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1.
Medicine (Baltimore) ; 98(51): e18077, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31860958

RESUMO

RATIONALE: Angelman syndrome (AS) is an uncommon genetic disease characterized as serious retarded mental development and ocular abnormality. PATIENT CONCERNS: This report aims to present the ophthalmological features, and identify the diagnosis and outcomes of strabismus surgery in AS patients. DIAGNOSIS: Three children with exotropia were diagnosed with AS based on their typical clinical features. INTERVENTIONS: All patients underwent multiplex ligation-dependent probe amplification (MLPA) analysis and accepted lateral rectus recession surgery with the assistance of intravenous combined inhalation anesthesia. OUTCOMES: The maternal heritage deletion of chromosome 15q11.2-q13 was verified in all patients by MLPA. All patients with strabismus could not cooperate during the vision test, and had astigmatism. The strabismus type of AS patients was horizontal exotropia, and no vertical strabismus was found. One of these patients was combined with high myopia. The hypopigmentation on the hair and iris was ubiquitous. However, retina pigmentation was normal. After different degrees of lateral rectus recession, the exotropia was significantly relieved, and the surgical effects were stable postoperatively. LESSONS: Horizontal exotropia is the major strabismus type. Severe intellectual disability, hyperactivity, and speech impairment are the common characteristics of AS children. Its examination and operation design remains challenging. Thus, repeated examinations and intelligence rehabilitation are essential.


Assuntos
Síndrome de Angelman/diagnóstico , Exotropia/diagnóstico , Exotropia/cirurgia , Movimentos Oculares/fisiologia , Músculos Oculomotores/cirurgia , Procedimentos Cirúrgicos Oftalmológicos/métodos , Síndrome de Angelman/complicações , Criança , Pré-Escolar , China , Exotropia/complicações , Feminino , Humanos , Masculino , Músculos Oculomotores/fisiopatologia , Prognóstico , Doenças Raras , Recuperação de Função Fisiológica , Estrabismo/complicações , Estrabismo/diagnóstico , Estrabismo/cirurgia , Resultado do Tratamento , Testes Visuais
2.
Mol Neurobiol ; 56(9): 5998-6016, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30706369

RESUMO

Angelman syndrome (AS) is a genetic disorder which entails autism, intellectual disability, lack of speech, motor deficits, and seizure susceptibility. It is caused by the lack of UBE3A protein expression, which is an E3-ubiquitin ligase. Despite AS equal prevalence in males and females, not much data on how sex affects the syndrome was reported. In the herein study, we thoroughly characterized many behavioral phenotypes of AS mice. The behavioral data acquired was analyzed with respect to sex. In addition, we generated a new mRNA sequencing dataset. We analyzed the coding transcriptome expression profiles with respect to the effects of genotype and sex observed in the behavioral phenotypes. We identified several neurobehavioral aspects, especially sensory perception, where AS mice either lack the male-to-female differences observed in wild-type littermates or even show opposed differences. However, motor phenotypes did not show male-to-female variation between wild-type (WT) and AS mice. In addition, by utilizing the mRNA sequencing, we identified genes and isoforms with expression profiles that mirror the sensory perception results. These genes are differentially regulated in the two sexes with inverse expression profiles in AS mice compared to WT littermates. Some of these are known pain-related and estrogen-dependent genes. The observed differences in sex-dependent neurobehavioral phenotypes and the differential transcriptome expression profiles in AS mice strengthen the evidence for molecular cross talk between Ube3a protein and sex hormone receptors or their elicited pathways. These interactions are essential for understanding Ube3a deletion effects, beyond its E3-ligase activity.


Assuntos
Síndrome de Angelman/genética , Caracteres Sexuais , Transcriptoma/genética , Síndrome de Angelman/complicações , Síndrome de Angelman/fisiopatologia , Animais , Ansiedade/complicações , Ansiedade/fisiopatologia , Comportamento Animal , Comportamento Exploratório , Medo , Feminino , Hipocampo/patologia , Hipocampo/fisiopatologia , Masculino , Memória , Camundongos Endogâmicos C57BL , Atividade Motora , Odorantes , Dor/complicações , Dor/genética , Dor/fisiopatologia , Percepção da Dor , Fenótipo , Aprendizagem Espacial , Temperatura
3.
Psychiatr Genet ; 29(2): 51-56, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30681431

RESUMO

OBJECTIVES: Angelman syndrome (AS) is a neurogenetic disorder associated with impaired expression of the ubiquitin-protein ligase E3A gene on chromosome 15. AS results in intellectual disability with limited expressive language, epilepsy, ataxia, sleep impairment, and problematic behavior which may include anxiety. Buspirone is a serotonin (5-HT)1A receptor partial agonist used in the treatment of anxiety disorders and may, therefore, have a treatment role for patients with AS. METHODS: We describe three patients who were given open-label buspirone for the treatment of behaviors thought to be related to anxiety. RESULTS: We found significant improvement in symptoms of anxiety with buspirone. Patients tolerated long-term usage of the medication. CONCLUSION: The findings of this study suggest that buspirone may be effective for the amelioration of behaviors related to anxiety in patients with AS, and well tolerated. Limitations include the open-label nature of these treatments, the small sample size and the absence of a control group.


Assuntos
Síndrome de Angelman/tratamento farmacológico , Ansiedade/tratamento farmacológico , Buspirona/farmacologia , Adulto , Síndrome de Angelman/complicações , Transtornos de Ansiedade/tratamento farmacológico , Feminino , Humanos , Deficiência Intelectual , Masculino , Receptor 5-HT1A de Serotonina , Serotonina , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
4.
J Neurodev Disord ; 10(1): 24, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-30081815

RESUMO

BACKGROUND: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurodevelopmental disorders that are caused by abnormal expression of imprinted genes in the 15q11-13 region. Dysregulation of genes located in this region has been proposed as a susceptibility factor for autism spectrum disorder (ASD) in both disorders. METHODS: This study aimed to explore symptoms of ASD in 25 PWS and 19 AS individuals aged between 1 and 39 years via objective assessment. Participants completed the Autism Diagnostic Observation Schedule-2nd Edition (ADOS-2) and a developmentally or age-appropriate intellectual functioning assessment. All participants had their genetic diagnosis confirmed using DNA methylation analysis and microarray testing of copy number changes within the 15q11-13 region. RESULTS: Participants with PWS had significantly higher overall and social affect calibrated severity scores (CSS) on the ADOS-2 compared to AS participants (p = .0055 and .0015, respectively), but the two groups did not differ significantly on CSS for the repetitive and restricted behaviour domain. CONCLUSIONS: PWS cases presented with greater symptoms associated with ASD compared to individuals with AS. Mental health issues associated with PWS may contribute to elevated symptoms of ASD, particularly in adolescents and adults with PWS.


Assuntos
Síndrome de Angelman/complicações , Transtorno Autístico/complicações , Transtorno Autístico/diagnóstico , Síndrome de Prader-Willi/complicações , Adolescente , Adulto , Síndrome de Angelman/epidemiologia , Austrália , Transtorno Autístico/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Síndrome de Prader-Willi/epidemiologia , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Adulto Jovem
5.
J Neurodev Disord ; 10(1): 9, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29490614

RESUMO

BACKGROUND: Sleep disturbance is common in children with neurodevelopmental disorders, with high rates identified in children with Smith-Magenis syndrome (SMS), Angelman syndrome (AS), autism spectrum disorder (ASD) and tuberous sclerosis complex (TSC). Phenotypic sleep profiles for these groups may implicate different pathways to sleep disturbance. At present, cross-group comparisons that might elucidate putative phenotypic sleep characteristics are limited by measurement differences between studies. In this study, a standardised questionnaire was administered across groups affording comparison of the prevalence and profile of sleep disturbance between groups and contrast to chronologically age-matched typically developing (TD) peers. METHODS: The modified version of Simonds and Parraga's sleep questionnaire, adapted for use in children with intellectual disabilities, was employed to assess sleep disturbance profiles in children aged 2-15 years with SMS (n = 26), AS (n = 70), ASD (n = 30), TSC (n = 20) and a TD contrast group (n = 47). Associations between sleep disturbance and age, obesity, health conditions and overactivity/impulsivity were explored for each neurodevelopmental disorder group. RESULTS: Children with SMS displayed severe night waking (81%) and early morning waking (73%). In contrast, children with ASD experienced difficulties with sleep onset (30%) and sleep maintenance (43%). Fewer children with ASD (43%) and AS (46%) experienced severe night waking compared to children with SMS (both p < .01). Higher sleep-disordered breathing scores were identified for children with SMS (p < .001) and AS (p < .001) compared to the TD group. Sleep disturbance in children with AS and TSC was associated with poorer health. Children experiencing symptoms indicative of gastro-oesophageal reflux had significantly higher sleep-disordered breathing scores in the AS, SMS and ASD groups (all p < .01). A number of associations between overactivity, impulsivity, gastro-oesophageal reflux, age and sleep disturbance were found for certain groups. CONCLUSIONS: These data reveal syndrome-specific profiles of sleep disturbance. The divergent associations between sleep parameters and person characteristics, specifically symptoms of gastro-oesophageal reflux, overactivity and impulsivity and age, implicate aetiology-specific mechanisms underpinning sleep disturbance. The differences in prevalence, severity and mechanisms implicated in sleep disturbance between groups support a syndrome-sensitive approach to assessment and treatment of sleep disturbance in children with neurodevelopmental disorders.


Assuntos
Síndrome de Angelman/epidemiologia , Transtorno do Espectro Autista/epidemiologia , Transtornos do Sono-Vigília/epidemiologia , Síndrome de Smith-Magenis/epidemiologia , Esclerose Tuberosa/epidemiologia , Síndrome de Angelman/complicações , Transtorno do Espectro Autista/complicações , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Transtornos do Sono-Vigília/complicações , Síndrome de Smith-Magenis/complicações , Inquéritos e Questionários , Esclerose Tuberosa/complicações
6.
Epilepsy Behav ; 82: 74-80, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29597185

RESUMO

Nonconvulsive status epilepticus (NCSE) is present in multiple pediatric neurogenetic syndromes with epileptic encephalopathies. While intravenous (IV) medications are used inpatient for treatment of critical illness-related NCSE, there is no consensus on treatment of ambulatory NCSE. Up to 50% of patients with Angelman syndrome (AS) have NCSE with myoclonic or atypical absence status. Here we report our experience in pediatric patients with AS and NCSE treated outpatient with a tapering course of oral diazepam. We conducted a chart review of 104 patients seen in the Angelman Syndrome Clinic at Massachusetts General Hospital from January 2008 to March 2017, who met the criteria. Response to treatment was defined as cessation of NCSE symptoms with electroencephalogram (EEG) confirmation when possible. Twenty-one patients with NCSE were identified, and 13 patients (9 male) with 25 episodes of NCSE were included. Mean age at NCSE episode was 5years 4months (15months-12years). Six patients had one episode of NCSE, and 7 patients had recurrent episodes (mean: 2.7; range: 2-4). Median diazepam treatment was 6days (4-12days), with a mean dose of 0.32mg/kg/day divided over 2-3 administrations, decreased every 2days. Nine episodes required multiple courses; however, oral diazepam alone was ultimately successful in 80% (20/25) of NCSE episodes. Oral diazepam was well-tolerated with no major side effects. A short course of oral diazepam is well-tolerated and effective in patients with AS who have ambulatory NCSE. It may be considered prior to escalating to inpatient care in AS and possibly other epilepsy syndromes.


Assuntos
Assistência Ambulatorial/métodos , Síndrome de Angelman/tratamento farmacológico , Anticonvulsivantes/uso terapêutico , Diazepam/uso terapêutico , Estado Epiléptico/tratamento farmacológico , Instituições de Assistência Ambulatorial , Síndrome de Angelman/complicações , Síndrome de Angelman/fisiopatologia , Criança , Pré-Escolar , Diazepam/farmacologia , Eletroencefalografia , Feminino , Humanos , Lactente , Masculino , Massachusetts , Estado Epiléptico/complicações , Estado Epiléptico/fisiopatologia , Resultado do Tratamento
7.
Epilepsy Behav ; 82: 170-174, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29555100

RESUMO

Angelman syndrome (AS) is a neurogenetic imprinting disorder caused by loss of the maternally inherited Ube3a gene and is characterized by generalized epilepsy, limited expressive speech, sleep dysfunction, and movement disorders. Myoclonic seizures are often the first seizure type to appear, and myoclonic status, associated with developmental regression, may occur in the first few years of life. Additionally, there have been rare reports of prolonged episodes of myoclonus without electrographic correlate in adults with AS. The medical records of 200 individuals seen in the Angelman Syndrome Clinic at the Massachusetts General Hospital and the Lurie Center for Autism were retrospectively reviewed to identify and characterize myoclonic seizures and episodes of nonepileptic myoclonus. Myoclonic seizures were reported in 14% of individuals with age of onset occurring before 8years. These are brief events, unless the individual was experiencing myoclonic status, and electroencephalographs show interictal generalized spike and wave activity. Nonepileptic myoclonus occurred in 40% of individuals over 10years of age, and prevalence appears to increase with age. The episodes of nonepileptic myoclonus arise during puberty or later, with age of onset ranging from 10 to 26years. These events were captured on 5 video electroencephalographs and had no electrographic correlate. They can last from seconds to hours, always occurring in the hands and spreading to the face and all extremities in some individuals. Episodes of nonepileptic myoclonus have a discrete beginning and end, lacks a postictal period, and are not associated with significant alteration of consciousness or developmental regression. These episodes can be difficult to treat and are often refractory to medication; however, levetiracetam, clobazam, and clonazepam appear to be effective for some individuals. Myoclonic seizures are common in AS, typically occurring in young children and associated with epileptiform changes on electroencephalographs. Prolonged episodes are associated with developmental regression. In contrast, nonepileptic myoclonus typically begins in adolescence or early adulthood and has no electroencephalogram (EEG) correlate, alteration in consciousness, or regression but can significantly impact quality of life.


Assuntos
Síndrome de Angelman/complicações , Epilepsias Mioclônicas , Adolescente , Adulto , Distribuição por Idade , Síndrome de Angelman/fisiopatologia , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Eletroencefalografia , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/epidemiologia , Epilepsias Mioclônicas/fisiopatologia , Feminino , Humanos , Lactente , Masculino , Prevalência , Qualidade de Vida , Estudos Retrospectivos , Convulsões/tratamento farmacológico , Convulsões/epidemiologia , Transtornos do Sono-Vigília , Adulto Jovem
9.
Childs Nerv Syst ; 34(3): 395-400, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29350262

RESUMO

BACKGROUND: We describe three children with Angelman syndrome and medically refractory epilepsy. METHODS: Case series of three pediatric patients with Angelman syndrome and medically refractory epilepsy. All three patients failed medical treatment and were recommended for vagal nerve stimulator (VNS) implantation. RESULTS: Following VNS implantation, all three patients experienced reduction in seizure frequency greater than that afforded by medication alone. CONCLUSION: We present vagal nerve stimulator implantation as a viable treatment option for medically refractory epilepsy associated with Angelman syndrome.


Assuntos
Síndrome de Angelman/diagnóstico , Síndrome de Angelman/terapia , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/terapia , Estimulação do Nervo Vago/métodos , Síndrome de Angelman/complicações , Criança , Pré-Escolar , Epilepsia Resistente a Medicamentos/complicações , Feminino , Humanos , Masculino , Estimulação do Nervo Vago/tendências
10.
Mol Autism ; 9: 2, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29340132

RESUMO

Background: Autism spectrum disorder and epilepsy often co-occur; however, the extent to which the association between autism symptoms and epilepsy is due to shared aetiology or to the direct effects of seizures is a topic of ongoing debate. Angelman syndrome (AS) is presented as a suitable disease model to explore this association. Methods: Data from medical records and questionnaires were used to examine the association between age of epilepsy onset, autism symptoms, genetic aberration and communication level. Forty-eight participants had genetically verified AS (median age 14.5 years; range 1-57 years). A measure of autism symptoms (the Social Communication Questionnaire; SCQ) was completed for 38 individuals aged ≥ 4 years. Genetic cause was subgrouped into deletion and other genetic aberrations of the 15q11-q13 area. The number of signs used to communicate (< 20 sign and ≥ 20 signs) was used as a measure of nonverbal communication. Results: Mean age of epilepsy onset was 3.0 years (range 3 months-7.8 years). Mean SCQ score for individuals without epilepsy was 13.6 (SD = 6.7) and with epilepsy 17.0 (SD = 5.6; p = 0.17); 58% used fewer than 20 signs to communicate. There were no age differences between groups according to presence of epilepsy, level of nonverbal communication or type of genetic aberration. SCQ scores were higher in individuals with the deletion than in those with other genetic aberrations (18.7 vs 10.8 p = 0.008) and higher in the group who used < 20 signs to communicate (19.4 vs 14.1 p = 0.007). Age of epilepsy onset was correlated with SCQ (r = - 0.61, p < 0.001). Multiple regression showed that age of seizure onset was significantly related to SCQ score (ß = - 0.90; p = 0.006), even when the type of genetic abnormality was controlled (R2 = 0.53; F = 10.7; p = 0.001). Conclusions: The study provides support for the notion that seizures themselves contribute more to autism symptoms than expected from the underlying genetic pathology alone. The study demonstrates how a rare genetic syndrome such as Angelman syndrome may be used to study the relation between epilepsy and autism symptomatology.


Assuntos
Síndrome de Angelman/diagnóstico , Transtorno Autístico/diagnóstico , Epilepsia/diagnóstico , Adolescente , Adulto , Síndrome de Angelman/complicações , Transtorno Autístico/epidemiologia , Criança , Pré-Escolar , Epilepsia/epidemiologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade
11.
Neurobiol Dis ; 110: 12-19, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29097328

RESUMO

Epilepsy is prevalent and often medically intractable in Angelman syndrome (AS). AS mouse model (Ube3am-/p+) shows reduced excitatory neurotransmission but lower seizure threshold. The neural mechanism linking the synaptic dysfunction to the seizure remains elusive. We show that the local circuits of Ube3am-/p+in vitro are hyperexcitable and display a unique epileptiform activity, a phenomenon that is reminiscent of the finding in fragile X syndrome (FXS) mouse model. Similar to the FXS model, lovastatin suppressed the epileptiform activity and audiogenic seizures in Ube3am-/p+. The in vitro model of Ube3am-/p+ is valuable for dissection of neural mechanism and epilepsy drug screening in vivo.


Assuntos
Síndrome de Angelman/fisiopatologia , Anticonvulsivantes/farmacologia , Modelos Animais de Doenças , Hipocampo/fisiopatologia , Lovastatina/farmacologia , Síndrome de Angelman/complicações , Síndrome de Angelman/genética , Animais , Epilepsia/etiologia , Epilepsia/fisiopatologia , Feminino , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Cultura de Órgãos/métodos , Convulsões/etiologia , Convulsões/fisiopatologia , Ubiquitina-Proteína Ligases/genética
12.
J Appl Res Intellect Disabil ; 31(3): 466-469, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28869323

RESUMO

BACKGROUND: The objective was to describe the main causes of hospitalization in people with Angelman syndrome (AS). METHOD: Population-based cross-sectional study in the Community of Madrid (CM), Spain. The information source for AS cases was the information system for rare diseases in the CM. Variables related to hospitalization, for the period 2006-2014, were the following: number of episodes, outcome, main cause, length of stay and type of admission. Main causes of hospitalization were described by age group and sex. RESULTS: The most frequent causes of hospitalization were the following: oral-dental care (28.9%), seizures (19.6%), orthopaedic problems (14.4%) and acute respiratory disorders (12.4%). The percentage of hospitalizations was higher for oral-dental care in women and for orthopaedic problems in men (p-value <.05). Hospitalizations for an acute respiratory disorder were higher in adults (p-value <.05). CONCLUSIONS: Some differences in the causes of hospitalization of people with AS were observed by sex and age.


Assuntos
Síndrome de Angelman/complicações , Hospitalização , Doenças Musculoesqueléticas/complicações , Transtornos Respiratórios/complicações , Convulsões/complicações , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Estudos Transversais , Assistência Odontológica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Adulto Jovem
13.
Sleep Med Rev ; 37: 69-84, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28784434

RESUMO

Sleep problems are reported to be extremely prevalent in individuals with developmental disabilities. The consensus guidelines for Angelman syndrome (AS) consider abnormal sleep-wake cycles and diminished need for sleep as associated features. We report an integrative research review and a meta-analysis of studies with sleep as the primary aim of investigation in an AS sample. 14 studies met eligibility criteria with half of them being surveys. Thirteen of the 17 conceptually formed sleep disorder item-groups showed to be significant for individuals with AS. There is evidence that arousal during sleep, somnolence and possibly short sleep duration are the primary sleep problems in individuals with AS. According to the results of this review and meta-analyses, there is clear evidence for sleep problems in individuals with AS. Individual effect sizes remain overall small, but nevertheless findings suggest disorders of arousal and sleepiness to be distinctive. In light of these findings, other sleep complaints in individuals with AS should be carefully examined. Consistent standards for research on sleep in individuals with AS are critical for new lines of investigation.


Assuntos
Síndrome de Angelman/complicações , Transtornos do Sono-Vigília/etiologia , Sono/fisiologia , Actigrafia , Nível de Alerta/fisiologia , Humanos , Polissonografia
14.
Epilepsy Behav ; 75: 225-229, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28827041

RESUMO

OBJECTIVE: Actual knowledge on evolution of Angelman syndrome (AS) relies on questionnaire-based cohort studies, phone interviews, or small retrospective cohort studies focused on specific clinical-genetic features. These reports provide conflicting results. The aim of this study was to assess the long-term outcome of epilepsy, sleep disorders, and EEG in a vast series of AS subjects. METHODS: We collected patients with genetically confirmed AS, aged ≥14years, followed in three tertiary epilepsy Centers or attending the meetings of the Italian Organization for AS (OrSA). Retrospective clinical and EEG data were retrieved from hospital archives or family documents. At index evaluation (IE) (last visit at tertiary Centers or single visit during OrSA meetings), caregivers were interviewed about anamnestic data and filled questionnaires on sleep disorders and daily-living skills. Patients underwent general and neurologic evaluation, and video-EEG recordings. All available EEGs were analyzed to compare evolution of spike-wave index (SWI) over the years. RESULTS: Forty-six subjects aged 14-45years were included: 24 from tertiary Centers, 22 from OrSA meetings. During childhood, 42/46 (91.3%) had seizures, which improved over the years in all subjects. Among patients with epilepsy, 27(64%) became seizure-free at a median age of 10years and 4 remained seizure-free even after antiepileptic withdrawal. During childhood, 39/46 (84.8%) had sleep disorders, which improved in 27/39 (69%) over the years. At IE, daily-living skills corresponded to age≤1.6years in 29/46 (63%). Electroencephalogram showed typical AS patterns in 35/46 (76.1%). In EEGs recorded from 10 patients, SWI was not significantly different between infancy/childhood and adolescence/adulthood. CONCLUSION: Improvement of epilepsy or sleep disorders should not disregard the clinical suspicion of AS in adolescent or adult patients with suggestive features. Drug withdrawal might be considered in the management of epilepsy despite the persistence of epileptiform abnormalities.


Assuntos
Síndrome de Angelman/complicações , Epilepsia/complicações , Transtornos do Sono-Vigília/etiologia , Adolescente , Adulto , Análise de Variância , Síndrome de Angelman/fisiopatologia , Eletroencefalografia , Epilepsia/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transtornos do Sono-Vigília/fisiopatologia , Adulto Jovem
15.
Am J Med Genet A ; 173(10): 2703-2709, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28816003

RESUMO

Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability, expressive speech impairment, movement disorder, epilepsy, and a happy demeanor. Children with AS are frequently reported to be poor feeders during infancy and as having gastrointestinal issues such as constipation, reflux, and abnormal food related behaviors throughout their lifetime. To assess the prevalence of gastrointestinal disorders in individuals with AS, we retrospectively analyzed medical records of 120 individuals seen at the Angelman Syndrome Clinic at Massachusetts General Hospital and 43 individuals seen at the University of North Carolina Comprehensive Angelman Clinic. The majority of patients' medical records indicated at least one symptom of gastrointestinal dysfunction, with constipation and gastroesophageal reflux disease (GERD) the most common. Other gastrointestinal issues reported were cyclic vomiting episodes, difficulty swallowing, excessive swallowing, and eosinophilic esophagitis. Upper gastrointestinal symptoms such as GERD, swallowing difficulties, cyclic vomiting, and eosinophilic esophagitis were more common in those with deletions and uniparental disomy, likely related to the involvement of multiple genes and subsequent hypotonia. The frequency of constipation is consistent among all genetic subtypes while early feeding issues appear to mainly affect those with deletions. Caregivers and healthcare providers should be aware of the high prevalence of these issues, as proper treatment may improve not only gastrointestinal dysfunction but also sleep and behavioral issues.


Assuntos
Síndrome de Angelman/complicações , Gastroenteropatias/epidemiologia , Adolescente , Adulto , Síndrome de Angelman/fisiopatologia , Criança , Pré-Escolar , Feminino , Gastroenteropatias/etiologia , Gastroenteropatias/patologia , Humanos , Lactente , Masculino , Massachusetts/epidemiologia , Prevalência , Prognóstico , Estudos Retrospectivos , Adulto Jovem
16.
Neurobiol Dis ; 105: 99-108, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28576709

RESUMO

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe intellectual and developmental disabilities. The disease is caused by the loss of function of maternally inherited UBE3A, a gene that exhibits paternal-specific imprinting in neuronal tissues. Ube3a-maternal deficient mice (AS mice) display many classical features of AS, although, the underlying mechanism of these behavioural deficits is poorly understood. Here we report that the absence of Ube3a in AS mice brain caused aberrant increase in HDAC1/2 along with decreased acetylation of histone H3/H4. Partial knockdown of Ube3a in cultured neuronal cells also lead to significant up-regulation of HDAC1/2 and consequent down-regulation of histones H3/H4 acetylation. Treatment of HDAC inhibitor, sodium valproate, to AS mice showed significant improvement in social, cognitive and motor impairment along with restoration of various proteins linked with synaptic function and plasticity. Interestingly, HDAC inhibitor also significantly increased the expression of Ube3a in cultured neuronal cells and in the brain of wild type mice but not in AS mice. These results indicate that anomalous HDAC1/2 activity might be linked with synaptic dysfunction and behavioural deficits in AS mice and suggests that HDAC inhibitors could be potential therapeutic molecule for the treatment of the disease.


Assuntos
Síndrome de Angelman/complicações , Síndrome de Angelman/enzimologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Histona Desacetilases/metabolismo , Transtornos Mentais/etiologia , Ácido Valproico/farmacologia , Síndrome de Angelman/tratamento farmacológico , Síndrome de Angelman/genética , Animais , Ansiedade/etiologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular Transformada , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Regulação Enzimológica da Expressão Gênica/genética , Histona Desacetilases/uso terapêutico , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ácido Valproico/uso terapêutico
17.
Exp Neurol ; 293: 137-143, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28411125

RESUMO

Deletions and reciprocal triplications of the human chromosomal 15q11-13 region cause two distinct neurodevelopmental disorders. Maternally-derived deletions or inactivating mutations of UBE3A, a 15q11-13 gene expressed exclusively from the maternal allele in neurons, cause Angelman syndrome, characterized by intellectual disability, motor deficits, seizures, and a characteristic increased social smiling, laughing, and eye contact. Conversely, maternally-derived triplications of 15q11-13 cause a behavioral disorder on the autism spectrum with clinical features that include decreased sociability that we recently reconstituted in mice with Ube3a alone. Based on the unique sociability features reported in Angelman syndrome and the repressed sociability observed when Ube3a gene dosage is increased, we hypothesized that mice with neuronal UBE3A loss that models Angelman syndrome would display evidence of hypersocial behavior. We report that mice with maternally-inherited Ube3a gene deletion (Ube3amKO) have a prolonged preference for, and interaction with, social stimuli in the three chamber social approach task. By contrast, interactions with a novel object are reduced. Further, ultrasonic vocalizations and physical contacts are increased in male and female Ube3amKO mice paired with an unfamiliar genotype-matched female. Single housing wild type mice increased these same social behavior parameters to levels observed in Ube3amKO mice where this effect was partially occluded. These results indicate sociability is repressed by social experience and the endogenous levels of UBE3A protein and suggest some social behavioral features observed in Angelman syndrome may reflect an increased social motivation.


Assuntos
Síndrome de Angelman/complicações , Transtornos do Comportamento Social/etiologia , Ubiquitina-Proteína Ligases/deficiência , Análise de Variância , Síndrome de Angelman/genética , Animais , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Feminino , Masculino , Camundongos , Camundongos Knockout , Atividade Motora/genética , Fatores de Tempo , Ubiquitina-Proteína Ligases/genética , Vocalização Animal/fisiologia
18.
Epilepsy Behav ; 68: 45-50, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28109989

RESUMO

The low glycemic index treatment, a dietary therapy that focuses on glycemic index and reduced carbohydrate intake, has been successful in reducing seizure frequency in the general epilepsy population. Epilepsy is a common feature of Angelman syndrome and seizures are often refractory to multiple medications, especially in those with maternal deletions. Dietary therapy has become a more frequently used option for treating epilepsy, often in combination with other antiepileptic drugs, due to its efficacy and favorable side effect profile. This study aimed to assess the effectiveness of the low glycemic index treatment for seizure control in Angelman syndrome. Through a retrospective medical record review of 23 subjects who utilized the low glycemic index treatment at the Clinic and Center for Dietary Therapy of Epilepsy at the Massachusetts General Hospital, we found that the high level of seizure control and favorable side effect profile make the low glycemic index treatment a viable treatment for seizures in Angelman syndrome. The majority of subjects in our cohort experienced some level of seizure reduction after initiating the diet, 5 (22%) maintained complete seizure freedom, 10 (43%) maintained seizure freedom except in the setting of illness or non-convulsive status epilepticus, 7 (30%) had a decrease in seizure frequency, and only 1 (4%) did not have enough information to determine seizure control post-initiation. The low glycemic index treatment monotherapy was successful for some subjects in our cohort but most subjects used an antiepileptic drug concurrently. Some subjects were able to maintain the same level of seizure control on a liberalized version of the low glycemic index treatment which included a larger amount of low glycemic carbohydrates. No correlation between the level of carbohydrate restriction and level of seizure control was found. Few subjects experienced side effects and those that did found them to be mild and easily treated. The efficacy of the low glycemic index treatment and its favorable side effect profile make it an excellent alternative or supplement to antiepileptic drug therapy for the treatment of seizures in Angelman syndrome.


Assuntos
Síndrome de Angelman/dietoterapia , Dieta Cetogênica , Índice Glicêmico , Convulsões/dietoterapia , Adolescente , Adulto , Síndrome de Angelman/complicações , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Massachusetts , Estudos Retrospectivos , Convulsões/etiologia , Resultado do Tratamento , Adulto Jovem
19.
Acta Orthop ; 88(2): 198-204, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27892801

RESUMO

Background and purpose - Studies have indicated that one-third of children with cerebral palsy (CP) develop dislocation of the hip that needs surgical intervention. When hip dislocation occurs during childhood surgical treatment consists of tenotomies, femoral varus derotation osteotomy (VDRO), and acetabuloplasty. Relapse is observed in one-fifth of cases during adolescence. In this prospective cohort study, we performed a descriptive evaluation of translation and rotation across VDROs in children with neuromuscular disorders and syndromes by radiostereometric analysis (RSA). We assessed "RSA stability" and migration across the VDROs. Patients and methods - Children with a neuromuscular disorder were set up for skeletal corrective surgery of the hip. RSA follow-ups were performed postoperatively, at 5 weeks, and 3, 6, and 12 months after surgery. Results - 27 femoral VDROs were included; 2 patients were excluded during the study period. RSA data showed stability across the VDRO in the majority of cases within the first 5 weeks. At the 1-year follow-up, the mean translations (SD) of the femoral shaft distal to the VDRO were 0.51 (1.12) mm medial, 0.69 (1.61) mm superior, and 0.21 (1.28) mm posterior. The mean rotations were 0.39° (2.90) anterior tilt, 0.02° (3.07) internal rotation, and 2.17° (2.29) varus angulation. Interpretation - The migration stagnates within the first 5 weeks, indicating stability across the VDRO in most patients.


Assuntos
Acetábulo/cirurgia , Paralisia Cerebral/complicações , Fêmur/cirurgia , Luxação do Quadril/cirurgia , Osteotomia/métodos , Tenotomia/métodos , Adolescente , Síndrome de Angelman/complicações , Criança , Pré-Escolar , Estudos de Coortes , Craniossinostoses/complicações , Feminino , Luxação do Quadril/etiologia , Humanos , Deficiência Intelectual/complicações , Instabilidade Articular , Masculino , Estudos Prospectivos , Procedimentos Cirúrgicos Reconstrutivos/métodos , Síndrome de Rett/complicações , Rotação , Resultado do Tratamento
20.
Eur J Pediatr ; 176(2): 225-232, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28000035

RESUMO

Angelman syndrome (AS) is a congenital syndrome with a prevalence of 1:15,000. Individuals with AS often have severe intellectual disability, typical dysmorphic signs, and behavioral problems. The aim of the study was to investigate the rate of incontinence and associated psychological problems in children and adults with AS. Ninety children (4-18 years) and 54 adults (18-31 years) with AS were recruited through a parent support group (55.6% male, mean age 15.1 years). The Parental Questionnaire: Enuresis/Urinary Incontinence, the Incontinence Questionnaire-Pediatric Lower Urinary Tract Symptoms (ICIQ-CLUTS), as well as the Developmental Behaviour Checklist for parents (DBC-P) or for adults (DBC-A) were filled out by parents or caregivers. 85.6% of individuals with AS were affected by at least one subtype of incontinence (82.7% nocturnal enuresis (NE), 64.7% daytime urinary incontinence (DUI), and 57.1% fecal incontinence (FI)). 52.5% of the children and 32.6% of adults reached a clinically relevant DBC score. Incontinence was not associated with behavioral problems. NE and DUI were associated with genotype and epilepsy. CONCLUSION: Children with AS have high rates of incontinence. Many adults are still affected by NE, DUI, or even FI. Screening, assessment, and treatment of incontinence in individuals with AS are recommended. What is Known: • Incontinence in persons with Angelman syndrome (AS) is associated with younger age, lower level of adaptive functioning, and epilepsy. What is New: • Children and teens with AS are at special risk for incontinence, but older persons are also affected. • Comorbid epilepsy is significantly associated not only with nocturnal enuresis (NE) but also with daytime urinary incontinence (DUI). Underlying genotype is significantly associated with incontinence.


Assuntos
Síndrome de Angelman/complicações , Enurese Diurna/epidemiologia , Incontinência Fecal/epidemiologia , Enurese Noturna/epidemiologia , Adolescente , Fatores Etários , Síndrome de Angelman/psicologia , Criança , Pré-Escolar , Enurese Diurna/diagnóstico , Epilepsia/complicações , Epilepsia/epidemiologia , Incontinência Fecal/diagnóstico , Feminino , Humanos , Incidência , Deficiência Intelectual/epidemiologia , Masculino , Enurese Noturna/diagnóstico , Pais , Índice de Gravidade de Doença , Transtornos do Sono-Vigília/epidemiologia , Estatísticas não Paramétricas , Inquéritos e Questionários , Adulto Jovem
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