Angelman Syndrome

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.

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.
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.
Findings typically present in affected individuals:

Normal prenatal and birth history, normal head circumference at birth, no major birth defects, normal metabolic, hematologic, and chemical laboratory profiles
Structurally normal brain by MRI or CT, although mild cortical atrophy or dysmyelination may be observed
Delayed attainment of developmental milestones without loss of skills
Evidence of developmental delay by age six to 12 months, eventually classified as severe Speech impairment, with minimal to no use of words; receptive language skills and nonverbal communication skills higher than expressive language skills
Movement or balance disorder, usually ataxia of gait and/or tremulous movement of the limbs
Behavioral uniqueness, including any combination of frequent laughter/smiling; apparent happy demeanor; excitability, often with hand-flapping movements and hypermotoric behavior