A neuropatia motora multifocal (NMM) é uma neuropatia inflamatória de baixa prevalência, 0,6/100.000 pacientes, caracterizada por uma fraqueza muscular progressiva, assimétrica e distal, sem comprometimento sensitivo. A NMM pode mimetizar a esclerose lateral amiotrófica (ELA), outras variantes da doença do neurônio motor e outras polineuropatias inflamatórias desmielinizantes crônicas, com início assimétrico. A diferenciação é importante, tendo em vista as especificidades da evolução e do tratamento das referidas neuropatias. O principal achado eletrofisiológico é o bloqueio de condução nervosa na ausência de anormalidades sensitivas. A fisiopatogenia da NMM é pouco conhecida. O frequente achado de anticorpos circulantes contra o monoassialogangliosídeo (GM1) é sugestivo de que possa haver seu comprometimento em alterações estruturais nodais e perinodais, com comprometimento multifocal da condução nervosa. O corolário desses distúrbios são paresias e paralisias, também de distribuição multifocal. A Imunoglobulina humana por via endovenosa em altas doses constitui o tratamento de escolha. Novas estratégias de tratamento alternativas são necessárias para prevenir fraqueza muscular permanente e incapacidade. Poucos estudos e revisões bibliográficas têm elucidado as características clínicas da NMM, com a ausência na literatura de publicações de série de casos nacionais. No presente estudo, a partir de uma revisão retrospectiva, serão avaliados os aspectos clínicos- eletrofisiológicos da NMM, a fim de se obter um maior entendimento da evolução da doença. / The multifocal motor neuropathy (MMN) is an inflammatory neuropathy that has low prevalence (0.6 / 100,000 patients). It is characterized by progressive, asymmetric and distal muscle weakness without sensory impairment. The MMN can mimic amyotrophic lateral sclerosis (ALS), other motor neuron disease variants and other chronic inflammatory demyelinating polyneuropathy, with asymmetric start. Differentiation is important, given the specificities of the development and treatment of these neuropathies. The main electrophysiological finding is the nerve conduction block in the absence of sensory abnormalities. The pathophysiology of MMN is little known. The frequent finding of circulating antibodies against monoassialogangliosides (GM1) is suggestive that there may be their involvement in nodal and perinodal structural changes with multifocal impairment of nerve conduction. The corollary of these disorders is paresis and paralysis, with also multifocal distribution. The human immunoglobulin intravenously in high doses constitutes the treatment of choice. New alternative treatment strategies are needed to prevent permanent muscle weakness and disability. Few studies and literature reviews have elucidated the clinical features of MMN and there are no case series publications in the national literature. In this study, from a retrospective review, will be assessed clinic and electrophysiological features of MMN in order to obtain a greater understanding of disease progression.

A herança autossômica recessiva pode ser responsável por aproximadamente 77% dos casos de surdez hereditária. Em 1996, Chaib e col. mapearam o loco responsável por surdez profunda neurossensorial de herança recessiva na região cromossômica 2p22-23 (DFNB9). Em 1999, Yasunaga e col. identificaram esse gene como o que codifica a proteína OTOFerlina (OTOF) nessa região. Até hoje, já foram descritas 31 mutações patogênicas diferentes no gene OTOF em populações de várias origens, com destaque a mutação Q829X que foi encontrada em ~3% dos casos de surdez na Espanha (Migliosi e col., 2002; Rodríguez-Ballesteros e col., 2003). Alguns pacientes com mutações no gene OTOF apresentavam neuropatia auditiva, um tipo de deficiência auditiva neurossensorial caracterizada pela ausência ou anomalia das ondas no exame dos Potenciais Evocados Auditivos do Tronco Encefálico ou BERA com a presença das emissões otoacústicas e/ou microfonismo coclear. O objetivo desse projeto foi investigar a contribuição relativa das mutações no gene OTOF ao casos de neuropatia auditiva e de outros tipos surdez em famílias brasileiras. Uma amostra de 343 propósitos portadores de deficiência auditiva foi submetida ao estudo da mutação Q829X. Não foi identificada em nenhum caso. Dessa casuística foram selecionados 48 propósitos de famílias com consangüinidade ou com 2 ou mais afetados na irmandade e quatro pacientes com neuropatia auditiva e com consangüinidade parental ou com dois ou mais afetados na irmandade. Além disso, foram também selecionados 7 casos isolados com neuropatia auditiva e 5 casos de portadores de alterações no tronco encefálico. Essa amostra totalizou 64 propósitos. Propósitos dessas 64 famílias foram genotipados em relação a cinco marcadores de microssatélites ligados ao gene OTOF. A análise dos haplótipos excluiu ligação ao gene OTOF em 34 casos, 19 não eram conclusivos e 11 indicaram possibilidade de ligação ao gene OTOF (incluindo uma família com pais consangüíneos e neuropatia auditiva e três propósitos com neuropatia auditiva). Simultaneamente, os 64 propósitos foram triados para mutações em oito exons do gene OTOF, nos quais mutações já haviam sido descritas, por meio de SSCP seguido de seqüenciamento. Os 11 casos com resultados compatíveis com ligação ao gene OTOF (4 com neuropatia auditiva) e os sete casos de neuropatia auditiva foram selecionados para o seqüenciamento de todos os exons (total de 18 propósitos). Identificamos no total 58 alterações diferentes. Onze variantes eram potencialmentes patogênicas, encontradas em sete dos propósitos, todos pertencentes ao grupo dos 18 selecionados. Quatro casos eram heterozigotos compostos [98G>A (R33Q) e 2401G>T e 2402A>T (E801L)]; [1841G>A (G614E) e 3239G>C (R1080P)], [3751T>G (C1251G) e 5431A>T (K1811X)] e [2348delG (G783fs) e 5800-5801insC (L1934fs)], dois eram heterozigotos [1552-1567del16 (R518fs); 2905- 2923del19ins11 (A969fs)] sem que uma segunda mutação fosse detectada e um apresentava a mutação em homozigose [3400C>T (R1134X)]. Desses sete propósitos com mutações patogênicas, somente um paciente com mutação em heterozigose não apresentava neuropatia auditiva. Dentre os 11 casos com neuropatia auditiva, seis tinham pelo menos uma mutação no gene OTOF que poderia ser a causa de surdez. Esse achado reforça a associação entre o fenótipo da neuropatia auditiva e mutações no gene OTOF. A variante Q829X não foi encontrada nenhuma vez em nossa amostra, portanto, não deve ser causa importante de surdez na nossa população. Porém, nosso estudo mostra que mutações no gene OTOF são causas freqüentes de neuropatia auditiva no Brasil (mais de 50% dos casos). Nossos resultados reforçam a hipótese que pacientes com neuropatia auditiva devem ser selecionados para pesquisa de mutações no gene OTOF e que talvez mais de 50% dos casos de neuropatia auditiva tenham causa genética. / 77% of nonsyndromic prelingual deafness have an autosomal recessive inheritance. In 1996, Chaib et al. mapped a locus associated with sensorineural nonsyndromic recessive deafness to chromosome region 2p22-23 (DFNB9) by linkage studies. In 1999, Yasunaga et al. identified the OTOF gene encoding OTOFerlin, in this region. To date, there are 31 different pathogenic mutations described in the OTOF gene, from populations of variable origins. A Q829X mutation was found at a frequency of ~3% of deafness in Spain (Migliosi e col., 2002; Rodríguez-Ballesteros e col., 2003). Some affected individuals with mutations in the OTOF gene were reported to present auditory neuropathy, a type of deafness characterized by an absent or severely abnormal auditory brainstem response, with preservation of otoacoustic emissions and/or cochlear microphonics. The main purpose of this project was to investigate the relative contribution of OTOF mutations to auditory neuropathy and other type of deafness, amongst Brazilian families. We enrolled 343 Brazilian unrelated subjects with nonsyndromic hearing loss. A specific test for the Q829X mutation was performed first. We failed to find any subjects carrying this mutation. From this group, we selected 48 probands from families with consanguinity or with two or more affected sibs and four probands with diagnosis of auditory neuropathy and from consanguineous unions or with two or more affected sibs. In addition, we selected 7 isolated subjects with auditory neuropathy and 5 cases with diagnosis of brainstem alteration. This gave a total of 64 probands. Subjects from the 64 families were genotyped for five microsatellites markers, linked to the OTOF gene. The analysis of the haplotype excluded linkage to the OTOF gene in 34 families, it was inconclusive in 19 families and it showed compatibility with linkage in the remaining 11 families (including one with consanguineous parents and auditory neuropathy and three with diagnosis of auditory neuropathy). Simultaneously, the 64 subjects were screened for mutations in 8 exons previously identified to other mutations using the SSCP technique. In positive cases, DNA sequencing was carried out. In the 11 subjects consistent with putative linkage to OTOF gene and the 7 isolated cases of auditory neuropathy, an exon by exon screening for mutations in the OTOF gene was performed using DNA sequencing (Total of 18 subjects). We found a total of 58 different variants. Eleven were possibly causative mutations and were found in seven of the 18 subjects. Amongst them, four cases were compound heterozygotes R33Q with E801L, G614E with E1080P, 2348delG with 5800-5801insC and K1811X with C1251G, two cases were heterozygotes [1552- 1567del16 and 2905-2923del19in11] without a second mutation and one presented a mutation in homozygous form [3400C>T (R1134X)]. Among these seven probands, only one patient with a heterozygote mutation did not have a diagnosis of auditory neuropathy. In the 11 cases of auditory neuropathy, six had at least one mutation in the OTOF gene that is the probable cause of their deafness. These findings support the association between auditory neuropathy and mutations in the OTOF gene. While we failed to confirm the high frequency of Q829X mutation found in Spain, our study shows that mutations in the OTOF gene are frequent causes of auditory neuropathy in Brazil (more than 50%). Our results reinforced that patients with auditory neuropathy must be selected for mutation detection in the OTOF gene and that more than 50% of cases of auditory neuropathy have a defined genetic etiology.

Submitted by Nadir Basilio (nadirsb@uninove.br) on 2016-05-18T14:21:17Z No. of bitstreams: 1 Mozania Reis de Matos.pdf: 2867660 bytes, checksum: ba235c77e42996f7aa6a0a4de5a2c5cd (MD5) / Made available in DSpace on 2016-05-18T14:21:17Z (GMT). No. of bitstreams: 1 Mozania Reis de Matos.pdf: 2867660 bytes, checksum: ba235c77e42996f7aa6a0a4de5a2c5cd (MD5) Previous issue date: 2015-03-03 / In practical prevention , the instruments that extend self-care are welcome. Added to this the stimulus promotion, health education and the interdisciplinary care. The Patient Interpretation of Neuropaty (PIN), is a questionnaire of Interpretation of neuropathy by patient, developed and validated in the USA and in England (UK). By means of this instrument, the patient makes the self-evaluation of your foot and health care to be carried out with it, aiming at the prevention of ulcer diabetic foot. Thus, the aim of the present study is to translate and validate the questionnaire of interpretation of neuropathy for the Portuguese and assess the degree of understanding of the patients on the questions of (PIN). Participated in this study 100 patients at the outpatient clinic of foot insensitive of the Institute of Orthopedics and Traumatology, University of Sao Paulo. Were used parametric and non-parametric tests in the analysis of data.The values obtainedwith the BrazilianversionPINare verysimilar to the valuesof the original versions, theUSAandtheUK.We think it isa valuabletool providingthe patientobserveneuropathicchangesthat increase the risk of ulcers on the feet. The questionnairetranslated and validatedfor the Portuguese language, soit seemsto be a reliableandapplicabletool to evaluate theself-careof the patientat the same timethat allows thehealthcare professionalto designeffective measuresforprevention ofdiabetic footulcer, resulting in a betterprognosisandquality of life ofdiabetes patientswithND. / Nas práticas de prevenção, os instrumentos que ampliem o autocuidado são bem vindos. Soma-se a isto o estimulo a promoção, a educação em saúde e o atendimento interdisciplinar. O PatientInterpretationofNeuropaty (PIN), é um questionário de Interpretação da Neuropatia pelo Paciente, desenvolvido e validado nos USA e na Inglaterra(UK). Por meio deste instrumento o paciente faz a auto avaliação do seu pé e dos cuidados de saúde a serem realizados com ele, visando à prevenção da úlcera de pé diabético. Sendo assim o presente estudo tem como objetivo traduzir e validar o questionário de interpretação da neuropatia para o português e avaliar o grau de compreensão dos pacientes sobre as indagações do (PIN). Participaram deste estudo 100 pacientes do ambulatório de pé insensível do Instituto de Ortopedia e Traumatologia da Universidade de São Paulo. Foram usados testes paramétricos e não paramétricos na análise de dados. Os valores obtidos com a versão Brasileira do PIN são muito semelhantes aos valores das versões originais, dos USA e da U.K. Julgamos ser um instrumento valioso que propicia ao paciente observar alterações neuropáticas que aumentam o risco de úlcera nos pés. O questionário traduzido e validado para a língua portuguesa, parece assim ser um instrumento confiável e aplicável paraavaliar o autocuidado do paciente,ao mesmo tempo quepermite ao profissional de saúde desenhar medidas efetivas para prevenção da úlcera de pé diabético,ocasionando um melhor prognostico e qualidade de vida dos portadores de diabetes com ND.

This study examined the association between neuropathy limitations and depression in chemotherapy patients currently on treatment with a taxane-based, platinum-based or plant alkaloid chemotherapy drug. The Overall Neuropathy Limitations Scale (ONLS) and the Beck Depression Inventory-Short Form (BDI-SF) were used to assess neuropathy limitations and depression in 24 chemotherapy patients with reported symptoms of peripheral neuropathy. Average age of patients was 65 years, 66.6% were female, and average number of chemotherapy cycles completed was 5.6. Of the 24 patients, 37.5% of patients were on a single agent taxane-based drug, 37.5% of patients were on a taxane-based drug with a platinum based drug, 16.6% of patients were on a plant alkaloid, and 8.3% were on a combination of a taxane-based and another non-neurotoxic chemotherapy drug. The scores on both the BDI-SF and ONLS were very low. The mean score on the BDI-SF was 4.1 with a standard deviation of 2.7. The mean score on the ONLS was 2.2 with a standard deviation of 1.5. The study showed a non-significant relationship between neuropathy limitations and depression in chemotherapy patients. These findings show no association between neuropathy limitations and depression. Although all of these patients had symptoms of peripheral neuropathy, they were not severe enough to interfere with daily activities. The lack of relationship was not unexpected given the low scores on both the BDI-SF and ONLS. Future research should re-evaluate this relationship with a larger, more diverse sample.

京都大学 / 0048 / 新制・課程博士 / 博士(社会健康医学) / 甲第22888号 / 社医博第112号 / 新制||社医||11(附属図書館) / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 川上 浩司, 教授 今中 雄一, 教授 稲垣 暢也 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM

This research focused on the identification and description of predictors of pediatric and adult cochlear implantation outcomes in a South African cohort and the depiction of profound childhood hearing loss in terms of risk and intervention profiles. Study I described profound childhood hearing loss in a South African cohort of pediatric cochlear implant (CI) recipients in terms of risk profile and age of diagnosis and intervention. A retrospective review of patient files for 264 pediatric CI recipients from five CI programs was conducted. For all subjects, permanent congenital and early onset hearing loss (PCEHL) was confirmed under the age of five years old. The most prevalent risks for profound PCEHL were neonatal intesive care unit (NICU) admittance (28.1%), family history of childhood hearing loss (19.6%) and prematurity (15.1%). An associated syndrome was diagnosed in 10% of children and 23.5% had at least one additional developmental condition. Hearing loss for most (77.6%) children was confirmed as congenital or early onset, while 20.3% presented with postnatal onset of hearing loss. Auditory Neuropathy Spectrum Disorder (ANSD) was diagnosed in 5% of children, with admittance to NICU (80%) and hyperbilirubinemia (50%) being the most prevalent risk factors for these cases. Hearing loss was typically diagnosed late (15.3 months), resulting in delayed initial hearing aid fitting (18.8 months), enrollment in early intervention services (19.5 months), and eventual cochlear implantation (43.6 months). Delayed diagnosis and intervention predispose this population to poorer outcomes. / Thesis (DPhil)--University of Pretoria, 2016. / Speech-Language Pathology and Audiology / DPhil / Unrestricted

Title: Evaluation of selected postural stability parameters of diabetic patients Objectives: The main objective of this thesis is to describe the level of postural stability using the selected parameters in diabetes mellitus type 2 and to try to find a relationship between the severity of disease. We also want to compare the level of postural stability for such an illness with respect to the values of selected parameters of the healthy population. Methods: It is a descriptive study. The theoretical part was the basis of the processing problems of diabetes mellitus, with a focus on neuropathy. After that we evaluate data of selected parameters of postural stability in diabetes mellitus type 2. The second part involves the experiment, which refers to the evaluation of this issue in terms of posturographic analysis. A group of 30 type 2 diabetic patients were divided according to their diabetologist disease severity into 4 groups. A control group of healthy subjects included a sample of 7 probands. The patient group was composed of 18 men and 12 women, whose average age was 62.63 ± 15.55 years, average weight 91.17 ± 19.97 kg, who were subjected to measurement using a pressure plate FootScan (RScan International, Belgium). Results: We managed to prove, that subjects with diabetic neuropathy have...

L’identification des mutations génétiques impliquées dans les maladies rares est un prérequis pour mieux les comprendre, les traiter et accompagner les patients. Pour se faire, des modèles animaux présentant des maladies spontanées homologues aux maladies humaines sont très prometteurs. Le chien développe spontanément des maladies génétiques, rares chez l’Homme, mais fréquentes dans certaines races de chiens, ce qui simplifie les analyses génétiques. Ma thèse a porté sur deux maladies neurologiques : l’épilepsie et la neuropathie. Pour l’épilepsie, l’objectif était d’identifier des variants génétiques à partir de données de génotypage et de séquençage de génomes complets de deux races canines prédisposées. Un locus lié à la maladie a été identifié dans une race et des variants ponctuels et structuraux candidats ont été identifiés dans les deux races et sont en cours de validation par séquençage ciblé. Pour la neuropathie, l’équipe avait identifié une mutation en amont du gène GDNF, responsable d’une neuropathie sensitive chez des chiens de chasse. J’ai participé à la validation fonctionnelle de cette mutation. De plus, GDNF étant un excellent gène candidat pour les neuropathies humaines, j’ai séquencé ce gène chez 111 patients et extrait les variants de GDNF d’une base de données d’exomes et de génomes de plus de 600 patients. J’ai ainsi identifié 21 variants rares ou inconnus et les ai priorisé selon leurs impacts prédits in silico. Ces deux projets, alliant analyses génétiques, génomiques et fonctionnelles, chez l’homme et le chien, montrent le potentiel du chien pour l’identification de gènes candidats dans des maladies rares et/ou complexes chez l’Homme. / The identification of genetic mutations involved in rare diseases is a prerequisite for a better understanding, therapies and care to patients. To this aim, animal models declaring spontaneous diseases, homologous to human diseases are very promising. Dogs spontaneously develop genetic diseases, rare in humans, but frequent in some dog breeds, which simplifies the genetic analyzes. My thesis focused on two neurological diseases: epilepsy and neuropathy. For epilepsy, the goal was to identify genetic variants from genotyping data and sequencing of whole genome of dogs from two predisposed breeds. A disease-related locus has been identified in one breed and candidate point mutations and structural variants were identified in the two breeds and are being validated by targeted sequencing. For neuropathy, the team previously identified a mutation upstream of the GDNF gene, responsible for sensory neuropathy in hunting dogs. I participated to the functional validation of this mutation. In addition, GDNF being an excellent candidate gene for human neuropathies, I sequenced this gene in 111 patients and extracted GDNF variants from a database of exomes and genomes from more than 600 patients. I identified 21 rare or unknown variants and prioritized them according to their in silico predicted impacts. These two projects, combining genetics, genomics and functional analyses, in humans and dogs, show the dog's potential for identifying candidate genes in rare and / or complex diseases in humans.

京都大学 / 新制・課程博士 / 博士(薬学) / 甲第23147号 / 薬博第847号 / 新制||薬||242(附属図書館) / 京都大学大学院薬学研究科薬学専攻 / (主査)教授 中山 和久, 教授 土居 雅夫, 准教授 中川 貴之 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

Factors associated with predisposition and vulnerability to neurodegenerative disorders may be described usefully within the context of gene-environment interplay. There are many identified genetic determinants for so-called genetic disorders, and it is possible to duplicate many elements of recognized human neurodegenerative disorders in either knock-in or knock-out mice. However, there are similarly, many identifiable environmental influences on outcomes of the genetic defects; and the course of a progressive neurodegenerative disorder can be greatly modified by environmental elements. Constituent cellular defense mechanisms responsive to the challenge of increased reactive oxygen species represent only one crossroad whereby environment can influence genetic predisposition. In this paper we highlight some of the major neurodegenerative disorders and discuss possible links of gene-environment interplay. The process of adult neurogenesis in brain is also presented as an additional element that influences gene-environment interplay. And the so-called priming processes (i.e., production of receptor supersensitization by repeated drug dosing), is introduced as yet another process that influences how genes and environment ultimately and co-dependently govern behavioral ontogeny and outcome. In studies attributing the influence of genetic alteration on behavioral phenotypy, it is essential to carefully control environmental influences.