Angelman syndrome

background

Angelman syndrome is a rare inherited genetic disorder that affects the nervous system. Classic characteristics of Angelman syndrome include developmental delays, intellectual disabilities, severely impaired speech, seizures, a small head, and movement and balance problems. People with Angelman syndrome are typically happy and excitable, may frequently smile and laugh, and may flap their hands often. Other symptoms may include short attention span and fair skin and hair.
The disorder was first described by Dr. Harry Angelman in 1965 when he observed three patients with severe intellectual disabilities, flat heads, jerky body movements, tongues that stuck out, and spontaneous bursts of laughter. Based on these symptoms, the syndrome was known early on as "happy puppet syndrome."
Angelman syndrome is caused by mutations or defects in the UBE3A gene on chromosome 15. The UBE3A gene provides instructions for making the enzyme ubiquitin protein ligase E3A. This enzyme is involved in targeting proteins to be degraded, or broken down, within cells. For example, the p53 protein, which controls cell growth and division, is one of the targets of ubiquitin protein ligase E3A. Protein degradation is a normal process that removes damaged or unnecessary proteins and helps maintain the normal functions of cells. A loss of UBE3A gene function likely causes many of the characteristic features of Angelman syndrome.
Changes in the OCA2 gene are also related to Angelman syndrome. The OCA2 gene provides instructions for making the P protein located in the melanocytes, specialized cells that produce the pigment melanin. Melanin is the substance that gives skin, hair, and eyes their color. Melanin is also found in the light-sensitive tissue of the retina at the back of the eye, where it plays a role in normal vision. Some people with Angelman syndrome have unusually light-colored hair and fair skin, which is thought to be caused by the loss of one copy of the OCA2 gene in each cell. This gene is located in a region of chromosome 15 that is often deleted in individuals with Angelman syndrome.
Most cases of Angelman syndrome are not inherited, or passed down among family members, although there is no indication that individuals with this syndrome are unable to have children. Rather, Angelman syndrome is usually caused by deletion or inactivation of genes on the maternally inherited chromosome 15 in the developing embryo. A healthy person receives two copies of chromosome 15, one from the mother and one from the father. However, in the region of the critical chromosome, the maternal and paternal contribution express certain genes very differently. In a normal individual, the maternal allele (one of two or more versions of a gene) is expressed and the paternal allele is silenced. If the maternal contribution is lost or mutated, the result is Angelman syndrome. Therefore, people affected by this disorder usually have no family history of Angelman syndrome.
The incidence of Angelman syndrome is estimated to be about one in 12,000-20,000 people. Limited data suggest that people with Angelman syndrome have nearly-normal life spans.

Related Terms

Angelman syndrome, chromosome 15q, DNA methylation, genetic counseling, happy puppet syndrome, imprinting, OCA2, UBE3A.