Angelman syndrome Health Article

Definition

Angelman syndrome (AS) is a genetic condition that causes severe mental retardation, severe speech impairment, and a characteristic happy and excitable demeanor.

Description

Individuals with AS show evidence of delayed development by 6–12 months of age. Eventually, this delay is recognized as severe mental retardation. Unlike some genetic conditions causing severe mental retardation, AS is not associated with developmental regression (loss of previously attained developmental milestones).

Severe speech impairment is a striking feature of AS. Speech is almost always limited to a few words or no words at all. However, receptive language skills (listening to and understanding the speech of others) and non-verbal communication are not as severely affected.

Individuals with AS have a balance disorder, causing unstable and jerky movements. This typically includes gait ataxia (a slow, unbalanced way of walking) and tremulous movements of the limbs.

AS is also associated with a unique "happy" behavior, which may be the best-known feature of the condition. This may include frequent laughter or smiling, often with no apparent stimulus. Children with AS often appear happy, excited, and active. They may also sometimes flap their hands repeatedly. Generally, they have a short attention span. These characteristic behaviors led to the original name of this condition, the "Happy Puppet" syndrome. However, this name is no longer used as it is considered insensitive to AS individuals and their families.

Genetic profile

The genetics of AS are complex. There are at least five different genetic abnormalities that can cause the condition, all of which involve a specific region of the chromosome 15 inherited from the mother. This region is designated 15q11-13 (bands 11 through 13 on the long arm of chromosome 15). The fact that AS occurs only when there are abnormalities in this region of the maternal copy of chromosome 15 reflects a unique phenomenon known as imprinting. Imprinting is a chemical modification of DNA which acts as an "identification tag" indicating which parent contributed the chromosome. Imprinted genes or chromosome regions are expressed or not expressed depending on which parent transmitted the chromosome. Abnormalities in the paternally inherited 15q11-13 region (from the father) cause a different genetic condition called Prader-Willi syndrome.

Chromosome deletion

The most common cause of AS is a small deletion (missing piece) in the maternally inherited chromosome 15. Specifically, the deletion occurs within 15q11-13. Approximately 70% of AS individuals have this deletion.

UBE3A mutation

In approximately 11% of AS cases, there is a mutation within the maternally inherited UBE3A gene. All the genetic mechanisms leading to AS appear to compromise expression of this gene, which is located within the 15q11-13 region. This gene is considered to be the "critical gene" responsible for AS, although its specific function is unknown.

Uniparental disomy

Some cases of AS result from inheritance of both chromosomes in the 15 pair from the father, an unusual genetic phenomenon known as uniparental disomy. In this circumstance, there is no chromosome 15 from the mother. Approximately 7% of AS cases result from this mechanism.

Imprinting defect

Approximately 3% of AS cases result from an imprinting defect on the maternally inherited chromosome 15. As noted above, imprinting is a chemical modification to the DNA which serves as a marker indicating the parent of origin and controls gene expression. If there is defective imprinting on the maternally inherited 15, then the genes in the 15q11-15q13 region may not be expressed, leading to AS.

Chromosome rearrangement

Rarely, AS may be caused by chromosomal breaks that occur in the maternal inherited 15q11-13 region. The breaks may occur as the result of a translocation (in which two chromosomes break and exchange material) or an inversion (in which a piece of a chromosome breaks and rejoins in the opposite orientation), or other disturbance of the chromosome structure involving the maternal 15q11-15q13. This mechanism is responsible for about 1% of AS cases.

Unknown mechanism(s)

In about 8% of individuals with AS, no genetic cause can be identified. This may reflect misdiagnosis, or the presence of additional, unrecognized mechanisms leading to AS.

Demographics

AS has been reported in individuals of diverse ethnic backgrounds. The incidence of the condition is estimated at 1/10,000 to 1/30,000.