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Ronald L Thibert – One of the best experts on this subject based on the ideXlab platform.

  • myoclonus in Angelman Syndrome
    Epilepsy & Behavior, 2018
    Co-Authors: Sarah F Pollack, Olivia Grocott, Anna M Larson, Kimberly Parkin, Ronald L Thibert

    Abstract:

    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.

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  • prevalence of gastrointestinal symptoms in Angelman Syndrome
    American Journal of Medical Genetics Part A, 2017
    Co-Authors: Laura W Glassman, Anna M Larson, Olivia Grocott, Portia A Kunz, Garrett C Zella, Kriston Ganguli, Ronald L Thibert

    Abstract:

    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.

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  • Delta rhythmicity is a reliable EEG biomarker in Angelman Syndrome: a parallel mouse and human analysis
    Journal of Neurodevelopmental Disorders, 2017
    Co-Authors: Michael S. Sidorov, Ronald L Thibert, Gina M. Deck, Marjan Dolatshahi, Lynne M. Bird, Catherine J. Chu, Benjamin D. Philpot

    Abstract:

    Clinicians have qualitatively described rhythmic delta activity as a prominent EEG abnormality in individuals with Angelman Syndrome, but this phenotype has yet to be rigorously quantified in the clinical population or validated in a preclinical model. Here, we sought to quantitatively measure delta rhythmicity and evaluate its fidelity as a biomarker. We quantified delta oscillations in mouse and human using parallel spectral analysis methods and measured regional, state-specific, and developmental changes in delta rhythms in a patient population. Delta power was broadly increased and more dynamic in both the Angelman Syndrome mouse model, relative to wild-type littermates, and in children with Angelman Syndrome, relative to age-matched neurotypical controls. Enhanced delta oscillations in children with Angelman Syndrome were present during wakefulness and sleep, were generalized across the neocortex, and were more pronounced at earlier ages. Delta rhythmicity phenotypes can serve as reliable biomarkers for Angelman Syndrome in both preclinical and clinical settings.

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Benjamin D. Philpot – One of the best experts on this subject based on the ideXlab platform.

  • Delta rhythmicity is a reliable EEG biomarker in Angelman Syndrome: a parallel mouse and human analysis
    Journal of Neurodevelopmental Disorders, 2017
    Co-Authors: Michael S. Sidorov, Ronald L Thibert, Gina M. Deck, Marjan Dolatshahi, Lynne M. Bird, Catherine J. Chu, Benjamin D. Philpot

    Abstract:

    Clinicians have qualitatively described rhythmic delta activity as a prominent EEG abnormality in individuals with Angelman Syndrome, but this phenotype has yet to be rigorously quantified in the clinical population or validated in a preclinical model. Here, we sought to quantitatively measure delta rhythmicity and evaluate its fidelity as a biomarker. We quantified delta oscillations in mouse and human using parallel spectral analysis methods and measured regional, state-specific, and developmental changes in delta rhythms in a patient population. Delta power was broadly increased and more dynamic in both the Angelman Syndrome mouse model, relative to wild-type littermates, and in children with Angelman Syndrome, relative to age-matched neurotypical controls. Enhanced delta oscillations in children with Angelman Syndrome were present during wakefulness and sleep, were generalized across the neocortex, and were more pronounced at earlier ages. Delta rhythmicity phenotypes can serve as reliable biomarkers for Angelman Syndrome in both preclinical and clinical settings.

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  • Delta rhythmicity is a reliable EEG biomarker in Angelman Syndrome: a parallel mouse and human analysis
    Journal of Neurodevelopmental Disorders, 2017
    Co-Authors: Michael S. Sidorov, Ronald L Thibert, Gina M. Deck, Marjan Dolatshahi, Lynne M. Bird, Benjamin D. Philpot

    Abstract:

    Background Clinicians have qualitatively described rhythmic delta activity as a prominent EEG abnormality in individuals with Angelman Syndrome, but this phenotype has yet to be rigorously quantified in the clinical population or validated in a preclinical model. Here, we sought to quantitatively measure delta rhythmicity and evaluate its fidelity as a biomarker. Methods We quantified delta oscillations in mouse and human using parallel spectral analysis methods and measured regional, state-specific, and developmental changes in delta rhythms in a patient population. Results Delta power was broadly increased and more dynamic in both the Angelman Syndrome mouse model, relative to wild-type littermates, and in children with Angelman Syndrome, relative to age-matched neurotypical controls. Enhanced delta oscillations in children with Angelman Syndrome were present during wakefulness and sleep, were generalized across the neocortex, and were more pronounced at earlier ages. Conclusions Delta rhythmicity phenotypes can serve as reliable biomarkers for Angelman Syndrome in both preclinical and clinical settings.

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  • Angelman Syndrome: advancing the research frontier of neurodevelopmental disorders.
    Journal of Neurodevelopmental Disorders, 2010
    Co-Authors: Benjamin D. Philpot, Lisa Franco, Coral E. Thompson, Charles A. Williams

    Abstract:

    This report is a meeting summary of the 2010 Angelman Syndrome Foundation’s scientific symposium on the neuroscience of UBE3A. Angelman Syndrome is characterized by loss of speech, severe developmental delay, seizures, and ataxia. These core symptoms are caused by maternal allele disruptions of a single gene—UBE3A. UBE3A encodes an E3 ubiquitin ligase that targets certain proteins for proteasomal degradation. This biology has led to the expectation that the identification of Ube3a protein targets will lead to therapies for Angelman Syndrome. The recent discovery of Ube3a substrates such as Arc (activity-regulated cytoskeletal protein) provides new insight into the mechanisms underlying the synaptic function and plasticity deficits caused by the loss of Ube3a. In addition to identifying Ube3a substrates, there have also been recent advances in understanding UBE3A’s integrated role in the neuronal repertoire of genes and protein interactions. A developmental picture is now emerging whereby UBE3A gene dosage on chromosome 15 alters synaptic function, with deficiencies leading to Angelman Syndrome and overexpression associated with classic autism symptomatology.

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Charles A. Williams – One of the best experts on this subject based on the ideXlab platform.

  • Angelman Syndrome – insights into a rare neurogenetic disorder.
    Nature Reviews Neurology, 2016
    Co-Authors: Karin Buiting, Charles A. Williams, Bernhard Horsthemke

    Abstract:

    Angelman Syndrome is a rare neurogenetic disorder that is characterized by microcephaly, severe intellectual deficit, speech impairment, epilepsy, EEG abnormalities, ataxic movements, tongue protrusion, paroxysms of laughter, abnormal sleep patterns, and hyperactivity. Angelman Syndrome results from loss of function of the imprinted UBE3A (ubiquitin-protein ligase E3A) gene on chromosome 15q11.2-q13. This loss of function can be caused by a mutation on the maternal allele, a 5-7 Mb deletion of the maternally inherited chromosomal region, paternal uniparental disomy of chromosome 15, or an imprinting defect. The chromosomal deletion tends to cause the most severe symptoms, possibly owing to co-deletion of GABA receptor genes. UBE3A mutations and imprinting defects can be associated with a high risk of recurrence within families. Disruption of UBE3A function in neurons seems to inhibit synapse formation and experience-dependent synapse remodelling. Clinical diagnosis of Angelman Syndrome in infants and young children is sometimes difficult, but can be verified by genetic tests. At present, treatment of symptoms such as seizures is the only medical strategy, but genetic therapies aimed at activating the silent copy of UBE3A on the paternal allele are conceivable.

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  • Molecular and Clinical Aspects of Angelman Syndrome.
    Molecular Syndromology, 2011
    Co-Authors: Aditi I Dagli, Karin Buiting, Charles A. Williams

    Abstract:

    The Angelman Syndrome is caused by disruption of the UBE3A gene and is clinically delineated by the combination of severe mental disability, seizures, absent speech, hypermotoric and ataxic movements, and certain remarkable behaviors. Those with the Syndrome have a predisposition toward apparent happiness and paroxysms of laughter, and this finding helps distinguish Angelman Syndrome from other conditions involving severe developmental handicap. Accurate diagnosis rests on a combination of clinical criteria and molecular and/or cytogenetic testing. Analysis of parent-specific DNA methylation imprints in the critical 15q11.2–q13 genomic region identifies 75–80% of all individuals with the Syndrome, including those with cytogenetic deletions, imprinting center defects and paternal uniparental disomy. In the remaining group, UBE3A sequence analysis identifies an additional percentage of patients, but 5–10% will remain who appear to have the major clinical phenotypic features but do not have any identifiable genetic abnormalities. Genetic counseling for recurrence risk is complicated because multiple genetic mechanisms can disrupt the UBE3A gene, and there is also a unique inheritance pattern associated with UBE3A imprinting. Angelman Syndrome is a prototypical developmental Syndrome due to its remarkable behavioral phenotype and because UBE3A is so crucial to normal synaptic function and neural plasticity.

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  • Angelman Syndrome: advancing the research frontier of neurodevelopmental disorders.
    Journal of Neurodevelopmental Disorders, 2010
    Co-Authors: Benjamin D. Philpot, Lisa Franco, Coral E. Thompson, Charles A. Williams

    Abstract:

    This report is a meeting summary of the 2010 Angelman Syndrome Foundation’s scientific symposium on the neuroscience of UBE3A. Angelman Syndrome is characterized by loss of speech, severe developmental delay, seizures, and ataxia. These core symptoms are caused by maternal allele disruptions of a single gene—UBE3A. UBE3A encodes an E3 ubiquitin ligase that targets certain proteins for proteasomal degradation. This biology has led to the expectation that the identification of Ube3a protein targets will lead to therapies for Angelman Syndrome. The recent discovery of Ube3a substrates such as Arc (activity-regulated cytoskeletal protein) provides new insight into the mechanisms underlying the synaptic function and plasticity deficits caused by the loss of Ube3a. In addition to identifying Ube3a substrates, there have also been recent advances in understanding UBE3A’s integrated role in the neuronal repertoire of genes and protein interactions. A developmental picture is now emerging whereby UBE3A gene dosage on chromosome 15 alters synaptic function, with deficiencies leading to Angelman Syndrome and overexpression associated with classic autism symptomatology.

    Free Register to Access Article