Mémoire (M.Sc.)-- Université du Québec à Chicoutimi, 1992. / Ce mémoire a été réalisé à l'UQAC dans le cadre du programme de maîtrise expérimentale (volet génétique), extensionné de l'Université Laval à l'UQAC. CaQCU Bibliogr.: f. 48-55. Document électronique également accessible en format PDF. CaQCU

Peripheral neuropathy associated with agenesis of the corpus callosum (ACCPN or HMSN/ACC) is a severe polyneuropathy affecting both the peripheral nervous system and the central nervous system. It is transmitted as an autosomal recessive trait and is particularly frequent in the French Canadian population of Quebec (Canada). The disease was linked to chromosome 15 in 1996 by Dr. Rouleau's team. / We genotyped polymorphic markers in the ACCPN candidate region on chromosome 15 in over 67 patients and 200 control individuals. Observation of affected haplotypes confirmed the presence of a founder effect in the French Canadian population. Recombination analysis reduced the candidate interval to approximately 2 cM between markers D15S1040 and ACTC on chromosome 15. Linkage disequilibrium analysis suggested the gene resides nearest marker D15S1232. A physical map of the newly refined candidate region was constructed using YAC, BAC and PAC clones. These clones were used to confirm the position of candidate ESTs and genes as being either within or outside the ACCPN candidate region. / The connexin 36 gene, which was confirmed to reside within the region, was excluded as the gene responsible for ACCPN using SSCP analysis. The SLC12A6 gene was also confirmed to reside within the candidate interval and was tested for mutations using SSCP, dHPLC and sequence analyses. We found a total of four disease-specific mutations in SLC12A6, all of which are expected to truncate the KCC3 protein (the protein produced by the SLC12A6 gene). Two of the four mutations were identified in the French Canadian population; 80 French Canadian ACCPN patients are homozygous for the c.2436delG in exon 18 and one French Canadian patient is a compound heterozygote, having the c.2436delG mutation as well as the 1584_1585delCTinsG mutation in exon 11. Two additional mutations were identified in one Turkish and one Italian family in exons 22 and 15 respectively. The effects of the c.2436delG mutation on KCC3 function was studied in X. laevis oocytes and the truncated protein is not functional. Finally, collaborators at Vanderbilt University disrupted the slc12a6 gene in the mouse and found a phenotype similar to the human disease. / Identification of SLC12A6 as the gene mutated in ACCPN will allow for accurate molecular diagnosis as well as carrier testing in the French Canadian population. It is also the first step in understanding the molecular mechanism leading to the disease.

No description available.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 6 uppsatser.

Introdução: Há poucos dados na literatura sobre a neuropatia periférica (NP) associada ao lúpus eritematoso sistêmico (LES). Objetivo: Descrever a NP atribuída exclusivamente ao LES e avaliar suas características clínicas, laboratoriais, tratamento e evolução a curto e longo prazo. Métodos: Pacientes com LES segundo critérios do American College of Rheumatology (ACR) de 1997, que tiveram NP sintomática comprovada por eletroneuromiografia foram identificados através de revisão do prontuário eletrônico. A NP foi classificada de acordo com a nomenclatura do ACR para síndromes neuropsiquiátricas do LES de 1999. Os critérios de exclusão foram qualquer outra condição clínica associada à ocorrência de NP: comorbidades, deficiência de vitamina B12, uso de drogas (álcool, talidomida, leflunomida, estatinas), infecções e outras doenças autoimunes. Controles com LES sem NP, pareados por idade e sexo, com duração de doença semelhante, foram selecionados. Resultados: NP devido exclusivamente ao LES foi identificada em 38 de 2074 pacientes (1,8%), sendo dois terços nos primeiros cinco anos da doença (63,2%). O tipo mais comum de NP foi a polineuropatia (71,1%), de padrão sensitivo-motor (68,4%). Pacientes com NP relacionada ao LES apresentaram maiores frequências de vasculite cutânea (50% vs. 21,1%, p=0,002), linfopenia (60,5% vs. 36,8%, p=0,027), anti-Sm (52,6% vs. 27,6%, p=0,013) e maiores escores de Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (11,5±10,5 vs. 4,9±6,7; p < 0,0001) comparados aos controles. Os escores de SLEDAI foram ainda mais altos em pacientes com início precoce da NP, com menos de um ano de diagnóstico da doença, comparados a pacientes com NP entre um e cinco anos e após cinco anos do início do LES (21,3±9,1 vs. 8,2±6,6 vs. 3,9±5,3; p < 0,001). Todos os pacientes com NP atribuída ao LES foram tratados com corticóides e 97,4% com terapia imunossupressora: ciclofosfamida intravenosa em 50% e azatioprina em 42,1% dos pacientes. Após um ano de acompanhamento, 92,1% dos pacientes apresentaram uma evolução favorável, com remissão total (36,8%) ou parcial (55,2%) do quadro neuropático, associada a redução da dose de prednisona (48,3±17,9 vs. 15,3±13,4mg/dia; p < 0,0001), da terapêutica sintomática (57,9% vs. 29,7%; p=0,02) e do escore SLEDAI (11,5±10,5 vs. 1,7±3,7; p < 0,0001). O grupo com início precoce da NP teve melhor resposta ao tratamento do que o grupo com início tardio (remissão completa após um ano: 61,5% vs. 25%, p=0,039). Após cinco anos de seguimento, 89,3% mantiveram remissão completa/parcial do quadro. Na análise multivariada, foi confirmada a associação significante entre NP e vasculite cutânea (OR 3,91; IC95% 1,59-9,54; p=0,003), anti-Sm (OR 2,77; IC95% 1,16-6,61; p=0,022) e linfopenia (OR 2,48; IC95% 1,05-5,89; p=0,039). Conclusão: a NP associada exclusivamente ao LES é uma manifestação incomum, caracterizada por um padrão bimodal, com um grupo de início precoce, associado a alta atividade de doença e maior taxa de remissão completa e um grupo de início mais tardio, com resposta parcial ao tratamento imunossupressor. Há um prognóstico geral favorável após um ano de tratamento, sem alterações significativas após cinco anos de seguimento / Introduction: There are few information in the literature regarding peripheral neuropathy (PN) associated to systemic lupus erythematosus (SLE). Objective: To describe PN attributed exclusively to SLE and evaluate its clinical, laboratorial characteristics, treatment, short and long-term outcome. Methods: SLE patients according to 1997 American College of Rheumatology (ACR) criteria were identified using an electronic medical record database. PN diagnosis was defined by neurological abnormalities associated with an altered electroneuromyography and classified according to 1999 ACR nomenclature for neuropsychiatric SLE syndromes. Clinical and laboratory data were evaluated at PN onset and after one and five years. Exclusion criteria were other conditions associated with PN: comorbidities, vitamin B12 deficiency, drugs (alcohol, thalidomide, leflunomide, statin), infections, and other autoimmune diseases. Age- sex- and disease duration-matched SLE patients without PN were selected as controls. Results: Lupus PN was identified in 38 of 2,074 patients (1.8%) and almost two-thirds had PN onset in the first five years of disease (63.2%). The most common type was polyneuropathy (71.1%) with sensory-motor pattern (68.4%). PN SLE had higher frequencies of cutaneous vasculitis (50% vs. 21.1%, p=0.002), lymphopenia (60.5% vs 36.8%, p=0.027), anti-Sm (52.6% vs. 27.6%, p=0.013) and higher Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores (11.5±10.5 vs. 4.9±6.7, p < 0.0001) compared to controls. SLEDAI scores were higher in patients who had PN with less than one year of disease diagnosis, compared to those with PN onset between one and five years or more than five years of SLE (21.3±9.1 vs. 8.2±6.6 vs. 3.9±5.3; p < 0.001). At PN diagnosis, all patients received glucocorticoids and 97.4% started immunosuppressive therapy (50% intravenous cyclophosphamide, 42.1% azathioprine). After one-year follow-up, 92.1% had a favorable outcome with complete (36.8%) or partial remission (55.2%), in parallel with a decrease in prednisone dose (48.3±17.9 vs. 15.3±13.4mg/d, p < 0.0001), symptomatic therapy (57.9% vs. 29.7%, p=0.02), and SLEDAI scores (11.5±10.5 vs. 1.7±3.7, p < 0.001). Early PN onset group had a better response to treatment compared to late PN onset (complete remission at one-year follow-up 61.5% vs. 25%, p=0.039). At five-year, 89.3% remained with complete/partial remission. In multivariate analysis, PN was associated to cutaneous vasculitis (OR 3.91; 95%CI 1.59-9.54; p=0.003), anti-Sm (OR 2.77; 95%CI 1.16-6.61; p=0.022), and lymphopenia (OR 2.48; 95%CI 1.05-5.89; p=0.039). Conclusion: PN attributed to SLE itself is a rare manifestation with a bimodal pattern, characterized by an early onset group associated with high disease activity and a higher rate of complete remission, and a late onset group with low disease activity and a partial therapy response. This study reveals a favorable outcome after one year of immunosuppressive therapy in most PN SLE patients, without significant changes at five years of follow-up

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and often dose-limiting side effect. Restless Legs Syndrome (RLS) is also a common sensory-motor neurological disorder, characterized by uncomfortable and unpleasant sensations in the legs, followed by an urgency to move them. The presence of CIPN has been associated with the risk of falls in cancer survivors. Objectives: To determine the frequency and factors associated with falls in chemotherapy patients, and to evaluate the possible association between suggestive symptoms of CIPN, RLS and falls. Design: A total of 234 oncological patients undergoing chemotherapy treatment were interviewed, with questions regarding sociodemographic data, diagnosis, treatment and occurrence of falls. Besides, it was used the Chemotherapy Induced Peripheral Neuropathy Assessment Tool (CIPNAT) and diagnostic criteria for SPI. Results: The mean age of the sample was 53.4 years (± 13.1), of which 73.9% were female. Suggestive symptoms of CIPN were present in 51.7% of the patients, and falls were reported in 30.7%. There was association between the presence of neuropathic symptoms and falls (p = 0.0191), with a 1.65 fold increase in the prevalence of falls compared to patients without neuropathic symptoms. In individuals younger than 65 years of age, we observed a greater association between CIPN symptoms and falls (p = 0.0016). Patients with falls had a higher score on items that assessed interference in daily life activities. In addition, there was also a statistically significant association of RLS with symptoms of CIPN (p = 0.0005), RLS with falls (p = 0.0152), and RLS associated with neuropathic symptoms with falls (p = 0.0061). Conclusions: The findings of the present study suggest that falls are common in chemotherapy patients, and symptoms of CIPN and RLS contribute to increased falls. Moreover, these two disorders, when associated, act synergistically, further increasing the prevalence of falls. / Introdução: A neuropatia periférica induzida por quimioterapia (NPIQ) é um efeito colateral comum e frequentemente dose-limitante. A Síndrome das Pernas Inquietas (SPI) também é uma desordem neurológica sensitivomotora comum, caracterizada por sensações desconfortáveis e desagradáveis nas pernas, seguidas de urgência em movimentá-las. A presença de NPQI tem sido associada ao risco de quedas em sobreviventes de câncer. Objetivos: Determinar a frequência e os fatores associados a quedas em pacientes em quimioterapia, e avaliar possível associação entre sintomas sugestivos de NPIQ, SPI e quedas. Métodos: Foram entrevistados 234 pacientes oncológicos em tratamento quimioterápico, com perguntas referentes a dados sociodemográficos, diagnóstico, tratamento e ocorrência de quedas, além de ter sido utilizada a Ferramenta de Avaliação de Neuropatia Periférica Induzida por Quimioterapia (FANPIQ) e aplicados critérios diagnósticos para SPI. Resultados: A média de idade da amostra foi de 53.4 anos (±13.1), sendo 73.9% do sexo feminino. Sintomas sugestivos de NPIQ estavam presentes em 51.7% dos pacientes, e em 30.7% foram relatadas quedas. Houve associação entre a presença de sintomas neuropáticos e quedas (p = 0.0191), com aumento de 1.65 vezes na prevalência de quedas em relação aos pacientes sem sintomas neuropáticos. Em indivíduos com menos de 65 anos observamos uma maior relação entre sintomas de NPIQ e quedas (p=0.0016). Pacientes com quedas apresentaram uma pontuação maior nos itens que avaliam a interferência nas atividades de vida diária. Além disso, também houve associação estatisticamente significante de SPI com sintomas de NPIQ (p=0.0005), SPI com quedas (p=0.0152), e SPI associada a sintomas neuropáticos com quedas (p=0.0061). Conclusões: Os achados do presente estudo sugerem que quedas são frequentes nos pacientes em quimioterapia, e sintomas de NPIQ e SPI contribuem para o aumento de quedas. E mais, que estas duas desordens, quando associadas, agem de forma sinérgica, aumentando ainda mais a prevalência de quedas. / Aracaju

Diss. (sammanfattning) Linköping : Linköpings universitet, 2005. / Härtill 4 uppsatser.