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Angelman Syndrome.

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GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.
1998 Sep 15 [updated 2017 Dec 21].

Author information

1
Division of Genetics and Metabolism, Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida
2
Division of Genetics and Metabolism, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Excerpt

CLINICAL CHARACTERISTICS:

Angelman syndrome (AS) is characterized by severe developmental delay or intellectual disability, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and a unique behavior with an inappropriate happy demeanor that includes frequent laughing, smiling, and excitability. Microcephaly and seizures are also common. Developmental delays are first noted at around age six months; however, the unique clinical features of AS do not become manifest until after age one year, and it can take several years before the correct clinical diagnosis is obvious.

DIAGNOSIS/TESTING:

The diagnosis of AS is established in a proband who meets the consensus clinical diagnostic criteria and/or who has findings on molecular genetic testing that suggest deficient expression or function of the maternally inherited UBE3A allele. Analysis of parent-specific DNA methylation imprints in the 15q11.2-q13 chromosome region detects approximately 80% of individuals with AS, including those with a deletion, uniparental disomy (UPD), or an imprinting defect (ID); fewer than 1% of individuals have a cytogenetically visible chromosome rearrangement (i.e., translocation or inversion). UBE3A sequence analysis detects pathogenic variants in an additional approximately 11% of individuals. Therefore, molecular genetic testing (methylation analysis and UBE3A sequence analysis) identifies alterations in approximately 90% of individuals. The remaining 10% of individuals with classic phenotypic features of AS have the disorder as a result of an as-yet unidentified genetic mechanism and thus are not amenable to diagnostic testing.

MANAGEMENT:

Treatment of manifestations: Routine management of feeding difficulties, constipation, gastroesophageal reflux, strabismus. Antiepileptic drugs for seizures. Physical therapy, occupational therapy, and speech therapy with an emphasis on nonverbal methods of communication, including augmentative communication aids (e.g., picture cards or communication boards) and signing. Individualization and flexibility in school settings. Sedatives for nighttime wakefulness. Thoraco-lumbar jackets and/or surgical intervention for scoliosis. Prevention of secondary complications: Children with seizures are at risk for medication overtreatment because movement abnormalities can be mistaken for seizures and because EEG abnormalities can persist even when seizures are controlled. Sedating agents such as risperidone or other atypical antipsychotic drugs can cause negative side effects. Surveillance: Annual clinical examination for scoliosis. Evaluation of older children for obesity associated with an excessive appetite. Agents/circumstances to avoid: Carbamezapine, vigabatrin, and tigabine as they may exacerbate seizures.

GENETIC COUNSELING:

AS is caused by disruption of maternally imprinted UBE3A located within the 15q11.2-q13 Angelman syndrome/Prader-Willi syndrome (AS/PWS) region. The risk to sibs of a proband depends on the genetic mechanism leading to the loss of UBE3A function: typically less than 1% risk for probands with a deletion or UPD, and as high as 50% for probands with an ID or a pathogenic variant of UBE3A. Members of the mother's extended family are also at increased risk when an ID or a UBE3A pathogenic variant is present. Cytogenetically visible chromosome rearrangements may be inherited but are usually de novo. Prenatal testing for pregnancies at increased risk is possible when the underlying genetic mechanism is a deletion, UPD, an ID, a UBE3A pathogenic variant, or a chromosome rearrangement.

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