Angelman Syndrome Fact Sheet

Clinical Features
Angelman syndrome (AS) is characterized by severe developmental delay or intellectual disability, severe speech impairment, gait ataxia and/or tremulousness of the limbs, autistic-like behaviors, hand-flapping, and an inappropriate happy affect. This unique behavior includes frequent laughing, smiling, and excitability. Individuals with Angelman syndrome usually have a normal prenatal history, as well as a normal birth weight and head circumference. Angelman syndrome may first be suspected in a toddler because of delayed gross motor milestones, muscular hypotonia, and/or speech delay. Microcephaly develops in about 50% by age 12 months. Seizures are common, and typically occur between ages one and three years. The average child with AS walks between ages 2.5 and six years and at that time may have a jerky, robot-like, stiff gait. Language impairment is severe, and appropriate use of even one or two words in a consistent manner is rare. Receptive language skills are more advanced than expressive language skills. Sleep problems are well known in individuals with AS; frequent awakening at night is common. Most young children with AS have some component of hyperactivity, and males and females appear equally affected. Independent living is not possible for adults with AS, so many live at home or in home-like placements.

Diagnosis
Molecular genetic testing is the most accurate way to diagnose an individual with Angelman syndrome.

Genetics
Angelman syndrome is caused by a disruption of maternally imprinted UBE3A gene located within the 15q11.2-q13 Angelman syndrome/Prader-Willi syndrome (AS/PWS) region. Several different mechanisms can lead to Angelman syndrome, including: Deletion of the AS/PWS region on the maternally inherited chromosome 15 (65-75%) Paternal UPD in which the father contributes both copies of chromosome 15 (3-7%) An imprinting defect (3%) A mutation in the UBE3A gene (5-11%)

Inheritance
Most cases of Angelman syndrome are not inherited, particularly those caused by a deletion in the maternal chromosome 15 or by paternal uniparental disomy. These genetic changes occur as random events during the formation of egg and sperm cells or in early embryonic development. Affected people typically have no history of the disorder in their family. Rarely, a genetic change responsible for Angelman syndrome can be inherited. For example, it is possible for a mutation in the UBE3A gene to be passed from one generation to the next. Recommendations for genetic testing of parents or siblings depend on the cause of Angelman syndrome in the proband.

Clinical testing
Testing begins with DNA methylation analysis of the critical region 15q11.2-q13, which should identify about 80% of cases. If this test is abnormal, then deletion/duplication analysis is the next step. Microdeletions can also be detected by fluorescent in situ hybridization (FISH) or chromosomal microarray (CMA). If methylation is normal, then UBE3A sequence analysis is the next step. If both methylation and UBE3A are completed, these together should diagnose Angelman syndrome in over 80%.

References
GeneReviews: Angelman syndrome at http://www.ncbi.nlm.nih.gov/books/NBK1144/ Genetics Home Reference: Angelman syndrome at http://ghr.nlm.nih.gov/condition/angelman-syndrome

Published June 2013 NCHPEG All rights reserved