Clinical and molecular genetic analysis of Angelman syndrome with oculocutaneous albinism type 2: A case report and literature review / 北京大学学报(医学版)

To summarize the clinical diagnosis and treatment process and genetic test results and characteristics of one child with Angelman syndrome (AS) complicated with oculocutaneous albinism type 2 (OCA2), and to review the literature. "Angelman syndrome" "P gene" and "Oculocutaneous albinism type 2" were used as keywords to search at CNKI, Wanfang, and PubMed databases (from creation to December 2019). Then all the patients were analyzed. The patient in this study was a girl aged 1 year. After birth, she was found to present as white body, yellow hair, and nystagmus. She could raise her head at the age of 2 months and turn over at the age of 7 months. The head circumference was 42 cm and she could not sit alone or speak at present. Trio-based exome sequencing revealed that the patient carried a homozygous mutation of c.168del (p.Gln58ArgfsTer44) in the P gene, and her father was heterozygous and her mother was wild-type. The detection of copy number variation showed deletion on the maternal chromosome at 15q11.2-13.1 region (P gene located in this region) in the patient. Until December 2019, a total of 4 cases in the 4 literature had been reported. Adding our case here, the 5 cases were summarized and found that all the cases showed white skin, golden hair, and shallow iris after birth. Comprehensive developmental delay was found around 6 months of age after birth, and the language remained undeveloped in 2 cases till follow-up into childhood. Seizures occurred in 4 patients. Two cases had ataxia. All the 5 cases had acquired microcephaly. Two cases had a family history of albinism. Electroencephalogram monitoring was completed in 3 cases and the results were abnormal. Genetic tests showed that all the 5 cases had deletion on maternal chromosome at 15q11-13 region. Four cases carried mutation of P gene on paternal chromosome. And 1 case was clinically diagnosed as OCA2 without P gene test. AS combined with OCA2 is relatively rare. OCA2 is easily diagnosed based on the obvious clinical manifestations after birth. When combined with clinical manifestations such as neurodevelopmental delay, it might indicate the possibility of AS that is hardly diagnosed clinically at an early stage. Genetic tests can reveal the cross-genetic phenomenon of AS and OCA2 and the complex of them can be eventually diagnosed.

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.

Progress in the pathogenesis and genotype-phenotype of Angelman syndrome / 中华实用儿科临床杂志

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe developmental delay, intellectual disability, exuberant behavior with happy demeanor, speech impairment, and epileptic seizures.The loss of UBE3A allele on maternal chromosome 15q11-13 is the main cause of AS.However, the pathogenesis and genotype-phenotype of AS is not yet clear.This study aims to review the research progress of AS.

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.

Clinical analysis of 103 children with Angelman syndrome / 中华实用儿科临床杂志

Objective To investigate the correlation between clinical phenotype,electroencephalogram(EEG) characteristics and genotype in children with Angelman syndrome(AS). Methods A total of 103 children with AS at Department of Neurology,Children′s Hospital of Fudan University from June 2017 to June 2018,were included in this study. The information of clinical characteristics,EEG manifestations,genotypes as well as the epileptic outcome were collected retrospectively. The correlations between clinical phenotype,genotype,and epileptic outcome were evaluated. Results (1)Of the 103 cases,48 were male(46. 6﹪)and 55 were female(53. 4﹪).(2)Genotypes on AS criti﹣cal region were maternal chromosome 15q11. 2－q13[86. 4﹪(89/103 cases)],paternal uniparental disomy[3. 9﹪(4/103 cases)],imprinting defects[1. 9﹪(2/103 cases)],and mutations in the maternal copy of UBE3A[7. 8﹪(8/103 cases)].(3)Apparent happy demeanor or smile and general developmental delay were observed in all AS children. Dyskinesia accounted for 98. 1﹪(101/103 cases),followed by oral movement or suck disorders[97. 1﹪(100/103 cases)]and abnormal posture[67. 0﹪(69/103 cases)]. The proportion of acquired small head circumfe﹣rence or microcephaly,flat occiput or occipital groove and wide－spaced teeth were 61. 2﹪(63/103 cases),85. 4﹪(88/103 cases)and 44. 7﹪(46/103 cases),respectively.(4)Behavioral problems like fascination with water,sleep problems and feeding difficulties were found in 86. 4﹪(89/103 cases),89. 3﹪(92/103 cases)and 85. 5﹪(88/103 cases)of the children,respectively. Sleep disorders[94. 4﹪(84/89 cases)νs. 57. 1﹪(8/14 cases)]and feeding difficulties[93. 3﹪(83/89 cases)νs. 35. 7﹪(5/14 cases)]were more frequently seen in children with maternal ab﹣sence group,compared those with no absence,and the differences were statistically significant(all P＜0. 05).(5)Epi﹣lepsy was present in 77. 7﹪(80/103 cases)of children with onset age varying from 8 to 72 months and 80. 8﹪(59/73 cases)were developing seizures prior to 3 years old. Children with maternal absence showed more multiple seizure types than those with no absence[41. 7﹪(32/68 cases)νs. 0(0 case)],and the difference was statistically significant (P＜0. 05). Children with well－controlled epilepsy had more atonic seizure,compared with those with poorly con﹣ trolled seizure[48. 3﹪(14/29 cases)νs. 18. 5﹪(4/27 cases)],and the difference was statistically significant( P＜0. 05). Conclusions Sleep disorders,feeding difficulties in infancy and multiple seizure types are more commonly seen in AS children with maternal absence. Atonic seizure is easier to be controlled over other types of seizures.

Clinical analysis of 103 children with Angelman syndrome / 中华实用儿科临床杂志

Objective@#To investigate the correlation between clinical phenotype, electroencephalogram (EEG) characteristics and genotype in children with Angelman syndrome(AS).@*Methods@#A total of 103 children with AS at Department of Neurology, Children′s Hospital of Fudan University from June 2017 to June 2018, were included in this study.The information of clinical characteristics, EEG manifestations, genotypes as well as the epileptic outcome were collected retrospectively.The correlations between clinical phenotype, genotype, and epileptic outcome were evaluated.@*Results@#(1) Of the 103 cases, 48 were male (46.6%) and 55 were female (53.4%). (2) Genotypes on AS critical region were maternal chromosome 15q11.2-q13 [86.4%(89/103 cases)], paternal uniparental disomy [3.9%(4/103 cases)], imprinting defects [1.9%(2/103 cases)], and mutations in the maternal copy of UBE3A [7.8%(8/103 cases)]. (3) Apparent happy demeanor or smile and general developmental delay were observed in all AS children.Dyskinesia accounted for 98.1% (101/103 cases), followed by oral movement or suck disorders [97.1%(100/103 cases)] and abnormal posture [67.0%(69/103 cases)]. The proportion of acquired small head circumfe-rence or microcephaly, flat occiput or occipital groove and wide-spaced teeth were 61.2%(63/103 cases), 85.4%(88/103 cases) and 44.7%(46/103 cases), respectively.(4) Behavioral problems like fascination with water, sleep problems and feeding difficulties were found in 86.4%(89/103 cases), 89.3%(92/103 cases) and 85.5%(88/103 cases) of the children, respectively.Sleep disorders [94.4%(84/89 cases) vs.57.1%(8/14 cases)] and feeding difficulties [93.3%(83/89 cases) vs.35.7%(5/14 cases)] were more frequently seen in children with maternal absence group, compared those with no absence, and the differences were statistically significant (all P<0.05). (5) Epilepsy was present in 77.7% (80/103 cases) of children with onset age varying from 8 to 72 months and 80.8% (59/73 cases) were developing seizures prior to 3 years old.Children with maternal absence showed more multiple seizure types than those with no absence[41.7%(32/68 cases) vs.0(0 case)], and the difference was statistically significant(P<0.05). Children with well-controlled epilepsy had more atonic seizure, compared with those with poorly controlled seizure [48.3%(14/29 cases) vs.18.5%(4/27 cases)], and the difference was statistically significant(P<0.05).@*Conclusions@#Sleep disorders, feeding difficulties in infancy and multiple seizure types are more commonly seen in AS children with maternal absence.Atonic seizure is easier to be controlled over other types of seizures.

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.

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.

Reseach progress of electroencephalogram features of Angelman syndrome / 国际儿科学杂志

Angelman syndrome is also called happy puppet syndrome.It is firstly reported by British sci-entist in 1965.It is a chromosome disorder disease,mainly of chromosome 15q11-13 regional anomaly.The An-gelman syndrome patients are often accompanied by mental retardation and special features,90% with epilepsy and the specific electroencephalogram patterns,and the prognosis is unfavorable.The diagnosis of Angelman syn-drome depends mainly on genetic testing,but some patients with genetic testing may show no abnormalities, these patients need referring the clinical diagnosis and the distinctive electroencephalogram.Before the distinctive clinical manifestation and genetic testing,the abnormal electroencephalogram can help diagnose Angelman syn-drome in advance,thereby improving the early detection rate of the disease.This review is mainly to summarize the electroencephalogram patterns in Angelman syndrome in recent years.

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.

Diagnostic value of array-based single nucleotide polymorphisms comparative genomic hybridization in An-gelman syndrome / 中华实用儿科临床杂志

Objective To analyze the genotype-phenotype correlations of Angelman syndrome ( AS ) , and to discuss the advantage of applying array-based single nucleotide polymorphisms comparative genomic hybridization ( SNP aCGH) in diagnosis of AS. Methods Examination of electroencephalogram( EEG) and intelligence quotient( IQ) evaluation were done for 11 cases diagnosed as AS clinically. Gesell scares were chosen as the evaluation criterion of IQ. The screening techniques was methylation polymerase chain reaction( MS-PCR) ,then SNP aCGH was used to make genetic diagnosis. Results (1)Eleven cases of AS were confirmed:1 case had UPD(uniparental disomy),10 cases were type of deletion, from which 6 cases were deletion (Ⅱ) , 4 cases were deletion (Ⅰ) . ( 2 ) The copy number variations were detected in the region of 15q11-q13,which contained genes like MKRN3,MAGEL2,NDN,SNRPN, SNURF,GABRB3,GABRA5,GABRG3,UBE3A,OCA2,ATP10A. To search online Mendelian inheritance in man,genes above were correlated with AS manifestation. (3)All cases of deletion were 3-5 standard deviation(SD) in weight and height to normal children at the same age and with the same sex,while UPD was below 1. 5 SD. Gesell scares showed that the deletion(Ⅰ) was the most serious in mental retardation,deletion(Ⅱ) was moderate,and the UPD was mild. Eight cases were hypopigmentation,and one was the UPD. EEG revealed that 1 case of deletion(Ⅰ) and the UPD were spike occasionally,another one deletion(Ⅰ) was limit EEG. The rest cases displayed slow and spike waves paroxysmal-ly,with amplitude of medium or high,2. 5-3. 0 Hz. Conclusions Not only can SNP aCGH make a diagnosis of AS but discriminate the types of genetic pathology. Since different type contributes to a diverse of clinical features and the rate of recurrence is also different,it is significant for family genetic consultation. Moreover,the technology is advantageous for the study on the pathogenesis and gene function.

Proposta de atuação fisioterapêutica em uma criança com síndrome de Angelman, enfatizando o equilíbrio postural: estudo de caso / Proposal for a physical therapy program in a child with Angelman syndrome, emphasizing postural balance: a case study / Propuesta de actuación fisioterapéutica en un niño con Síndrome de Angelman, enfatizando el equilibrio postural: estudio de caso

A síndrome de Angelman (SA) é caracterizada por alterações neuromotoras como marcha atáxica e atraso na aquisição de habilidades motoras, porém são escassos os estudos investigando o efeito de intervenções aplicadas a essa população. O objetivo do estudo foi verificar o efeito de um treino de equilíbrio em uma criança com SA. Participou do estudo uma criança de nove anos de idade com diagnóstico de SA, sexo feminino. Foi aplicado um protocolo para treino de equilíbrio por oito semanas, com frequência de duas vezes por semana. O treino consistiu em atividades envolvendo equilíbrio estático sob diversas condições de dificuldade. Após o treino, a análise de biofotogrametria computadorizada do equilíbrio estático revelou redução do grau de oscilação, que passou de 38° para 13,78°. A pontuação na escala de Berg passou de 27 pontos, na avaliação, para 37 pontos na reavaliação. No teste Timed Up & Go, a criança realizou a tarefa em 15 segundos, na avaliação, e, na reavaliação, em 12 segundos. Em conjunto, os resultados sugerem que o treino favoreceu melhora no equilíbrio estático e dinâmico, bem como na mobilidade funcional.

The Angelman syndrome is characterized by neuromotor difficulties, such as ataxic gait and delayed acquisition of motor skills. However, there are few studies investigating the effect of interventions directed to this population. This study aimed to investigate the effect of a balance training in a child with Angelman syndrome. The participant was a nine-year-old girl. The training protocol was implemented during an eight-week period, twice a week, and consisted of activities involving static balance under various difficulty levels. After the training, the postural sway measured by biophotogrammetry changed from 38° to 13.78°. The scores in the Berg scale changed from 27 points to 37 points. In the Timed Up & Go test, the child's time to complete the task changed from 15 to 12 seconds. Taken together, the results suggest that the training led to improved static and dynamic balance, as well as functional mobility.

El síndrome de Angelman (SA) es caracterizado por alteraciones neuromotoras como marcha atáxica y atraso en la adquisición de habilidades motoras, pero son escasos los estudios investigando el efecto de intervenciones aplicadas a esta población. El objetivo de este estudio fue verificar el efecto de un entrenamiento del equilibrio en un niño con SA. Participó del estudio un niño de 9 años de edad con diagnóstico de SA, sexo femenino. Fue aplicado un protocolo de entrenamiento para el equilibrio por 8 semanas, con frecuencia de 2 veces por semana. El entrenamiento consistió en actividades involucrando el equilibrio estático sobre diversas condiciones de dificultad. Después del entrenamiento el análisis de biofotogrametría computarizada del equilibrio estático reveló reducción de los grados de oscilación, que pasó de 38° para 13,78°. La puntuación en la escala de Berg pasó de 27 puntos en la evaluación para 37 puntos en la reevaluación. En el test Timed up and go la niña realizó la tarea en 15 segundos en la evaluación y 12 segundos en la reevaluación. En conjunto, los resultados sugieren que el entrenamiento favoreció la mejora en el equilibrio estático y dinámico, así como de la movilidad funcional.

Epilepsy in Korean patients with Angelman syndrome / 소아과

PURPOSE: The aim of this study was to investigate the natural history of epilepsy and response to anti-epileptic drug treatment in patients with Angelman syndrome (AS) in Korea. METHODS: We retrospectively reviewed the clinical records of 14 patients diagnosed with epilepsy out of a total of 17 patients with a genetic diagnosis of AS. These patients were seen at the Department of Pediatric Neurology at Severance Children's Hospital from March 2005 to March 2011. RESULTS: Fourteen (9 males and 5 females) subjects (82.3%) were diagnosed with epilepsy in AS. The most common seizure types were generalized tonic-clonic (n=9, 27%) and myoclonic (n=9, 27%), followed by atonic (n=8, 24%), atypical absence (n=4, 12%) and complex partial seizure (n=3, 9%). The most commonly prescribed antiepileptic drug (AED) was valproic acid (VPA, n=12, 86%), followed by lamotrigine (LTG, n=9, 64%), and topiramate (n=8, 57%). According to questionnaires that determined whether each AED was efficacious or not, VPA had the highest response rate and LTG was associated with the highest rate of seizure exacerbation. Complete control of seizures was achieved in 6 patients. Partial control was achieved in 7 patients, while one patient was not controlled. CONCLUSION: Epilepsy is observed in the great majority of AS patients. It may have early onset and is often refractory to treatment. There are few reports about epilepsy in AS in Korea. This study will be helpful in understanding epilepsy in AS in Korea.

Clinical and Genetic Characteristics of Prader-Willi Syndrome and Angelman Syndrome

PURPOSE: Two different disorders, Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are caused by the deletion of 15q11-13 or the maternal/paternal uniparental disomy of chromosome 15 (mUPD(15)/pUPD(15)) through the genomic imprinting phenomenon. We studied the clinical manifestations of both diseases and genotype-phenotype correlations in PWS. METHODS: We retrospectively analyzed medical records of patients who had been genetically confirmed as PWS or AS from December 1998 to March 2010 at Asan Medical Center. Clinical characteristics at diagnosis and genetic causes were reviewed. In PWS, clinical characteristics of the patients with microdeletions were compared with those with mUPD(15). RESULTS: During the study period, we found 90 patients with PWS and 30 with AS. In cases of PWS, the male to female ratio was 1.65:1 and the mean age at initial diagnosis was 41 months. Symptoms at first diagnosis were hypotonia (70 cases) and developmental delay (66 cases). More hypopigmentation and eye abnormalities occurred in the microdeletion group (n=62) than in the mUPD(15) group (n=21). In AS, the male to female ratio was 1.3:1 and the mean age at initial diagnosis was 23 months. Distinguishing symptoms were speech impairment, seizure, and behavioral uniqueness. Microdeletion by FISH was detected in 19 patients among 20 patients and one of the non-deletion patient showed pUPD(15) on a DNA methylation test. CONCLUSION: PWS and AS, two distinct neurogenetic disorders with different clinical presentations were the first known examples of human diseases involving imprinted genes. This study about clinical characteristics and genetic analysis of PWS and AS may help our understanding of these diseases and thus, assist in making correct diagnoses.

A patogênese genética e molecular da síndrome de Angelman / The genetic and molecular pathogenesis of the Angelman syndrome

Objetivo: Fornecer uma revisão atualizada em língua portuguesa sobre a síndrome de Angelman, com ênfase nos mecanismos genéticos e moleculares dessa patologia, uma causa de deficiência mental severa que em alguns casos pode apresentar recorrência familiar. Método: Foi feita uma revisão bibliográfica utilizando a base de dados do PubMed, tendo como critérios de busca o termo "Angelman syndrome" isoladamente e combinado com "UBE3A", "clinical", "genetics" e "molecular" no título dos artigos. Dentre esses, foram selecionados artigos de revisão e artigos originais sobre a fisiopatologia da síndrome, com ênfase nos últimos dez anos. Resultados: Utilizando-se "Angelman syndrome" na busca, apareceram cerca de 1.100 artigos, incluindo 240 de revisão. Nos últimos dez anos são mais de 600 artigos, aproximadamente 120 de revisão, 50 por cento dos quais publicados nos últimos cinco anos. Na base de dados SciELO, são apenas nove artigos sobre a síndrome, dos quais três em português e nenhum artigo atual de revisão. Conclusão: Após ter sido uma das principais causas que atraíram atenção ao estudo e ao entendimento dos mecanismos do imprinting genômico, a síndrome de Angelman está agora se revelando como uma patologia das sinapses. Apesar de o entendimento da fisiopatologia molecular da síndrome de Angelman ainda estar longe de ser compreendida, seu estudo está fornecendo uma visão extraordinária sobre os mecanismos que regem a plasticidade sináptica, novamente atraindo a atenção de pesquisadores que trabalham na fronteira do conhecimento.

Objective: The aim of this work is to provide an actualized review in Portuguese language of the main clinical and behavioral features and in particular of the genetic and molecular aspects of Angelman syndrome, a cause of severe intellectual disability, which in rare cases can be recurrent in the family. Method: This paper is a literature review that used as a source of research, scientific papers with the terms "Angelman syndrome" or combined with UBE3A, clinical, genetics, and molecular in their title, retrieved trough the PubMed database. Among those, mainly review articles and original papers about cellular and molecular aspects of the pathology were selected, prioritarily, those published in the last ten years. Results: The term Angelman syndrome retrieved about 1100 papers, including close to 240 review articles. During the last ten years there were over 600 publications, with approximately 120 reviews, 50 percent of whom published in the last five years. The SciELO database was also searched and nine publications about the syndrome were found, three of which in Portuguese and no recent review article. Conclusion: After being one of the main causes to attract attention and stimulate studies to unravel the mechanisms of the genetic imprinting, Angelman syndrome is again in the spotlight because it is revealing itself as pathology of synaptic dysfunction. Albeit still long from understood, the molecular and cellular alterations in Angelman syndrome are allowing an extraordinary insight into the mechanisms which control synaptic plasticity.

Novel deletion of the E3A ubiquitin protein ligase gene detected by multiplex ligation-dependent probe amplification in a patient with Angelman syndrome

Angelman syndrome (AS) is a severe neurobehavioural disorder caused by failure of expression of the maternal copy of the imprinted domain located on 15q11-q13. There are different mechanisms leading to AS: maternal microdeletion, uniparental disomy, defects in a putative imprinting centre, mutations of the E3 ubiquitin protein ligase (UBE3A) gene. However, some of suspected cases of AS are still scored negative to all the latter mutations. Recently, it has been shown that a proportion of negative cases bear large deletions overlapping one or more exons of the UBE3A gene. These deletions are difficult to detect by conventional gene-scanning methods due to the masking effect by the non-deleted allele. In this study, we have used for the first time multiplex ligation-dependent probe amplification (MLPA) and comparative multiplex dosage analysis (CMDA) to search for large deletions affecting the UBE3A gene. Using this approach, we identified a novel causative deletion involving exon 8 in an affected sibling. Based on our results, we propose the use of MLPA as a fast, accurate and inexpensive test to detect large deletions in the UBE3A gene in a small but significant percentage of AS patients.

Anesthesia of a dental patient with Angelman syndrome: A case report / 대한마취과학회지

Angelman syndrome is characterized by a partial deficit of paired autosomal chromosome 15, which contains a subunit of the GABA (Gamma-Amino Butyric Acid) receptor. Many drugs that act on the CNS (Central Nerve System) during anesthesia are believed to exert their effects via the GABA receptors. We describe the anesthesia of a 7 year-old female patient with Angelman syndrome who underwent surgery for dental caries. The basic factors that needed to be considered when administering anesthesia to this patient were epilepsy, significant dominance of the vagal tone, craniofacial abnormalities and peripheral muscular atrophy. Inhalational anesthetics (sevoflurane) were employed for this patient. The patient had an uneventful peri-operative period and was discharged home on the same day of the operation.

Anesthesia of a dental patient with Angelman syndrome: A case report / 대한마취과학회지

Angelman syndrome is characterized by a partial deficit of paired autosomal chromosome 15, which contains a subunit of the GABA (Gamma-Amino Butyric Acid) receptor. Many drugs that act on the CNS (Central Nerve System) during anesthesia are believed to exert their effects via the GABA receptors. We describe the anesthesia of a 7 year-old female patient with Angelman syndrome who underwent surgery for dental caries. The basic factors that needed to be considered when administering anesthesia to this patient were epilepsy, significant dominance of the vagal tone, craniofacial abnormalities and peripheral muscular atrophy. Inhalational anesthetics (sevoflurane) were employed for this patient. The patient had an uneventful peri-operative period and was discharged home on the same day of the operation.

Introdução e desenvolvimento do uso da comunicação alternativa na Síndrome de Angelman: estudo de caso / Introduction and developing alternative communication in Syndrome of Angelman: case study

TEMA: Síndrome de Angelman (SA) e comunicação alternativa. PROCEDIMENTOS: com o objetivo de descrever o processo de introdução e desenvolvimento do uso do Sistema Alternativo de Comunicação (SAC) na SA. Foi utilizado um estudo de caso, realizado na Clínica de Fonoaudiologia da Faculdade Estácio de Sá de Santa Catarina. E., diagnosticada com SA, 17 anos, sem linguagem oral. A coleta de dados foi realizada com 8 trechos de terapias filmadas durante o primeiro semestre de 2007 e anotações no diário de campo. RESULTADOS: o programa de comunicação escolhido foi o Picture Communication Symbols System (PCS). Para seleção dos símbolos, foi utilizado centros de interesse da paciente. O processo de inserção de símbolos aconteceu de maneira lenta e gradativa. A terapeuta realizava a apresentação do objeto concreto, em seguida, correlacionava o símbolo com o objeto. Os dois eram postos em cima da mesa, correlacionandoos várias vezes. Para introdução da paciente ao uso do sistema a terapeuta pegava a mão da paciente e colocava sobre o símbolo e simultaneamente entregava o objeto. Com o passar das sessões foram introduzidos novos símbolos. E. mostrou-se "perdida" negando categorias apresentadas, direcionando sua escolha para os símbolos que já lhe eram familiar. Dos 15 símbolos trabalhados, adquiriu funcionalidade para 5 símbolos. CONCLUSÃO: o SAC torna-se um meio viável de comunicação para SA. O processo de introdução e desenvolvimento de uso de SAC foi composto pela: apresentação, correlação e introdução da paciente ao uso do sistema. Salienta-se que é um trabalho lento que exige participação da família.

BACKGROUND: Syndrome of Angelman (SA) and alternative communication. PURPOSE: with the objective to describe the process for introducing and developing the use of an Alternative Communication System(SAC) in the SA, we used a case study, carried through in the Clinic of Speech Therapy of Faculdade Estácio de Sá of Santa Catarina. E., diagnosed with SA, 17year old, without verbal language. Collection of data carried through with 8 stretches of therapies recorded during the first half of 2007 and notations in the field daily record. RESULTS: the program of communication chosen was the Picture Communication Symbols System (PCS). For electing the symbols, we used interest centers of the patient. The process for inserting symbols happened in a slow and gradual manner. The therapist carried through the presentation of the concrete object, after that, she correlated the symbol with the object. Both were placed on top of the table correlating them several times. For introducing the patient to the use of the system, the therapist took the hand of the patient and placed it on the symbol and simultaneously delivered the object. With the passing of the sessions, new symbols were introduced. E. revealed being "lost" denying the presented categories, directing its choice for the symbols that already were familiar. Of the 15 worked symbols, 5 symbols acquired functionality. CONCLUSION: SAC becomes a feasible communication mode for SA. The process of introducing and developing SAC use was made up by: presentation, correlation and introduction of the patient to the use of the system. We stress out that this is a slow work that demands participation of the family.

Anesthetic experience for strabismus surgery in a patient with Angelman syndrome: A case report / 대한마취과학회지

Angelman syndrome (AS) is a rare, neurodevelopmental disorder caused by a variety of genetic abnormalities involving the chromosome 15q11-13 region. Clinical manifestations include severe psychomotor retardation, epilepsy, lack of speech, cerebellar ataxia, frequent bouts of laughing, morphological defect of the facial bones and sleep disturbance. The main anesthetic considerations in AS patients are significant dominance of vagal tone, profound disorders of GABA system with defects in its receptor function, epilepsy and peripheral muscular atrophy. We report the experience of anesthetic management for strabismus surgery in a patient with AS.