Angelman syndrome

Infobox_Disease
Name = Angelman Syndrome


Caption =
DiseasesDB = 712
ICD10 = ICD10|Q|93|5|q|90
ICD9 = ICD9|759.89
ICDO =
OMIM = 105830
MeshID = D017204
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 demeanour. AS is a classic example of genetic imprinting in that it is usually caused by deletion or inactivation of genes on the maternally inherited chromosome 15. The sister syndrome, Prader-Willi syndrome, is caused by a similar loss of paternally-inherited genes.

AS is named after a British pediatrician, Dr. Harry Angelman, who first described the syndrome in 1965.WhoNamedIt|synd|225|Angelman's syndrome] An older, alternative term for AS, happy puppet syndrome, is generally considered pejorative and stigmatizing so it is no longer used, though it remains useful as a diagnostic heuristic.

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 (then in Lancashire) first reported three children with this condition in 1965. He titled the paper "Puppet Children" and later explained that this was because of an oil painting he had seen::"I happened to see an oil painting...called... "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."

The condition was initially incorrectly 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").

Prevalence

Though the prevalence of Angelman syndrome is not precisely known, there are 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 1/20,000cite journal |author=Steffenburg S, Gillberg CL, Steffenburg U, Kyllerman M |title=Autism in Angelman syndrome: a population-based study |journal=Pediatr. Neurol. |volume=14 |issue=2 |pages=131–6 |year=1996 |pmid=8703225 |doi=10.1016/0887-8994(96)00011-2] and the Danish study showed a minimum AS prevalence of about 1/10,000.cite journal |author=Petersen MB, Brøndum-Nielsen K, Hansen LK, Wulff K |title=Clinical, cytogenetic, and molecular diagnosis of Angelman syndrome: estimated prevalence rate in a Danish county; the disorder predominantly affects Anglo-Saxons. |journal=Am. J. Med. Genet. |volume=60 |issue=3 |pages=261–2 |year=1995 |pmid=7573182 |doi=10.1002/ajmg.1320600317] 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.

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 sex-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.) Please note 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). [cite journal |author=White HE, Durston VJ, Harvey JF, Cross NC |title=Quantitative analysis of SNRPN(correction of SRNPN) gene methylation by pyrosequencing as a diagnostic test for Prader-Willi syndrome and Angelman syndrome |journal=Clin. Chem. |volume=52 |issue=6 |pages=1005–13 |year=2006 |pmid=16574761 |doi=10.1373/clinchem.2005.065086]

Angelman syndrome can also be the result of mutation of a single gene. This gene ("UBE3A", [cite journal | author = Weeber E, Levenson J, Sweatt J | title = Molecular genetics of human cognition. | journal = Mol Interv | volume = 2 | issue = 6 | pages = 376–91, 339 | year = 2002 | pmid = 14993414 | doi = 10.1124/mi.2.6.376 ] 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 (poor suck and poor weight gain) in 75%
* 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 inappropriate 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) in 40%
* Scoliosis (abnormal 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

The Angelman Syndrome Foundation, which first defined criteria for diagnosis in 1995cite journal |author=Williams CA, Angelman H, Clayton-Smith J, "et al" |title=Angelman syndrome: consensus for diagnostic criteria. Angelman Syndrome Foundation |journal=Am. J. Med. Genet. |volume=56 |issue=2 |pages=237–8 |year=1995 |pmid=7625452 |doi=10.1002/ajmg.1320560224] , has been updated in 2005.cite journal |author=Williams CA, Beaudet AL, Clayton-Smith J, "et al" |title=Angelman syndrome 2005: updated consensus for diagnostic criteria |journal=Am. J. Med. Genet. A |volume=140 |issue=5 |pages=413–8 |year=2006 |pmid=16470747 |doi=10.1002/ajmg.a.31074]

Treatment

Because Angelman syndrome is not an illness, but a genetic condition, there is no currently available cure. 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 is 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. 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 does not need to be life destroying. Individuals with Angelman Syndrome are generally happy and contented individuals, who like human contact and play. 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 afflicted individuals will not develop more than 5-10 words, if at all.cite journal |author=Andersen WH, Rasmussen RK, Strømme P |title=Levels of cognitive and linguistic development in Angelman syndrome: a study of 20 children |journal=Logopedics, phoniatrics, vocology |volume=26 |issue=1 |pages=2–9 |year=2001 |pmid=11432411| doi = 10.1080/140154301300109044 ]

Actor Colin Farrell, author Ian Rankin, and professional hockey player Peter McDuffe have sons with AS.

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 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 AS 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 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. [cite journal | author = Lossie A, Driscoll D | title = Transmission of Angelman syndrome by an affected mother. | journal = Genet Med | volume = 1 | issue = 6 | pages = 262–6 | year = | pmid = 11258627]

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 scoliosiscite journal |author=Laan LA, den Boer AT, Hennekam RC, Renier WO, Brouwer OF |title=Angelman syndrome in adulthood |journal=Am. J. Med. Genet. |volume=66 |issue=3 |pages=356–60 |year=1996 |pmid=9072912 | doi=10.1002/(SICI)1096-8628(19961218)66:3<356::AID-AJMG21>3.0.CO;2-K] 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.

See also

* Epigenetics
* Prader-Willi Syndrome

References

External links

*dmoz|Health/Conditions_and_Diseases/Neurological_Disorders/Movement_Disorders/Angelman_Syndrome|Angelman syndrome
*GeneTests|angelman|Angelman Syndrome
* [http://www.cureangelman.org Foundation for Angelman Syndrome Therapeutics]
* [http://www.angelman.org Angelman Syndrome Foundation USA]
* [http://www.angelmanuk.org Angelman Syndrome Support Education & Research Trust - UK]