Angelman syndrome

Angelman syndrome is a complex genetic disorder that affects the nervous system. Characteristic features of this condition include developmental delay or intellectual disability, severe speech impairment, seizures, small head size (microcephaly), and problems with movement and balance (ataxia). Delayed development can be noted by 6 months to 12 months of age, and other common signs and symptoms usually become apparent in early childhood. People with Angelman syndrome typically have a happy, excitable demeanor with frequent smiling and laughter, a short attention span, and hand-flapping movements. Some affected individuals also have unusually fair skin and light-colored hair.

Angelman syndrome affects an estimated 1 in 12,000 to 20,000 people.

Angelman syndrome is related to chromosome 15.

Mutations in the UBE3A gene cause Angelman syndrome.

The OCA2 gene is associated with Angelman syndrome.

People normally inherit one copy of the UBE3A gene from each parent. Both copies of this gene are active in many of the body's tissues. In the brain, however, only the copy inherited from a person's mother (the maternal copy) is active. This parent-specific gene activation is called genomic imprinting. If the maternal copy of the UBE3A gene is lost because of a chromosomal change or a gene mutation, a person will have no active copies of the gene in the brain. This loss of gene function likely causes many of the characteristic features of Angelman syndrome.

Several different genetic mechanisms can result in the inactivation or absence of the maternal copy of the UBE3A gene. Most cases of Angelman syndrome (about 70 percent) occur when a segment of the maternal chromosome 15 containing this gene is deleted. In other cases (about 11 percent), Angelman syndrome is caused by a mutation in the maternal copy of the UBE3A gene.

In a small percentage of cases, a person with Angelman syndrome inherits two copies of chromosome 15 from his or her father (paternal copies) instead of one copy from each parent. This phenomenon is called paternal uniparental disomy. Rarely, Angelman syndrome can also be caused by a chromosomal rearrangement called a translocation, or by a mutation or other defect in the DNA region that controls activation of the UBE3A gene. Both of these genetic changes can abnormally inactivate UBE3A or other genes on the maternal copy of chromosome 15.

The OCA2 gene is located on the segment of chromosome 15 that is often deleted in Angelman syndrome. The protein produced from this gene helps determine the coloring (pigmentation) of the skin, hair, and eyes. A deletion of the OCA2 gene is associated with light-colored hair and fair skin in some people with this condition.

The causes of Angelman syndrome are unknown in 10 to 15 percent of cases. Changes involving other genes or chromosomes may be responsible for the features of Angelman syndrome in these cases.

Read more about the OCA2 and UBE3A genes and chromosome 15.

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 reproductive cells or in early fetal 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 or in the nearby DNA region that controls gene activation to be passed from one generation to the next.