Yes / Attempts have been made to treat nonsense-associated genetic disorders by chemical agents and hence an improved mechanistic insight into the decoding of readthrough signals is essential for the identification and characterisation of factors for the treatment of these disorders. To identify either novel compounds or genes that modulate translation readthrough, we have employed dual reporter-based high-throughput screens that use enzymatic and fluorescence activities and screened bio-active NINDS compounds (n = 1000) and siRNA (n = 288) libraries. Whilst siRNAs targeting kinases such as CSNK1G3 and NME3 negatively regulate readthrough, neither the bio-active NINDS compounds nor PTC124 promote readthrough. Of note, PTC124 has previously been shown to promote readthrough. Furthermore, the impacts of G418 on the components of eukaryotic selenocysteine incorporation machinery have also been investigated. The selenocysteine machinery decodes the stop codon UGA specifying selenocysteine in natural selenoprotein genes. We have found that the eukaryotic SelC gene promotes the selenocysteine insertion sequence (SECIS)-mediated readthrough but inhibits the readthrough activity induced by G418. We have previously reported that SECIS-mediated readthrough at UGA codons follows a non-processive mechanism. Here, we show that G418-mediated promotion of readthrough also occurs through a non-processive mechanism which competes with translation termination. Based on our observations, we suggest that proteins generated through a non-processive mechanism may be therapeutically beneficial for the resolution of nonsense-associated genetic disorders. / Fellowship (awarded to MTN) from the Department of Health via the NIHR Comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London, Heptagon Life Science Proof of Concept Fund (grant KCL24 to MTN), the Great Britain Sasakawa 22 Foundation (grant B70 to MTN), the Royal Society (grant 43049 to MTN) and the University of Bradford (grants 003200 and DH005 to MTN).

No description available.

Thesis (DMed (Medicine. Internal Medicine))--University of Stellenbosch, 2009. / ENGLISH ABSTRACT: Progressive Myoclonic Epilepsies (PME) are characterized by progressive neurological impairment with myoclonus, seizures and dementia. In contradistinction, Familial Adult Myoclonic Epilepsy (FAME) is characterized by a benign course with rare seizures and cortical tremor. Both conditions have neurophysiological features suggestive of a cortical origin for their myoclonus. This dissertation reports on a novel form of PME. Many of those who were affected had no or minimal progression of their illness, low seizure frequency and were cognitively intact, suggestive of non-progressive disorders linked to the FAME loci. The majority of patients had features of cortical myoclonus, with generalized spike and wave discharges on electroencephalography, enlarged evoked potentials, enhanced C reflexes, and evidence of cortical excitability with magnetic stimulation. However, there was evidence of cerebellar dysfunction both pathologically and on imaging. With regard to similar conditions, dentatorubral pallidoluysian atrophy and Unverricht-Lundborg syndrome were excluded by linkage analysis. Similarly, linkage was not present for either the FAME 1 or FAME 2 loci. This syndrome is both clinically and genetically novel, and has a nosology which is difficult to characterize, in which the condition appears to lie on the spectrum between FAME and PME. The dissociation between the pathological and radiological findings which suggest subcortical dysfunction, and the neurophysiological findings of cortical myoclonus is striking. Review of the literature associated with the neurophysiology of related conditions associated with PME and FAME suggests that: 1. The assumption that generalized forms of myoclonic disorders represent multifocal forms of focal cortical discharges is an oversimplification. 2. The dissociation between initial and later components of the evoked potential is less robust than is generally supposed, and that subcortical inputs may affect later components of the evoked potential. 3. In a high proportion of cases the latency from cortical spike discharge to myoclonic jerk obtained with jerk locked averaging is incompatible with a cortical origin for the spike discharge. 4. The proposal that myoclonus is a form of long latency reflex and that myoclonus represents a reflex arising from subclinical sensory input, is unproven. / AFRIKAANSE OPSOMMING: Progressiewe Miokloniese Epilepsie (PME) word gekenmerk deur progressiewe neurologiese agteruitgang met mioklonus, konvulsies en demensie. Daarenteen word Familiële Volwasse Miokloniese Epilepsie (FAME) gekenmerk deur 'n benigne verloop met ongereelde konvulsies en kortikale tremor. Beide entiteite het neurofisiologiese kenmerke suggestief van 'n kortikale oorsprong vir die mioklonus. Hierdie manuskrip beskryf 'n nuwe vorm van PME. Baie van die aangetaste persone toon geen of min agteruitgang van die siekte oor tyd nie, met 'n lae frekwensie van konvulsies en is kognitief intak, wat suggestief is van 'n nie-progressiewe siekte gekoppel aan die FAME loci. Die oorgrote meerderheid van pasiente het kenmerke van kortikale mioklonus gehad, met algemene spits en boog ontladings op elektroensefalografie, hoë amplitude ontlokte potensiale, versterkte C-reflekse, en tekens van kortikale eksiteerbaarheid met magnetiese stimulasie. Met neurobeelding en patologie was daar egter bewyse van serebellêre disfunksie. Soortgelyke toestande, naamlik dentatorubro-pallidoluysiese atrofie en Unverricht-Lundborg sindroom is uitgeskakel deur middel van koppelingsanalise. Koppeling met die FAME1 of FAME2 loci kon ook nie aangetoon word nie. Die sindroom is beide klinies sowel as geneties nuut en het 'n nosologie wat moeilik gekaraktiseer kan word. Dit wil voorkom of die siekte op 'n spektrum lê tussen FAME en PME. Die dissosiasie tussen die patologiese en radiologiese bevindinge, wat suggestief is van subkortikale disfunksie, en die neurofisiologiese bevindinge van kortikale mioklonus is opmerklik. ’n Oorsig van die literatuur in verband met die neurofisiologie van toestande geassosieer met PME en FAME suggesteer die volgende: 1. Die aanname dat algemene vorme van miokloniese toestande multifokale vorme van fokale kortikale ontladings verteenwoordig, is ’n oorvereenvoudiging. 2. Die dissosiasie tussen inisiële en latere komponente van die ontlokte potensiaal is minder robuust as wat algemeen aanvaar word, en subkortikale invoer mag latere komponente van die ontlokte potensiaal beïnvloed. 3. In ’n groot proporsie van gevalle is die latensie van kortikale spits ontlading tot miokloniese ruk, verkry deur “jerk locked averaging”, nie verenigbaar met met ’n kortikale oorsprong vir die spits ontlading nie. 4. Geen bewyse bestaan vir die teorie dat mioklonus ’n vorm van ’n lang latensie refleks is en dat mioklonus ’n refleks is wat ontstaan uit subkliniese sensoriese invoer nie.

This thesis aims to understand the sociocultural aspects of the practice of consanguinity and the implications for healthcare. Consanguinity refers to intra-familial marriage and is commonly used to refer to cousin marriage. While consanguinity remains a global phenomenon, in the recent past, it has mostly been associated with non-Western populations, and has become a taboo in Western culture. Consanguinity is linked with negative health outcomes, mostly due to genetic disorders, although the extent of this link remains debatable. In the UK, consanguinity is linked mostly with the Pakistani community, which also have an overrepresentation of children with genetic disorders. In Luton, local health reports have suggested that consanguinity in the large Pakistani community plays a role in increased infant deaths. This makes Luton and the local Pakistani community, ideally placed for understanding the practice of consanguinity and the implications for healthcare. This thesis is conceptually grounded within a constructionist approach to understanding consanguinity with a critical analysis based on theories of discourse and power and knowledge. A qualitative research design was employed using an instrumental case study approach which focused on understanding consanguinity through Luton’s Pakistani community. Three main sample groups were selected, members of the Pakistani community who are not married to their cousins and are defined as lay members in this research, members of the Pakistani community in consanguineous marriages, and local service providers (primary and secondary care).

A síndrome de Noonan é uma doença autossômica dominante geneticamente heterogênea. Apesar de relativa alta prevalência, possui poucas informações referentes ao perfil cognitivo de seus portadores. Em literatura atual seus portadores são descritos com moderado prejuízo na cognição social em termos de reconhecimento das emoções e expressão do afeto, além de variável nível de inteligência. Em virtude da raridade de pesquisas na área psicológica acerca desta síndrome e, tomando por base recentes estudos, o presente estudo buscou esclarecer o perfil cognitivo de portadores da síndrome de Noonan decorrente de mutação do gene PTPN11, visando a contribuir para o estabelecimento de seu fenótipo comportamental. Foram estudadas 19 pessoas com a síndrome, de ambos os sexos, diagnosticadas clínica e laboratorialmente. A avaliação psicológica foi realizada por meio das escalas Wechsler de inteligência, pelo teste Figuras Complexas de Rey e pelo Teste Wisconsin de Classificação de Cartas. Os resultados obtidos indicaram uma variação entre inteligência normal a retardo mental leve, além de inflexibilidade mental e resposta não adaptada ao feedback ambiental. A avaliação aferiu presença de prejuízos em categorização e, ainda, falha no planejamento do ato motor (praxia) como responsável pelos escores rebaixados em memória episódica visuo-construtiva gráfica. Estes resultados sugerem a necessidade de ampliação de estudos que correlacionem aspectos cognitivos nas mais variadas patologias genéticas / Noonan syndrome is an autosomal dominant genetically heterogeneous disorder. Although relatively high prevalence, there are few information about the cognitive profile of people with the syndorme. Current literature describes moderately impaired social cognition in terms of emotion recognition and emotion affection, besides a variable level of intelligence. Because of rarely researches about psychological area in this syndrome and, based on recent studies, the present study looked for clarify the cognitive profile of people with Noonan syndrome with mutation in the PTPN11 gene, trying to contribute for the establishment of a phenotypic behavior. 19 persons with the syndrome were studied, both male and female, diagnosticaded clinical and laboratorilly. Psychological assessment was realized by using Wechsler intelligence Scales, Rey Complex Figure Test and Wisconsin Card Sorting Test. The results indicated a variation of normal intelligence to mild mental retardation, besides inflexibility and not adapted responses using environmental feedback. The assessment checked the presence of lacked in categories achieved and, even, fault in planning of motor act (praxis) as responsible for low scores in graphic visuoconstruction episodic memory. These results suggest the necessity of expansion of studies which correlated cognitive aspects in the most variables genetic pathologics

A síndrome de Noonan é uma doença autossômica dominante geneticamente heterogênea caracterizada por aspectos faciais distintos, atraso no desenvolvimento, dificuldades de aprendizado, baixa estatura, defeitos cardíacos congênitos, pectus excavatum e pescoço alado. Mutações que alteram genes que codificam proteínas com atuação na via RAS-MAPK causam a síndrome de Noonan e têm sido bastante estudadas. No entanto, há poucas informações sobre o perfil cognitivo da síndrome de Noonan. Neste estudo, diferentes aspectos da cognição foram avaliados (inteligência, funções executivas e habilidade viso-construtiva) em um grupo de 28 pacientes com a síndrome de Noonan, incluindo crianças e adultos, por meio das Escalas Wechsler de Inteligência, pelo Teste Wisconsin de Classificação de Cartas e pelo Teste Figuras Complexas de Rey. Houve uma variação de QI entre 59 e 119, além de melhores resultados em pacientes com mutação no gene PTPN11. No domínio das funções executivas, pacientes tiveram pior desempenho em categorização e flexibilidade cognitiva, embora sem prejuízos em sustentação atencional. Os pacientes demonstraram importantes falhas no planejamento do ato motor no teste de viso-construção e melhores resultados no grupo de pacientes com mutação no gene SOS1. Apesar da eficiência intelectual relativamente intacta, pacientes com a síndrome de Noonan mostraram prejuízos significativos em outros domínios cognitivos, indicando que a avaliação neuropsicológica é importante no manejo clínico da síndrome e um valioso recurso em seu planejamento terapêutico / Noonan syndrome is an autosomal dominant genetically heterogeneous disorder characterized by distinctive facial features, developmental delay, learning difficulties, short stature, congenital heart defects, pectus excavatum and webbed neck. Mutations that alter genes encoding proteins with roles in the RAS-MAPK pathway cause Noonan syndrome and have been well studied. However, there are few information about the cognitive profile of the Noonan syndrome. In this study, different aspects of cognition were assessed (intelligence, executive functions and visuo-construction ability) in a group of 28 patients with Noonan syndrome, including children and adults, by using Wechsler Intelligence Scales, Wisconsin Card Sorting Test and Rey Complex Figure Test. There was a variation of IQ between 59 and 119, besides better results in patients with mutation in PTPN11 gene. On the domain executive functions patients performed worse in categories achieved and cognitive flexibility, although no impairments in sustained attention. Patients showed important faults in planning of motor act in visuo-construction test and better results in the group of patients with mutation in SOS1 gene. Despite the relatively intact intelligence level, patients with Noonan syndrome showed significant impairments in other cognitive domains, indicating that neuropsychological assessment is important in clinical management of the syndrome and valiable resource of treatment planning

Prader-Willi syndrome (PWS) is caused by a loss of paternally expressed genes in an imprinted region of chromosome 15q. Among the canonical PWS phenotypes are hyperphagic obesity, central hypogonadism, and low growth hormone. Rare microdeletion PWS patients define a 91 kb minimum critical deletion region encompassing three genes, including the non-coding SNORD116. Induced pluripotent stem cells were generated from skin cells of three large deletion (5-6 Mb) PWS patients and one novel microdeletion (118 kb) PWS patient. We found that genes within the PWS region, including SNRPN and NDN, showed persistence of DNA methylation after iPSC reprogramming and differentiation to neurons. Genes within the PWS minimum critical deletion region remain silenced in both PWS large deletion and microdeletion iPSC following reprogramming. We find that NHLH2 and PC1 (protein and transcript) are reduced in PWS patient iPSC-derived neurons. Nhlh2 and Pcsk1 expression are reduced in hypothalami of fasted Snord116p-/m+ mice while hypothalamic AgRP and Npy remain elevated following refeeding in association with relative hyperphagia. Nhlh2-/- mice have growth deficiencies from 4-7 weeks of age, develop hyperphagic obesity as adults, and are hypogonadal. Nhlh2 promotes expression of the prohormone convertase, Pcsk1 (PC1). PC1 is a neuroendocrine prohormone convertase that catalyzes the processing of hormones to “mature,” active hormones. Humans and mice deficient in PC1 display hyperphagic obesity, hypogonadism, decreased growth hormone, and hypoinsulinemic diabetes due to impaired prohormone processing. Snord116p-/m+ mice display in vivo functional defects in prohormone processing of proinsulin, proGHRH, and proghrelin in association with reductions in islet, hypothalamic, and stomach PC1 content. Our findings suggest that the major neuroendocrine features of PWS are due to PC1 deficiency which results from absence of functional SNORD116. In addition to hyperphagic obesity and endocrinopathies, global developmental delay (delayed motor milestones, delayed language development) is a major characteristic of the Prader-Willi syndrome (PWS). We identified neuroanatomical defects in iPSC-derived neurons of individuals with PWS and mice deficient for Snord116. iPSC-derived neurons from PWS patients and neurons from Snord116p-/m+ mice, have smaller soma and decreased numbers of neurites. Reduced neuron cell body size is apparent in utero and persists at least until 4 weeks of age in Snord116p-/m+ mice. The reduction in neuronal soma size is associated with smaller neuronal nucleoli. There are also developmental defects in the endocrine pancreas of Snord116p-/m+ animals that persist into adulthood (≥20 weeks). Mice lacking Snord116 have smaller pancreatic islets and within the islet the percentage of δ-cells is increased, while the percentage of α-cells is reduced. In Snord116p-/m+ isolated islets, Sst and Hhex are upregulated while Ins1, Ins2, Pdx1, Nkx6-1, and Pax6 are downregulated. There is a 3-fold increase in the percentage of polyhormonal cells in the neonatal islets of Snord116p-/m+ mice, which was due to an increase in cells co-positive with somatostatin. Snord116 may play a role in islet cell lineage specification. Overall, this work suggests that the Snord116 gene cluster is important for developmental processes in the brain as well as endocrine pancreas and prohormone processing in multiple tissues. Loss of elements within this cluster could account for the PWS by virtue of effects on the expression of PCSK1.

A síndrome de Noonan é uma doença autossômica dominante geneticamente heterogênea caracterizada por aspectos faciais distintos, atraso no desenvolvimento, dificuldades de aprendizado, baixa estatura, defeitos cardíacos congênitos, pectus excavatum e pescoço alado. Mutações que alteram genes que codificam proteínas com atuação na via RAS-MAPK causam a síndrome de Noonan e têm sido bastante estudadas. No entanto, há poucas informações sobre o perfil cognitivo da síndrome de Noonan. Neste estudo, diferentes aspectos da cognição foram avaliados (inteligência, funções executivas e habilidade viso-construtiva) em um grupo de 28 pacientes com a síndrome de Noonan, incluindo crianças e adultos, por meio das Escalas Wechsler de Inteligência, pelo Teste Wisconsin de Classificação de Cartas e pelo Teste Figuras Complexas de Rey. Houve uma variação de QI entre 59 e 119, além de melhores resultados em pacientes com mutação no gene PTPN11. No domínio das funções executivas, pacientes tiveram pior desempenho em categorização e flexibilidade cognitiva, embora sem prejuízos em sustentação atencional. Os pacientes demonstraram importantes falhas no planejamento do ato motor no teste de viso-construção e melhores resultados no grupo de pacientes com mutação no gene SOS1. Apesar da eficiência intelectual relativamente intacta, pacientes com a síndrome de Noonan mostraram prejuízos significativos em outros domínios cognitivos, indicando que a avaliação neuropsicológica é importante no manejo clínico da síndrome e um valioso recurso em seu planejamento terapêutico / Noonan syndrome is an autosomal dominant genetically heterogeneous disorder characterized by distinctive facial features, developmental delay, learning difficulties, short stature, congenital heart defects, pectus excavatum and webbed neck. Mutations that alter genes encoding proteins with roles in the RAS-MAPK pathway cause Noonan syndrome and have been well studied. However, there are few information about the cognitive profile of the Noonan syndrome. In this study, different aspects of cognition were assessed (intelligence, executive functions and visuo-construction ability) in a group of 28 patients with Noonan syndrome, including children and adults, by using Wechsler Intelligence Scales, Wisconsin Card Sorting Test and Rey Complex Figure Test. There was a variation of IQ between 59 and 119, besides better results in patients with mutation in PTPN11 gene. On the domain executive functions patients performed worse in categories achieved and cognitive flexibility, although no impairments in sustained attention. Patients showed important faults in planning of motor act in visuo-construction test and better results in the group of patients with mutation in SOS1 gene. Despite the relatively intact intelligence level, patients with Noonan syndrome showed significant impairments in other cognitive domains, indicating that neuropsychological assessment is important in clinical management of the syndrome and valiable resource of treatment planning

The researcher examined the relationships between tuberous sclerosis, a multi-system genetic disorder, and school functioning through the use of a parent questionnaire and behavior rating scale. Information was gathered on the typical school experiences of children with tuberous sclerosis, including educational placement and services, behavioral functioning, parent involvement, and parent satisfaction. The results indicated that the majority of students with tuberous sclerosis are in special education and receiving related services. Three-quarters received one or more related services through the public school, and 30% received private related services paid for by their parents. Parent involvement was positively correlated with parent satisfaction, and negatively correlated with t-scores on the Withdrawn/Depressed subscale of the CBCL. Parents of children receiving Autism services were generally less satisfied with their children's school experiences than other parents. Parent satisfaction was negatively correlated with the Attention Problems scale of the CBCL. Student age was negatively correlated with time in inclusion and with related services. This information forms the basis for a discussion of school psychologists' roles in the educational success of students with tuberous sclerosis and the critical areas towards which interventions should be directed.

Bibliography: leaves 457-506. / 2 v. (506 leaves) : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Addresses the problem of giving genetic counselling to parents of a "sporadic" case of severe osteogenesis imperfecta, either of the perinatally lethal or severe deforming variety. / Thesis (M.D.)--University of Adelaide, Dept. of Paediatrics, 1994