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Helen Andrade, João Pedro Nunes Gonçalves, Vitor Tumas, Leonardo Cruz de Souza, Rinaldo Claudino, Tauana Bernardes Leoni, Wilson Marques, Rafael Esteves Duarte Couteiro, Melina Pazian Martins, Iscia Lopes-Cendes, Laura de Godoy Rousseff Prado, Antônio Lúcio Teixeira, Fabrício Castro de Borba, Acary Souza Bulle Oliveira, Marcos Vinicius Magno Gonçalves, Daniel Sabino de Oliveira, Milena de Albuquerque, Vívian Pedigone Cintra, Mario Emilio Dourado, Marcondes C. França, Luciana Cardoso Bonadia, and Anamarli Nucci
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Oncology ,medicine.medical_specialty ,Ataxia ,DEMÊNCIA ,Ataxin 1 ,Disease ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Amyotrophic lateral sclerosis ,Ataxin-1 ,Genetic Association Studies ,Ataxin-2 ,biology ,business.industry ,Amyotrophic Lateral Sclerosis ,medicine.disease ,Phenotype ,Pathophysiology ,Europe ,Neurology ,Cohort ,biology.protein ,Neurology (clinical) ,medicine.symptom ,business ,Trinucleotide Repeat Expansion ,030217 neurology & neurosurgery ,Brazil ,Frontotemporal dementia - Abstract
Little is known about the genetic basis of amyotrophic lateral sclerosis (ALS) outside Europe and US. In this study, we investigated whether intermediate CAG expansions at ATXN1 were associated to ALS in the Brazilian population. To accomplish that, representative samples from 411 unrelated patients and 436 neurologically normal controls from 6 centers spread over the territory were genotyped to quantify ATXN1 expansions. We found that ATXN1 intermediate-length expansion (≥34 CAG repeats) are associated with the disease (odds ratio = 2.19, 95% CI = 1.081–4.441, p = .026). Most ATXN1-positive patients had classical phenotype, but some of them presented predominant lower motor neuron involvement. None of them had associated ataxia. Frontotemporal dementia was concomitantly found in 12.5% of patients carrying the intermediate ATXN1 expansion. Further studies are needed to validate these findings and to understand the pathophysiological mechanisms that connect ataxin-1 and ALS.
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- 2019
22. Genome-wide association study identifies genetic factors that modify age at onset in Machado-Joseph disease
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Olaf Riess, Laura Bannach Jardim, Manuela Lima, Mafalda Raposo, Cynthia V. Bourassa, Marcondes C. França, Jorge Sequeiros, João Vasconcelos, Sandra Martins, Calwing Liao, Patrick A. Dion, Hélène Catoire, Guy A. Rouleau, Maria Luiza Saraiva-Pereira, Fulya Akçimen, Garth A. Nicholson, and Iscia Lopes-Cendes
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Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,Ataxia ,medicine ,Genome-wide association study ,Disease ,Biology ,medicine.symptom ,medicine.disease ,Gene ,Machado–Joseph disease - Abstract
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 MJD patients from five different geographical origins, a genome-wide association study (GWAS) was conducted to identify additional AO modifying factors that could explain some of the residual AO variability. We identified nine suggestively associated loci (P < 1 × 10−5). These loci were enriched for genes involved in vesicle transport, olfactory signaling, and synaptic pathways. Furthermore, associations between AO and the TRIM29 and RAG genes suggests that DNA repair mechanisms might be implicated in MJD pathogenesis. Our study demonstrates the existence of several additional genetic factors, along with CAG expansion, that may lead to a better understanding of the genotype-phenotype correlation in MJD.
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- 2019
23. Dysregulation ofNEUROG2plays a key role in focal cortical dysplasia
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Iscia Lopes-Cendes, Fábio R. Torres, Rodrigo Secolin, Ana Carolina Coan, Luciano de Souza Queiroz, Fabio Rogerio, Murilo Guimarães Borges, Fernando Cendes, Patricia Aline Oliveira Ribeiro de Aguiar Araujo, Clarissa L. Yasuda, D.B. Dogini, Benilton S. Carvalho, Marcia Elisabete Morita, André Schwambach Vieira, Simoni Helena Avansini, Marilisa M. Guerreiro, and Vanessa S. Almeida
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0301 basic medicine ,Regulation of gene expression ,In situ hybridization ,Cortical dysplasia ,Biology ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,Real-time polymerase chain reaction ,Neurology ,Downregulation and upregulation ,embryonic structures ,microRNA ,medicine ,Cancer research ,Neurology (clinical) ,Transcription factor ,PI3K/AKT/mTOR pathway - Abstract
OBJECTIVE Focal cortical dysplasias (FCDs) are an important cause of drug-resistant epilepsy. In this work, we aimed to investigate whether abnormal gene regulation, mediated by microRNA, could be involved in FCD type II. METHODS We used total RNA from the brain tissue of 16 patients with FCD type II and 28 controls. MicroRNA expression was initially assessed by microarray. Quantitative polymerase chain reaction, in situ hybridization, luciferase reporter assays, and deep sequencing for genes in the mTOR pathway were performed to validate and further explore our initial study. RESULTS hsa-let-7f (p = 0.039), hsa-miR-31 (p = 0.0078), and hsa-miR34a (p = 0.021) were downregulated in FCD type II, whereas a transcription factor involved in neuronal and glial fate specification, NEUROG2 (p
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- 2018
24. Role of Pharmacogenomics in Antiepileptic Drug Therapy: Current Status and Future Perspectives
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Iscia Lopes-Cendes, Fernando Cendes, Laura Mumoli, Antonio Gambardella, and Angelo Labate
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0301 basic medicine ,medicine.medical_specialty ,Future studies ,Antiepileptic drug ,Pharmacology ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Drug Discovery ,medicine ,Humans ,Precision Medicine ,Intensive care medicine ,business.industry ,Small sample ,medicine.disease ,Precision medicine ,Phenotype ,030104 developmental biology ,Tolerability ,Targeted drug delivery ,Pharmacogenetics ,Pharmacogenomics ,Anticonvulsants ,business ,030217 neurology & neurosurgery - Abstract
BACKGROUND Growing evidence indicates that pharmacogenomics will positively impact treatment for patients with epilepsy in the near future, leading to the implementation of a precision-based use of antiepileptic drug (AED) therapy, thereby providing a cornerstone for precision medicine. OBJECTIVE In this review, we briefly summarize the studies of pharmacogenomics in epilepsy, recent advances, and how it may progress in the future. METHODS We subdivided the review into two main sections: genetic variants that may modulate response to AEDs through pharmacokinetics or pharmacodynamics mechanisms; and gene variants that may affect tolerability and safety of AEDs. RESULTS Results from most studies have been contradictory, due to several flaws, including small sample sizes, inaccurate phenotyping, and genotyping strategies. However, even with these limitations, very recent developments indicate that the goal of incorporating genetic data into clinical practice may be attainable in the near future. In addition, recent pharmacogenomic studies of hypersensitivity reactions to AEDs have also made important strides, as its prevention appears attainable with the identification of HLA-A genotypes for patients at high risk of carbamazepine hypersensitivity. CONCLUSION To better clarify the relationship between genetic factors and AEDs, future studies will require more precise epilepsy phenotypes, larger sample sizes, and astute use of new genotyping strategies. Reasonably, this will lead to novel therapeutic approaches in drug targeting and antiepileptogenesis.
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- 2018
25. Acute liver failure is associated with altered cerebral expression profiles of long non-coding RNAs
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Iscia Lopes-Cendes, Raghu Vemuganti, Vinícius R. Silva, Alan S. Hazell, and Rodrigo Secolin
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Male ,0301 basic medicine ,medicine.medical_specialty ,Inflammation ,Cerebral edema ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Internal medicine ,Gene expression ,medicine ,Animals ,Hepatic encephalopathy ,Cerebral Cortex ,Monocarboxylate transporter ,biology ,General Neuroscience ,Liver Failure, Acute ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,Cancer research ,biology.protein ,RNA, Long Noncoding ,Signal transduction ,medicine.symptom ,030217 neurology & neurosurgery - Abstract
Hepatic encephalopathy (HE) represents a serious complication of acute liver failure (ALF) in which cerebral edema leading to brainstem herniation as a result of increased intracranial hypertension is a major consequence. Long non-coding RNAs (lncRNAs) play a significant role in coordinating gene expression, with recent studies indicating an influence in the pathogenesis of several diseases. To investigate their involvement in the cerebral pathophysiology of ALF, we profiled the expression of lncRNAs in the frontal cortex of mice at coma stage following treatment with the hepatotoxin azoxymethane. Of the 35,923 lncRNAs profiled using microarrays, 868 transcripts were found to be differentially expressed in the ALF-treated group compared to the sham control group. Of these, 382 lncRNAs were upregulated and 486 lncRNAs downregulated. Pathway analysis revealed these lncRNAs target a number of biological and molecular pathways that include cytokine-cytokine receptor interaction, the mitogen activated protein kinase signaling pathway, the insulin signaling pathway, and the nuclear factor-κB signaling pathway. False discovery rate adjustment identified 9 upregulated lncRNAs, 2 of which are associated with neuroepithelial transforming gene 1 (NET1) and the monocarboxylate transporter 2 (Slc16a7), potential contributors to astrocyte cytoskeletal disruption/swelling and lactate production, respectively. Our findings suggest an important role for lncRNAs in the brain in ALF in relation to inflammation, neuropathology, and in terms of the functional basis of HE. Further work on these non-coding RNAs may lead to new therapeutic approaches for the treatment and management of cerebral dysfunction resulting from this potentially life-threatening disorder.
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- 2017
26. Structural signature of classical versus late-onset friedreich's ataxia by Multimodality brain MRI
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Thiago Junqueira Ribeiro de Rezende, Ingrid Faber, Andreia V. Faria, Orlando Graziani Povoas Barsottini, Marcondes C. França, Karen Girotto, José Luiz Pedroso, Fernando Cendes, Iscia Lopes-Cendes, and Alberto R. M. Martinez
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Pathology ,medicine.medical_specialty ,Ataxia ,Pyramidal tracts ,Radiological and Ultrasound Technology ,medicine.diagnostic_test ,Magnetic resonance imaging ,medicine.disease ,030218 nuclear medicine & medical imaging ,White matter ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,medicine.anatomical_structure ,Neurology ,Neuroimaging ,Corticospinal tract ,medicine ,Radiology, Nuclear Medicine and imaging ,Neurology (clinical) ,Anatomy ,medicine.symptom ,Psychology ,030217 neurology & neurosurgery ,Diffusion MRI - Abstract
Introduction Friedreich's ataxia (FRDA) is the most common autosomal-recessive ataxia worldwide. It is characterized by early onset, sensory abnormalities, and slowly progressive ataxia. However, some individuals manifest the disease after the age of 25 years and are classified as late-onset FRDA (LOFA). Therefore, we propose a transversal multimodal MRI-based study to investigate which anatomical substrates are involved in classical (cFRDA) and LOFA. Methods We enrolled 36 patients (13 with LOFA) and 29 healthy controls. All subjects underwent magnetic resonance imaging in a 3 T device; three-dimensional high-resolution T1-weighted images and diffusion tensor images were used to assess gray and white matter, respectively. We used T1 multiatlas approach to assess deep gray matter and cortical thickness measures to evaluate cerebral cortex and DTI multiatlas approach to assess white matter. All analyses were corrected for multiple comparisons. Results Group comparison showed that both groups presented gray matter atrophy mostly in the motor cortex. Regarding white matter, we found abnormalities in the cerebellar peduncles, pyramidal tracts, midbrain, pons, and medulla oblongata for both groups, but the microstructural abnormalities in the cFRDA group were more widespread. In addition, we found that the corticospinal tract presented more severe microstructural damage in the LOFA group. Finally, the midbrain volume of the cFRDA, but not of the LOFA group, correlated with disease duration (R = −0.552, P = 0.012) and severity (R = −0.783, P
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- 2017
27. Cdc2-like kinase 2 in the hypothalamus is necessary to maintain energy homeostasis
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Iscia Lopes-Cendes, Jackson C. Bittencourt, Fernando Moreira Simabuco, Tamires Marques Zanotto, Laís Weissmann, Paula G.F. Quaresma, Patrícia O. Prada, A H B de Matos, Andressa Cristina dos Santos, Isadora C. Furigo, and Jose Donato
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Male ,0301 basic medicine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Hypothalamus ,Medicine (miscellaneous) ,030209 endocrinology & metabolism ,Diet, High-Fat ,Energy homeostasis ,Eating ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,Internal medicine ,CDC2-CDC28 Kinases ,medicine ,Animals ,Homeostasis ,Obesity ,Phosphorylation ,Nutrition and Dietetics ,Chemistry ,Kinase ,Insulin ,Leptin ,digestive, oral, and skin physiology ,Lipid Metabolism ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Diabetes Mellitus, Type 2 ,Insulin Resistance ,Energy Metabolism ,Phosphoenolpyruvate carboxykinase ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction - Abstract
To investigate whether the Cdc2-like kinase 2 (CLK2) is expressed in hypothalamic neurons and if it is, whether the hypothalamic CLK2 has a role in the regulation of energy balance. Swiss mice on chow or high-fat diet (HFD) and db/db mice on chow diet were used to address the role of CLK2 in the hypothalamus. Hypothalamic CLK2Thr343 phosphorylation, which induces CLK2 activity, is regulated in vivo by refeeding, insulin and leptin, in a PI3K (phosphoinositide 3-kinase)-dependent manner. The reduction of CLK2 expression in the hypothalamus, by chronic pharmacological inhibition with TG003 or by chronic knockdown with small interfering RNA was sufficient to abolish the anorexigenic effect of insulin and leptin, to increase body weight, fat mass, food intake and to decrease energy expenditure in mice on chow. In contrast, CLK2Thr343 phosphorylation in the hypothalamus in response to insulin, leptin or refeeding was impaired in mice on HFD or in db/db mice. Chronic CLK2 inhibition in the hypothalamus was associated with a slight increase in the fasting blood glucose levels, reduction in PEPCK (phosphoenolpyruvate carboxykinase) expression in the liver and enhanced glucose production from pyruvate, suggesting a regulation of hepatic glucose production. Further, overexpressing CLK2 in the mediobasal hypothalami of mice on HFD or in db/db mice by adenovirus partially reversed the obese phenotype. Thus, our results suggest that protein CLK2 integrates some important hypothalamic pathways, and may be a promising molecule for new therapeutic approaches for obesity and diabetes.
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- 2016
28. Copy number alterations associated with clinical features in an underrepresented population with breast cancer
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Luis Otávio Sarian, Benilton S. Carvalho, Iscia Lopes-Cendes, Geisilene R. Paiva, Livia Conz, Susana Ramalho, Sophie Françoise Mauricette Derchain, Meenakshi Anurag, Jonathan T. Lei, Cassio Cardoso Filho, Rodrigo Franco Gonçalves, Raquel Mary Rodrigues-Peres, and Matthew J. Ellis
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0301 basic medicine ,Oncology ,Adult ,medicine.medical_specialty ,copy number alteration ,Microarray ,lcsh:QH426-470 ,mucinous ,DNA Copy Number Variations ,Population ,Breast Neoplasms ,Disease ,030105 genetics & heredity ,Cohort Studies ,03 medical and health sciences ,Breast cancer ,breast cancer ,Internal medicine ,Genetics ,medicine ,Tumor Microenvironment ,Humans ,Copy-number variation ,Family history ,education ,Molecular Biology ,Pathological ,Genetics (clinical) ,Oligonucleotide Array Sequence Analysis ,education.field_of_study ,Tumor microenvironment ,family history ,business.industry ,Carcinoma, Ductal, Breast ,Original Articles ,Genomics ,Middle Aged ,medicine.disease ,stage ,Adenocarcinoma, Mucinous ,lcsh:Genetics ,030104 developmental biology ,ethnicity ,Original Article ,Female ,business ,Brazil - Abstract
Background As the most incident tumor among women worldwide, breast cancer is a heterogeneous disease. Tremendous efforts have been made to understand how tumor characteristics as histological type, molecular subtype, and tumor microenvironment collectively influence disease diagnosis to treatment, which impact outcomes. Differences between populations and environmental and cultural factors have impacts on the origin and evolution of the disease, as well as the therapeutic challenges that arise due to these factors. We, then, compared copy number variations (CNVs) in mucinous and nonmucinous luminal breast tumors from a Brazilian cohort to investigate major CNV imbalances in mucinous tumors versus non‐mucinous luminal tumors, taking into account their clinical and pathological features. Methods 48 breast tumor samples and 48 matched control blood samples from Brazilian women were assessed for CNVs by chromosome microarray. Logistic regression and random forest models were used in order to assess CNVs in chromosomal regions from tumors. Results CNVs that were identified in chromosomes 1, 5, 8, 17, 19, and 21 classify tumors according to their histological type, ethnicity, disease stage, and familial history. Conclusion Copy number alterations described in this study provide a better understanding of the landscape of genomic aberrations in mucinous breast cancers that are associated with clinical features.
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- 2019
29. Multimodal Analysis of SCN1A Missense Variants Improves Interpretation of Clinically Relevant Variants in Dravet Syndrome
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Ana Carolina Coan, Paula Preto, Benilton S. Carvalho, Marina C. Gonsales, Iscia Lopes-Cendes, Maria Augusta Montenegro, Marilisa M. Guerreiro, and Monica Paiva Quast
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0301 basic medicine ,variants of uncertain significance ,ion channel gene defects ,Computational biology ,Biology ,clinical genetic testing ,lcsh:RC346-429 ,03 medical and health sciences ,0302 clinical medicine ,Dravet syndrome ,Multimodal analysis ,medicine ,Missense mutation ,In patient ,Allele frequency ,Likely pathogenic ,lcsh:Neurology. Diseases of the nervous system ,Original Research ,Epileptic encephalopathy ,medicine.disease ,Pathogenicity ,VUS ,030104 developmental biology ,epileptic encephalopathy ,Neurology ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
Objective: We aimed to improve the classification of SCN1A missense variants in patients with Dravet syndrome (DS) by combining and modifying the current variants classification criteria to minimize inconclusive test results. Methods: We established a score classification workflow based on evidence of pathogenicity to adapt the classification of DS-related SCN1A missense variants. In addition, we compiled the variants reported in the literature and our cohort and assessed the proposed pathogenic classification criteria. We combined information regarding previously established pathogenic amino acid changes, mode of inheritance, population-specific allele frequencies, localization within protein domains, and deleterious effect prediction analysis. Results: Our meta-analysis showed that 46% (506/1,101) of DS-associated SCN1A variants are missense. We applied the score classification workflow and 56.5% (286/506) of the variants had their classification changed from VUS: 17.8% (90/506) into “pathogenic” and 38.7% (196/506) as “likely pathogenic.” Conclusion: Our results indicate that using multimodal analysis seems to be the best approach to interpret the pathogenic impact of SCN1A missense changes for the molecular diagnosis of patients with DS. By applying the proposed workflow, most DS related SCN1A variants had their classification improved.
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- 2019
30. Laser microdissection-based microproteomics of the hippocampus of a rat epilepsy model reveals regional differences in protein abundances
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Barbara Henning, Alexandre Hilário Berenguer de Matos, Braxton A. Norwood, Fernando Cendes, Rovilson Gilioli, Felix Rosenow, Sebastian Bauer, André Schwambach Vieira, Iscia Lopes-Cendes, Amanda Morato do Canto, and Benilton S. Carvalho
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Proteomics ,Central nervous system ,Protein Deglycase DJ-1 ,Connexin ,lcsh:Medicine ,Laser Capture Microdissection ,Biology ,Receptors for Activated C Kinase ,Molecular neuroscience ,Hippocampus ,Connexins ,Article ,Epilepsy ,medicine ,Animals ,Humans ,Protein Interaction Maps ,lcsh:Science ,Laser capture microdissection ,Hippocampal sclerosis ,Multidisciplinary ,Dentate gyrus ,lcsh:R ,PARK7 ,Gap junction ,medicine.disease ,Rats ,Disease Models, Animal ,medicine.anatomical_structure ,Epilepsy, Temporal Lobe ,Gene Expression Regulation ,Organ Specificity ,lcsh:Q ,Neuroscience ,Signal Transduction - Abstract
Mesial temporal lobe epilepsy (MTLE) is a chronic neurological disorder affecting almost 40% of adult patients with epilepsy. Hippocampal sclerosis (HS) is a common histopathological abnormality found in patients with MTLE. HS is characterised by extensive neuronal loss in different hippocampus sub-regions. In this study, we used laser microdissection-based microproteomics to determine the protein abundances in different regions and layers of the hippocampus dentate gyrus (DG) in an electric stimulation rodent model which displays classical HS damage similar to that found in patients with MTLE. Our results indicate that there are differences in the proteomic profiles of different layers (granule cell and molecular), as well as different regions, of the DG (ventral and dorsal). We have identified new signalling pathways and proteins present in specific layers and regions of the DG, such as PARK7, RACK1, and connexin 31/gap junction. We also found two major signalling pathways that are common to all layers and regions: inflammation and energy metabolism. Finally, our results highlight the utility of high-throughput microproteomics and spatial-limited isolation of tissues in the study of complex disorders to fully appreciate the large biological heterogeneity present in different cell populations within the central nervous system.
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- 2019
31. Normal cerebral cortical thickness in first-degree relatives of temporal lobe epilepsy patients
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Meng-Han Tsai, Magdalena A. Kowalczyk, Marina K. M. Alvim, Clarissa L. Yasuda, Colin P. Doherty, Graeme D. Jackson, Fernando Cendes, Saud Alhusaini, Marilise Katsurayama, Gianpiero L. Cavalleri, Mira Semmelroch, Tamires Araujo Zanao, Iscia Lopes-Cendes, Mary Fitzsimons, Norman Delanty, Mateus Henrique Nogueira, Victória R. Ferraz, and Matheus Zabin
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Adult ,Male ,medicine.medical_specialty ,Hippocampal formation ,Asymptomatic ,Hippocampus ,Statistics, Nonparametric ,Temporal lobe ,Cohort Studies ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Imaging, Three-Dimensional ,volumetric MRI use in epilepsy ,Internal medicine ,medicine ,Humans ,Family ,030212 general & internal medicine ,First-degree relatives ,Cerebral Cortex ,Hippocampal sclerosis ,Sclerosis ,medicine.diagnostic_test ,business.industry ,Magnetic resonance imaging ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,medicine.anatomical_structure ,Epilepsy, Temporal Lobe ,Cerebral cortex ,hippocampal sclerosis ,Cardiology ,Female ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery ,MRI - Abstract
ObjectiveTo examine cerebral cortex thickness in asymptomatic first-degree relatives of patients with mesial temporal lobe epilepsy (MTLE).MethodsWe investigated 127 asymptomatic first-degree relatives of patients with MTLE due to hippocampal sclerosis (HS) (mean age ± SD = 39.4 ± 13 years) and 203 healthy control individuals (mean age ± SD = 36.0 ± 11 years). Participants underwent a comprehensive clinical evaluation and structural brain MRI at 3 study sites. Images were processed simultaneously at each site using a surface-based morphometry method to quantify global brain measures, hippocampal volumes, and cerebral cortical thickness. Differences in brain measures between relatives of patients and controls were examined using generalized models, while controlling for relevant covariates, including age and sex.ResultsNone of the asymptomatic first-degree relatives of MTLE + HS patients showed evidence of HS on qualitative image assessments. Compared to the healthy controls, the asymptomatic relatives of patients displayed no significant differences in intracranial volume, average hemispheric surface area, or hippocampal volume. Similarly, no significant cerebral cortical thinning was identified in the relatives of patients. This was consistent across the 3 cohorts.ConclusionLack of cortical thickness changes in the asymptomatic relatives of patients indicates that the previously characterized MTLE + HS-related cortical thinning is not heritable, and is likely driven by disease-related factors. This finding therefore argues for early and aggressive intervention in patients with medically intractable epilepsy.
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- 2019
32. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies
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Christian E. Elger, Wolfgang Lieb, Claudia B. Catarino, Pasquale Striano, Andreja Avbersek, Daniel H. Lowenstein, Philip E. M. Smith, G. Neil Thomas, Dick Lindhout, Erin L. Heinzen, Sanjay M. Sisodiya, Orrin Devinsky, Alexander R. H. Smith, Rainer Surges, Stefan Wolking, Patrick Cossette, Annapurna Poduri, Eric B. Geller, Stacey S. Cherny, Maria Stella Vari, Peter De Jonghe, Kevin Haas, Andres Ingason, Reetta Kälviäinen, Krishna Chinthapalli, Dennis Lal, Graeme J. Sills, Martina Moerzinger, Jonathan P. Bradfield, Mark R Newton, Federico Zara, Sheryl R. Haut, Warren D. Lo, Holger Lerche, Felix Rosenow, Robert C. Knowlton, Mark McCormack, Sarah Rau, Felicitas Becker, Andre Franke, Heidi E. Kirsch, Patrick Kwan, Remi Stevelink, Rodney A. Radtke, Michele Iacomino, Faith Pangilinan, Ulrich Stephani, David F. Smith, Eva M. Reinthaler, Chantal Depondt, Hiltrud Muhle, Russell J. Buono, Alison J. Coffey, Ellen Campbell, Marvin Johnson, Bernhard J. Steinhoff, Sarah von Spiczak, Yvonne G. Weber, Ping-Wing Ng, Kerstin Hallmann, Philipp S. Reif, David Goldstein, Bettina Schmitz, Antonietta Coppola, Jerry J. Shih, Karen Oliver, Anne-Mari Kantanen, Rossana Tozzi, Markus Wolff, Albert J. Becker, Anne M. Molloy, Lisa Slattery, James L. Mills, Judith L.Z. Weisenberg, Jacqueline A. French, Lawrence C. Brody, Int League Against Epilepsy Conso, Peter Widdess-Walsh, Helle Hjalgrim, Christian Hengsbach, Christoph J. Schankin, Johan G. Eriksson, Tracy A. Glauser, Yu-Lung Lau, Larry Baum, Anna-Elina Lehesjoki, Nicole M. Walley, Josemir W. Sander, Markus M. Noethen, Simon Glynn, Jennifer Jamnadas-Khoda, Thomas Bast, Susanne Schoch, Iscia Lopes-Cendes, Doug Speed, Anja C M Sonsma, John Craig, Ingo Helbig, Marian Todaro, Gregory D. Cascino, Steven C. Schachter, Fritz Zimprich, Samuel F. Berkovic, Michael Privitera, Ben Francis, Martin Krenn, Rikke S. Møller, Eileen P.G. Vining, Martha Feucht, Bobby P. C. Koeleman, Ruben Kuzniecky, Christian Gieger, K. Meng Tan, Dalia Kasperaviciute, Pauls Auce, Gianpiero L. Cavalleri, Melanie Bahlo, Zhi Wei, Nasir Mirza, David J. Balding, Mike Smith, Liu Lin Thio, Alastair Compston, Katja E. Boysen, Gerrit-Jan de Haan, Hongsheng Gui, Hakon Hakonarson, Christopher D. Whelan, Colin P. Doherty, Youling Guo, Aarno Palotie, Wolfram S. Kunz, Slavé Petrovski, Thomas Sander, Frank Visscher, Bianca Berghuis, Costin Leu, Verena Gaus, Dennis J. Dlugos, Ingrid E. Scheffer, Alberto Malovini, Konstantin Strauch, Wanling Yang, Saskia Freytag, H. Stroink, Pak C. Sham, Norman Delanty, Terence J. O'Brien, Carolien G.F. de Kovel, Thomas U. Mayer, Anthony G Marson, Bassel Abou-Khalil, Thomas N. Ferraro, Dorothée G.A. Kasteleijn-Nolst Trenité, Roland Krause, Sarah Peter, Peter Nuernberg, Theresa Scattergood, Michael R. Sperling, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Clinicum, Department of Medical and Clinical Genetics, Medicum, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Int League Against Epilepsy Conso, Abou-Khalil, Bassel, Auce, Paul, Avbersek, Andreja, Bahlo, Melanie, J Balding, David, Bast, Thoma, Baum, Larry, J Becker, Albert, Becker, Felicita, Berghuis, Bianca, F Berkovic, Samuel, E Boysen, Katja, P Bradfield, Jonathan, C Brody, Lawrence, J Buono, Russell, Campbell, Ellen, D Cascino, Gregory, B Catarino, Claudia, L Cavalleri, Gianpiero, S Cherny, Stacey, Chinthapalli, Krishna, J Coffey, Alison, Compston, Alastair, Coppola, Antonietta, Cossette, Patrick, J Craig, John, de Haan, Gerrit-Jan, De Jonghe, Peter, F de Kovel, Carolien G, Delanty, Norman, Depondt, Chantal, Devinsky, Orrin, J Dlugos, Denni, P Doherty, Colin, E Elger, Christian, G Eriksson, Johan, N Ferraro, Thoma, Feucht, Martha, Francis, Ben, Franke, Andre, A French, Jacqueline, Freytag, Saskia, Gaus, Verena, B Geller, Eric, Gieger, Christian, Glauser, Tracy, Glynn, Simon, B Goldstein, David, Gui, Hongsheng, Guo, Youling, F Haas, Kevin, Hakonarson, Hakon, Hallmann, Kerstin, Haut, Sheryl, L Heinzen, Erin, Helbig, Ingo, Hengsbach, Christian, Hjalgrim, Helle, Iacomino, Michele, Ingason, André, Jamnadas-Khoda, Jennifer, R Johnson, Michael, Kälviäinen, Reetta, Kantanen, Anne-Mari, Kasperavičiūte, Dalia, Kasteleijn-Nolst Trenite, Dorothee, E Kirsch, Heidi, C Knowlton, Robert, C Koeleman, Bobby P, Krause, Roland, Krenn, Martin, S Kunz, Wolfram, Kuzniecky, Ruben, Kwan, Patrick, Lal, Denni, Lau, Yu-Lung, Lehesjoki, Anna-Elina, Lerche, Holger, Leu, Costin, Lieb, Wolfgang, Lindhout, Dick, D Lo, Warren, Lopes-Cendes, Iscia, H Lowenstein, Daniel, Malovini, Alberto, G Marson, Anthony, Mayer, Thoma, Mccormack, Mark, L Mills, Jame, Mirza, Nasir, Moerzinger, Martina, S Møller, Rikke, M Molloy, Anne, Muhle, Hiltrud, Newton, Mark, Ng, Ping-Wing, M Nöthen, Marku, Nürnberg, Peter, J O'Brien, Terence, L Oliver, Karen, Palotie, Aarno, Pangilinan, Faith, Peter, Sarah, Petrovski, Slavé, Poduri, Annapurna, Privitera, Michael, Radtke, Rodney, Rau, Sarah, S Reif, Philipp, M Reinthaler, Eva, Rosenow, Felix, W Sander, Josemir, Sander, Thoma, Scattergood, Theresa, C Schachter, Steven, J Schankin, Christoph, E Scheffer, Ingrid, Schmitz, Bettina, Schoch, Susanne, C Sham, Pak, J Shih, Jerry, J Sills, Graeme, M Sisodiya, Sanjay, Slattery, Lisa, Smith, Alexander, F Smith, David, C Smith, Michael, E Smith, Philip, M Sonsma, Anja C, Speed, Doug, R Sperling, Michael, J Steinhoff, Bernhard, Stephani, Ulrich, Stevelink, Remi, Strauch, Konstantin, Striano, Pasquale, Stroink, Han, Surges, Rainer, Meng Tan, K, Lin Thio, Liu, Neil Thomas, G, Todaro, Marian, Tozzi, Rossana, S Vari, Maria, G Vining, Eileen P, Visscher, Frank, von Spiczak, Sarah, M Walley, Nicole, G Weber, Yvonne, Wei, Zhi, Weisenberg, Judith, D Whelan, Christopher, Widdess-Walsh, Peter, Wolff, Marku, Wolking, Stefan, Yang, Wanling, Zara, Federico, Zimprich, Fritz, Wellcome Trust, GlaxoSmithKline Services Unlimited, Commission of the European Communities, Medical Research Council (MRC), and Imperial College Healthcare NHS Trust- BRC Funding
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0301 basic medicine ,Linkage disequilibrium ,LD SCORE REGRESSION ,Neurology [D14] [Human health sciences] ,General Physics and Astronomy ,Genome-wide association study ,ILAE COMMISSION ,Neurodegenerative ,Genome ,Linkage Disequilibrium ,Epilepsy ,Gene Frequency ,Missing heritability problem ,2.1 Biological and endogenous factors ,Aetiology ,lcsh:Science ,International League Against Epilepsy Consortium on Complex Epilepsies ,Multidisciplinary ,Genetic Predisposition to Disease/genetics ,Chromosome Mapping ,ASSOCIATION ,Epilepsy/classification ,Single Nucleotide ,ABSENCE ,3. Good health ,Technologie de l'environnement, contrôle de la pollution ,SNP HERITABILITY ,Neurological ,Genome-Wide Association Study/methods ,Case-Control Studie ,Engineering sciences. Technology ,Human ,Biotechnology ,EXPRESSION ,SUSCEPTIBILITY LOCI ,Genotype ,Science ,Quantitative Trait Loci ,610 Medicine & health ,Computational biology ,Biology ,Quantitative trait locus ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Article ,GENETIC ARCHITECTURE ,03 medical and health sciences ,MD Multidisciplinary ,medicine ,Genetics ,SNP ,Chimie ,FRONTAL-LOBE ,Humans ,Genetic Predisposition to Disease ,Polymorphism ,METAANALYSIS ,Neurologie [D14] [Sciences de la santé humaine] ,Physique ,Human Genome ,Neurosciences ,General Chemistry ,Astronomie ,medicine.disease ,Genetic architecture ,Brain Disorders ,030104 developmental biology ,Gene Expression Regulation ,Case-Control Studies ,epilepsy ,lcsh:Q ,3111 Biomedicine ,Quantitative Trait Loci/genetics ,Genome-Wide Association Study - Abstract
The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology., SCOPUS: ar.j, info:eu-repo/semantics/published
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- 2018
33. Revisiting the clinical impact of variants in EFHC1 in patients with different phenotypes of genetic generalized epilepsy
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Daniel Leite Góes Gitaí, Fernando Cendes, Marina C. Gonsales, C. A. M. Guerreiro, Iscia Lopes-Cendes, Marina K. M. Alvim, Luiz Eduardo Betting, Clarissa L. Yasuda, Patrícia A. O. Ribeiro, Universidade Estadual de Campinas (UNICAMP), Brazilian Inst Neurosci & Neurotechnol BRAINN, Fed Univ Alagoas UFAL, and Universidade Estadual Paulista (Unesp)
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Proband ,medicine.medical_specialty ,Genetic testing ,Genomics ,Biology ,03 medical and health sciences ,Behavioral Neuroscience ,Epilepsy ,Juvenile myoclonic epilepsy ,0302 clinical medicine ,medicine ,Humans ,Missense mutation ,030212 general & internal medicine ,Genetics ,medicine.diagnostic_test ,Molecular pathology ,Calcium-Binding Proteins ,Myoclonic Epilepsy, Juvenile ,medicine.disease ,Pedigree ,Phenotype ,Neurology ,Medical genetics ,Epilepsy, Generalized ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
Made available in DSpace on 2021-06-25T12:24:37Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-11-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) The most common form of genetic generalized epilepsy (GGE) is juvenile myodonic epilepsy (JME), which accounts for 5 to 10% of all epilepsy cases. The gene EFHC1 has been implicated as a putative cause of JME. However, it remains debatable whether testing for EFHC1 mutations should be included in the diagnostic epilepsy gene panels. To investigate the clinical utility of EFHC1 testing, we studied 125 individuals: 100 with JME and 25 with other GGEs. We amplified and sequenced all EFHC1 coding exons. Then, we predicted the pathogenicity or benign impact of the variants using the analyses proposed by the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP). Mutation screening revealed 11 missense variants in 44 probands with JME (44%) and one of the seven individuals with generalized tonic-clonic seizures on awakening (14%). Six of the 11 variants ( 54%) were classified as 'benign,' and the remaining variants were considered variants of uncertain significance (VUS). There is currently a limitation to test for genes that predispose an individual to complex, nonmonogenic phenotypes. Thus, we show suggestive evidence that EFHC1 testing lacks a scientific foundation based on the disputed nature of the gene-disease relationship and should be currently limited to research purposes. (C) 2020 Elsevier Inc. All rights reserved. Univ Campinas UNICAMP, Sch Med Sci, Dept Med Genet & Genom Med, Tessalia Vieira Camargo 126, BR-13083887 Campinas, SP, Brazil Univ Campinas UNICAMP, Sch Med Sci, Dept Neurol, Campinas, SP, Brazil Brazilian Inst Neurosci & Neurotechnol BRAINN, Campinas, SP, Brazil Fed Univ Alagoas UFAL, Inst Biol Sci & Hlth, Maceio, Alagoas, Brazil Sao Paulo State Univ UNESP, Sch Med, Dept Neurol & Psychiat, Botucatu, SP, Brazil Sao Paulo State Univ UNESP, Sch Med, Dept Neurol & Psychiat, Botucatu, SP, Brazil FAPESP: FAPESP: 2013/07559-3 CNPq: 143189/2009-3 CNPq: 403299/2016-0 CNPq: 309494/2014-1
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- 2020
34. Avaliação da resposta terapêutica ao tratamento de manutenção com lítio em pacientes com transtorno afetivo bipolar
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Stephany Caroline Raposo Franco, Rodrigo Secolin, Luiz Fernando de Almeida Lima e Silva, Marilza L. Santos, Claudio E. M. Banzato, Iscia Lopes-Cendes, Júlia Cunha Loureiro, and Clarissa de Rosalmeida Dantas
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Pediatrics ,medicine.medical_specialty ,Lithium (medication) ,Bipolar disorder ,lcsh:RC435-571 ,transtornos psicóticos ,tobacco ,03 medical and health sciences ,0302 clinical medicine ,psychotic disorders ,lcsh:Psychiatry ,Epidemiology ,medicine ,In patient ,LITHIUM USE ,Psychiatry ,lítio ,resultado do tratamento ,Confounding ,Transtorno bipolar ,medicine.disease ,030227 psychiatry ,tabaco ,Psychiatry and Mental health ,Mood ,lithium ,Concomitant ,treatment outcome ,Psychology ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Objetive To identify potential clinical and epidemiological predictors of long-term response to lithium treatment. Methods A total of 40 adult outpatients followed in an university hospital, with confirmed diagnosis of bipolar disorder and with history of lithium use for at least a six months period, had their response to this medication assessed through the use of a standardized instrument. The ALDA scale is based on retrospective clinical data, in our study assessed through a thoroughly reviewed of the medical charts, and is used to evaluate the clinical improvement with the treatment (Criterion A), corrected by the acknowledgement of possible confounding factors, such as duration of the treatment, compliance and concomitant use of additional medications (Criterion B), in order to estimate the response that can be specifically attributable to lithium. Results Our study found an inverse relation between the number of mood episodes with psychotic symptoms and lithium treatment outcome. Conclusion The results reinforce the hypothesis that lithium seems to be less efficacious in patients with bipolar disorder who present psychotic symptoms. RESUMO Objetivo Identificar potenciais preditores clínicos e epidemiológicos de resposta terapêutica ao uso prolongado de lítio. Métodos Um total de 40 pacientes adultos em tratamento ambulatorial em um hospital universitário, com diagnóstico confirmado de transtorno afetivo bipolar e história de pelo menos seis meses de uso de lítio, teve sua resposta a essa medicação avaliada com a utilização de um instrumento padronizado. A escala ALDA leva em consideração informações clínicas obtidas de forma retrospectiva, em nosso estudo, por meio de minuciosa revisão dos prontuários médicos, para julgar a melhora clínica obtida com o tratamento (Critério A), corrigida pela identificação de possíveis fatores confundidores, tais como duração do tratamento, adesão e uso concomitante de outras drogas (Critério B), de forma a estimar a resposta que pode ser atribuída especificamente ao uso do lítio. Resultados Nosso estudo encontrou uma relação inversa entre o número de episódios de humor com a presença de sintomas psicóticos e o desfecho no tratamento com lítio. Conclusão Esses resultados reforçam a hipótese de que o lítio parece ser menos eficaz em pacientes com transtorno afetivo bipolar que manifestam sintomas psicóticos.
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- 2016
35. Non-motor symptoms in patients with hereditary spastic paraplegia caused by SPG4 mutations
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Katiane R. Servelhere, Anelyssa D'Abreu, Iscia Lopes-Cendes, Jonas Alex Morales Saute, Ingrid Faber, H.A.G. Teive, Mariana Moscovich, Marcondes C. França, and Laura Bannach Jardim
- Subjects
Adult ,Male ,medicine.medical_specialty ,Spastin ,Hereditary spastic paraplegia ,Degenerative Disorder ,Mutation, Missense ,Pain ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Humans ,Medicine ,Clinical significance ,In patient ,030212 general & internal medicine ,Brief Pain Inventory ,Fatigue ,Depression (differential diagnoses) ,Adenosine Triphosphatases ,Depression ,Spastic Paraplegia, Hereditary ,business.industry ,Epworth Sleepiness Scale ,Beck Depression Inventory ,Middle Aged ,medicine.disease ,Neurology ,Physical therapy ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Background and purpose Non-motor manifestations are frequently overlooked in degenerative disorders and little is known about their frequency and clinical relevance in SPG4 hereditary spastic paraplegia (SPG4-HSP). Methods Thirty patients with SPG4-HSP and 30 healthy controls answered the Modified Fatigue Impact Scale, Epworth Sleepiness Scale, Brief Pain Inventory and Beck Depression Inventory. Student's t test was used to compare groups and linear regression was used to assess correlations. Results Patients had higher fatigue scores than controls (31.0 ± 16.5 vs. 14.5 ± 16.0, P = 0.002) as well as pain (3.4 ± 2.7 vs. 1.0 ± 1.6, P = 0.001) and depression (12.7 ± 8.9 vs. 4.4 ± 3.8, P
- Published
- 2016
36. Nonneurological Involvement in Late-Onset Friedreich Ataxia (LOFA): Exploring the Phenotypes
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Walter Oleschko Arruda, Mariana Moscovich, Anelyssa D'Abreu, Sandra Leistner Segal, Carlos Roberto Martins, José Luiz Pedroso, Laura Bannach Jardim, Renato P. Munhoz, Maria Luiza Saraiva-Pereira, Marcondes C. França, Simone Karuta, Orlando Graziani Povoas Barsottini, Hélio A.G. Teive, Conrado Borges, Ingrid Faber, Iscia Lopes-Cendes, Alberto R. M. Martinez, Adriana Moro, Thiago Junqueira Ribeiro de Rezende, and Agessandro Abrahao
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Pes cavus ,Neurology ,Ataxia ,Adolescent ,Cardiomyopathy ,Late onset ,Scoliosis ,Impaired glucose tolerance ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Spasticity ,Age of Onset ,business.industry ,medicine.disease ,Phenotype ,030104 developmental biology ,Friedreich Ataxia ,Physical therapy ,Female ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Friedreich’s ataxia (FDRA) is the most common inherited ataxia worldwide, caused by homozygous GAA expansions in the FXN gene. Patients usually have early onset ataxia, areflexia, Babinski sign, scoliosis and pes cavus, but at least 25 % of cases have atypical phenotypes. Disease begins after the age of 25 in occasional patients (late-onset Friedreich ataxia (LOFA)). Little is known about the frequency and clinical profile of LOFA patients. One hundred six patients with molecular confirmation of FDRA and followed in three Brazilian outpatient centers were enrolled. General demographics, GAA expansion size, age at onset, cardiac, endocrine, and skeletal manifestations were evaluated and compared between LOFA and classic FDRA (cFDRA) groups. We used Mann–Whitney and Fisher tests to compare means and proportions between groups; p values
- Published
- 2016
37. Longitudinal magnetic resonance imaging study shows progressive pyramidal and callosal damage in Friedreich's ataxia
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Thiago Junqueira Ribeiro de Rezende, Cynthia B. da Silva, Iscia Lopes-Cendes, Fernando Cendes, Anelyssa D'Abreu, Marcondes C. França, Brunno Machado de Campos, and Clarissa L. Yassuda
- Subjects
0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Cerebellum ,Pathology ,medicine.medical_specialty ,Ataxia ,Pyramidal tracts ,medicine.disease ,Corpus callosum ,White matter ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Atrophy ,medicine.anatomical_structure ,Neurology ,medicine ,Neurology (clinical) ,Brainstem ,medicine.symptom ,Psychology ,030217 neurology & neurosurgery ,Diffusion MRI - Abstract
Introduction Spinal cord and peripheral nerves are classically known to be damaged in Friedreich's ataxia, but the extent of cerebral involvement in the disease and its progression over time are not yet characterized. The aim of this study was to evaluate longitudinally cerebral damage in Friedreich's ataxia Methods We enrolled 31 patients and 40 controls, which were evaluated at baseline and after 1 and 2 years. To assess gray matter, we employed voxel-based morphometry and cortical thickness measurements. White matter was evaluated using diffusion tensor imaging. Statistical analyses were both cross-sectional and longitudinal (corrected for multiple comparisons). Results Group comparison between patients and controls revealed widespread macrostructural differences at baseline: gray matter atrophy in the dentate nuclei, brainstem, and precentral gyri; and white matter atrophy in the cerebellum and superior cerebellar peduncles, brainstem, and periventricular areas. We did not identify any longitudinal volumetric change over time. There were extensive microstructural alterations, including superior cerebellar peduncles, corpus callosum, and pyramidal tracts. Longitudinal analyses identified progressive microstructural abnormalities at the corpus callosum, pyramidal tracts, and superior cerebellar peduncles after 1 year of follow-up. Conclusion Patients with Friedreich's ataxia present more widespread gray and white matter damage than previously reported, including not only infratentorial areas, but also supratentorial structures. Furthermore, patients with Friedreich's ataxia have progressive microstructural abnormalities amenable to detection in a short-term follow-up. © 2015 International Parkinson and Movement Disorder Society
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- 2015
38. Association and interaction of genetic variants with occurrence of ischemic stroke among Brazilian patients
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Paulo Henrique Condeixa de França, Norberto Luiz Cabral, Leslie Ecker Ferreira, Iscia Lopes-Cendes, and Rodrigo Secolin
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0301 basic medicine ,Male ,Genotype ,Population ,Context (language use) ,Biology ,Polymorphism, Single Nucleotide ,Brain Ischemia ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Allele ,education ,Stroke ,Genetic Association Studies ,Aged ,education.field_of_study ,Genetic heterogeneity ,Mortality rate ,Case-control study ,General Medicine ,Middle Aged ,medicine.disease ,Atherosclerosis ,030104 developmental biology ,Logistic Models ,030220 oncology & carcinogenesis ,Female ,RNA, Long Noncoding ,Dyslipidemia ,Brazil - Abstract
Ischemic Stroke (IS) is a severe and complex disorder of high morbidity and mortality rates associated with clinical, environmental, and genetic predisposing factors. Despite previous studies have associated genetic variants to stroke, inconsistent results from different populations pointed to the genetic heterogeneity for IS. Therefore, we may hypothesize that an interaction effect among genetic variants could contribute to IS occurrence rather than genetic variants independently. In this context, we investigated the association and interaction between genetic variants and large-artery atherosclerosis IS (LAAS-IS) and cardioembolic IS (CE-IS). We genotyped 435 patients (195 LAAS-IS; 240 CE-IS) and 535 controls from a population of Joinville, Santa Catarina, Brazil. Association and interaction analysis were performed by chi-square test and Multifactor-dimensionality Reduction test. We found an association between rs2383207*A allele, nearby CDKN2B-AS1, and LAAS-IS [OR 2.35 (95% CI = 1.79–3.08); p = 4.66 × 10−10]. We found an interaction among rs2910829, rs966221 and rs152312, with an accuracy of 0.62 (p = 4.3 × 10−5) demonstrating the interaction effect among variants from different genes can contribute to CE-IS risk. Further prediction analysis confirmed that clinical information, such as hypertension and dyslipidemia, presented high accuracy to predict LAAS-IS (86.47%) and CE-IS (90.47%); however, the inclusion of genetic variant information did not increase the accuracy.
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- 2018
39. Role of non-coding RNAs in non-aging-related neurological disorders
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Iscia Lopes-Cendes, André Schwambach Vieira, and D.B. Dogini
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Genetic Markers ,0301 basic medicine ,Ataxia ,Physiology ,Immunology ,Biophysics ,Ocean Engineering ,Review ,Disease ,Biology ,Bioinformatics ,Biochemistry ,03 medical and health sciences ,microRNA ,medicine ,Humans ,Circulating MicroRNA ,Epigenetics ,General Pharmacology, Toxicology and Pharmaceutics ,lcsh:QH301-705.5 ,Regulation of gene expression ,Molecular biomarkers ,lcsh:R5-920 ,General Neuroscience ,RNA ,Neurodegenerative Diseases ,Neuromuscular Diseases ,Cell Biology ,General Medicine ,medicine.disease ,Gene regulation ,MicroRNAs ,030104 developmental biology ,Gene Expression Regulation ,lcsh:Biology (General) ,Spinocerebellar ataxia ,RNA, Long Noncoding ,Human genome ,Nervous System Diseases ,medicine.symptom ,lcsh:Medicine (General) - Abstract
Protein coding sequences represent only 2% of the human genome. Recent advances have demonstrated that a significant portion of the genome is actively transcribed as non-coding RNA molecules. These non-coding RNAs are emerging as key players in the regulation of biological processes, and act as "fine-tuners" of gene expression. Neurological disorders are caused by a wide range of genetic mutations, epigenetic and environmental factors, and the exact pathophysiology of many of these conditions is still unknown. It is currently recognized that dysregulations in the expression of non-coding RNAs are present in many neurological disorders and may be relevant in the mechanisms leading to disease. In addition, circulating non-coding RNAs are emerging as potential biomarkers with great potential impact in clinical practice. In this review, we discuss mainly the role of microRNAs and long non-coding RNAs in several neurological disorders, such as epilepsy, Huntington disease, fragile X-associated ataxia, spinocerebellar ataxias, amyotrophic lateral sclerosis (ALS), and pain. In addition, we give information about the conditions where microRNAs have demonstrated to be potential biomarkers such as in epilepsy, pain, and ALS.
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- 2018
40. Transcriptome of the Wistar audiogenic rat (WAR) strain following audiogenic seizures
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Nathália Bustamante de Menezes, Márcio Flávio Dutra Moraes, André Schwambach Vieira, A.S. Martins, Cristiane S. Rocha, Alexandre Hilário Berenguer de Matos, Iscia Lopes-Cendes, Ana Lúcia Brunialti Godard, and Samara Damasceno
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Stimulation ,Biology ,Corpora quadrigemina ,Epilepsy, Reflex ,Receptors, G-Protein-Coupled ,Transcriptome ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Internal medicine ,medicine ,Kindling, Neurologic ,Animals ,RNA, Messenger ,Rats, Wistar ,Gene ,Regulation of gene expression ,Principal Component Analysis ,Tectum Mesencephali ,Gene Expression Profiling ,social sciences ,medicine.disease ,Phenotype ,humanities ,Rats ,QDPR ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Neurology ,Acoustic Stimulation ,Spectrophotometry ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
The Wistar Audiogenic Rat (WAR) is a model whose rats are predisposed to develop seizures following acoustic stimulation. We aimed to establish the transcriptional profile of the WAR model, searching for genes that help in understanding the molecular mechanisms involved in the predisposition and seizures expression of this strain. RNA-Seq of the corpora quadrigemina of WAR and Wistar rats subjected to acoustic stimulation revealed 64 genes differentially regulated in WAR. We validated twelve of these genes by qPCR in stimulated and naive (non-stimulated) WAR and Wistar rats. Among these, Acsm3 was upregulated in WAR in comparison with both control groups. In contrast, Gpr126 and Rtel1 were downregulated in naive and stimulated WAR rats in comparison with the Wistar controls. Qdpr was upregulated only in stimulated WAR rats that exhibited audiogenic seizures. Our data show that there are genes with differential intrinsic regulation in the WAR model and that seizures can alter gene regulation. We identified new genes that might be involved in the epileptic phenotype and comorbidities of the WAR model.
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- 2018
41. Structural signature in SCA1: clinical correlates, determinants and natural history
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Thiago Junqueira Ribeiro de Rezende, Orlando Graziani Povoas Barsottini, Ingrid Faber Vasconcelos, Marcondes C. França, Carlos Roberto Martins Junior, Iscia Lopes-Cendes, Alberto R. M. Martinez, Raphael F. Casseb, and José Luiz Pedroso
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Pathology ,Spinocerebellar Ataxia Type 1 ,Cerebellum ,Ataxia ,Neurology ,Neuropsychological Tests ,White matter ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,Medicine ,Verbal fluency test ,Humans ,Spinocerebellar Ataxias ,Gray Matter ,business.industry ,Neuropsychology ,Brain ,Organ Size ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,030104 developmental biology ,medicine.anatomical_structure ,Diffusion Tensor Imaging ,Phenotype ,Spinal Cord ,Disease Progression ,Female ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Spinocerebellar ataxia type 1 is an autosomal dominant disorder caused by a CAG repeat expansion in ATXN1, characterized by progressive cerebellar and extracerebellar symptoms. MRI-based studies in SCA1 focused in the cerebellum and connections, but there are few data about supratentorial/spinal damage and its clinical relevance. We have thus designed this multimodal MRI study to uncover the structural signature of SCA1. To accomplish that, a group of 33 patients and 33 age-and gender-matched healthy controls underwent MRI on a 3T scanner. All patients underwent a comprehensive neurological and neuropsychological evaluation. We correlated the structural findings with the clinical features of the disease. In addition, we evaluated the disease progression looking at differences in SCA1 subgroups defined by disease duration. Ataxia and pyramidal signs were the main symptoms. Neuropsychological evaluation disclosed cognitive impairment in 53% with predominant frontotemporal dysfunction. Gray matter analysis unfolded cortical thinning of primary and associative motor areas with more restricted impairment of deep structures. Deep gray matter atrophy was associated with motor handicap and poor cognition skills. White matter integrity loss was diffuse in the brainstem but restricted in supratentorial structures. Cerebellar cortical thinning was found in multiple areas and correlated not only with motor disability but also with verbal fluency. Spinal cord atrophy correlated with motor handicap. Comparison of MRI findings in disease duration-defined subgroups identified a peculiar pattern of progressive degeneration.
- Published
- 2018
42. Intermediate-length CAG repeat in ATXN2 is associated with increased risk for amyotrophic lateral sclerosis in Brazilian patients
- Author
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Vitor Tumas, Rinaldo Claudino, Antônio Lúcio Teixeira, Mario Emilio Dourado, Milena de Albuquerque, Rafael Esteves Duarte Couteiro, Marcondes C. França, Daniel Sabino de Oliveira, Helen Andrade, Anamarli Nucci, Wilson Marques, Acary Souza Bulle Oliveira, Laura de Godoy Rousseff Prado, Camila Piccinin, Iscia Lopes-Cendes, Leonardo Cruz de Souza, Marcos Vinicius Magno Gonçalves, Luciana Cardoso Bonadia, and Vívian Pedigone Cintra
- Subjects
0301 basic medicine ,Aging ,law.invention ,Pathogenesis ,POPULAÇÃO ,03 medical and health sciences ,0302 clinical medicine ,law ,Risk Factors ,Medicine ,Humans ,Genetic Predisposition to Disease ,Allele ,Amyotrophic lateral sclerosis ,Risk factor ,Polymerase chain reaction ,Genetic Association Studies ,Ataxin-2 ,Genetics ,business.industry ,General Neuroscience ,Amyotrophic Lateral Sclerosis ,medicine.disease ,Phenotype ,Confidence interval ,030104 developmental biology ,Increased risk ,Neurology (clinical) ,Geriatrics and Gerontology ,business ,Trinucleotide Repeat Expansion ,030217 neurology & neurosurgery ,Brazil ,Developmental Biology - Abstract
Intermediate-length cytosine-adenine-guanine nucleotide repeat expansions in the ATXN2 gene (which encodes for the protein Ataxin-2) have been linked to increased risk for amyotrophic lateral sclerosis (ALS) in different populations. There is no such study in the Brazilian population, which has a mixed ethnic background. We have thus selected 459 patients with ALS (372 Sporadic ALS and 87 Familial ALS) and 468 control subjects from 6 Brazilian centers to investigate this point. We performed polymerase chain reaction to determine the length of the ATXN2 alleles. Polymerase chain reaction products were resolved using capillary electrophoresis on ABI 3500 × l capillary sequencer. We found that ATXN2 intermediate-length expansions (larger than 26 repeats) were associated with an increased risk for ALS (odds ratio = 2.56, 95% confidence interval: 1.29–5.08, p = 0.005). Phenotype in patients with and without ATXN2 expansions was similar. Our findings support the hypothesis that ATXN2 plays an important role in the pathogenesis of ALS also in the Brazilian population.
- Published
- 2018
43. SPG11 mutations cause widespread white matter and basal ganglia abnormalities, but restricted cortical damage
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Orlando Graziani Povoas Barsottini, Ingrid Faber, Wilson Marques, Marcondes C. França, Melina Pazian Martins, Thiago Junqueira Ribeiro de Rezende, Carlos Roberto Martins, Charles Marques Lourenço, Antonio Orlacchio, Iscia Lopes-Cendes, Alberto R. M. Martinez, José Luiz Pedroso, and Celeste Montecchiani
- Subjects
0301 basic medicine ,Nervous system ,Pathology ,CA, cord area ,LH, left hemisphere ,ROI, region of interest ,SPRS, Spastic Paraplegia Rating Scale ,lcsh:RC346-429 ,CE, cord eccentricity ,0302 clinical medicine ,Basal ganglia ,FA, fractional anisotropy ,CST, corticospinal tract ,Spinal cord ,CMAP, compound muscle action potential ,White matter ,PNP, sensory-motor polyneuropathy ,Regular Article ,ALS, amyotrophic lateral sclerosis ,NPI, neuropsychiatric inventory ,medicine.anatomical_structure ,Neurology ,RH, right hemisphere ,lcsh:R858-859.7 ,STS, cortex adjacent to the superior temporal sulcus ,WES, whole exome sequencing ,medicine.medical_specialty ,Grey matter ,Thinning of the corpus callosum ,Hereditary spastic paraplegia ,Cognitive Neuroscience ,SC, spinal cord ,lcsh:Computer applications to medicine. Medical informatics ,MOCA, Montreal cognitive assessment ,03 medical and health sciences ,Neuroimaging ,medicine ,Complicated hereditary spastic paraplegia ,Motor neuron disorder ,SPG11 ,Radiology, Nuclear Medicine and imaging ,ACE-R, Addenbrooke's Cognitive Examination Revised ,WM, white matter ,lcsh:Neurology. Diseases of the nervous system ,MD, mean diffusivity ,HSP, hereditary spastic paraplegia ,business.industry ,GM, grey matter ,medicine.disease ,SNAP, sensory nerve action potential ,030104 developmental biology ,Corticospinal tract ,PNS, peripheral nervous system ,DTI, diffusion tensor imaging ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
SPG11 mutations are the major cause of autosomal recessive Hereditary Spastic Paraplegia. The disease has a wide phenotypic variability indicating many regions of the nervous system besides the corticospinal tract are affected. Despite this, anatomical and phenotypic characterization is restricted. In the present study, we investigate the anatomical abnormalities related to SPG11 mutations and how they relate to clinical and cognitive measures. Moreover, we aim to depict how the disease course influences the regions affected, unraveling different susceptibility of specific neuronal populations. We performed clinical and paraclinical studies encompassing neuropsychological, neuroimaging, and neurophysiological tools in a cohort of twenty-five patients and age matched controls. We assessed cortical thickness (FreeSurfer software), deep grey matter volumes (T1-MultiAtlas tool), white matter microstructural damage (DTI-MultiAtlas) and spinal cord morphometry (Spineseg software) on a 3 T MRI scan. Mean age and disease duration were 29 and 13.2 years respectively. Sixty-four percent of the patients were wheelchair bound while 84% were demented. We were able to unfold a diffuse pattern of white matter integrity loss as well as basal ganglia and spinal cord atrophy. Such findings contrasted with a restricted pattern of cortical thinning (motor, limbic and parietal cortices). Electromyography revealed motor neuronopathy affecting 96% of the probands. Correlations with disease duration pointed towards a progressive degeneration of multiple grey matter structures and spinal cord, but not of the white matter. SPG11-related hereditary spastic paraplegia is characterized by selective neuronal vulnerability, in which a precocious and widespread white matter involvement is later followed by a restricted but clearly progressive grey matter degeneration., Highlights • SPG11 leads to widespread White matter (WM) and deep grey matter (GM) damage. • Cortical thinning is restricted to motor, limbic and parietal regions. • Motor Cortex thinning as well as Spinal Cord and basal ganglia atrophy correlate with motor handicap and disease duration. • WM and thalamic damage correlate with cognitive impairment. • Progressive damage of GM contrasts with an apparently static WM involvement.
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- 2018
44. Joinville stroke biobank: study protocol and first year’s results
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Rui Martins, Vivian Nagel, Leslie Ecker Ferreira, Norberto Luiz Cabral, Felipe Ibiapina dos Reis, Iscia Lopes-Cendes, Octavio M. Pontes-Neto, Paulo Henrique Condeixa de França, Luís Edmundo Teixeira de Arruda Furtado, Vanessa G. Venancio, Gustavo Weiss, Elder Oda, and Juliana Safanelli
- Subjects
Male ,0301 basic medicine ,Stroke registry ,medicine.medical_specialty ,Subarachnoid hemorrhage ,Cardiovascular risk factors ,MEDLINE ,lcsh:RC321-571 ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine ,Humans ,genetics ,cardiovascular diseases ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Stroke ,Aged ,Biological Specimen Banks ,Genome, Human ,business.industry ,Case-control study ,acidente vascular cerebral ,genética ,Middle Aged ,medicine.disease ,biobancos ,Biobank ,stroke ,biobank ,030104 developmental biology ,Socioeconomic Factors ,Neurology ,Case-Control Studies ,Female ,Genomic information ,Neurology (clinical) ,business ,Brazil ,030217 neurology & neurosurgery - Abstract
Aiming to contribute to studies that use detailed clinical and genomic information of biobanks, we present the initial results of the first Latin American Stroke Biobank. Methods: Blood samples were collected from patients included in the Joinville Stroke Registry and four Brazilian cities. Demographic socio-economic data, cardiovascular risk factors, Causative Classification System for Ischemic Stroke, Trial of Org 10172 in Acute Stroke Treatment and National Institutes of Health scores, functional stroke status (modified Rankin) and brain images were recorded. Additionally, controls from both geographic regions were recruited. High-molecular-weight genomic DNA was obtained from all participants. Results: A total of 2,688 patients and 3,282 controls were included. Among the patients, 76% had ischemic stroke, 12% transient ischemic attacks, 9% hemorrhagic stroke and 3% subarachnoid hemorrhage. Patients with undetermined ischemic stroke were most common according the Trial of Org 10172 in Acute Stroke Treatment (40%) and Causative Classification System for Ischemic Stroke (47%) criteria. A quarter of the patients were under 55 years of age at the first-ever episode. Conclusions: We established the Joinville Stroke Biobank and discuss its potential for contributing to the understanding of the risk factors leading to stroke.
- Published
- 2017
45. Spinal Cord Damage in Machado-Joseph Disease
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Lucas M. T. Branco, Anelyssa D'Abreu, Iscia Lopes-Cendes, Felipe P. G. Bergo, Marcondes C. França, and Camila Nayara Fahl
- Subjects
Male ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Ataxia ,Cord ,Severity of Illness Index ,Gastroenterology ,Pattern Recognition, Automated ,Imaging, Three-Dimensional ,Atrophy ,Cerebellum ,Internal medicine ,medicine ,Humans ,medicine.diagnostic_test ,Cervical Cord ,Magnetic resonance imaging ,Machado-Joseph Disease ,Organ Size ,Middle Aged ,Spinal cord ,medicine.disease ,Magnetic Resonance Imaging ,Surgery ,medicine.anatomical_structure ,Neurology ,Spinocerebellar ataxia ,Biomarker (medicine) ,Female ,Neurology (clinical) ,medicine.symptom ,Trinucleotide Repeat Expansion ,Psychology ,Machado–Joseph disease - Abstract
Machado-Joseph disease (SCA3) is the most frequent spinocerebellar ataxia worldwide and characterized by remarkable phenotypic heterogeneity. MRI-based studies in SCA3 focused in the cerebellum and connections, but little is known about cord damage in the disease and its clinical relevance. To evaluate the spinal cord damage in SCA3 through quantitative analysis of MRI scans. A group of 48 patients with SCA3 and 48 age and gender-matched healthy controls underwent MRI on a 3T scanner. We used T1-weighted 3D images to estimate the cervical spinal cord area (CA) and eccentricity (CE) at three C2/C3 levels based on a semi-automatic image segmentation protocol. The scale for assessment and rating of ataxia (SARA) was employed to quantify disease severity. The two groups-SCA3 and controls-were significantly different regarding CA (49.5 ± 7.3 vs 67.2 ± 6.3 mm(2), p 0.001) and CE values (0.79 ± 0.06 vs 0.75 ± 0.05, p = 0.005). In addition, CA presented a significant correlation with SARA scores in the patient group (p = 0.010). CE was not associated with SARA scores (p = 0.857). In the multiple variable regression, we found that disease duration was the only variable associated with CA (coefficient = -0.629, p = 0.025). SCA3 is characterized by cervical cord atrophy and antero-posterior flattening. In addition, the spinal cord areas did correlate with disease severity. This suggests that quantitative analyses of the spinal cord MRI might be a useful biomarker in SCA3.
- Published
- 2014
46. Is cerebral microbleed prevalence relevant as a biomarker in amnestic mild cognitive impairment and mild Alzheimer’s disease?
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Augusto Celso Scarparo Amato Filho, Iscia Lopes-Cendes, Leda Leme Talib, Fernando Cendes, Rodrigo Secolin, Ana Flávia Mac Knight Carletti-Cassani, Patrícia A. O. Ribeiro, Ana Gabriela Bicalho Rabelo, Camila Vieira Ligo Teixeira, Thamires Naela Cardoso Magalhães, Orestes Vicente Forlenza, Helena Passarelli Giroud Joaquim, and Marcio Luiz Figueredo Balthazar
- Subjects
0301 basic medicine ,Apolipoprotein E ,Oncology ,Male ,medicine.medical_specialty ,Genotype ,Trail Making Test ,Tau protein ,tau Proteins ,Neuropsychological Tests ,Polymerase Chain Reaction ,03 medical and health sciences ,0302 clinical medicine ,Apolipoproteins E ,Neuroimaging ,Alzheimer Disease ,Internal medicine ,medicine ,Prevalence ,Humans ,Radiology, Nuclear Medicine and imaging ,Cognitive Dysfunction ,Aged ,Cerebral Hemorrhage ,Brain Imaging ,Mini–Mental State Examination ,Amyloid beta-Peptides ,medicine.diagnostic_test ,biology ,business.industry ,General Medicine ,Neuropsychological test ,medicine.disease ,Magnetic Resonance Imaging ,030104 developmental biology ,Case-Control Studies ,biology.protein ,Biomarker (medicine) ,Female ,Neurology (clinical) ,Alzheimer's disease ,business ,030217 neurology & neurosurgery ,Biomarkers - Abstract
Introduction The search for a reliable neuroimaging biomarker in Alzheimer’s disease is a matter of intense research. The presence of cerebral microbleeds seems to be a potential biomarker. However, it is not clear if the presence of microbleeds has clinical usefulness to differentiate mild Alzheimer’s disease and amnestic mild cognitive impairment from normal aging. We aimed to verify if microbleed prevalence differs among three groups: mild Alzheimer’s disease, amnestic mild cognitive impairment due to Alzheimer’s disease, and normal controls. Moreover, we studied whether microbleeds were associated with apolipoprotein E allele ɛ4 status, cerebrospinal fluid amyloid-beta, total and phosphorylated tau protein levels, vascular factors, and cognition. Methods Twenty-eight mild Alzheimer’s disease patients, 34 with amnestic mild cognitive impairment and 36 cognitively normal elderly subjects underwent: magnetic resonance imaging with a susceptibility-weighted imaging sequence on a 3T scanner, apolipoprotein E genotyping and a full neuropsychological evaluation. Only amnestic mild cognitive impairment and mild Alzheimer’s disease underwent cerebrospinal fluid analysis. We compared the groups and verified if microbleeds were predicted by all other variables. Results Mild Alzheimer’s disease presented a higher prevalence of apolipoprotein E allele ɛ4 in relation to amnestic mild cognitive impairment and control group. No significant differences were found between groups when considering microbleed presence. Logistic regression tests failed to find any relationship between microbleeds and the variables. We performed three different regression models using different independent variables: Model 1 - amyloid-beta, phosphorylated tau protein, total tau, apolipoprotein E allele ɛ4 status, age, and sex; Model 2 - vascular risk factors, age, and sex; Model 3 - cognitive scores sex, age, and education. Conclusion Although microbleeds might be related to the Alzheimer’s disease process, their presence is not a good candidate for a neuroimaging biomarker of the disease, especially in its early phases.
- Published
- 2017
47. Spinal Cord Damage in Spinocerebellar Ataxia Type 1
- Author
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Iscia Lopes-Cendes, Lucas M. T. Branco, Thiago Junqueira Ribeiro de Rezende, Marcondes C. França, Carlos Roberto Martins, Alberto R. M. Martinez, Orlando Graziani Povoas Barsottini, and José Luiz Pedroso
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Spinocerebellar Ataxia Type 1 ,Pathology ,Cerebellum ,Neurology ,Cord ,Ataxia ,Gastroenterology ,Pattern Recognition, Automated ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,Imaging, Three-Dimensional ,Internal medicine ,medicine ,Humans ,Spinocerebellar Ataxias ,Cervical Cord ,Organ Size ,Middle Aged ,Spinal cord ,medicine.disease ,Magnetic Resonance Imaging ,030104 developmental biology ,medicine.anatomical_structure ,Cross-Sectional Studies ,Disease Progression ,Regression Analysis ,Female ,Neurology (clinical) ,medicine.symptom ,Trinucleotide repeat expansion ,Psychology ,030217 neurology & neurosurgery - Abstract
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant disorder caused by a CAG repeat expansion, characterized by progressive cerebellar ataxia and pyramidal signs. Non-motor and extracerebellar symptoms may occur. MRI-based studies in SCA1 focused in the cerebellum and connections, but there are no data about cord damage in the disease and its clinical relevance. To evaluate in vivo spinal cord damage in SCA1, a group of 31 patients with SCA1 and 31 age- and gender-matched healthy controls underwent MRI on a 3T scanner. We used T1-weighted 3D images to estimate the cervical spinal cord area (CA) and eccentricity (CE) at three C2/C3 levels based on a semi-automatic image segmentation protocol. The scale for assessment and rating of ataxia (SARA) was used to quantify disease severity. The groups were significantly different regarding CA (47.26 ± 7.4 vs. 68.8 ± 5.7 mm2, p
- Published
- 2017
48. MicroRNA hsa-miR-134 is a circulating biomarker for mesial temporal lobe epilepsy
- Author
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Rodrigo Secolin, Simoni Helena Avansini, Beatriz Pereira de Sousa Lima, Benilton S. Carvalho, Iscia Lopes-Cendes, Marina K. M. Alvim, Ana Carolina Coan, Luciana Ramalho Pimentel-Silva, Fernando Cendes, Marilza L. Santos, Fábio R. Torres, D.B. Dogini, André Schwambach Vieira, Fabio Rogerio, Clarissa L. Yasuda, and Marcia Elisabete Morita
- Subjects
Male ,0301 basic medicine ,Oncology ,Physiology ,lcsh:Medicine ,Biochemistry ,Diagnostic Radiology ,Cohort Studies ,Epilepsy ,0302 clinical medicine ,Temporal Lobe Epilepsy ,Medicine and Health Sciences ,lcsh:Science ,Multidisciplinary ,medicine.diagnostic_test ,Pharmaceutics ,Radiology and Imaging ,Area under the curve ,Magnetic Resonance Imaging ,Body Fluids ,Nucleic acids ,Blood ,Neurology ,Cohort ,Biomarker (medicine) ,Female ,Anatomy ,Research Article ,Cohort study ,medicine.medical_specialty ,Imaging Techniques ,Research and Analysis Methods ,Blood Plasma ,03 medical and health sciences ,Drug Therapy ,Diagnostic Medicine ,Internal medicine ,Genetics ,medicine ,Humans ,Tonic-Clonic Seizures ,Non-coding RNA ,Hippocampal sclerosis ,Biology and life sciences ,business.industry ,lcsh:R ,Magnetic resonance imaging ,Epileptic Seizures ,Reverse Transcription ,Cortical dysplasia ,medicine.disease ,Gene regulation ,nervous system diseases ,MicroRNAs ,030104 developmental biology ,Epilepsy, Temporal Lobe ,RNA ,lcsh:Q ,Gene expression ,business ,Biomarkers ,030217 neurology & neurosurgery - Abstract
Epilepsy is misdiagnosed in up to 25% of patients, leading to serious and long-lasting consequences. Recently, circulating microRNAs have emerged as potential biomarkers in a number of clinical scenarios. The purpose of this study was to identify and to validate circulating microRNAs that could be used as biomarkers in the diagnosis of epilepsy. Quantitative real-time PCR was used to measure plasma levels of three candidate microRNAs in two phases of study: an initial discovery phase with 14 patients with mesial temporal lobe epilepsy (MTLE), 13 with focal cortical dysplasia (FCD) and 16 controls; and a validation cohort constituted of an independent cohort of 65 patients with MTLE and 83 controls. We found hsa-miR-134 downregulated in patients with MTLE (p = 0.018) but not in patients with FCD, when compared to controls. Furthermore, hsa-miR-134 expression could be used to discriminate MTLE patients with an area under the curve (AUC) of 0.75. To further assess the robustness of hsa-miR-134 as a biomarker for MTLE, we studied an independent cohort of 65 patients with MTLE, 27 of whom MTLE patients were responsive to pharmacotherapy, and 38 patients were pharmacoresistant and 83 controls. We confirmed that hsa-miR-134 was significantly downregulated in the plasma of patients with MTLE when compared with controls (p < 0.001). In addition, hsa-miR-134 identified patients with MTLE regardless of their response to pharmacotherapy or the presence of MRI signs of hippocampal sclerosis. We revealed that decreased expression of hsa-miR-134 could be a potential non-invasive biomarker to support the diagnosis of patients with MTLE.
- Published
- 2017
49. Clinical features and management of hereditary spastic paraplegia
- Author
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Iscia Lopes-Cendes, Marcondes C. França, Anelyssa D’ Abreu, Ingrid Faber, Katiane R. Servelhere, and Alberto R. M. Martinez
- Subjects
Adult ,Weakness ,spastic paraplegia ,Hereditary spastic paraplegia ,Genes, Recessive ,Degeneration (medical) ,lcsh:RC321-571 ,espasticidade muscular ,paraplegia espástica hereditária ,Spastic ,medicine ,Humans ,genetics ,hereditary spastic paraplegia ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,muscle spasticity ,Genes, Dominant ,Spastic Paraplegia, Hereditary ,business.industry ,Mechanism (biology) ,mutação ,Genetic Diseases, X-Linked ,Motor neuron ,genética ,medicine.disease ,Magnetic Resonance Imaging ,nervous system diseases ,paraplegia espástica ,medicine.anatomical_structure ,Neurology ,Mutation ,Progressive spasticity ,Neurology (clinical) ,medicine.symptom ,mutation ,business ,Paraplegia ,Neuroscience - Abstract
Hereditary spastic paraplegia (HSP) is a group of genetically-determined disorders characterized by progressive spasticity and weakness of lower limbs. An apparently sporadic case of adult-onset spastic paraplegia is a frequent clinical problem and a significant proportion of cases are likely to be of genetic origin. HSP is clinically divided into pure and complicated forms. The later present with a wide range of additional neurological and systemic features. To date, there are up to 60 genetic subtypes described. All modes of monogenic inheritance have been described: autosomal dominant, autosomal recessive, X-linked and mitochondrial traits. Recent advances point to abnormal axonal transport as a key mechanism leading to the degeneration of the long motor neuron axons in the central nervous system in HSP. In this review we aim to address recent advances in the field, placing emphasis on key diagnostic features that will help practicing neurologists to identify and manage these conditions. Paraplegias espásticas hereditárias (PEH) constituem um grupo de desordens geneticamente determinadas caracterizadas por espasticidade e paraparesia de progressão insidiosa. Paraplegia espástica aparentemente esporádica de início no adulto constitui problema frequente na prática neurológica. Evidências recentes sugerem que uma proporção significativa destes casos é geneticamente determinada. O grupo das PEH é dividido clinicamente em formas puras e complicadas de acordo com a concomitância de outras manifestações clinicas e neurológicas. Até o momento 60 tipos genéticos foram identificados. Todos os modos de herança monogênica já foram descritos: autossômica dominante, autossômica recessiva, ligada ao X e mitocondrial. Avanços recentes indicam que alterações do transporte axonal estão implicadas na degeneração dos longos axônios motores no sistema nervoso central na PEH. Nesta revisão abordamos recentes avanços na área com ênfase nos aspectos clínicos chave que ajudam o neurologista geral no diagnóstico e manejo correto deste grupo de doenças.
- Published
- 2014
50. Lithium carbonate and coenzyme Q10 reduce cell death in a cell model of Machado-Joseph disease
- Author
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D.B. Dogini, Tiago Campos Pereira, Rovilson Gilioli, Iscia Lopes-Cendes, and Camila M. Lopes-Ramos
- Subjects
0301 basic medicine ,Programmed cell death ,congenital, hereditary, and neonatal diseases and abnormalities ,Lithium carbonate ,Physiology ,Ubiquinone ,Machado-Joseph disease ,Immunology ,Biophysics ,Ocean Engineering ,Biology ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Drug treatment ,0302 clinical medicine ,Spinocerebellar ataxia type 3 ,medicine ,Humans ,Propidium iodide ,Viability assay ,General Pharmacology, Toxicology and Pharmaceutics ,Ataxin-3 ,lcsh:QH301-705.5 ,Cell Proliferation ,Coenzyme Q10 ,lcsh:R5-920 ,Cell Death ,General Neuroscience ,Biomedical Sciences ,Cell Differentiation ,Cell Biology ,General Medicine ,medicine.disease ,Molecular biology ,Repressor Proteins ,030104 developmental biology ,lcsh:Biology (General) ,chemistry ,Apoptosis ,Spinocerebellar ataxia ,lcsh:Medicine (General) ,Machado–Joseph disease ,030217 neurology & neurosurgery - Abstract
Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by expansion of the polyglutamine domain of the ataxin-3 (ATX3) protein. MJD/SCA3 is the most frequent autosomal dominant ataxia in many countries. The mechanism underlying MJD/SCA3 is thought to be mainly related to protein misfolding and aggregation leading to neuronal dysfunction followed by cell death. Currently, there are no effective treatments for patients with MJD/SCA3. Here, we report on the potential use of lithium carbonate and coenzyme Q10 to reduce cell death caused by the expanded ATX3 in cell culture. Cell viability and apoptosis were evaluated by MTT assay and by flow cytometry after staining with annexin V-FITC/propidium iodide. Treatment with lithium carbonate and coenzyme Q10 led to a significant increase in viability of cells expressing expanded ATX3 (Q84). In addition, we found that the increase in cell viability resulted from a significant reduction in the proportion of apoptotic cells. Furthermore, there was a significant change in the expanded ATX3 monomer/aggregate ratio after lithium carbonate and coenzyme Q10 treatment, with an increase in the monomer fraction and decrease in aggregates. The safety and tolerance of both drugs are well established; thus, our results indicate that lithium carbonate and coenzyme Q10 are good candidates for further in vivo therapeutic trials.
- Published
- 2016
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