Angelman Syndrome

Disease characteristics. Angelman syndrome (AS) is characterized by severe developmental delay or mental retardation, 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. In addition, microcephaly and seizures are common. Developmental delays are first noted at around six months of age; however, the unique clinical features of AS do not become manifest until after one year of age, and it can take several years before the correct clinical diagnosis is obvious. The diagnosis of Angelman syndrome rests upon a combination of clinical features and molecular genetic testing and/or cytogenetic analysis. Consensus clinical diagnostic criteria for AS have been developed. Analysis of parent-specific DNA methylation imprints in the 15q11.2-q13 chromosome region detects approximately 78% 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 (i.e., translocation or inversion). UBE3A sequence analysis detects mutations in an additional ~11% of individuals. Accordingly, molecular genetic testing (methylation analysis and UBE3A sequence analysis) identifies alterations in about 90% of individuals. The remaining 10% of individuals with classic phenotypic features of AS have a presently unidentified genetic mechanism and thus are not amenable to diagnostic testing. Management. Feeding difficulties in newborns with AS may require special nipples; gastroesophageal reflux associated with poor weight gain and emesis is treated with upright positioning and motility drugs; fundoplication is sometimes required. Anticonvulsant medications such as valproic acid, clonazepam, topiramate, lamotrigine, and ethosuximid, are used to treat seizures; vigabatrin and tigabine should be avoided. Unstable or non-ambulatory children may benefit from physical therapy. Occupational therapy may help improve fine motor and oral-motor control. Adaptive chairs or positioners may be required for extremely ataxic children. Speech therapy should focus on nonverbal methods of communication; augmentative communication aids such as picture cards or communication boards are used at the earliest appropriate time and signing should be taught as soon as the child is sufficiently attentive. Children with AS with excessive hypermotoric behaviors need an accommodating classroom space; some children may benefit from the use of stimulant medications such as methylphenidate. Individualization and flexibility in the school are important educational strategies. Sedatives such as chloral hydrate or diphenylhydramines may accommodate nighttime wakefulness. Strabismus may require surgical correction. Laxatives such as high fiber or lubricating agents are used to treat constipation. Orthopedic problems can be corrected by orthotic bracing or surgery. Thoraco-lumbar jackets may be needed for scoliosis; individuals with severe spinal curvature may benefit from surgical rod stabilization. Genetic counseling. AS is caused by the loss of the maternally imprinted contribution in the 15q11.2-q13 (AS/PWS) region that can occur by one of at least five different known genetic mechanisms. The risk to sibs of an affected child of having AS depends upon the genetic mechanism of the loss of the maternally contributed AS/PWS region. The risk to sibs of an affected child who has a deletion or uniparental disomy is typically less than 1%. The risk is as high as 50% to the sibs of a child with an imprinting defect or a mutation of the UBE3A gene. Members of the mother's extended family are also at increased risk when an imprinting defect or a UBE3A mutation is present. Cytogenetically visible chromosome rearrangements may be inherited or de novo. Prenatal testing is possible when the underlying genetic mechanism is a deletion, uniparental disomy, an imprinting defect, a UBE3A mutation, or a chromosome rearrangement.