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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
151

Functionaland structural studies of human frataxin: An iron chaperone protein for mitochondrial iron-sulfur cluster and heme biosyntheses

Yoon, Taejin 24 August 2005 (has links)
No description available.
152

Fisiopatología de la ataxia de Friedreich: Transporte y degeneración axonal

Muñoz Lasso, Diana Carolina 15 December 2017 (has links)
Friedreich ataxia (FRDA) is a recessive human disease of central and peripheral nervous system that affects children and young adults. FRDA is a peripheral neuropathy characterized by a initial degeneration of the large neurons of the dorsal root ganglia (DRG) or proprioceptive neurons. Most of the patients with FRDA have a homozygous guanine-adenine-adenine (GAA) expansion within the first intron of the gen that codifies for a small mitochondrial protein, frataxin (FXN). This mutation leads to a reduction of frataxin expression in all human cells, which produces changes in both the cell and mitochondrial physiology, resulting in a dysfunction of the mitochondrial energetic metabolism linked to the increase of oxidative stress and calcium dyshomeostasis. These cellular proceses are tightly related with the regulation of the actin and microtubule cytoskeletons and with vesicle trafficking. Here, we show how the absence of frataxin in the mouse models YG8R and YG8sR affects the axonal cytoskeleton of adult sensory neurons. Changes of actin and microtubule cytoskeletons and the failure of Ca 2+ signaling induce alterations of dynamics growth cones of sensory neurons, which in turn produce a reduction of their capacity to grow and regenerate their axons. This study shows how these events can lead to the neurodegeneration in Friedreich's ataxia. / La Ataxia de Friedreich (FRDA) es una enfermedad autosómica recesiva del sistema nervioso central y periférico que afecta a niños y adultos jóvenes. Esta neuropatía sensitiva está caracterizada por una degeneración primaria de las neuronas sensitivas largas del ganglio dorsal (DRG). En la mayoría de los pacientes con FRDA, la mutación consiste en una expansión homocigota del trinucleótido guanina-adenina-adenina (GAA) en el intrón 1 del gen que codifica para una proteína mitocondrial, la frataxina (FXN). La consecuencia de la mutación es la deficiencia de la frataxina, lo cual condiciona cambios en la fisiología mitocondrial y celular, teniendo como resultado una disfunción del metabolismo energético mitocondrial asociado con el incremento del estrés oxidativo en la célula y a una alteración de la homeostasis del calcio. Estos procesos están estrechamente relacionados con la regulación del citoesqueleto de actina, microtúbulos, y con el tráfico de vesículas. En este trabajo de tesis se demuestra cómo la estabilidad del citoesqueleto axonal de las neuronas sensitivas de dos modelos murinos YG8R e YG8sR están afectados debido a la falta de frataxina. Cambios en el citoesqueleto de actina y microtúbulos, unido al fallo en la señalización por Ca 2+ provocan una alteración en la dinámica de la forma del cono de crecimiento, disminuyendo el crecimiento y la regeneración axonal y afectando a la guía axonal en las neuronas sensitivas adultas. Este estudio muestra cómo estos eventos conducen a la neurodegeneración en la ataxia de Friedreich. / L'Ataxia de Friedreich (FRDA) és una malaltia autosómica recessiva del sistema nerviós central i perifèric que afecta a xiquets i adults joves. Aquesta neuropatia sensitiva ve caracteritzada per una degeneració primaria de les neurones sensitives llargues del gangli dorsal (DRG). En la majoria dels pacientes de FRDA la mutació consisteix en una expansió homozigòtica del trinucleòtid guanina-adenina-adenina (GAA) en l'intró 1 del gen que codifica per a la proteïna mitocondrial frataxina (FXN). La conseqüència d'aquesta mutació és la deficiencia de frataxina, aquest fet condiciona canvis en la fisiologia mitocondrial i cel.lular, tenint com a resultat una disfunció del metabolisme energètic mitocondrial associat a l'increment de l'estrés oxidatiu en la cèl.lula i una alteració de la homeòstasi del calci. Aquestos processos estàn íntimament relacionats amb la regulació del citoesquelet d'actina, microtúbuls i el tràfic de vesícules. En aquest treball de tesi doctoral es mostra com l'estabilitat del citoesquelet axonal de les neurones sensitives de dos models murins YG8R i YG8sR es troben afectats a causa de la deficiencia de frataxina. Canvis en el citoesquelet d'actina i microtúbuls, juntament a la fallida en la senyalitzación per Ca2+ provoquen una alteració en la dinámica de la forma del con de creixement, disminuint-lo junt amb la regeneració axonal i afectat la guia axonal en les neurones sensitives adultes. Aquest estudi posa de manifest com aquestos events condueixen a la neurodegeneració en la ataxia de Friedreich. / Muñoz Lasso, DC. (2017). Fisiopatología de la ataxia de Friedreich: Transporte y degeneración axonal [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/92842
153

Efeitos colaterais tardios na bexiga após radioterapia por câncer de colo de útero: avaliação da associação com polimorfismos de TP53, ATM e MDM2 / Late urinary bladder side effects after radiotherapy for cervical cancer: evaluation of the association with TP53, ATM and MDM2 polymorphisms

Pinezi, Juliana Castro Dourado 13 October 2014 (has links)
Introdução: Na prática clínica se observa que há diferenças na incidência de efeitos colaterais entre pacientes submetidos ao mesmo esquema terapêutico de radioterapia. Tais diferenças podem ser entendidas como uma radiossensibilidade individual determinada geneticamente. Objetivos: Este estudo teve como objetivo avaliar os efeitos tardios na bexiga em pacientes com câncer do colo uterino tratadas com radioterapia, com ou sem cirurgia, e o valor prognóstico de três polimorfismos genéticos de base única com relação ao desenvolvimento de cistite actínica. Material e métodos: Foi realizada uma análise retrospectiva de 50 pacientes com carcinoma cervical tratadas entre 1999 e 2004, com um mínimo de 6,5 anos de seguimento. A dose de radioterapia na bexiga foi considerada como a soma da dose da radioterapia externa com a dose de braquiterapia no ponto de bexiga definido pelo ICRU 38 (Relato número 38 da Comissão Internacional de Unidades e Medidas em Radiação). Para as correlações entre dose e efeito, foi calculada a dose biológica efetiva (BED) para cada caso. Para a avaliação dos efeitos tardios em bexiga, além dos dados descritos em prontuário, foi feito um questionário específico dirigido aos sintomas urinários, foi realizada cistoscopia em todas as pacientes e a escala LENTSOMA (efeitos tardios no tecido normal/ subjetivo-objetivo tratamento e exames) foi aplicada, utilizando o pior grau do efeito encontrado nos diferentes métodos de avaliação. Variantes genéticas do códon 72 da p53 (Arginina / Prolina), MDM2 SNP309 T/G e ATMex39 5557 G>A foram identificadas usando o método de genotipagem de SNP ABI SNaPshot e os resultados foram correlacionados com a incidência e grau de cistite actínica. Resultados: Complicações clínicas tardias da bexiga foram registradas em 17 (34%) pacientes usando dados coletados dos prontuários e em 41 (82%) pacientes pelo questionário de existência e gravidade dos efeitos tardios da irradiação. Essas complicações foram diretamente correlacionadas com a BED. Vinte e oito pacientes (56%) desenvolveram cistite diagnosticada por cistoscopia (16% Grau 2-4). MDM2 SNP309 TT associado a TP53 (P72R) GG foram relacionados com o aumento da incidência de cistite. Conclusões: Cistite actínica, em grau 2 ou maior, foi elevada nessa população e apresentou uma maior incidência quando realizado um questionário específico para tal. Houve associação com maior dose de radioterapia (BED Gy3 > 100 Gy) e com MDM2 SNP309 TT associado a TP53 (P72R) GG. / Introduction: In clinical practice it is observed that there are differences in the incidence of side effects among patients undergoing the same regimen of radiotherapy. Such differences can be understood as a genetically determined individual radiosensitivity. Purposes: This study aimed to evaluate urinary bladder late effects in patients with uterine cervix cancer treated with radiotherapy with or without surgery and the prognostic value of three single nucleotide polymorphisms (SNPs) related to radiation cystitis. Material and methods: retrospective analysis of 50 patients with cervical carcinoma treated between 1999 and 2004 with a minimum of 6.5 years of follow-up was performed. The radiation dose in the bladder was considered as the dose delivered by external beam irradiation plus the brachytherapy dose in the ICRU Report 38 (International Commission of Radiation Units and Measurements report number 38) bladder point. For dose-effect correlations the biological effective dose (BED) was calculated for each case. For evaluation of bladder late effects, besides the data collected from the charts review, a specific query directed to urinary symptoms was applied to the patients and also a cystoscopy was performed in all of them. The LENTSOMA (late effects of normal tissues/subjective-objective management analytic) scale for bladder late effects was applied. Genetic variants of p53 codon72 (arginine/proline) polymorphism, MDM2 SNP309 T/G and ATMex39 5557G>A were identified by using ABI SNaPshot SNP genotyping method. And the results were correlated with the incidence and grade of radiation cystitis. Results: Clinical late bladder complications were recorded in 17 (34%) patients using data collected from the charts and in 41 (82%) patients by the questionnaire for the existence and severity of late irradiation effects. These complications were directly related with the BED. Twenty eight patients (56%) developed cystitis diagnosed by cystoscopy (16% Grade 2-4). MDM2 SNP309 TT associated with TP53 (P72R) GG was related with increased incidence of cystitis. Conclusions: Late radiation cystitis grade 2 or greater were high in this population and presented a higher incidence when a specific questionnaire was used. Higher radiation dose (BED Gy3 > 100 Gy) and MDM2 SNP309 TT associated with TP53 (P72R) GG were correlated with bladder late effects
154

Regulation of innate immunity by DNA damage signaling

Harbort, Christopher 16 May 2017 (has links)
Neutrophile sind Zellen des Immunsystems von Säugetieren. Ihre zerstörerische Kraft spielt eine essentielle Rolle bei der Bekämpfung von Mikroorganismen, birgt aber auch das Potential erheblicher Kollateralschäden. Um chronische Entzündungen zu vermeiden, müssen diese Zellen streng reguliert werden. Die Neutrophilen selber nehmen an dieser Regulierung durch das Freisetzen von pro- und antiinflammatorischen Signalen Teil, unter anderem produzieren sie Zytokine oder initiieren rechtzeitig die Apoptose. Ein Eckpfeiler der Regulierung dieser Funktionen ist der oxidative Burst, bei dem Neutrophile reaktive Sauerstoffspezies (ROS) bilden. Die molekularen Ziele von ROS, welche diese Mechanismen regulieren, sind nicht alle identifiziert. Wir haben ataxia-telangiectasia mutated (ATM) Kinase, ein Regulator der DNA-Schadensantwort (DDR), als einen ROS-abhängigen Modulator von Neutrophilen identifiziert. Mutationen in ATM führen zu der Erkrankung Ataxia Telangiectasia (AT). AT Patienten leiden nicht nur unter den Folgen der fehlerhaften DNA-Reparatur sondern zeigen auch inflammationsassoziierte Krankheitserscheinigungen. Diese Beobachtung veranlasste uns, die Neutrophilen von AT Patienten genauer zu untersuchen. Wir zeigen, dass Neutrophile von AT Patienten erhöhte Menge an Zytokinen produzieren und Apoptose verzögern. Wir zeigen auch, dass DNA Schaden die Zytokinproduktion unterdrückt und Apoptose durch einen Mechanismus, der ATM, p38, und Chk2 verwendet initiiert. ROS sind notwendig für die endogene Regulierung dieser Prozesse. Diese Arbeit enthüllt einen neuartigen Mechanismus der Regulierung von Neutrophilen und etabliert die DDR als ein Ziel der ROS-gesteuerten Immunmodulation. Im Zusammenhang wird auch gezeigt, dass dysregulierte Neutrophilenaktivitäten einem inflammatorischen Phänotyp in AT zugrundeliegen könnte. Wir glauben, dass Entzündung eine treibende Kraft hinter Teilen der Pathologie von AT sein könnte und somit ein Ziel für klinische Intervention darstellt. / Neutrophils are cells of the mammalian innate immune system whose inflammatory functions are essential for microbial clearance but cause collateral tissue damage. Inflammation is regulated by both pro- and anti-inflammatory signals, including cytokine production and initiation of apoptosis. A cornerstone of the regulation of these functions is the oxidative burst, by which neutrophils generate reactive oxygen species (ROS). The downstream targets of ROS responsible for regulating these functions are not fully identified. We have identified ataxia telangiectasia mutated (ATM) kinase, a master regulator of the DNA damage response (DDR), as a ROS-dependent modulator of neutrophil responses. Mutations in ATM cause the disease Ataxia-telangiectasia (AT). In addition to disorders resulting from defective DNA repair, AT patients suffer from symptoms linked to inflammation, leading us to examine their neutrophil responses. We report that neutrophils from AT patients overproduce pro-inflammatory cytokines and delay apoptosis. We further show that DNA damage in neutrophils suppresses cytokine production and can initiate apoptosis via a mechanism involving ATM, p38, and Chk2. Furthermore, the oxidative burst was required for activation of ATM to regulate these processes.. This work reveals a novel mechanism for the regulation of neutrophil functions, establishing the DDR as a mediator of immune regulation by ROS. Furthermore, it indicates that neutrophil dysregulation may underlie chronic inflammation in AT patients. We propose that inflammation may be a driving force behind some of the pathology of AT, providing a potential target for clinical intervention for some symptoms of this currently untreatable disease.
155

Efeitos colaterais tardios na bexiga após radioterapia por câncer de colo de útero: avaliação da associação com polimorfismos de TP53, ATM e MDM2 / Late urinary bladder side effects after radiotherapy for cervical cancer: evaluation of the association with TP53, ATM and MDM2 polymorphisms

Juliana Castro Dourado Pinezi 13 October 2014 (has links)
Introdução: Na prática clínica se observa que há diferenças na incidência de efeitos colaterais entre pacientes submetidos ao mesmo esquema terapêutico de radioterapia. Tais diferenças podem ser entendidas como uma radiossensibilidade individual determinada geneticamente. Objetivos: Este estudo teve como objetivo avaliar os efeitos tardios na bexiga em pacientes com câncer do colo uterino tratadas com radioterapia, com ou sem cirurgia, e o valor prognóstico de três polimorfismos genéticos de base única com relação ao desenvolvimento de cistite actínica. Material e métodos: Foi realizada uma análise retrospectiva de 50 pacientes com carcinoma cervical tratadas entre 1999 e 2004, com um mínimo de 6,5 anos de seguimento. A dose de radioterapia na bexiga foi considerada como a soma da dose da radioterapia externa com a dose de braquiterapia no ponto de bexiga definido pelo ICRU 38 (Relato número 38 da Comissão Internacional de Unidades e Medidas em Radiação). Para as correlações entre dose e efeito, foi calculada a dose biológica efetiva (BED) para cada caso. Para a avaliação dos efeitos tardios em bexiga, além dos dados descritos em prontuário, foi feito um questionário específico dirigido aos sintomas urinários, foi realizada cistoscopia em todas as pacientes e a escala LENTSOMA (efeitos tardios no tecido normal/ subjetivo-objetivo tratamento e exames) foi aplicada, utilizando o pior grau do efeito encontrado nos diferentes métodos de avaliação. Variantes genéticas do códon 72 da p53 (Arginina / Prolina), MDM2 SNP309 T/G e ATMex39 5557 G>A foram identificadas usando o método de genotipagem de SNP ABI SNaPshot e os resultados foram correlacionados com a incidência e grau de cistite actínica. Resultados: Complicações clínicas tardias da bexiga foram registradas em 17 (34%) pacientes usando dados coletados dos prontuários e em 41 (82%) pacientes pelo questionário de existência e gravidade dos efeitos tardios da irradiação. Essas complicações foram diretamente correlacionadas com a BED. Vinte e oito pacientes (56%) desenvolveram cistite diagnosticada por cistoscopia (16% Grau 2-4). MDM2 SNP309 TT associado a TP53 (P72R) GG foram relacionados com o aumento da incidência de cistite. Conclusões: Cistite actínica, em grau 2 ou maior, foi elevada nessa população e apresentou uma maior incidência quando realizado um questionário específico para tal. Houve associação com maior dose de radioterapia (BED Gy3 > 100 Gy) e com MDM2 SNP309 TT associado a TP53 (P72R) GG. / Introduction: In clinical practice it is observed that there are differences in the incidence of side effects among patients undergoing the same regimen of radiotherapy. Such differences can be understood as a genetically determined individual radiosensitivity. Purposes: This study aimed to evaluate urinary bladder late effects in patients with uterine cervix cancer treated with radiotherapy with or without surgery and the prognostic value of three single nucleotide polymorphisms (SNPs) related to radiation cystitis. Material and methods: retrospective analysis of 50 patients with cervical carcinoma treated between 1999 and 2004 with a minimum of 6.5 years of follow-up was performed. The radiation dose in the bladder was considered as the dose delivered by external beam irradiation plus the brachytherapy dose in the ICRU Report 38 (International Commission of Radiation Units and Measurements report number 38) bladder point. For dose-effect correlations the biological effective dose (BED) was calculated for each case. For evaluation of bladder late effects, besides the data collected from the charts review, a specific query directed to urinary symptoms was applied to the patients and also a cystoscopy was performed in all of them. The LENTSOMA (late effects of normal tissues/subjective-objective management analytic) scale for bladder late effects was applied. Genetic variants of p53 codon72 (arginine/proline) polymorphism, MDM2 SNP309 T/G and ATMex39 5557G>A were identified by using ABI SNaPshot SNP genotyping method. And the results were correlated with the incidence and grade of radiation cystitis. Results: Clinical late bladder complications were recorded in 17 (34%) patients using data collected from the charts and in 41 (82%) patients by the questionnaire for the existence and severity of late irradiation effects. These complications were directly related with the BED. Twenty eight patients (56%) developed cystitis diagnosed by cystoscopy (16% Grade 2-4). MDM2 SNP309 TT associated with TP53 (P72R) GG was related with increased incidence of cystitis. Conclusions: Late radiation cystitis grade 2 or greater were high in this population and presented a higher incidence when a specific questionnaire was used. Higher radiation dose (BED Gy3 > 100 Gy) and MDM2 SNP309 TT associated with TP53 (P72R) GG were correlated with bladder late effects
156

Neural precursor cells: interaction with blood-brain barrier and neuroprotective effect in an animal model of cerebellar degeneration

Chintawar, Satyan 26 November 2009 (has links)
Adult neural precursor cells (NPCs) are a heterogeneous population of mitotically active, self-renewing multipotent cells of both adult and developing CNS. They can be expanded in vitro in the presence of mitogens. The B05 transgenic SCA1 mice, expressing human ataxin-1 with an expanded polyglutamine tract in cerebellar Purkinje cells (PCs), recapitulate many pathological and behavioral characteristics of the neurodegenerative disease spinocerebellar ataxia type 1 (SCA1), including progressive ataxia and PC loss. We transplanted neural precursor cells (NPCs) derived from the subventricular zone of GFP-expressing adult mice into the cerebellar white matter of SCA1 mice when they showed absent (5 weeks), initial (13 weeks) and significant PC loss (24 weeks). A stereological count demonstrates that mice with significant cell loss exhibit highest survival of grafted NPCs and migration to the vicinity of PCs as compared to wt and younger grafted animals. These animals showed improved motor skills as compared to sham animals. Confocal analysis and profiling shows that many of implanted cells present in the cerebellar cortex have formed gap junctions with host PCs and express connexin43. Grafted cells did not adopt characteristics of PCs, but stereological and morphometric analysis of the cerebellar cortex revealed that grafted animals had more surviving PCs and a better preserved morphology of these cells than the control groups. Perforated patch clamp recordings revealed a normalization of the PC basal membrane potential, which was abnormally depolarized in sham-treated animals. No significant increase in levels of several neurotrophic factors was observed, suggesting, along with morphological observation, that the neuroprotective effect of grafted NPCs was mediated by direct contact with the host PCs. In this study, evidence for a neuroprotective effect came, in addition to motor behavior improvement, from stereological and electrophysiological analyses and suggest that timing of stem cell delivery is important to determine its therapeutic effect.<p>In a brain stem cell niche, NSCs reside in a complex cellular and extracellular microenvironment comprising their own progeny, ependymal cells, numerous blood vessels and various extracellular matrix molecules. Recently, it was reported that blood vessel ECs-NSCs crosstalk plays an important role in tissue homeostasis. Bloodstream offers a natural delivery vehicle especially in case of diffuse neurodegenerative diseases which require widespread distribution of exogenous cells. As NSCs are confronted with blood-brain barrier endothelial cells (BBB-ECs) before they can enter into brain parenchyma, we investigated their interaction using primary cultures in an in vitro BBB model. We isolated human fetal neural precursor cells (hfNPCs) from aborted fetal brain tissues and expanded in vitro. We showed that in an in vitro model, human BBB endothelium induces the rapid differentiation of hfNPCs and allows them to cross the endothelial monolayer, with the differentiated progeny remaining in close contact with endothelial cells. These results are not reproduced when using a non-BBB endothelium and are partly dependent on the cytokine MCP1. Our data suggest that, in the presence of attractive signals released by a damaged brain, intravascularly administered NPCs can move across an intact BBB endothelium and differentiate in its vicinity. Overall, our findings have implications for the development of cellular therapies for cerebellar degenerative diseases and understanding of the brain stem cell niche. / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished
157

Études génétiques de familles récessives d’ataxies et de paraplégies spastiques

Noreau, Anne 07 1900 (has links)
Au cours des dernières années, la génétique a subi une progression phénoménale suite au développement de nouvelles technologies de séquençage. En effet, le séquençage de l’exome entier chez des familles a permis l’identification de nouveaux gènes impliqués pour plusieurs maladies. La neurologie a d’ailleurs bénéficié de ces avancées et plusieurs gènes ont été mis en évidence comme causatifs pour différents désordres neurologiques. Dans ce travail il sera question de deux désordres du mouvement pour lequel nous avons utilisés des technologies de séquençage traditionnelles, en l’occurrence le séquençage par Sanger, ainsi que de nouvelles technologies pour le séquençage de l’exome entier afin d’identifier de nouveaux gènes causatifs. Le premier désordre du mouvement qui sera décrit est l’ataxie, où ne seront abordées que les ataxies de cause génétiques, à transmission récessive. Le premier chapitre relatera les nouvelles mutations qui ont été trouvées chez des canadiens-français souffrant de l’ataxie de Beauce. Il sera aussi question de nouvelles mutations retrouvées dans deux autres populations, confirmant l’implication du gène SYNE1 dans les cas d’ataxie cérébelleuse à travers le monde. Le second chapitre fera la démonstration qu’il est souhaitable d’utiliser le séquençage de l’exome entier dans le but de poser un diagnostic clinique. En effet, il a été possible de trouver la cause génétique d’une famille comportant deux membres atteints d’atrophie congénitale du cervelet, où le symptôme prédominant est l’ataxie. Le séquençage de l’exome a permis la mise en évidence de mutations dans le gène PMM2, déjà connues pour cause le syndrome des glycoprotéines déficientes en hydrates de carbone. Dans un second temps, il sera question d’un autre désordre du mouvement la paraplégie spastique familiale (PSF). Le chapitre 3 relatera les mutations trouvées dans le gène CYP7B1 dans notre cohorte de patients PSF. / Over the past years, genetics has undergone a phenomenal growth due to the development of new sequencing technologies. Indeed, whole exome sequencing in families led to the identification of new genes involved in many diseases. Neurosciences were also able to benefit from these discoveries, where several new genes have been identified in several neurological diseases. This thesis will covered two different movement disorders for which we have used traditional sequencing technology, in this case by Sanger sequencing, combined with whole exome sequencing for new gene discovery. The first movement disorder that is described is ataxia, which will be focused on autosomal recessive mode of inheritance. The first chapter will relate the new mutations found in French-Canadian with ataxia of Beauce. We will also discuss new mutations found in two other populations, confirming the involvement of the gene SYNE1 in worldwide cases of cerebellar ataxia. The second chapter will demonstrate that it is desirable to use whole exome sequencing in order to make a clinical diagnosis. Indeed, it has been possible to find the genetic cause for a family with two members with congenital cerebellar atrophy, which the predominant symptom is ataxia. Exome sequencing allowed the identification of mutations in the PMM2 gene, already known to cause a syndrome leading to glycosylation deficit of glycoprotein. For the second part, we will cover another movement disorder call hereditary spastic paraplegia (HSP). Chapter 3 relates the mutations found in the CYP7B1 gene in our cohort of HSP patients.
158

Radiological studies of LMNB1-related autosomal dominant leukodystrophy and Marinesco-Sjögren syndrome

Finnsson, Johannes January 2016 (has links)
There are approximately 6000 to 8000 rare diseases, each with a prevalence of less than 1 / 10 000, but in aggregate affecting 6 to 8% of the population. It is important to evaluate disease development and progression to know the natural course of any disease. This information can be utilized in diagnostics and in assessing effects of therapeutic interventions as they become available. This thesis describes the natural clinical history and evolution of imaging findings of two rare diseases over approximately two decades. Papers I, II and III present clinical, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) findings in LMNB1-related autosomal dominant leukodystrophy (ADLD). MRI was found to be very sensitive in finding pathology in patients with LMNB1-related ADLD, even before the onset of clinical symptoms. However, even patients with widespread MRI changes can have a relatively mild symptomatology and present only slight disturbances in metabolic examinations such as MRS and FDG-PET. This is compatible with relatively intact axons, even as myelin impairment is widespread. Paper IV presents clinical and MRI findings in the brain and musculature in SIL1-positive Marinesco-Sjögren syndrome (MSS), and describes a new, mild phenotype of the disease with no intellectual disabilities and only slight motor disabilities. With a 19-year-long radiological follow-up, a slow progressive atrophic process in the cerebellum and brainstem could be demonstrated. MRI of the musculature shows early involvement of the quadriceps and gastrocnemii but not the tibialis anterior, progressing to widespread atrophy in the back and upper and lower limbs at the age of 20 years. In the mildest phenotype, the most severely affected muscles were the m gluteus maximus, m sartorius, m peroneus longus, and the lateral head of the m gastrocnemius.
159

Caractérisation clinique et génétique d’une nouvelle forme d’ataxie autosomique récessive dans la population québécoise

Thiffault, 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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Vliv rehabilitace elektrotaktilní stimulací jazyka na stabilitu stoje a chůze u pacientů s degenerativní cerebelární ataxií / The influence of rehabilitation by electrotactile stimulation through the tongue on stability of stance and gait in patients with degenerative cerebellar ataxia

Kodríková, Kateřina January 2011 (has links)
INTRODUCTION This graduation theses considers with the influence of rehabilitation by electrotactile stimulation of the tongue on stability of stance and gait in patients with degenerative cerebellar ataxia. Electrotactile stimulation of the tongue is an innovative method based on biofeedback principle, which uses additive sensory information about the position of the head to train the postural stability METHOD We used this method in six patients (four men and two women) with this disease. Patients went through intensive twelve-day therapy. The duration of the lessons was 30 minutes twice a day. We examined postural stability of the patients by using clinical evaluations (Balance Evaluation Systems Test, Dynamic Gait Index), posturography (modified Clinical Test of Sensory Interaction for Balance) and questionnaires (Activities -specific Balance Confidence, Dizziness Handicap Inventory) before and after the therapy. RESULTS The patients showed significant improvement in both clinical tests after the therapy. The results of posturography measurement are not so definite - the significant improvement was achieved only in some measured parameters. Both questionnaires did not show significant improvement. CONCLUSION The results of this study show, that electrotactile stimulation tongue could have a...

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