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Vliv jednorázového tréninku posturální stability u pacientů se spinocerebelární ataxií / The effekct of one training of postural stability in patiens with spinocerebellar ataxiaFilipovičová, Jana January 2014 (has links)
We followed the immediate effect of sensorimotor training on postural stability in patients with spinocerebellar ataxia (SCA). We have tried to explain the possible mechanisms of adaptation to change COP, motor learning and neuroplasticity in the field of neurodegenerative changes in the cerebellum. Research Methods: A total of 10 patients with spinocerebellar ataxia (6 men, 4 women) aged 34-71 years, with an average disease duration of 11.6 years participated in the measurement of postural stability. First, we measured the patients with SCA before and after a 15-minute sensorimotor-training exercise, then this group underwent another day of the same measurement without sensorimotor training. As a second control group of 10 healthy subjects served a similar age, who also underwent sensorimotor training. Then we compared the results of posturographic measurement. Results: In the group of SCA patients, sensorimotor training was found significantly lower values in the monitored parameters LENGTH (t stat = 3,537731 > t krit = 2,262157), VELOCITY (t stat = 3,537731 > t krit = 2,262157) and energy to sustain COP (t stat = 2,715085 > t krit = 2,262157), measured on a foam pad with eyes closed. Measurement without making sensorimotor training produced no significant improvement in the results of monitored...
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Vyšetření mozečkových funkcí u pacientů se skoliózou / Examination of cerebeller function in patients with scoliosisDrdáková, Lenka January 2011 (has links)
Purpose: The aim of this research was to determine whether there is a difference in the presence of minimal cerebellar signs, hypermobility and dyspraxia in the group of patients with idiopathic scoliosis (IS) and a control group of individuals without IS. Methods: 11 patients have been selected for this research with IS and 11 individuals without IS as a control group. The International Cooperative Ataxia Rating Scale (ICARS) was used for examination of cerebellar signs. Hypermobility was evaluated with ten tests according to Janda. The presence of pendulum reflexes was determined by examination of patellar and triceps reflex, while dyspraxia was analyzed by means of the Czechoslovak test. Results: Patients with IS scored significantly worse in ICARS than the control group (p < 0,05). IS patients presented with significantly more pronounced hypermobility in head rotation (p = 0,0384) and forward bending (p = 0,0409) tests comparing to the control group. No significant difference between the two groups was identified in pendulum reflexes and the Czechoslovak dyspraxia test. Conclusion: The study confirms significantly more positive signs of ataxia and asynergy in a group of patients with IS comparing to control group. Hypermobility was significantly more pronounced in head rotation and forward...
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Compréhension de la neurophysiopathologie de l'ataxie de Friedreich et développement d'une approche de thérapie génique dans un nouveau modèle murin / Understanding Friedreich’s ataxia neuropathophysiology and development of a gene therapy approach using a new mouse modelDe Montigny, Charline 12 September 2018 (has links)
L’ataxie de Friedreich (AF) est une maladie mitochondriale caractérisée par une ataxie sensitive et spinocérébelleuse, une cardiomyopathie et du diabète, pour laquelle il n’existe pas de traitement. L’AF résulte de niveaux réduits de frataxine (FXN), une protéine mitochondriale impliquée dans la biosynthèse des centres Fe-S. La neurophysiopathologie précise de la maladie n’est pas identifiée et malgré d’intenses progrès ces dernières années, il n’existait pas de bon modèle pour développer des approches thérapeutiques visant à stopper ou réverser l’atteinte sensitive de l’AF. Nous avons donc généré un nouveau modèle murin qui récapitule l’ataxie sensitive et la neuropathie associée au déficit en FXN. Plusieurs mécanismes moléculaires affectés en absence de FXN dans les neurones proprioceptifs, primairement affectés dans l’AF, ont été identifiés. Nous avons également démontré l’efficacité d’une approche de thérapie génique, basée sur l’utilisation de vecteur adéno-associés (AAV) exprimant la FXN humaine, pour réverser la neuropathie, établissant la preuve de concept du potentiel d’une telle approche pour l’atteinte sensitive de l’AF. / Friedreich ataxia (FA) is a rare mitochondrial disease characterized by sensory and spinocerebellar ataxia, hypertrophic cardiomyopathy, and diabetes, for which there is no treatment. FA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in the biosynthesis of Fe-S clusters. To date, FA precise neuropathophysiology is not identified and despite significant progresses in recent the years, there was no good model to develop therapeutic approaches in order to stop or reverse the sensory ataxia associated to the FA. Thus, we have generated a new neuronal mouse model that recapitulates the sensory ataxia and the neuropathy associated to FXN deficiency. Several molecular mechanisms dysregulated in the absence of FXN in the proprioceptive neurons, primarily affected in FA, were identified. Furthermore, we have demonstrated the efficacy of a gene therapy (GT) approach, based on the delivery of adeno-associated vectors (AAV) expressing the human FXN, to reverse the sensitive neuropathy, thus establishing the preclinical proof of concept for the potential of GT in treating FA sensitive neuropathy.
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Protein complexes in neurodegenerative diseasesHouston, Nicola Patricia January 2012 (has links)
The 14-3-3 family of proteins are important signalling proteins involved in a number of cellular processes. These include cell cycle regulation, apoptosis, signal transduction and cell signalling. There is also considerable evidence in the literature that 14-3-3 proteins play a vital role in the pathology of neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s and Prion disease. The neurodegenerative disease of focus in this research is Spinocerebellar Ataxia Type 1 (SCA1). SCA1 is a polyglutamine-repeat disease and the interaction of the disease protein ataxin-1 with 14-3-3 proteins leads to the toxic accumulation and subsequent protein aggregation which is characteristic of this disease. This study focused on attempting to elucidate the structure of various domains of the disease protein and also in identifying potential inhibitors of this deleterious interaction. Unfortunately, structural studies were not successful due to a number of caveats encountered in the expression and purification of the ataxin-1 protein domains. By utilising computational methods and small molecule inhibitors, a number of potential lead compounds which possess the ability to at least partly disrupt the interaction of 14- 3-3ζ have been identified. As 14-3-3 proteins play roles in other neurodegenerative diseases, successful identification of potential drug lead treatments can have far reaching benefits in a number of neurodegenerative diseases including SCA1. Lipid rafts are also involved in neurodegenerative disease pathology. Lipid rafts are cholesterol and sphingolipid rich domains which organise the plasma membrane into discrete microdomains and act as signalling platforms and processing centres which attach specific proteins and lipids. A number of disease proteins are processed at these membrane regions, including those involved in Alzheimer’s, Parkinson’s and Prion disease. This processing is a step which is critical in the pathology of disease and abnormal processing leads to the formation of toxic protein aggregates. Previous research in the lab identified the association of low levels of the five main brain isoforms of 14-3-3 proteins with rafts. This study expanded on this to positively identify the presence of the two phospho-forms of 14-3-3, α and δ. The mechanism by which 14-3-3 proteins associate with rafts was also investigated, indicating that 14-3-3 associates with rafts via an unidentified raftbound protein(s). In addition, the phosphorylation status and quaternary structure of 14-3-3 in the presence of sphingolipids has been explored.
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A frequência de câncer na doença de Machado-JosephSouza, Gabriele Nunes January 2015 (has links)
Introdução: A doença de Machado-Joseph, também conhecida como ataxia espinocerebelar tipo 3 (DMJ/SCA3), é de inicio na vida adulta, uma doença neurodegenerativa autossômica dominante causada por uma expansão CAG no gene ATXN3. A DMJ/SCA3 pertence ao grupo de doenças chamado de poliglutaminopatias (PoliQ). A redução do risco de câncer em indivíduos com PolyQ tais como a doença de Huntington foi previamente relatada em um população diferente. Nenhum estudo buscando essa associação em DMJ/SCA3 já foi realizada.Objetivos: comparar os 15 anos de incidência cumulativa de câncer (ICC) e a proporção de câncer como causa de morte em portadores de DMJ/SCA3 sintomáticos observados e nos controles. Métodos: Indivíduos com DMJ/SCA3 pertencentes ao Rio Grande do Sul em uma coorte de 2000 a 2015 foram identificados. Entrevistas estruturadas foram feitas com indivíduos afetados e com controles não relacionados. A CIC conforme publicado pelo Instituto Nacional de Câncer (INCA), do Brasil, foi usado como um controle populacional. As causas de morte entre as famílias com DMJ/SCA3 e controles não relacionados pareados também foram obtidos pelo Sistema de Informações sobre Mortalidade Pública. Foram entrevistados 154 pacientes com DMJ/SCA3 e 80 controles não relacionados: Resultados: A CIC foi de 7/154 (4,5%) e 5/80 (6,3%) entre DMJ/SCA3 e nos indivíduos controles não relacionados, respectivamente. Para obter uma redução do risco absoluto de 1,8 entre os casos e controles, seriam necessários 1.938 indivíduos por grupo para detectar uma diferença significativa entre os grupos. A população total de sintomáticos com DMJ/SCA3 igualou-se a 625 indivíduos em 2015, esse estudo foi interrompido. O câncer foi a causa da morte em 9/101 (8,9%) DMJ/SCA3 e em 52/202 (26,2%) controles, com uma redução do risco absoluto de 17,3% no grupo DMJ/SCA3 (χ² = 12,421; p = 0,001 ; OR 0,27, IC 95% 0,13-0,58). Indivíduos com DMJ/SCA3 que morreram de câncer eram mais velhos e tinham uma menor CAGexp que os casos que faleceram de outras causas.Discussão: Devido à raridade da DMJ/SCA3, estudos de CIC em indivíduos vivos com poder estatístico são inviáveis. No entanto, uma redução significativa de câncer como uma causa de morte foi detectada em DMJ/SCA3. Estes dados confirmam a associação de polyQ com proteção contra o câncer e sugerem que polyQ de fato são doenças de multissistemas. / Introduction: Machado-Joseph disease, also known as Spinocerebellar Ataxia type 3 (MJD/SCA3), is an adult-onset autosomal dominant neurodegenerative disease caused by an expanded CAG repeat in the ATXN3 gene. MJD/SCA3 belongs to the so-called group of polyglutamine disorders (PolyQ). Reduced risk of câncer in individuals with PolyQ such as Huntington disease was previously reported in different population. No study searching for this association in MJD/SCA3 was already performed. Objectives: We aimed to compare the 15 years cumulative incidence of câncer (ICC) and the proportion of câncer as a cause of death in symptomatic SCA3/MJD carriers with those observed in controls. Methods: SCA3/MJD individuals belonging to the Rio Grande do Sul cohort from 2000 to 2015 were identified. A structured interview was done with affected individuals and with unrelated controls. CIC as published by the National Institute of Câncer (INCA), Brazil, was used as a population control. Causes of death among SCA3/MJD families and paired unrelated controls were also obtained from the Public Information System on Mortality. Results: 154 SCA3/MJD patients and 80 unrelated controls were interviewed. CIC were 7/154 (4.5%) and 5/80 (6.3%) among SCA3/MJD and unrelated control individuals, respectively. For an absolute risk reduction of 1.8 between cases and controls, 1,938 individuals per group would be needed to detect a significant difference between groups. Since the total symptomatic SCA3/MJD population equaled 625 individuals in 2015, this study was interrupted. Câncer was a cause of death in 9/101 (8.9%) SCA3/MJD and in 52/202 (26.2%) controls, with an absolute reduction risk of 17.3% in the SCA3/MJD group (χ²=12.421; p=0.001; OR 0.27, IC95% 0.13 to 0.58). SCA3/MJD individuals who died from câncer were older and carried shorter CAGexp than those SCA3/MJD cases who died from other causes. Discussion: Due to the rarity of SCA3/MJD, CIC studies in living individuals with statistical power are unfeasible. However, a significant reduction of câncer as a cause of death was detected in SCA3/MJD. This data confirm the association of PolyQ with protection against câncer and suggest that PolyQ are indeed multisystem disorders.
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Effectiveness of Physical Therapy Intervention in Patients with Degenerative Cerebellar AtaxiaHeusel-Gillig, Lisa, Hall, Courtney D. 21 January 2013 (has links)
Abstract available through Journal of Neurologic Physical Therapy.
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Biomarkers Identification and Disease Modeling using Multimodal Neuroimaging Approaches in Polyglutamine Diseases / Identification de biomarqueurs et modélisation de la maladie en utilisant des approches multimodales de neuroimagerie dans les maladies polyglutamineAdanyeguh, Isaac Mawusi 15 September 2017 (has links)
Les maladies par expansion de polyglutamines sont des maladies neurodégénératives dues à l’expansion du trinucléotide cytosine-adénine-guanine (CAG) dans les gènes correspondants codant pour une expansion d’homopolymère de glutamine dans les protéines mutées. Ce projet concerne les formes les plus courantes qui sont la maladie de Huntington (MH) et les ataxies spinocérébelleuses (SCA) types 1, 2, 3 et 7. Ce sont des maladies autosomiques dominantes, responsables de troubles graves de la motricité partageant des voies physiopathologiques communes, avec un effet notable sur la dysfonction métabolique. La disponibilité des tests génétiques et le fait que la plupart du temps la maladie débute à l’âge adulte offre la possibilité d’une intervention thérapeutique avant l’apparition de symptômes. Toutefois, les échelles cliniques ne sont pas assez sensibles et ne peuvent effectivement être utilisés pour évaluer les personnes au stade présymptomatique de la maladie. Les techniques d’imagerie par résonance magnétique (IRM) et de spectroscopie (SRM) sont des approches non invasives qui permettent de recueillir des informations pertinentes et sensibles. Ainsi, dans ce travail, nous présentons une combinaison de différentes techniques d’IRM et SRM afin d’identifier de robustes biomarqueurs de la MH et des SCA. Nous présentons aussi des approches thérapeutiques prometteuses dans la MH. De la même manière, nous voulons démontrer que des biomarqueurs d’imagerie sont plus sensibles que des échelles cliniques. Pour conclure, nous combinons des données multimodales – volumétrie, SRM, métabolomique et lipidomique – à partir de SCA dans un modèle qui explique mieux la pathologie. / Mutations in different gene loci that lead to the encoding of the unstable and expanded glutamine-encoding cytosine-adenine-guanine (CAG) repeats results in the group of diseases known as the polyglutamine diseases. This project focuses on the most common forms which are Huntington disease (HD) and spinocerebellar ataxia (SCA) types 1, 2, 3 and 7. These are autosomal dominant diseases responsible for severe movement disorders and are thought to share common pathophysiological pathways with a major emphasis on metabolic dysfunction. The availability of genetic testing and their predominantly adult onset opens a window for therapeutic intervention before symptoms onset. However, current clinical scales are not sensitive and cannot effectively be used to evaluate individuals at the presymptomatic stage of the diseases. This prompts the need for biomarkers that are sensitive to macroscopic and microscopic changes that may occur prior to disease onset. Magnetic resonance imaging (MRI) and spectroscopy (MRS) techniques present non-invasive approaches to extract pertinent information that otherwise would not be possible with clinical scales. In this work therefore, we present a combination of different MRI and MRS techniques to identify robust biomarkers in HD and SCA. We also present therapeutic approaches that hold promise in HD. Likewise, we show that imaging biomarkers have higher effect sizes than clinical scales. Finally, we combine multimodal data – volumetry, MRS, metabolomics and lipidomic – from SCA into a model that best explains the pathology.
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Genetic and Molecular analysis of the Spinocerebellar ataxia type 7 (SCA7) disease geneJonasson, Jenni January 2000 (has links)
Spinocerebellar ataxia type 7 (SCA7) is a hereditary neurodegenerative disorder affecting the cerebellum, pons and retina. SCA7 patients present with gait ataxia and visual impairment as the main symptoms. Anticipation, commonly observed in SCA7 families, is a phenomenon where an earlier age at onset and a more severe progression of disease is seen in successive generations. In order to identify the gene responsible for SCA7, we performed linkage analysis on a Swedish SCA7 kindred. Evidence for linkage of the SCA7 disease locus to a 32 cM region on chromosome 3p12-21.1, between markers D3S1547 and D3S1274, was established. A number of neurodegenerative disorders associated with anticipation are caused by expanded (CAG)n repeats in their respective disease genes. In order to isolate the SCA7 disease gene we, therefore, screened a human infant brain stem cDNA library for CAG repeat containing clones, mapping to chromosome 3. Four candidate clones were isolated and analysed, but could all be excluded as the SCA7 disease gene. In 1997, the SCA7 disease gene was identified and, as expected, shown to harbour a CAG repeat, expanded in SCA7 patients. Analysis of the SCA7 CAG repeat region in Swedish SCA7 patients demonstrated that CAG repeat size was negatively correlated to age at onset of disease. Furthermore, patients with larger repeats presented with visual impairment, whereas patients with smaller repeats presented with ataxia as the initial symptom. SCA7 is the most common autosomal dominant cerebellar ataxia in Sweden and Finland, but rare in other populations. In order to investigate if the relatively high frequency of SCA7 in these countries is the result of a founder effect in the region, a haplotype analysis was performed on all SCA7 families available. All 7 families shared a common haplotype of at least 1.9 cM surrounding the SCA7 locus. In addition, strong linkage disequilibrium was demonstrated for marker D3S1287 closely linked to the SCA7 gene, suggesting a founder effect for the SCA7 mutation in Sweden and Finland. The function of the SCA7 protein, ataxin-7, is not known and it does not show significant homologies to any previously known proteins. In order to gain insight into the function of ataxin-7 we analysed the expression of ataxin-7 in brain and peripheral tissue from SCA7 patients and controls. In brain, expression was found to be mainly neuronal with a nuclear subcellular localisation. Ataxin-7 expression was found throughout the CNS, not restricted to sites of pathology. We also confirmed previously reported findings of neuronal intranuclear inclusions (NIls) in the brains of SCA7 patients. Based on our findings, we conclude that the cell type specific neurodegeneration in SCA7 is not due to differences in expression pattern in affected and non-affected tissue or the distribution pattern of aggregated protein.
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Caractérisation clinique et génétique d’une nouvelle forme d’ataxie autosomique récessive dans la population québécoiseThiffault, Isabelle 10 1900 (has links)
Les ataxies autosomiques récessives sont un groupe de troubles neurologiques hétérogènes caractérisés par une incoordination brute des mouvements musculaires impliquant le dysfonctionnement nerveux du cervelet qui coordonne le mouvement. Plusieurs formes héréditaires ont été décrites dont la plus connue : l’ataxie de Friedriech. Dans cette thèse nous rapportons l'identification et la caractérisation d’une nouvelle forme dans la population québécoise. L’ataxie récessive spastique avec leucoencéphalopathie (ARSAL; aussi connue comme l’ataxie autosomique récessive spastique de type 3 (SPAX3); OMIM 611390) est la deuxième ataxie spastique décrite dans la population canadienne française. En effet, près de 50 % de nos cas sont originaires de la région de Portneuf. En 2006, nous avons décrit les caractéristiques cliniques de cette nouvelle forme d’ataxie. Un premier criblage du génome entier, constitué de plus de 500 marqueurs microsatellites, a permis la localisation du locus sur le chromosome 2q33-34. Suite au séquençage de plus de 37 gènes candidats et afin de rétrécir cet intervalle candidat, nous avons utilisé une micro-puce d’ADN constituée de marqueurs SNP «single nucleotide polymorphism» et nous avons identifié un deuxième intervalle candidat de 0.658Mb au locus 2q33 dans lequel se trouvent moins de 9 gènes. L’identification et la caractérisation de ces mutations a nécessité l’utilisation de diverses technologies de pointe. Trois mutations (une délétion et deux réarrangements complexes) dans le gène mitochondrial tRNA-synthetase (MARS2) ont été identifiées dans notre cohorte. Nous émettons l’hypothèse que la nature des mutations complexes est responsable d’un dérèglement de la transcription du gène, ce qui a un impact néfaste sur la fonction mitochondriale et le tissu neuronal. / Autosomal Recessive Ataxias are a group of heterogeneous neurological disorders consisting of gross incoordination of muscle movements implying dysfunction of parts of the nervous system that coordinate movement such as the cerebellum. Several hereditary forms exist for these patterns of neurological dysfunction. In this thesis we reported the identification and characterization of a new form in the French-Canadian population. Autosomal Recessive Spastic Ataxia with frequent Leukoencephalopathy (ARSAL; also referred to as Autosomal Recessive Spastic Ataxia type 3 (SPAX3); OMIM 611390) is the second recessive spastic ataxia originally described in the French-Canadian population. Furthermore, close to 50% of our cases share a Portneuf region origin. In 2006 we described the cardinal features of this new form of ataxia. A first genome wide scan was performed on three informative families with microsatellite (single tandem repeat) markers and a parametric linkage analysis. This allowed us to identify a candidate interval on chromosome 2q33-34. Sequencing of more than 37 genes did not uncover the putative mutation. In order to refine this candidate interval, we have a second genome scan using single nucleotide polymorphism SNP markers and we have identified a smaller candidate interval of 0.658 Mb in which there are nine genes. The use of a multimodal approach was required to uncover and characterize the three mutations (one deletion and two complex rearrangements) in the mitochondrial met-tRNA synthetase gene (MARS2). We suggest that complex rearrangement of the 5’ region of the gene has a great impact on the gene transcription regulation, which affect its mitochondrial function and impair the neuronal tissue.
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Functional Characterization and Surface Mapping of Frataxin (FXN) Interactions with the Fe-S Cluster Assembly ComplexThorstad, Melissa 16 December 2013 (has links)
In 1996, scientists discovered a connection between the gene for the human protein frataxin (FXN) and the neurodegenerative disease Friedreich’s ataxia (FRDA). Decreased FXN levels result in a variety of aberrant phenotypes including loss of activity for iron-sulfur containing enzymes, mitochondrial iron accumulation, and susceptibility to oxidative stress. These symptoms are the primary focus of current therapeutic efforts. In contrast our group is pursuing an alternate strategy of first defining FXN function at a molecular level then using this information to identify small molecule functional replacements. Recently, our group has discovered that FXN functions as an allosteric activator for the human Fe-S cluster assembly complex. The work presented here helps to further define molecular details of FXN activation and explain how FRDA missense mutants are functionally compromised. First, the FRDA missense mutants L182H and L182F were investigated. Unlike other characterized FRDA missense mutants, the L182F variant was not compromised in its ability to bind and activate the Fe-S assembly complex. The L182H variant exhibited an altered circular dichroism signature; suggesting a change in secondary structure relative to native FXN, and rapidly degraded. Together these studies suggest that L182 variants are less stable than native FXN and are likely prone to degradation in FRDA patients. Second, as a regulatory role of FXN suggests that its function is likely controlled by environmental stimuli, different maturation forms of FXN as well as post-translational modification mimics were tested as mechanisms to control FXN regulation. Here experiments were designed to test if a larger polypeptide form of FXN represents a functional form of the protein. Kinetic and analytical ultracentrifugation studies revealed a complex heterogeneous mixture of species some of which can activate the Fe-S assembly complex. A previously identified acetylation site was also tested using mutants that mimic acetylation. These mutants had little effect on the ability of FXN to bind and activate the assembly complex. Third, mutagenesis experiments were designed in which the FXN surface residues were replaced with alanine and the resulting variants were tested in binding and activity assays. These experiments revealed a localized “hot-spot” on the surface of FXN that suggests small cyclic peptide mimics might be able to replace FXN and function as FRDA therapeutics. Unexpectedly, one of the FXN variants exhibited significantly tighter binding and could have relevance for therapeutic development.
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