Angelman Syndrome
Angelman syndrome (AS) is a genetic condition that causes severe mental retardation, severe speech impairment, and a characteristic happy and excitable demeanor.
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 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, 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.
The genetics of AS are complex. There are at least five different genetic abnormalities, which 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 cause a different genetic condition, Prader-Willi syndrome.
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.
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 it's specific function is unknown.
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.
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.
Rarely, AS may be caused by chromosomal breaks, which occur in the maternal inherited 15q11-13 region. This break 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.
In about 11% of individuals with AS, no genetic cause can be identified. This may reflect misdiagnosis, or the presence of additional, unrecognized mechanisms leading to AS.
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.
The first abnormalities noted in a child 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 3 years of age. No major brain lesions are typically seen on cranial imaging studies, in contrast to some other syndromic causes of seizures.
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 social behavior with 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.
In some cases, a physician may make the diagnosis of AS on the basis of physical examination and medical and developmental history (a clinical diagnosis). More commonly, however, the diagnosis is based on 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 determine if the normal imprinting pattern associated with the maternal 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 chromosome deletion of this region on the maternal number 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 is occurring.
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.
FISH studies may be necessary to detect chromosome rearrangements, which 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.
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.
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