Angelman Syndrome

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 unique behavior with an apparent 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.

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, or an imprinting defect; fewer than 1% of individuals have a cytogenetically visible chromosome rearrangement (e.g., 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.

Management: Treatment of manifestations: Anti-seizure medication for seizures. Accommodation for hypermotoric behaviors and disruptive nighttime wakefulness. Behavior modification can be effective for disruptive or self-injurious behaviors. Physical therapy, occupational therapy, and speech therapy with an emphasis on nonverbal methods of communication, including augmentative communication aids (e.g., picture cards, communication boards) and signing. Individualization and flexibility in school settings. Routine management of gastroesophageal reflux, feeding difficulties, constipation, and strabismus. Thoraco-lumbar jackets and/or surgical intervention for scoliosis. Bracing or surgery as needed for subluxed or pronated ankles or tight Achilles tendons.

Surveillance: Monitor for new seizures and/or changes in seizures, developmental progress, behavior issues, mobility, motor skills, gastroesophageal reflux, constipation, and feeding issues at each visit. Evaluation of older children for obesity associated with an excessive appetite. Annual clinical examination for scoliosis; ophthalmology examination in the first year if strabismus is present; ophthalmology exam at age two years with follow up per ophthalmologist; clinical examination for scoliosis annually.

Agents/circumstances to avoid: Overtreatment with sedating medications in order to reduce hyperexcitable and hypermotoric behavior. Overtreatment with anti-seizure medication when movement abnormalities are mistaken for seizures and/or when EEG abnormalities persist even as seizures are controlled.

Genetic counseling: Individuals with AS typically represent simplex cases (i.e., a single affected family member) and have the disorder as the result of a de novo genetic alteration associated with a very low recurrence risk. Less commonly, an individual with AS has the disorder as the result of a genetic alteration associated with an imprinting pattern of autosomal dominant inheritance or variable recurrence risk. Reliable recurrence risk assessment therefore requires identification of the underlying genetic mechanism in the proband and confirmation of the genetic status of the parents. Prenatal detection of all the known molecular genetic alterations in the 15q11.2-q13 region that give rise to AS is possible and is an option for families once the underlying genetic mechanism in the proband has been identified.