Neurologic Manifestations of Angelman Syndrome

Thibert, Ronald L.; Larson, Anna M.; Hsieh, David T.; Raby, Annabel R.; Thiele, Elizabeth A.

doi:10.1016/j.pediatrneurol.2012.09.015

Cited by 159 publications

(164 citation statements)

References 87 publications

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“…Treatment is supportive and includes 1) therapies to mitigate gross and fine motor delays; 2) augmentative communication strategies such as the use of communication devices, picture exchange cards, and modified sign language; and 3) intervention for comorbid ASD when present [2][3][4][8][9][10]. The remainder of treatment is limited to managing the problems associated with AS [66]. Gastrointestinal problems such as gastroesophageal reflux disease and constipation are managed with pharmacological agents when dietary modifications are insufficient.…”

Section: Treatment Currentmentioning

confidence: 99%

Angelman Syndrome

et al. 2015

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In this review we summarize the clinical and genetic aspects of Angelman syndrome (AS), its molecular and cellular underpinnings, and current treatment strategies. AS is a neurodevelopmental disorder characterized by severe cognitive disability, motor dysfunction, speech impairment, hyperactivity, and frequent seizures. AS is caused by disruption of the maternally expressed and paternally imprinted UBE3A, which encodes an E3 ubiquitin ligase. Four mechanisms that render the maternally inherited UBE3A nonfunctional are recognized, the most common of which is deletion of the maternal chromosomal region 15q11-q13. Remarkably, duplication of the same chromosomal region is one of the few characterized persistent genetic abnormalities associated with autistic spectrum disorder, occurring in >1-2 % of all cases of autism spectrum disorder. While the overall morphology of the brain and connectivity of neural projections appear largely normal in AS mouse models, major functional defects are detected at the level of context-dependent learning, as well as impaired maturation of hippocampal and neocortical circuits. While these findings demonstrate a crucial role for ubiquitin protein ligase E3A in synaptic development, the mechanisms by which deficiency of ubiquitin protein ligase E3A leads to AS pathophysiology in humans remain poorly understood. However, recent efforts have shown promise in restoring functions disrupted in AS mice, renewing hope that an effective treatment strategy can be found.Key Words Angelman syndrome . neurodevelopmental disorders . autism . ubiquitin ligase . Ube3a . Imprinting. Clinical OverviewIn 1965, the English physician Harry Angelman described 3 patients who presented with a stiff, jerky gait, absence of speech, excessive laughter, and seizures. The disorder that came to bear his name [Angelman syndrome (AS)] is now recognized to affect approximately 1 in 15,000 individuals and is characterized by motor dysfunction, severe intellectual disability, speech impairment, seizures, hyperactivity, and autism spectrum disorder (ASD) as a common comorbidity [1].Developmental delay in individuals with AS is usually observed within the first year of life. Though most individuals lack speech entirely, some who are mildly affected can acquire a few words. Receptive language is less impaired. Seizures occur in >80 % of patients, and onset is usually before the age of 3 years. Movement disorders include tremors, jerkiness, and ataxia. The characteristic behaviors of AS include mouthing of objects, happy demeanor with easily provoked laughter, attraction to water, hyperactivity, short attention span, and decreased sleeping (see recent reviews for more detailed description of the clinical phenotype [2][3][4]). These features of AS can be seen in other neurodevelopmental disorders, leading to a broad differential diagnosis [5], which has recently been reviewed (Table 1) [6]. Overlapping clinical features may indicate common neurophysiological pathways,

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Section: Treatment Currentmentioning

confidence: 99%

Angelman Syndrome

et al. 2015

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“…El vigabatrin, fenobarbital, carbamazepina y oxcarbazepina pueden no mejorar e, incluso, exacerbar las crisis. 11 Dentro de los movimientos anormales, el hallazgo de las distonías paroxísticas del caso 6, de acuerdo con nuestro conocimiento, no ha sido reportado en SA pero sí en SA-like ligado a X, 7 y se ha logrado buena respuesta con levetiracetam.…”

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Del fenotipo neuropsiquiátrico al cuidado clínico del síndrome de Angelman: descripción de siete casos

2017

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RESUMENEl 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. Palabras clave: síndrome de Angelman, cromosoma 15q11-13, UBE3A, niño, impronta molecular. ABSTRACTAngelman 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.

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“…One possible explanation for the disparate findings is that these studies have been conducted using adult mice at a time when the aberrant AS behaviors may have begun to subside. Indeed, seizures are prominent in AS in early childhood (<3 y of age) but begin to vary considerably in frequency and severity as children with AS age (2,23,24). In addition, some core features of human AS that are seen in early childhood, such as abnormal communication,…”

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confidence: 99%

Seizure-like activity in a juvenile Angelman syndrome mouse model is attenuated by reducing Arc expression

Mandel‐Brehm

Salogiannis

Dhamne

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Angelman syndrome (AS) is a neurodevelopmental disorder arising from loss-of-function mutations in the maternally inherited copy of the UBE3A gene, and is characterized by an absence of speech, excessive laughter, cognitive delay, motor deficits, and seizures. Despite the fact that the symptoms of AS occur in early childhood, behavioral characterization of AS mouse models has focused primarily on adult phenotypes. In this report we describe juvenile behaviors in AS mice that are strain-independent and clinically relevant. We find that young AS mice, compared with their wild-type littermates, produce an increased number of ultrasonic vocalizations. In addition, young AS mice have defects in motor coordination, as well as abnormal brain activity that results in an enhanced seizure-like response to an audiogenic challenge. The enhanced seizure-like activity, but not the increased ultrasonic vocalizations or motor deficits, is rescued in juvenile AS mice by genetically reducing the expression level of the activity-regulated cytoskeleton-associated protein, Arc. These findings suggest that therapeutic interventions that reduce the level of Arc expression have the potential to reverse the seizures associated with AS. In addition, the identification of aberrant behaviors in young AS mice may provide clues regarding the neural circuit defects that occur in AS and ultimately allow new approaches for treating this disorder.Angelman syndrome | ARC | EPHEXIN5 | ultrasonic vocalizations | EEG

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Neurologic Manifestations of Angelman Syndrome

Cited by 159 publications

References 87 publications

Angelman Syndrome

Angelman Syndrome

Del fenotipo neuropsiquiátrico al cuidado clínico del síndrome de Angelman: descripción de siete casos

Seizure-like activity in a juvenile Angelman syndrome mouse model is attenuated by reducing Arc expression

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