Angelman syndrome Health Article

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.

Diagnosis

The clinical diagnosis of AS is made on the basis of physical examination and medical and developmental history. Confirmation requires specialized laboratory testing.

There is no single laboratory test that can identify all cases of AS. Several different tests may be performed to look for the various genetic causes of AS. When positive, these tests are considered diagnostic for AS.

DNA methylation studies

DNA methylation studies determine if the normal imprinting pattern associated with the maternal (mother's) copy of the number 15 chromosome is present. The 15q11-q13 region is differently methylated (or "imprinted") depending on which parent contributed the chromosome. If an individual has a deletion of this region on the maternal chromosome 15, paternal uniparental disomy of the number 15 chromosomes (with no number 15 chromosome from the mother), or a defective imprinting mechanism, DNA methylation studies will be abnormal and indicate AS. This test detects the majority (approximately 78%) of cases of AS. Additional studies are then required to determine which of these three mechanisms lead to AS development.

UBE3A mutation analysis

Direct DNA testing of the UBE3A gene is necessary to detect cases of AS caused by mutations in this gene. Cases of AS caused by UBE3A mutations usually have a normal imprinting pattern.

Fluorescent in situ hybridization (FISH)

FISH studies may be necessary to detect chromosome rearrangements that disrupt the 15q11-q13 region on the maternal copy of chromosome 15. The FISH method is a special way of checking for the presence, absence, or rearrangement of very small pieces of chromosomes. FISH testing can also readily detect AS caused by chromosome deletions, which account for approximately 70% of AS cases. FISH testing is often performed following an abnormal methylation study to determine if a chromosome deletion accounts for the abnormal methylation pattern.

Treatment and management

There is no specific treatment for AS. A variety of symptomatic management strategies may be offered for hyperactivity, seizures, mental retardation, speech impairment, and other medical problems.

The typical hyperactivity in AS may not respond to traditional behavior modification strategies. Children with AS may have a decreased need for sleep and a tendency to awaken during the night. Drug therapy may be prescribed to counteract hyperactivity or aid sleep. Most families make special accommodations for their child by providing a safe yet confining environment.

Seizures in AS are usually controllable with one or more anti-seizure medications. In some individuals with severe seizures, dietary manipulations may be tried in combination with medication.

Children with AS appear to benefit from targeted educational training. Physical and occupational therapy may improve the disordered, unbalanced movements typical of AS. Children with a severe balance disorder may require special supportive chairs. Speech therapy is often directed towards the development of nonverbal communication strategies, such as picture cards, communication boards, or basic signing gestures.

Individuals with AS may be more likely to develop particular medical problems which are treated accordingly. Newborn babies may have difficulty feeding and special bottle nipples or other interventions may be necessary. Gastroesophageal reflux (heartburn) may lead to vomiting or poor weight gain and may be treated with drugs or surgery. Constipation is a frequent problem and is treated with laxative medications. Many individuals with AS have strabismus (crossed eyes), which may require surgical correction. Orthopedic problems, such as tightening of tendons or scoliosis, are common. These problems may be treated with physical therapy, bracing, or surgery.