Angelman syndrome
Angelman syndrome, rare genetic disorder that affects the nervous system. The syndrome is named for English physician Harry Angelman, who first described its characteristic symptoms in 1965 after observing children who were affected by ataxia (an inability to coordinate voluntary muscular movements) and who exhibited an unusual laughing, happy demeanor. Angelman syndrome occurs in approximately 1 in 12,000 to 1 in 20,000 live births; its incidence is suspected of being higher, however, owing to underreporting and possible misdiagnosis. The disorder affects females and males equally, and typically there is no family history of the disorder.
Symptoms
Angelman syndrome is recognized as a congenital disorder, though affected infants may only exhibit difficulties with feeding in the first few months of life. More serious signs emerge at about 6 to 12 months of age, typically as an absence of behaviors such as babbling and crawling. At about 2 to 3 years of age, affected individuals begin to experience seizures, and other symptoms, including ataxia, delayed development of walking, speech impairment, and severe intellectual disability, become apparent.
A defining characteristic of individuals with Angelman syndrome is a happy, excitable demeanor, with frequent smiling and laughing that often is unrelated to the context of what is going on around them. Most affected individuals are hyperactive and have a short attention span, and they often display unusual behaviors, such as hand flapping. Sleep problems are common, and the need for sleep may be significantly reduced.
Cause
Angelman syndrome is caused by loss-of-function mutations in a gene known as UBE3A. Most often, these mutations occur as sporadic (random) deletions of base pairs within the gene. In rare instances, such mutations are inherited on the maternal allele of UBE3A. (UBE3A is an imprinted gene; its expression is driven by the maternal allele, while the paternal allele is silenced.)
The mechanism by which mutations in UBE3A result in Angelman syndrome is not fully understood. UBE3A expression, however, is known to be essential for normal brain development. The gene encodes ubiquitin protein ligase E3A, an enzyme that targets other proteins for destruction. This activity serves a critical role in maintaining protein homeostasis and appears to have an especially important function at synapses (junctions of communication between neurons).
Diagnosis, prognosis, and treatment
The symptoms and characteristics of Angelman syndrome are similar to those of autism, Prader-Willi syndrome, and cerebral palsy, which can lead to misdiagnosis and delayed treatment and care. Thus, genetic testing is needed to provide a definitive diagnosis of Angelman syndrome.
There is no cure for Angelman syndrome. However, many of its symptoms can be managed, and some symptoms may become less severe over time. Examples of symptom management include the use of a high-calorie formula for infants with feeding difficulties and the use of medication and dietary therapies for seizures. Sleep problems, which often lessen with age, can be treated with medications and sleep training. Hyperactivity often also decreases with age. Physical, occupational, and speech therapies can help improve motor and speech skills, and some individuals may learn to communicate nonverbally or by using specialized devices.
Individuals with Angelman syndrome are unable to live independently and require lifelong care. Affected persons have a typical or near-typical life expectancy, though some complications, such as seizures or falls from ataxia, can cause premature death.