Síndrome de Angelman

Introducción: El síndrome de Angelman es un trastorno del neurodesarrollo hereditario poco frecuente que afecta a 1 de cada 10 mil a 24 mil nacimientos. Esta condición incluye retraso del desarrollo, discapacidad intelectual, discapacidad severa para hablar, problemas con el movimiento y el equilibrio (ataxia), epilepsia y cabeza muy pequeña. Las personas con síndrome de Angelman parecen estar siempre de buen humor y sonríen mucho. Objetivo: Sistematizar los conocimientos sobre las características del síndrome de Angelman, los aspectos clínicos y genéticos de la enfermedad y las estrategias de tratamientos actuales. Método: Se realizó una revisión bibliográfica en la Universidad Regional Autónoma de los Andes, mediante la búsqueda en bases de datos tanto nacionales como internacionales, como PubMed, Scopus, SciELO, Web of Science y Google Scholar. Para la investigación se empleó una estrategia de búsqueda. Se encontraron 45 artículos, de los cuales 15 fueron seleccionados para esta revisión. Resultados: Se elaboró un texto sintetizado donde se abordaron aspectos tales como: etiología, diagnóstico, principales síntomas clínicos y tratamiento de este trastorno genético. Conclusiones: Por su naturaleza de necesidades clínicas que no son satisfechas en cuanto al área motora, la comunicación, el sueño y el comportamiento, el síndrome de Angelman hace necesario que los profesionales de enfermería desarrollen un plan de acción que permita un diagnóstico precoz y desarrollen un plan de cuidados específico para el individuo y el entorno íntimo de actuación para responder a las necesidades a demanda.

Introduction: Angelman Syndrome is a rare inherited neurodevelopmental disorder that affects 1 in 10,000 to 24,000 newborns. This condition includes developmental desability, intellectual disability, severe speech disability, movement and balance problems (ataxia), seizures and very small head. People with Angelman Syndrome always seem to be in a good mood and smile a lot. Objective: To systematize knowledge about the characteristics of Angelman Syndrome, clinical and genetic aspects of the disease and current treatment strategies. Method: A bibliographic review was carried out at the Universidad Regional Autónoma de los Andes, by searching in national and international databases such as PubMed, Scopus, SciELO, Web of Science and Google Scholar. For the investigation a search strategy was used. Forty-five articles were found, of which 15 were selected for this review. Results: A synthesized text was elaborated where aspects such as etiology, diagnosis, main clinical symptoms and treatment of this genetic disorder were addressed. Conclusions: Due to its nature of clinical needs that are not met in terms of the motor area, communication, sleep and behavior, Angelman syndrome makes it necessary for nursing professionals to develop an action plan that allows an early diagnosis and develop a plan specific care for the individual and the intimate environment of action to respond to the needs on demand.

Introdução: A síndrome de Angelman é um distúrbio hereditário raro do neurodesenvolvimento que afeta 1 em 10.000 a 24.000 nascimentos. Essa condição inclui atraso no desenvolvimento, deficiência intelectual, deficiência grave da fala, problemas de movimento e equilíbrio (ataxia), epilepsia e cabeça muito pequena. Pessoas com síndrome de Angelman parecem estar sempre de bom humor e sorrir muito. Objetivo: Sistematizar o conhecimento sobre as características da síndrome de Angelman, os aspectos clínicos e genéticos da doença e as estratégias atuais de tratamento. Método: Foi realizada revisão bibliográfica na Universidad Regional Autónoma de los Andes, por meio de busca em bases de dados nacionais e internacionais, como PubMed, Scopus, SciELO, Web of Science e Google Acadêmico. Para a investigação, foi utilizada uma estratégia de busca. Foram encontrados 45 artigos, dos quais 15 foram selecionados para esta revisão. Resultados: Foi elaborado um texto sintetizado onde foram abordados aspectos como: etiologia, diagnóstico, principais sintomas clínicos e tratamento desta doença genética. Conclusões: Devido à sua natureza de necessidades clínicas não satisfeitas ao nível da área motora, comunicação, sono e comportamento, a síndrome de Angelman torna necessário que os profissionais de enfermagem desenvolvam um plano de ação que permita o diagnóstico precoce e desenvolvam um plano de cuidados específico para o indivíduo e o ambiente íntimo de ação para responder às necessidades sob demanda.

[Prader-Willi and Angelman syndromes: case series diagnosed by MS-MLPA assay]. / Síndromes Prader-Willi y Angelman: serie de casos diagnosticados mediante la técnica de MS-MLPA.

BACKGROUND: Prader Willi syndrome (PWS) and Angelman syndrome (AS) are neurodevelopmental disorders caused by deletions or methylation defects, making a loss of expression of imprinted genes located in the 15q11-q13 region, and these can be assessed by different cytogenomic and molecular techniques. We report a case series of patients with PWS and AS evaluated through the MS-MLPA assay. CLINICAL CASES: We studied four patients with a clinical diagnosis of PWS and another with AS, evaluated as far as possible with karyotype and FISH, and with MS-MLPA assay for the 15q11-q13 region in all cases. In patients with PWS, neonatal hypotonia was the main reason for consultation and in three of them we identified a deletion of 15q11-q13 by MS-MLPA, also confirmed by FISH; and in the other one, an abnormal methylation pattern consistent with a maternal uniparental disomy. The patient with AS presented with a typical picture which led to the identification of a deletion in 15q11-q13 by MS-MLPA, also confirmed by FISH. CONCLUSIONS: The use of the MS-MLPA assay for the 15q11-q13 region was very useful for the diagnosis and identification of the genomic and epigenetic defects involved in either PWS and AS.

INTRODUCCIÓN: el síndrome Prader-Willi (SPW) y el síndrome de Angelman (SA) son trastornos del neurodesarrollo producidos por deleciones o defectos de metilación que producen pérdida de expresión en los genes improntados de la región 15q11 q13, mismos que pueden ser evaluados por diferentes técnicas citogenómicas y moleculares. Presentamos una serie de pacientes con SPW y SA en los que se identificó el tipo de defecto de la región 15q11-q13 mediante la técnica de MS-MLPA. CASOS CLÍNICOS: estudiamos cuatro pacientes con diagnóstico clínico de SPW y uno con SA, evaluados en lo posible con cariotipo, FISH y todos con ensayo MS-MLPA para la región 15q11-q13. En los pacientes con SPW, la hipotonía neonatal fue el motivo principal de consulta. En tres de ellos se identificó deleción de 15q11-q13 por MS-MLPA, confirmada por FISH, y en uno el patrón de metilación anormal fue compatible con una disomía uniparental materna. El paciente con SA presentó un cuadró típico y también se identificó una deleción en 15q11-q13 por MS-MLPA, confirmada por FISH. CONCLUSIONES: confirmamos que el uso de la técnica de MS-MLPA para la región 15q11 q13 mostró ser de gran utilidad para identificar los mecanismos genómicos y epigenéticos implicados en el SPW y el SA.

[Epigenetics of Prader-Willi Syndrome: A good example of translational medicine]. / Epigenética del síndrome de Prader-Willi: un buen ejemplo de medicina traslacional.

In this editorial the author presents a study, concerning Prader-Willi syndrome, which is paradigmatic for translational medicine, given that it creates a synergy between genetics and molecular biology, in order to improve the care for patients suffering from this syndrome.

En el presente editorial el autor expone un estudio, relacionado con el síndrome de Prader-Willi, que es paradigmático para la medicina traslacional, dado que crea una sinergia entre la genética y la biología molecular, a fin de mejorar la atención a los pacientes que padecen este síndrome.

Case Report: A Severe SARS-CoV-2 Infection in a Teenager With Angelman Syndrome.

Teenagers generally present mild to no symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the present report, we present the case of a 14-year-old boy with Angelman syndrome (AS) who presented with severe COVID-19 symptoms. He spent 20 days in the ICU with elevated inflammatory biomarkers (C-reactive protein and D-dimer) and increased peaks of neutrophil-to-lymphocyte ratio, which is uncommon for teenagers diagnosed with COVID-19. Although he showed physiological instability, he was able to produce neutralizing antibodies, suggesting a functional immune response. The literature concerning the immune response to infections in patients with AS is still poor, and to our knowledge, this was the first report of a patient with AS diagnosed with COVID-19. As such, the present study may alert other patients with AS or other rare diseases that they lack a competent immune response and could suffer severe consequences of SARS-CoV-2 infection.

Spastic Diplegia in a Haitian Girl with Angelman Syndrome.

Spastic diplegia, a muscle hypertonia motor syndrome, can occur in conjunction with the characteristic abnormal movement features of Angelman syndrome (AS), a neurodevelopmental disorder with primary features of ataxic gait, happy demeanor, developmental delay, speech impairment, intellectual disability, microcephaly, and seizures. Spastic diplegia is classically associated with cerebral palsy (CP), an umbrella term encompassing developmental delay, abnormal brain magnetic resonance imaging findings, and various types of CP including spastic, ataxic, dyskinetic, and mixed types. We present a 12-year-old Haitian patient of African descent with AS due to a microdeletion involving the entire UBE3A (ubiquitin-protein ligase E3A) gene and spastic diplegia. She was initially given a clinical diagnosis of CP. Cases of AS in patients of African descent have been rarely reported and this case of severe spastic diplegia, unresponsive to medical intervention, reflects a rarely reported presentation of AS in patients of African descent and possibly the first reported case of a Haitian patient with this clinical presentation. Given that deletions are the most common mechanism resulting in AS, this case report provides supportive evidence that chromosome 15q11 deletion-type AS is most frequently associated with spastic diplegia, a more severe motor impairment phenotype in AS.

Thinking outside the box: cataplexy without narcolepsy.

Cataplexy is a transient loss of muscle tone that can be triggered by emotions such as laughter, excitement or fear. Other causes of cataplexy include Niemann-Pick type C Disease, Angelman Syndrome, Norrie Disease, Prader-Willi Syndrome. In addition, cataplexy can be a side effect of several drugs (eg, lamotrigine, clozapine, and gamma-hydroxybutyrate). Yet, the most prevalent causes of cataplexy without narcolepsy are rare genetic diseases; which explains why cataplexy is classically linked to narcolepsy. Therefore, it is essential disconnecting cataplexy from narcolepsy especially in pediatric population and after use of a few medications. In this review, we described few conditions of cataplexy not related to narcolepsy. We performed a review of literature (MEDLINE and EMBASE database), without limited date or publication restrictions.

A rapid and accurate methylation-sensitive high-resolution melting analysis assay for the diagnosis of Prader Willi and Angelman patients.

BACKGROUND: Prader Willi (PWS) and Angelman (AS) syndromes are rare genetic disorders characterized by deletions, uniparental disomy, and imprinting defects at chromosome 15. The loss of function of specific genes caused by genetic alterations in paternal allele causes PWS while the absence in maternal allele results AS. The laboratory diagnosis of PWS and AS is complex and demands molecular biology and cytogenetics techniques to identify the genetic mechanism related to the development of the disease. The DNA methylation analysis in chromosome 15 at the SNURF-SNRPN locus through MS-PCR confirms the diagnosis and distinguishes between PWS and AS. Our study aimed to establish the MS-PCR technique associated with High-Resolution Melting (MS-HRM) in PWS and AS diagnostic with a single pair of primers. METHODS: We collected blood samples from 43 suspected patients to a cytogenetic and methylation analysis. The extracted DNA was treated with bisulfite to perform comparative methylation analysis. RESULTS: MS-HRM and MS-PCR agreed in 100% of cases, identifying 19(44%) PWS, 3(7%) AS, and 21(49%) Normal. FISH analysis detected four cases of PWS caused by deletions in chromosome 15. CONCLUSION: The MS-HRM showed good performance with a unique pair of primers, dispensing electrophoresis gel analysis, offering a quick and reproducible diagnostic.

Linguagem, neurodesenvolvimento e comportamento na Síndrome de Angelman: relato de caso / Language, neurodevelopment, and behavior in Angelman syndrome: a case report

RESUMO Objetivo O objetivo deste estudo é apresentar achados de linguagem, comportamento e neurodesenvolvimento de uma menina com diagnóstico da Síndrome de Angelman, avaliada aos três e aos oito anos. Método Os instrumentos de avaliação foram Observação do Comportamento Comunicativo, Early Language Milestone Scale (ELM) e Teste de Screening de Desenvolvimento DENVER-II (TSDD-II). Resultados No caso apresentado, verifica-se a presença dos sinais fenotípicos da SA, tais como boca larga, dentes espaçados, língua protuberante, estrabismo, fissuras palpebrais ascendentes e sialorreia. Na avaliação de linguagem, foram verificados déficits expressivos e receptivos, com ausência de oralidade e prejuízos na compreensão. O TSDD-II e a ELMS indicaram grave comprometimento de todas as habilidades avaliadas aos três e aos oito anos. O desempenho encontrado, nas duas avaliações, foi muito semelhante em todas as áreas do desenvolvimento infantil. Ao longo dos anos, verificou-se pouca evolução, apesar do grande investimento terapêutico e educacional. Conclusão A presença de um quadro complexo como a SA demanda necessidades clínicas de alta complexidade, situação agravada frente à escassez de recursos terapêuticos que possam minimizar os impactos deletérios da síndrome, culminando em comprometimento da qualidade de vida da população com a SA, bem como de suas famílias.

ABSTRACT Purpose This study aimed to present findings on language, behavior, and neurodevelopment in a girl diagnosed with Angelman Syndrome, evaluated when she was three and eight years old. Methods The following evaluation instruments were used: Observation of Communication Behavior, Early Language Milestone (ELM) Scale, and Denver Developmental Screening Test, 2nd edition (DDST-II). Results In this case report, presence of AS phenotype signals such as wide mouth and wide-spaced teeth, tongue thrusting, strabismus, up slanting palpebral fissures, and sialorrhea are verified. Expressive and receptive deficits were verified in the language assessment, with the absence of orality and loss of comprehension with very similar performances in both evaluations. The ELM and DDST-II tests indicated severe impairment of all abilities evaluated at both three and eight years of age. Performance was quite similar in both evaluations in all areas of child development. Little progress was observed over time despite the great therapeutic and educational investment. Conclusion The presence of a complex scenario such as AS demands high complexity clinical needs, a situation that is worsened due to scarcity of therapeutic resources that could minimize the harmful impacts of AS and culminate in increased quality of life for the AS population and their families.

[Aging in people with autism spectrum disorder].

Autism spectrum disorder is characterized by a qualitative alteration in social interaction and communication associated with restricted interests and stereotyped behaviors. This condition will accompany people throughout their lives, with variations in their evolution. Our objectives were to know the evolutionary characteristics of people with autistic spectrum disorder, analyzing cognitive, behavioral, health, mortality and their needs in the aging stage, which will guide the planning of specific support resources. We analyze studies related to the evolution in adult life in people with this disorder, with or without identified entities, and socio-health conditions that should be considered in the aging process. The knowledge about aging in people with autism is still scarce and it is difficult to define a specific pattern because this will depend, among other factors, on the etiology, the degree, the presence of intellectual disability and/or epilepsy, and the scope in where live, which can even condition the life expectancy. Aging has been associated with mood disorders, depression, deterioration in executive functions and episodic memory, although it is difficult to differentiate it from natural aging in people with typical development. The identification of a specific entity will allow to know the possible evolution and prevent complications in syndromes that may be associated with autism: fragile X, Down, Angelman, Rett and Williams, for that reason we rank the genetic and neurological consultation.

Envejecimiento en personas con trastorno del espectro autista / Aging in people with autism spectrum disorder

El trastorno del espectro autista se caracteriza por una alteración cualitativa en la interacción social y la comunicación, asociada a intereses restringidos y conductas estereotipadas. Esta condición acompañará a las personas a lo largo de toda la vida, con variaciones en su evolución. Nuestros objetivos fueron conocer las características evolutivas de las personas con trastorno del espectro autista, analizando aspectos cognitivos, conductuales, salud, mortalidad y sus necesidades en la etapa de envejecimiento, que permitan orientar la planificación de recursos específicos de apoyo. Se analizaron estudios relacionados con la evolución en la vida adulta en personas con este trastorno, con o sin entidades identificadas, y las condiciones sociosanitarias que deben ser consideradas en los procesos de envejecimiento. El conocimiento sobre el envejecimiento en personas con autismo es aún escaso y resulta difícil definir un patrón específico pues este dependerá, entre otros factores, de la etiología, el grado, la presencia de discapacidad intelectual y/o epilepsia, y el ámbito en el que viven, los cuales pueden incluso condicionar la expectativa de vida. El envejecimiento se ha asociado a trastornos del humor, depresión, deterioro en funciones ejecutivas y memoria episódica, aunque resulta difícil diferenciarlo del envejecimiento natural en personas con desarrollo típico. La identificación de una entidad específica permitirá conocer la posible evolución y prevenir complicaciones en síndromes que pueden estar asociados con autismo: X frágil, Down, Angelman, Rett y Williams, por ello jerarquizamos la consulta genética y neurológica.

Autism spectrum disorder is characterized by a qualitative alteration in social interaction and communication associated with restricted interests and stereotyped behaviors. This condition will accompany people throughout their lives, with variations in their evolution. Our objectives were to know the evolutionary characteristics of people with autistic spectrum disorder, analyzing cognitive, behavioral, health, mortality and their needs in the aging stage, which will guide the planning of specific support resources. We analyze studies related to the evolution in adult life in people with this disorder, with or without identified entities, and socio-health conditions that should be considered in the aging process. The knowledge about aging in people with autism is still scarce and it is difficult to define a specific pattern because this will depend, among other factors, on the etiology, the degree, the presence of intellectual disability and/or epilepsy, and the scope in where live, which can even condition the life expectancy. Aging has been associated with mood disorders, depression, deterioration in executive functions and episodic memory, although it is difficult to differentiate it from natural aging in people with typical development. The identification of a specific entity will allow to know the possible evolution and prevent complications in syndromes that may be associated with autism: fragile X, Down, Angelman, Rett and Williams, for that reason we rank the genetic and neurological consultation.

Análisis de variación del número de copias y de patrones de metilación en la región 15q11-q13 / Variation analysis of the number of copies and methylene patterns in region 15q11-q13

La región q11-q13 del cromosoma 15 humano es proclive a sufrir alteraciones genéticas. Algunos genes de la región presentan expresión parental diferencial monoalélica, regulada por imprinting (EI). Errores en la regulación del EI, disomías uniparentales (DSU), así como también el cambio en el número de copias genómicas (CNV) producidos por sitios susceptibles de quiebre cromosómico (BP), producen alteraciones en esta región. Las enfermedades más frecuentes asociadas son el síndrome de Prader-Willi, el síndrome de Angelman y el síndrome de microduplicación 15q11-q13. En el presente trabajo analizamos la región 15q11-q13 por Methyl specific-multiplex ligation-dependent probe amplification (MS-MLPA) en 181 muestras de ADN derivadas a nuestro servicio de análisis genético molecular. En este trabajo mostramos que, de las 181 muestras, 39 presentaron alteraciones detectables por MS-MLPA. El 61.5% (24/39) de esas alteraciones detectadas fueron deleciones, el 5.1% (2/39) duplicaciones y el 33.3%(13/39) DSU/EI. Los CNV fueron 4 veces más frecuentes que las DSU/EI (OR = 4; IC 95%: 1.56-10.25) consistente con la literatura. Entre los CNV, dos casos atípicos permiten postular posibles sitios BP que no han sido informados en la literatura previamente.

Human chromosome 15q11-q13 region is prone to suffer genetic alterations. Some genes of this region have a differential monoallelic imprinting-regulated expression pattern. Defects in imprinting regulation (IE), uniparental disomy (UPD) or copy number variation (CNV) due to chromosomal breakpoints (BP) in 15q11-q13 region, are associated with several diseases. The most frequent are Prader-Willi syndrome, Angelman syndrome and 15q11-q13 microduplication syndrome. In this work, we analyzed DNA samples from 181 patients with phenotypes which were compatible with the above-mentioned diseases, using Methyl specific-multiplex ligation-dependent probe amplification (MS-MLPA). We show that, of the 181 samples, 39 presented alterations detectable by MS-MLPA. Of those alterations, 61.5% (24/39) were deletions, 5.1% (2/39) duplications and 33.3% (13/39) UPD/IE. The CNV cases were 4 times more frequent than UPD/IE (OR= 4; IC 95%: 1.56-10.25), consistent with the literature. Among the CNVs, two atypical cases allow to postulate new possible BP sites that have not been reported previously in the literature.

[Variation analysis of the number of copies and methylene patterns in region 15q11-q13]. / Análisis de variación del número de copias y de patrones de metilación en la región 15q11-q13.

Human chromosome 15q11-q13 region is prone to suffer genetic alterations. Some genes of this region have a differential monoallelic imprinting-regulated expression pattern. Defects in imprinting regulation (IE), uniparental disomy (UPD) or copy number variation (CNV) due to chromosomal breakpoints (BP) in 15q11-q13 region, are associated with several diseases. The most frequent are Prader-Willi syndrome, Angelman syndrome and 15q11-q13 microduplication syndrome. In this work, we analyzed DNA samples from 181 patients with phenotypes which were compatible with the above-mentioned diseases, using Methyl specific-multiplex ligation-dependent probe amplification (MS-MLPA). We show that, of the 181 samples, 39 presented alterations detectable by MS-MLPA. Of those alterations, 61.5% (24/39) were deletions, 5.1% (2/39) duplications and 33.3% (13/39) UPD/IE. The CNV cases were 4 times more frequent than UPD/IE (OR= 4; IC 95%: 1.56-10.25), consistent with the literature. Among the CNVs, two atypical cases allow to postulate new possible BP sites that have not been reported previously in the literature.

Del fenotipo neuropsiquiátrico al cuidado clínico del síndrome de Angelman: descripción de siete casos / Neuropsychiatrie phenotype of Angelman syndrome and clinical care: report of seven cases

El síndrome de Angelman es un trastorno neurogenético debido a la falta o reducción en la expresión del gen UBE3A en el cromosoma 15, el cual codifica la proteína ubiquitina ligasa E3A, que tiene un papel integral en el desarrollo sinóptico y la plasticidad neuronal. Se manifiesta por retraso en el neurodesarrollo o discapacidad intelectual, comportamiento característico y epilepsia. Se describen las características clínicas de siete pacientes con deleción del cromosoma 15q11-13 y su manejo integral. Por la expectativa de vida, es importante conocer y manejar las comorbilidades de forma interdisciplinaria para lograr mejorar la calidad de vida de los afectados. Se realiza una revisión de la literatura sobre la aproximación integral al diagnóstico y cuidado clínico a largo plazo de los pacientes con síndrome de Angelman.

Angelman syndrome is a neurogenetic disorder caused by a lack or reduction of expression of UBE3A located within chromosome 15, which codes for ubiquitin protein ligase E3A, which has a key role in synaptic development and neural plasticity. Its main features are developmental delay/intellectual disability, lack of speech, a characteristic behavioural profile, and epilepsy. We describe clinical features and management of seven cases with 15q11-13 deletion. Due to their life expectancy, knowing and managing its comorbidities is crucial to improve their quality of life. We review the diagnosis and long-term clinical care of patients with Angelman syndrome.

[Neuropsychiatric phenotype of Angelman syndrome and clinical care: report of seven cases]. / Del fenotipo neuropsiquiátrico al cuidado clínico del síndrome de Angelman: descripción de siete casos.

Angelman syndrome is a neurogenetic disorder caused by a lack or reduction of expression of UBE3A located within chromosome 15, which codes for ubiquitin protein ligase E3A, which has a key role in synaptic development and neural plasticity. Its main features are developmental delay/intellectual disability, lack of speech, a characteristic behavioural profile, and epilepsy. We describe clinical features and management of seven cases with 15q11-13 deletion. Due to their life expectancy, knowing and managing its comorbidities is crucial to improve their quality of life. We review the diagnosis and long-term clinical care of patients with Angelman syndrome.

El síndrome de Angelman es un trastorno neurogenético debido a la falta o reducción en la expresión del gen UBE3A en el cromosoma 15, el cual codifica la proteína ubiquitina ligasa E3A, que tiene un papel integral en el desarrollo sináptico y la plasticidad neuronal. Se manifiesta por retraso en el neurodesarrollo o discapacidad intelectual, comportamiento característico y epilepsia. Se describen las características clínicas de siete pacientes con deleción del cromosoma 15q11-13 y su manejo integral. Por la expectativa de vida, es importante conocer y manejar las comorbilidades de forma interdisciplinaria para lograr mejorar la calidad de vida de los afectados. Se realiza una revisión de la literatura sobre la aproximación integral al diagnóstico y cuidado clínico a largo plazo de los pacientes con síndrome de Angelman.

Evaluación clínica y tratamiento estomatológico de un caso con aparente Síndrome de Angelman / Stomatologycal clinical evaluation and treatment of an apparent case with Angelman Syndrome

Enfermedad genética desconocida e insanable, producida por una alteración cromosómica de la región 15q11-13; las manifestaciones de orden físico, neurológico y psicológico están relacionadas con la pérdida de funciones como la deambulación, el habla, cognitivos y alimentarios. Según la OMS se ha identificado cerca de 7 mil enfermedades raras o huérfanas que afectan al 7% de la población mundial. Estas personas generalmente son desatendidas y aisladas por lsaociedad y políticas de salud, debido a la incapacidad y falta de autonomía personal, la salud general y particularmente del sistema estomatognático de estos pacientes, merece cuidados especializados y prolongados con participación multidisciplinaria, con el único fin de proporcionar servicios de salud con calidad, seguridad y oportunidad. Presentamos el caso de un paciente de sexo masculino de 21 años de edad, en el que no se pudo realizar diagnóstico genético por falta de medios tecnológicos y económicos, pero la presencia de los signos clínicos indica que adolece del síndrome de Angelman. (AU)

Unknown and incurable genetic disease caused by a chromosomal abnormality in the region 15q11-13; manifestations of physical, neurological and psychological are related to the loss of functions such as walking, speech, cognitive and food. According to WHO has identified about 7,000 rare or orphan diseases that affect 7% of the world population. These people are generally neglected and isolated by society and health policy, due to the inability and lack of personal autonomy overall, health and particularly the stomatognathic system of these patients deserve specialized and long-term care with multidisciplinary participation, with the sole purpose of provide quality health services, security and opportunity. We report the case of a male patient of 21 years, which could not be performed genetic diagnosis for lack of technological and financial resources, but the presence of clinical signs indicating that suffers from Angelman syndrome. (AU)

Sedation with dexmedetomidine for conducting electroencephalogram in a patient with Angelman syndrome: a case report / Sedação com dexmedetomidina para realização de eletroencefalograma em paciente portadora de síndrome de Angelmann: relato de caso

ABSTRACT INTRODUCTION: Angelman syndrome is characterized by severe mental retardation and speech and seizure disorders. This rare genetic condition is associated with changes in GABAA receptor. Patients with Angelman syndrome need to be sedated during an electroencephalogram ordered for diagnostic purposes or evolutionary control. Dexmedetomidine, whose action is independent of GABA receptor, promotes a sleep similar to physiological sleep and can facilitate the performing of this examination in patients with Angelman syndrome. CASE REPORT: Female patient, 14 years old, with Angelman syndrome; electroencephalogram done under sedation with dexmedetomidine. The procedure was uneventful and bradycardia or respiratory depression was not recorded. The examination was successfully interpreted and epileptiform activity was not observed. CONCLUSION: Dexmedetomidine promoted satisfactory sedation, was well tolerated and enabled the interpretation of the electroencephalogram in a patient with Angelman syndrome and seizure disorder.

RESUMO INTRODUÇÃO: a síndrome de Angelman (SA) é caracterizada por retardo mental grave, distúrbio da fala e desordem convulsiva. Essa condição genética rara está associada a alterações do receptor GABA-A. Pacientes portadores de SA necessitam ser sedados durante a feitura de eletroencefalograma (EEG), indicado para fins diagnósticos ou controle evolutivo. A dexmedetomidina, cuja ação independe do receptor GABA, promove sono semelhante ao fisiológico e pode viabilizar a feitura desse exame em pacientes com SA. RELATO DE CASO: paciente feminina, 14 anos, portadora de SA, fez EEG sob sedação com dexmedetomidina. O procedimento transcorreu sem intercorrências e não foi registrada bradicardia ou depressão respiratória. O exame foi interpretado com sucesso e atividade epileptiforme não foi observada. CONCLUSÃO: a dexmedetomidina promoveu sedação satisfatória, foi bem tolerada e possibilitou a interpretação do EEG em paciente com SA e desordem convulsiva.

Sedation with dexmedetomidine for conducting electroencephalogram in a patient with Angelman syndrome: a case report.

INTRODUCTION: Angelman syndrome is characterized by severe mental retardation and speech and seizure disorders. This rare genetic condition is associated with changes in GABAA receptor. Patients with Angelman syndrome need to be sedated during an electroencephalogram ordered for diagnostic purposes or evolutionary control. Dexmedetomidine, whose action is independent of GABA receptor, promotes a sleep similar to physiological sleep and can facilitate the performing of this examination in patients with Angelman syndrome. CASE REPORT: Female patient, 14 years old, with Angelman syndrome; electroencephalogram done under sedation with dexmedetomidine. The procedure was uneventful and bradycardia or respiratory depression was not recorded. The examination was successfully interpreted and epileptiform activity was not observed. CONCLUSION: Dexmedetomidine promoted satisfactory sedation, was well tolerated and enabled the interpretation of the electroencephalogram in a patient with Angelman syndrome and seizure disorder.

Análise comparativa entre as metodologias de PCR metilação-específica (MSP), southern blot (SB) e FISH utilizadas no diagnóstico genético molecular de pacientes com suspeita clínica das síndromes de Prader-Willi ou Angelman / Comparative analysis of methylation-specific PCR (MSP), southern blot (SB) and FISH in molecular genetic diagnosis of patients with clinical picture suggestive of Prader-Willi or Angelman syndromes

Introdução: Prader-Willi (SPW) e Angelman (SA) são síndromes clinicamente distintas, causadas pela perda de expressão de genes na região cromossômica 15q11.2-q13, de origem paterna ou materna, respectivamente. Ambas compartilham os mesmos métodos diagnósticos. Nossos objetivos foram: a) analisar por PCR metilação-específica (MSP) pacientes com suspeita clínica de SPW/SA; b) comparar resultados de diferentes metodologias de diagnóstico molecular; c) aplicar a técnica MSP na rotina assistencial de pacientes encaminhados ao Serviço de Genética Médica/Hospital de Clínicas de Porto Alegre (SGM/HCPA). Métodos: Foram analisados 123 pacientes com suspeita clínica de SPW (n = 71) ou SA (n = 52) por MSP. Desses, 79 possuíam análise prévia por hibridação in situ fluorescente (FISH) e/ou Southern blot (SB). Resultados: Foram detectados 21 casos positivos – 15 de SPW (12,19%) e 6 de SA (4,88%). Nove pacientes tiveram etiologia molecular determinada, sendo sete com diagnóstico de SPW (quatro dissomias uniparentais – UPD15 materna – e três deleções na região 15q11-13) e dois com diagnóstico de SA (um com UPD15 paterna e um com deleção na região 15q11-13). Foram observados resultados equivalentes entre MSP e SB e resultados discrepantes entre MSP e FISH (n = 4). Foram padronizados dois protocolos de MSP para confirmação dos resultados e controle interno de qualidade. Conclusão: O perfil de detecção de cada técnica varia de acordo com o mecanismo etiológico presente. A análise por MSP detecta alterações no padrão de metilação geradas por deleção, UPD e defeitos de imprinting, sem identificar o mecanismo etiológico responsável...

Introduction: Prader-Willi (PWS) and Angelman (AS) are clinically different syndromes caused by loss of expression of genes located on the chromosome 15q11.2-q13, of paternal or maternal origin, respectively. Both syndromes have the same diagnostic methods. The aims of the present study were: a) to perform a molecular analysis of 123 patients with clinical findings suggestive of PWS or AS using methylation-specific PCR (MSP); b) to compare the results obtained using different molecular diagnostic methodologies; c) to standardize MSP to be used in the routine care of patients at Medical Genetics Service/Hospital de Clínicas de Porto Alegre (SGM/HCPA). Methods: 123 patients with clinical findings suggestive of PWS (n = 71) or AS (n = 52) were analyzed by MSP. 79 had undergone previous laboratory analysis by fluorescence in situ hybridization (FISH) and/or Southern blot (SB). Results: MSP detected 21 positive cases – 15 PWS (12,19%) and 6 AS (4,88%). Molecular etiology was determined in 9 patients only – 7 were diagnosed with PWS (4 had uniparental disomy – maternal UPD15 – and 3 had deletions at 15q11-13) and 2 were diagnosed with AS (1 of paternal UPD15 and 1 deletion at 15q11-13). Comparing both methodologies, it was possible to observe concordant results between MSP and SB and discordant results between MSP and FISH (n = 4). We standardized two MSP methods in order to confirm the results and for internal quality control. Conclusion: The resulting profile of each technique varies according to the existing etiological mechanism. The methylation analysis by MSP technique detects changes on methylation pattern caused by deletion, UPD and imprinting defects, but it does not identify the responsible etiologic mechanism...

Angelman syndrome in adulthood.

Angelman syndrome (AS) is a neurogenetic disorder. The goal of this study was to investigate the primary health issues affecting adults with AS and to further characterize the natural history and genotype-phenotype correlations. Standardized phone interviews with caregivers for 110 adolescents and adults with AS were conducted. The impact of age, sex, and genotype on specific outcomes in neurology, orthopedics, internal medicine, and psychiatry were investigated. The mean age of individuals with AS was 24 years (range 16-50y). Active seizures were present in 41% of individuals, and 72% had sleep dysfunction. Significant constipation was present in 85%, and 32% were overweight or obese, with obesity disproportionately affecting women. Scoliosis affected 50% with a mean age at diagnosis of 12 years, and 24% of those diagnosed with scoliosis required surgery, an intervention disproportionately affecting men. Sixty-eight percent were able to walk independently, and 13% were able to speak 5 or more words. Self-injurious behavior was exhibited in 52% of individuals. The results of this study indicate that epilepsy severity may assume a bimodal age distribution: seizures are typically most severe in early childhood but may recur in adulthood. While late-adolescent and adult sleep patterns were improved when compared to the degree of sleep dysfunction present during infancy and childhood, the prevalence of poor sleep in adults remained quite high. Primary areas of clinical management identified include the following: seizures, sleep, aspiration risk, GERD, constipation, dental care, vision, obesity, scoliosis, bone density, mobility, communication, behavior, and anxiety.

[Autism and epigenetics. A model of explanation for the understanding of the genesis in autism spectrum disorders]. / Autismo y epigenética. Un modelo de explicación para la comprensión de la génesis en los trastornos del espectro autista.

Autism spectrum disorders are characterized by impairment of social integration and language development and restricted interests. Autism spectrum disorders manifest during childhood and may have a varying clinical expression over the years related to different therapeutic approaches, behavior-modifying drugs, and environmental factors, among others. So far, the genetic alterations identified are not sufficient to explain the genesis of all these processes, as many of the mutations found are also present in unaffected individuals. Findings on the underlying biological and pathophysiological mechanisms of entities strongly associated with autism spectrum disorders, such as Rett, fragile X, Angelman, and fetal alcohol syndromes, point to the role of epigenetic changes in disorders of neurodevelopment. Epigenetic phenomena are normal biological processes necessary for cell and thus human life, especially related to embryonic development. Different phenomena that affect epigenetic processes (changes that change operation or expression of a gene, without modifying the DNA structure) have also been shown to be important in the genesis of neurodevelopmental disorders. Alterations in the epigenetic mechanism may be reversible, which may explain the variation in the autism phenotype over time. Here we analyze the normal epigenetic mechanisms, autism spectrum disorders, their association with specific entities associated with altered epigenetic mechanisms, and possible therapeutic approaches targeting these alterations.