Rett syndrome is the manifestation of an X linked, mainly female, genetic, neurodevelopmental disorder that usually produces profound intellectual and physical disabilities including abnormal muscle tone, with a tendency to develop limb contractures, scoliosis, epilepsy and irregular respiration. There is characteristic hand stereotypy with· poor voluntary hand use, locomotion is compromised and speech is rare. Although the disorder is not progressive many sequele shorten life especially in the most severely affected. Subtle abnormalities, present from birth, are frequently overlooked because there is some developmental progress until a period of regression at around one year of age when speech and hand use diminish. This thesis gives an account of clinical, physiological and genetic studies carried out between 1982 and 2005 with the aim of recording the natural history of the disorder and understanding its clinical manifestations. The subjects of these studies have been people of all ages, mainly from the British Isles, reported to have Rett syndrome by their physicians and families or carers (British Isles Survey, n=l228). Most have been examined and recorded on video by myself, many repeatedly. Fully informed parental consent and appropriate ethical approval has been given for all procedures. The early manifestations of the disorder were investigated from developmental histories and donated videos (78) taken by families before they were aware of the problem. The abnormal respiratory rhythms were investigated and characterised, using non-invasive measures of respiratory rhythm, carbon dioxide, oxygen, heart rate and blood pressure. The poor control of voluntary movement was investigated using electromagnetic stimulation of the cortex to record conduction in the motor pathways. Stereotyped hand movements were analysed from three-dimensional live recording and informal two-dimensional video. The prevalence of a toe anomaly was estimated, visual evoked potentials were recorded and a reported increase in urinary neopterin was investigated. The health of people in the British Survey was monitored longitudinally from family and physician reports and direct clinical examinations, data being stored on computer. Simple scores were generated to indicate separately the severity of the condition and health of the individual. The survey data has been used to estimate the prevalence of the disorder (I in 10,000 females), natural history from birth to death, the predictive value of the earliest signs, survival at different levels of severity, the impact of scoliosis surgery on health and has provided a foundation for studies relating clinical manifestations to specific mutations on the affected gene MECP 2 (Xq28). The studies have indicated the nature of the Rett disorder to be developmental and non-progressive, with primary impact on the processing functions of the brain, probably beginning in the brain stem before birth.

Postítulo en terapias de arte, mención musicoterapia / La presente monografía tiene por objetivo dar a conocer el proceso de práctica profesional del Postítulo en Terapias de Artes, mención musicoterapia, realizado en la Universidad de Chile. Éste se desarrolló en el Centro de rehabilitación Manantial, durante los meses de Septiembre a Diciembre del año 2012. El trabajo se basa en el proceso terapéutico junto a una joven de 26 años a la que en adelante nos referiremos como N, cuyo diagnóstico previo es de Síndrome de Rett. Se realizaron 14 sesiones en modalidad individual, las que se llevaron a cabo una vez por semana.

Introducción: El autismo es un trastorno infantil del desarrollo, que afecta el nivel cognitivo, conductual y lingüístico; esto se evidencia en el niño según los signos y síntomas a partir de los 3 años. En los últimos años a nivel mundial está ascendiendo, en Latinoamérica y en el Perú no existen estadísticas precisas sobre el número de niños con autismo, pues se considera dentro del grupo de discapacitados, constituyendo el 31.4% de la población total. Objetivo: Determinar el nivel de conocimiento sobre autismo y su relación con la participación de los padres en el tratamiento en la Asociación de padres y amigos de personas con autismo. Metodología: El tipo de investigación es cuantitativa de diseño correlacional, transversal y prospectivo. El área de estudio fue en Asociación de Padres y Amigos de personas con autismo, la población estuvo constituida por 50 padres de familia aplicando el muestreo no probabilístico. La técnica que se utilizó fue la encuesta y observación, los instrumentos fueron sometidos a pruebas de validez y confiabilidad. Los resultados fueron procesados en el programa Excel y SPSS v. 19, presentando tablas y gráficos estadísticos. Resultados: Se determinó que los padres tienen nivel de conocimiento medio sobre la enfermedad de sus hijos 68%, bajo 18% y alto 14%. Con respecto a la participación en el tratamiento de sus hijos se obtiene de forma adecuada 82% e inadecuadamente 18%. Conclusiones: Según los datos obtenidos, nos permite definir que a mayor conocimiento de los padres de niños autistas será proporcional la participación en el tratamiento respectivo, en el cual existe una correlación entre las variables establecidas.

Magisteruppsats i musikpedagogik (80 poäng)

DNA methylation is a common epigenetic mark that affects gene regulation, genomic stability and chromatin structure. In mammals, methylation is mainly found in the CpG dinucleotides. The CpG methylation signals can be recognised by the Methyl-CpG-Binding Protein (MBP) family which includes MeCP2, MBD1, MBD2, MBD3, MBD4 and Kiaso. MeCP2 and MBD1-4 (except mammalian MBD3) recognise methyl-CpG via their MBD domain whereas Kaiso interprets methylation through its Zn finger DNA binding domain. The TRD domains of MeCP2, MBD1 and MBD2 have been reported to recruit transcriptional co-repressors to the methylated DNA. A thymine DNA glycosylase domain is located at the C-terminal region of MBD4. This study concerns the molecular details of the methyl-CpG recognition by the MBD domain of MeCP2. To achieve this, the MeCP2 MBD domain has been expressed, purified and co-crystallised with a 20 bp DNA fragment from the BDNF promoter. The DNA-protein cocrystal diffracted X-rays to a maximum resolution of 2.5Å using synchrotron sources. It belongs to space group C2 with unit cell dimensions: a = 79.71Å, b = 53.60Å, c = 65.73Å, and β = 132.1°. The X-ray structure of the MeCP2 MBD-DNA complex was solved using the SAD method. Structural analyses of the refined X-ray structure reveal that the methyl groups of the DNA make contact with a predominantly hydrophilic surface that includes tightly bound water molecules. From a structure of the MBD domain in MBD1, established by NMR, the binding specificity of the MBD domain had been thought to depend on hydrophobic interactions between the cytosine methyl groups and a hydrophobic patch within the MBD domain. The findings of this study suggest that MeCP2 recognises the hydration pattern of the major groove of methylated DNA rather than cytosine methylation per se. The X-ray structure also identifies a unique role of T158 and R106, the sites of the two most frequent Rett missense mutations. Both residues stabilise the tandem Asx-ST motif at the C-terminal region of MBD domain. Disruption of this tandem motif destabilises the DNA-protein interaction. The BDNF sequence in this study contains an AT run which displays unique properties of AT tract DNA. Previously, mutation of the AT run has been reported to decrease MeCP2 binding specificity. This study however demonstrated that a significant reduction can only be observed when both AT runs close to the methyl-CpG have been mutated. The X-ray structure of the MeCP2 MBD-DNA complex in this study rationalises the effects of the most common Rett mutations and provides a general model for methylated DNA binding that is dependent on structured water molecules.

Rett syndrome is a neurological condition that affects primarily girls. Approximately 40% of Rett syndrome cases arise from nonsense mutations. Several studies have shown that certain aminoglycosides can suppress some types of nonsense mutations in a context dependent manner, and allow the generation of a full length protein. It remains mostly unclear whether different nonsense mutations of MECP2 will be responsive to aminoglycoside treatment. In this study I tested whether some nonsense mutations of MECP2 seen clinically in Rett syndrome girls can be partially suppressed by aminoglycoside administration. My results show that aminoglycosides allow different mutant forms of MECP2 to be overcome in transiently transfected HEK-293 cells, but with differing levels of efficiency. Furthermore, I also show that aminoglycosides increased the prevalence of full length MeCP2 protein in a lymphocyte cell line derived from a Rett girl with R255X mutation. This study establishes the “proof of principle” that some nonsense mutations causing Rett syndrome can be suppressed by drμg treatment.

Rett syndrome is a neurological condition that affects primarily girls. Approximately 40% of Rett syndrome cases arise from nonsense mutations. Several studies have shown that certain aminoglycosides can suppress some types of nonsense mutations in a context dependent manner, and allow the generation of a full length protein. It remains mostly unclear whether different nonsense mutations of MECP2 will be responsive to aminoglycoside treatment. In this study I tested whether some nonsense mutations of MECP2 seen clinically in Rett syndrome girls can be partially suppressed by aminoglycoside administration. My results show that aminoglycosides allow different mutant forms of MECP2 to be overcome in transiently transfected HEK-293 cells, but with differing levels of efficiency. Furthermore, I also show that aminoglycosides increased the prevalence of full length MeCP2 protein in a lymphocyte cell line derived from a Rett girl with R255X mutation. This study establishes the “proof of principle” that some nonsense mutations causing Rett syndrome can be suppressed by drμg treatment.

Thesis (Ph.D.)--University of Delaware, 2009. / Principal faculty advisors: N. Carolyn Schanen and Mary C. Farach-Carson, Dept. of Biological Sciences. Includes bibliographical references.

Proefschrift Universiteit Maastricht. / Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.

Tese (doutorado)—Universidade de Brasília, Faculdade de Medicina, 2009. / Submitted by Larissa Ferreira dos Angelos (ferreirangelos@gmail.com) on 2010-04-05T19:16:20Z No. of bitstreams: 1 2009_LucianoFarage_sem_artigos_1_e_2_noPW.pdf: 2942784 bytes, checksum: f634e919b657549bb56016ffc57281b3 (MD5) / Approved for entry into archive by Lucila Saraiva(lucilasaraiva1@gmail.com) on 2010-05-18T01:02:43Z (GMT) No. of bitstreams: 1 2009_LucianoFarage_sem_artigos_1_e_2_noPW.pdf: 2942784 bytes, checksum: f634e919b657549bb56016ffc57281b3 (MD5) / Made available in DSpace on 2010-05-18T01:02:43Z (GMT). No. of bitstreams: 1 2009_LucianoFarage_sem_artigos_1_e_2_noPW.pdf: 2942784 bytes, checksum: f634e919b657549bb56016ffc57281b3 (MD5) Previous issue date: 2009 / Introdução: A Síndrome de Rett é uma desordem do neurodesenvolvimento ligada ao cromossomo X com um acometimento precoce na infância, que afeta, primariamente meninas. O lobo frontal é particularmente afetado. A base genética da doença, em 80% das meninas acometidas, está cionada às mutações no gene da proteína methyl-CpG binding protein 2 (MeCP2). Casuística e Métodos: Dois grupos de meninas afetadas, que preenchem os critérios clínicos e são positivas para mutações, foram avaliadas com espectroscopia (MRS) e tensor de difusão (DTI). Os dados foram comparados com controles pareados por idade e sexo. O fenótipo foi avaliado pelo perímetro cefálico, história de crises convulsivas, irregularidades respiratórias, alterações de marcha e fala. O genótipo foi avaliado pelo tipo de mutação existente. Os exames de ressonância magnética (RM) foram realizados em aparelho de 1,5T e incluíram avaliação anatômica (sagital T1, axial T2 e axial FLAIR). Quarenta meninas (idade média de 6,1 anos) foram submetidas à MRS uni-voxel, na substância branca do lobo frontal esquerdo, com TE de 35 ms.Foram obtidas as relações de N-acetil-aspartato (NAA), Colina (Co), mio-inositol (mI), Glutamato e Glutamina (Glx) sobre Creatina (Cr) e suas respectivas concentrações. Trinta e duas meninas (idade média de 5,5 anos) foram avaliadas com DTI, obtidos com single-shot echo-planar com SENSE (fator de 2,5), espessura de 2,5 mm, 30 orientações e valor b de 700 s/mm2. As medidas de anisotropia fracionada (FA) foram obtidas com o delineamento manual de dezesseis regiões de interesse nos compartimentos supra e infratentorial. Assimetrias entre os lados foram avaliadas pela medida da FA e pelo índice de lateralidade. Resultados: Os resultados demonstraram que a NAA/Cr diminuiu e a mI/Cr aumentaram com a idade (p<0,03), enquanto essas razões permanecem estáveis no grupo controle. A razão de Glx/Cr foi 36% maior nas pacientes (p=0,043). A razão de NAA/Cr foi 12,6% menor na presença de crises convulsivas (p=0,017). Houve decréscimo da NAA/Cr com a gravidade clínica (p=0,031). A presença da mutação R168X tem pior grau de gravidade clínica (0,01 ? p ? 0,11) e uma razão NAA/Cr mais baixa (0,029 ? p <0,14), quando comparados com outras mutações. Houve redução da FA no joelho e esplênio do corpo caloso, cápsulas interna e externa, cíngulo anterior, radiação talâmica e substância branca frontal. A FA do fascículo longitudinal superior foi semelhante aos controles (p=0,542) e nas pacientes com fala preservada e reduzida (p<0,001) nas pacientes com mutismo. Não houve alteração nos valores de FA na presença de crises convulsivas ou de alterações motoras. Conclusão A redução da NAA/Cr e o aumento do mI/Cr com a idade sugere que haja uma lesão axonal progressiva e reação astrocitária. O aumento do Glx/Cr pode ser secundário ao aumento do ciclo de glutamato e glutamina nas sinapses. As alterações do NAA/Cr na presença de crises convulsivas e associadas à gravidade da doença e a redução da FA nos casos de comprometimento da fala sugerem que a MRS e DTI podem ser úteis na avaliação evolutiva do comprometimento cerebral da Síndrome de Rett. _______________________________________________________________________________ ABSTRACT / Introduction Rett syndrome is a X-linked neurodevelopmental disorder that affects almost exclusively girls from early childhood. Frontal lobe is particularly affected. Mutations in the methyl-CpG binding protein 2 (MeCP2) gene are identified in more than 80% of affected girls. Patients and Methods Two groups of patients who fulfill clinical criteria and were positive for MeCP2 mutations underwent for spectroscopy (MRS) and diffusion tensor imaging (DTI) evaluation. Data were compared with age and sex matched controls. Clinical assessments included neurological status, head circumference, and history of seizures, respiratory irregularities, gait, and speech. Genotype assessment was performed by mutation analysis. Magnetic resonance imaging was performed at 1.5T unit and includes anatomical images. Forty girls (mean age 6.1 years) underwent single voxel MRS in the left frontal lobe white matter, TE 35 ms. Individual metabolite ratios were obtained from N-acetylaspartate (NAA), coline (Co), myoinositol (mI), glutamate e glutamine (Glx) over creatine (Cr) and their concentrations. Thirty-two girls (mean 5.5 years) underwent DTI evaluation, data were acquired using single-shot echo-planar with SENSE (reduction factor of 2.5), thickness of 2.5 mm, 30 encoding directions and b value of 700 s/mm2. Fractional anisotropy (FA) was obtained by manually delineated regions of interest of major white matter tracts. Asymmetry between the hemispheres was evaluated by comparison of left and right FA values and laterality index. Results NAA/Cr ratios decreased and mI/Cr ratios increased with age in RTT patients (both p<0.03), whereas these ratios were stable in control. The mean glutamate and glutamine/Cr ratio was 36% greater in RTT patients than in control (p=0.043). The mean NAA/Cr ratio was 12.6% lower in RTT patients with seizures compared with those without seizures (p=0.017). NAA/Cr ratios decreased with increasing clinical severity score (p=0.031). Patients with the R168X mutation tended to have the greatest severity score (0.01 X ! p ! 0.11) and the lowest NAA/Cr ratio (0.029 ! p <0.14). Significant reductions in FA were noted in the genu and splenium of corpus callosum and external capsule with regional reductions in the anterior cingulated, internal capsule, posterior thalamic radiation, and frontal white matter. Differences of FA in superior longitudinal fasciculus (SLF), which has strong correlation with speech, were noted in RTT with preserved speech (phrases and sentences) where FA in SLF was equal to controls (p=0.542) while FA was reduced (p<0.001) in those who were non-verbal or with single words. No correlation with FA values for tracts associated with seizures, gross or fine motor skills were identified. Conclusion Decreasing NAA/Cr and increasing mI/Cr with age are suggestive of progressive axonal damage and astroglyosis, respectively, whereas increased Glx/Cr ratio may be secondary to increasing glutamate/ glutamine cycling at the synaptic level. The relations between NAA/Cr, presence or absence of seizures, and disease severity, and also reduction of FA at superior longitudinal fasciculus at impaired speech patients suggest that MRS and DTI may provides a noninvasive measure of cerebral involvement in Rett syndrome.