Angelman syndrome

Angelman syndrome (AS) is a neuro-genetic disorder characterized by intellectual and developmental delay, sleep disturbance, seizures, jerky movements (especially hand-flapping), frequent laughter or smiling, and usually a happy demeanor.

AS is a classic example of genomic imprinting in that it is usually caused by deletion or inactivation of genes on the maternally inherited chromosome 15 while the paternal copy, which may be of normal sequence, is imprinted and therefore silenced. The sister syndrome, Prader-Willi syndrome, is caused by a similar loss of paternally inherited genes and maternal imprinting. AS is named after a British pediatrician, Dr. Harry Angelman, who first described the syndrome in 1965. An older, alternative term for AS, happy puppet syndrome, is generally considered pejorative and stigmatizing so it is no longer the accepted term, though it is sometimes still used as an informal term of diagnosis. People with AS are sometimes known as "angels", both because of the syndrome's name and because of their youthful, happy appearance.

History


Dr. Harry Angelman, a pediatrician working in Warrington, England, first reported three children with this condition in 1965. Angelman later described his choice of the title "Puppet Children" to describe these cases as being related to an oil painting he had seen while vacationing in Italy:

"The history of medicine is full of interesting stories about the discovery of illnesses. The saga of Angelman's syndrome is one such story. It was purely by chance that nearly thirty years ago (e.g., circa 1964) three handicapped children were admitted at various times to my children's ward in England. They had a variety of disabilities and although at first sight they seemed to be suffering from different conditions I felt that there was a common cause for their illness. The diagnosis was purely a clinical one because in spite of technical investigations which today are more refined I was unable to establish scientific proof that the three children all had the same handicap. In view of this I hesitated to write about them in the medical journals. However, when on holiday in Italy I happened to see an oil painting in the Castelvecchio Museum in Verona called . . . a Boy with a Puppet. The boy's laughing face and the fact that my patients exhibited jerky movements gave me the idea of writing an article about the three children with a title of Puppet Children. It was not a name that pleased all parents but it served as a means of combining the three little patients into a single group. Later the name was changed to Angelman syndrome. This article was published in 1965 and after some initial interest lay almost forgotten until the early eighties."

Case reports from the United States first began appearing in the medical literature in the early 1980s. In 1987, it was first noted that around half of the children with AS have a small piece of chromosome 15 missing (chromosome 15q partial deletion).

Prevalence
Though the prevalence of Angelman syndrome is not precisely known, there are some estimates. The best data available are 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 1/20,000 and the Danish study showed a minimum AS prevalence of about 1/10,000.

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 the mother, the other from the 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 gender-related epigenetic imprinting; the biochemical mechanism is DNA methylation. In a normal individual, the maternal allele is expressed and the paternal allele is silenced. 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.) It should be noted that the methylation test that is performed for Angelman syndrome (a defect in UBE3A) is actually looking for the gene's neighbour SNRPN (which has the opposite pattern of methylation).

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; in the hippocampus and cerebellum, the maternal allele is almost exclusively the active one. 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 paternally 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 Angelman syndrome in humans.

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 vivo, and the molecular pathology of Angelman syndrome.

Clinical features
The following list features of Angelman syndrome and their relative frequency in affected individuals.

Consistent (100%)
 * Developmental delay, functionally severe
 * Speech impairment, no or minimal use of words; receptive and non-verbal communication skills higher than verbal ones
 * Movement or balance disorder, usually ataxia of gait and/or tremulous movement of limbs
 * Behavioral uniqueness: any combination of frequent laughter/smiling; apparent happy demeanor; easily excitable personality, often with hand flapping movements; hypermotoric behavior; short attention span

Frequent (more than 80%)
 * Delayed, disproportionate growth in head circumference, usually resulting in microcephaly (absolute or relative) by age 2
 * Seizures, onset usually < 3 years of age
 * Abnormal EEG, characteristic pattern with large amplitude slow-spike waves

Associated (20 - 80%)
 * Strabismus
 * Hypopigmented skin and eyes
 * Tongue thrusting; suck/swallowing disorders
 * Hyperactive tendon reflexes
 * Feeding problems during infancy
 * Uplifted, flexed arms during walking
 * Prominent mandible
 * Increased sensitivity to heat
 * Wide mouth, wide-spaced teeth
 * Sleep disturbance
 * Frequent drooling, protruding tongue
 * Attraction to/fascination with water
 * Excessive chewing/mouthing behaviors
 * Flat back of head
 * Smooth palms

Neurophysiology
One of the more notable features of Angelman Syndrome (AS) is the syndrome’s pathognomonic neurophysiological  findings. The electroencephalogram (EEG) in AS is usually very abnormal, and more abnormal than clinically expected. Three distinct interictal patterns are seen in these patients (see Fig.). The most common pattern is a very large amplitude 2–3 Hz rhythm most prominent in prefrontal leads (A). Next most common is a symmetrical 4–6 Hz high voltage rhythm (B). The third pattern, 3–6 Hz activity punctuated by spikes and sharp waves in occipital leads, is associated with eye closure (C). Paroxysms of laughter have no relation to the EEG, ruling out this feature as a gelastic phenomenon (Williams 2005).

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 or inactivity on chromosome 15 by array comparative genomic hybridization (aCGH) or by BACs-on-Beads technology.

Diagnostic criteria for the disorder were initially established in 1995 in collaboration with the Angelman syndrome Foundation (USA); these criteria have undergone revision in 2005.

Treatment and care
There is currently no cure available. The epilepsy can be controlled by the use of one or more types of anticonvulsant medications. However, 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 in normal cases of epilepsy. Many families use melatonin to promote sleep in a condition which often affects sleep patterns. Many individuals with Angelman syndrome 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.

Those with the syndrome are generally happy and contented people who like human contact and play. People with AS exhibit a profound desire for personal interaction with others. Communication can be difficult at first, but as a child with AS develops, there is a definite character and ability to make themselves understood. People with AS tend to develop strong non-verbal skills to compensate for their limited use of speech. It is widely accepted that their understanding of communication directed to them is much larger than their ability to return conversation. Most afflicted people will not develop more than 5-10 words, if any at all.

Seizures are a consequence, but so is excessive laughter, which is a major hindrance to early diagnosis.

Prognosis
The severity of the symptoms associated with Angelman syndrome varies significantly across the population of those affected. 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 individuals affected by AS. 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 Angelman syndrome girls but do not seem to affect long-term health.

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

Puberty and menstruation begin at around the average age. Sexual development is thought to be unaffected, 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. Angelman syndrome is not a degenerative syndrome. Many people with AS improve their living skills with support.

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 average. 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.

Notable cases
Actor Colin Farrell, author Ian Rankin, professional baseball player Dave Henderson, and professional hockey player Peter McDuffe have sons with AS.