Angelman syndrome Health Article

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.

Signs and symptoms

The first abnormalities noted in an infant with AS are often delays in motor milestones (those related to physical skills, such as sitting up or walking), muscular hypotonia (poor muscle tone), and speech impairment. Some infants seem unaccountably happy and may exhibit fits of laughter. By age 12 months, 50% of infants with AS have microcephaly (a small head size). Tremulous movements are often noted during the first year of life.

Seizures occur in 80% of children with AS, usually by three years of age. No major brain lesions are typically seen on cranial imaging studies.

The achievement of walking is delayed, usually occurring between two-and-a-half and six years of age. The child with AS typically exhibits a jerky, stiff gait, often with uplifted and bent arms. About 10% of individuals with AS do not walk. Additionally, children may have drooling, protrusion of the tongue, hyperactivity, and a short attention span.

Many children have a decreased need for sleep and abnormal sleep/wake cycles. This problem may emerge in infancy and persist throughout childhood. Upon awakening at night, children may become very active and destructive to bedroom surroundings.

The language impairment associated with AS is severe. Most children with AS fail to learn appropriate and consistent use of more than a few words. Receptive language skills are less severely affected. Older children and adults are able to communicate by using gestures or communication boards (special devices bearing visual symbols corresponding to commonly used expressions or words).

Some individuals with AS caused by a deletion of the 15q11-q13 chromosomal region may have a lighter skin complexion than would be expected given their family background.