Angelman syndrome

Angelman Syndrome (AS) is a rare neuro-genetic disorder named after an English pediatrician, Dr. Harry Angelman, who first described the syndrome in 1965. A syndrome is a collection of features which occur together as a group and indicate a particular condition. AS is characterised by intellectual and developmental delay, speech impediment, sleep disturbance, unstable jerky gait, seizures, hand flapping movements, frequent laughter/smiling and usually a happy demeanour. AS is a classic example of genetic imprinting caused by deletion or inactivation of critical genes on the maternally inherited chromosome 15. The sister syndrome Prader-Willi syndrome is caused by paternal genes.

An older, alternative term for AS, happy puppet syndrome, is generally considered pejorative and stigmatizing and is no longer used.

History
Dr. Harry Angelman, a pediatrician working in Warrington, Cheshire, first reported three children with this condition in 1965. It was initially presumed to be rare. In 1987, it was first noted that around half of the children with Angelman syndrome have a small piece of chromosome 15 missing (chromosome 15q partial deletion). Since this time the condition has been reported more frequently and the incidence is now thought to be much higher.

How Common is Angelman Syndrome?
The answer to this question is not precisely known, but we do have some estimates. The best data available is from studies of school age children, ages 6-13 years, living in Sweden and from Denmark where the diagnosis of AS children in medical clinics was compared to an 8 year period of about 45,000 births. The Swedish study showed an AS prevalence of about 1/12,000 (Steffenburg et al., 1996) and the Danish study showed a minimum AS prevalence of about 1/10,000 (Petersen et al., 1995). Note that it is desirable to use the term prevalence, since estimates of AS diagnosis have been made in relatively small cohorts of children over various periods of time.

There appears to be no reported prevalence studies that have screened newborns to detect rates of AS. Population wide prevalence figures would need to take into consideration that longevity in AS is probably reduced (severe mental delay and seizure presence would be risk factors) but no actuarial or other data are available on life span shortening. Likewise, it is not known what percent of individuals with AS are undiagnosed, although this is expected to be significant. Accordingly, to estimate the number of people with AS living in the society, it would be inaccurate to divide any estimated AS prevalence figure into a total population number.

Given this information, it appears that the prevalence of AS among children and young adults is between 1/10,000 and 1/20,000. It is suggested to use a 1/15,000 figure if a single figure is needed. For population projections, estimates using birth rates can be used. For example, if an area has a birth rate of about 200,000/year it would be estimated that about 13 babies would be born each year with AS.

Pathophysiology
Angelman syndrome is caused by the loss of the normal maternal contribution to a region of chromosome 15, most commonly by deletion of a segment of that chromosome. Other causes include uniparental disomy, translocation, or single gene mutation in that region. A healthy person receives two copies of chromosome 15, one from mother, the other from father. However, in the region of the chromosome that is critical for Angelman syndrome, the maternal and paternal contribution express certain genes very differently. This is due to sex-related epigenetic imprinting; the biochemical mechanism is DNA methylation. If the maternal contribution is lost or mutated, the result is Angelman syndrome. (When the paternal contribution is lost, by similar mechanisms, the result is Prader-Willi syndrome.)

Angelman syndrome can also be the result of mutation of a single gene. This gene (Ube3a, part of the ubiquitin pathway) is present on both the maternal and paternal chromosomes, but differs in the pattern of methylation (Imprinting). The paternal silencing of the Ube3a gene occurs in a brain region-specific manner; the maternal allele is active almost exclusively in the hippocampus and cerebellum. The most common genetic defect leading to Angelman syndrome is an ~4Mb (mega base) maternal deletion in chromosomal region 15q11-13 causing an absence of Ube3a expression in the maternally imprinted brain regions. Ube3a codes for an E6-AP ubiquitin ligase, which chooses its substrates very selectively and the four identified E6-AP substrates have shed little light on the possible molecular mechanisms underlying the human Angelman syndrome mental retardation state.

Initial studies of mice that do not express maternal Ube3a show severe impairments in hippocampal memory formation. Most notably, there is a deficit in a learning paradigm that involves hippocampus-dependent contextual fear conditioning. In addition, maintenance of long-term synaptic plasticity in hippocampal area CA1 in vitro is disrupted in Ube3a -/- mice. These results provide links amongst hippocampal synaptic plasticity in vitro, formation of hippocampus-dependent memory in vitro, and the molecular pathology of Angelman syndrome.

Features

 * Feeding problems during infancy(75%) (poor suck and poor weight gain)
 * Delay in sitting and walking
 * Absent or little speech (not in all cases - some children have a vocabulary of up to 50 words)
 * Receptive and non-verbal communication skills higher than verbal ones
 * Poor attention span and hyperactivity
 * Severe learning disabilities
 * Epilepsy (80%) and an abnormal EEG
 * Unusual movements (fine tremors, hand flapping, jerking movements)
 * Affectionate nature and frequent laughter
 * Wide-based stiff-legged gait, with tendency to hold arms up and flexed while walking.
 * Below average head size, often with flattening at the back
 * Subtle, but sometimes characteristic facial features (wide mouth, widely spaced teeth, prominent chin, tendency to tongue thrust)
 * Poor sleeping pattern
 * Strabismus (Squint - crossed eye/s) (40%)
 * Scoliosis (curvature of the spine) in 10%
 * Increased sensitivity to heat
 * Attraction to/fascination with water

Diagnosis
The diagnosis of Angelman syndrome is based on:


 * A history of delayed motor milestones and then later a delay in general development, especially of speech
 * Unusual movements including fine tremors, jerky limb movements, hand flapping and a wide-based, stiff-legged gait.
 * Characteristic facial appearance (but not in all cases).
 * A history of epilepsy and an abnormal EEG tracing.
 * A happy disposition with frequent laughter
 * A deletion on chromosome 15

Treatment
Because Angelman Syndrome is not an illness, but a genetic condition, there is no currently available cure for AS. The epilepsy can be controlled by the use of one or more types of anticonvulsant medications. Although there are difficulties in ascertaining the levels and types of anticonvulsant medications needed to establish control, because AS is usually associated with having multiple varieties of seizures, rather than just the one as is normal cases of epilepsy. Many families use melatonin to promote sleep in a condition which often affects sleep patterns. Many angels (as they are commonly referred to) sleep for a maximum of 5 hours at any one time. Mild laxatives are also used frequently to encourage regular bowel movements and early intervention with physiotherapy is important to encourage joint mobility and prevent stiffening of the joints. Occupational therapy, speech therapy, hydrotherapy and music therapy are also used in the management of this condition.

Living with Angelman syndrome
Although a diagnosis of AS is life changing, it needn't be life destroying. Angels are generally happy and contented individuals, who like human contact and play. Although often considered part of the autistic spectrum, AS individuals exhibit a profound desire for personal interaction with others. Communication can be difficult at first, but as an AS child develops, there is a definite character and ability to make themselves understood. It is widely accepted that their understanding of communication directed to them is much larger than their ability to return conversation. Most angels will not develop more than 5-10 words, if at all. The infectious laughter, coupled with the desire for play can and does lead to a fantastic parental relationship.

Prognosis
Note that the severity of the symptoms associated with AS varies significantly across the population of affected persons. Some speech and a greater degree of self-care are possible among the least profoundly affected. Unfortunately, walking and the use of simple sign language may be beyond the reach of the more profoundly affected. Early and continued participation in physical, occupational (related to the development of fine-motor control skills), and communication (speech) therapies are believed to improve significantly the prognosis (in the areas of cognition and communication) of AS affected people. Further, the specific genetic mechanism underlying the condition is thought to correlate to the general prognosis of the affected person. On one end of the spectrum, a mutation to the UBE3A gene is thought to correlate to the least affected, whereas larger deletions on chromosome 15 are thought to correspond to the most affected.

The clinical features of Angelman syndrome alter with age. As adulthood approaches, hyperactivity and poor sleep patterns improve. The seizures decrease in frequency and often cease altogether and the EEG abnormalities are less obvious. Medication is typically advisable to those with seizure disorders. Often overlooked is the contribution of the poor sleep patterns to the frequency and/or severity of the seizures. Medication may be worthwhile in order to help deal with this issue and improve the prognosis with respect to seizures and sleep. Also noteworthy are the reports that the frequency and severity of seizures temporarily escalate in pubescent AS girls but do not seem to affect long-term health.

The facial features remain recognizable but many Angelman adults look remarkably youthful for their age.

Puberty and menstruation begin at around the normal time. Sexual development is thought to be normal, as evidenced by a single reported case of a woman with Angelman syndrome conceiving a female child who also had Angelman syndrome.

The majority of those with AS achieve continence by day and some by night.

Dressing skills are variable and usually limited to items of clothing without buttons or zippers. Most adults are able to eat with a knife or spoon and fork and can learn to perform simple household tasks. General health is fairly good and life-span near normal. Particular problems which have arisen in adults are a tendency to obesity (more in females), and worsening of scoliosis if it is present. The affectionate nature which is also a positive aspect in the younger children may also persist into adult life where it can pose a problem socially, but this problem is not insurmountable.