='''Angelman Syndrome'''=

==Introduction==

[[File:Dr Harry Angelman.jpg|thumb|130px|right|Dr Harry Angelman]]
Angelman syndrome (AS) is a rare [[#Glossary | '''neurogenetic''']] disorder first described by Dr. Harry Angelman in 1956.<ref name="PMID18754889"><pubmed>18754889</pubmed></ref> Dr. Angelman was an English paediatrician who first diagnosed the disease in 3 children with a developmental delay.<ref>http://www.ncbi.nlm.nih.gov/books/NBK22221/</ref> AS occurs in 1 in 10000-20000 births, the exact number is still unknown.<ref name="PMID7573182"><pubmed>7573182</pubmed></ref><ref name="PMID8703225"><pubmed>8703225</pubmed></ref> It is caused by maternal [[#Glossary | '''allele''']] disruptions of a single gene- UBE3A. Either mutations or deletions of the UBE3A gene results in AS.

AS presents with well known [[#Glossary | '''phenotypes''']] during infancy and adulthood, such as [[#Glossary | '''microcephaly''']] and [[#Glossary | '''maxillary hypoplasia''']]. However, these features become more marked with age. Most frequent clinical features include delayed development,[[#Glossary | '''seizures''']],[[#Glossary | '''ataxia''']], impairment of speech, happy demeanor, behavioural problems such as hyperactivity, short attention span and sleeping difficulty.<ref><pubmed>21592595</pubmed></ref><ref><pubmed>21484597</pubmed></ref><ref name="ASAwebsite">http://www.angelmansyndrome.org/home.html</ref>

At present, there is no cure for the syndrome, though current research is focused at improving life quality of patients with Angelman syndrome through management of daily tasks.<ref>http://www.bbc.co.uk/health/physical_health/conditions/angelman1.shtml</ref>

==History==

Dr. Harry Angelman first reported Angelman Syndrome on three handicapped children that were admitted to his ward in England in 1964.<ref name="PMID18754889" /> He reported how these three independent and unconnected clinical cases all had the same characteristic features of severe developmental delay, jerky movements, seizures and a happy disposition. However it was only when he stumbled upon an oil painting called ‘a Boy with a Puppet” while on a holiday in Italy he was able to connect the symptoms of all three children under one common cause. He linked the happy face of the boy depicted on the painting with the jerky movements and happy disposition he observed on his three patients back in England. He reported his findings on a paper entitled “Puppet children (a report on three cases)” which was published in 1965.

The [[#Glossary | '''syndrome''']] was initialled named ‘Puppet Syndrome’ but was later changed to Angelman Syndrome. Due to the extreme rarity of the syndrome and lack of sufficient clinical evidence the syndrome was soon forgotten.<ref name="PMID18754889" />
[[File:Dr Charles Williams.jpg|thumb|right|150px|Dr Charles Williams]]

In 1987, a physician named Ellen Magenis, came across children with deletions on [[#Glossary | '''chromosome''']] 15 that were suffering from seizures and severe developmental delay. Even though genetically the children were expected to have [[#Glossary | '''Prader-Willi syndrome''']] that was characterised by deletions on chromosome 15, their characteristic symptoms of seizures and lack of development did not correspond with that of the syndrome. This led to the realization that these children had deletions on the maternally derived chromosome 15 and not on the paternally derived chromosome as was observed in Prader-Willi syndrome.

In 1997, UBE3A gene was isolated by Dr. Joseph Wagstaff and Dr. Arthur Beaudet as the cause of Angelman Syndrome. The discovery of this [[#Glossary | '''gene''']] led to the subsequent development of animal models and research aimed at finding a causal link between UBE3A gene abnormalities and characteristic features observed in Angelman Syndrome.

Currently, four different genetic abnormalities for Angelman Syndrome have been confirmed by genetic testing. They include: Deletion, [[#Glossary | '''Uniparental Disomy''']] (UPD), [[#Glossary | '''Imprinting''']] and UBE3A mutation.

Below is a timeline, summarising the key discoveries and advancements of the Angelman Syndrome:

{| style="width:100%"
|- bgcolor="lightpink"
!Year
!Milestone
|-style="width:100%"
|'''1964'''
|First observed by Dr Harry Angelman on three handicapped children.
|-style="width:100%"
|'''1965'''
|Harry Angelman publishes his finding in a report entitled 'Puppet Children'(a report on three cases).<ref name="PMID18754889" />
|-style="width:100%"
|'''1980s'''
|First reports of AS reaches US and research into the disorder being at the University of Florida under the direction of Dr. Charles Williams.
|-style="width:100%"
|'''1982'''
|Name changed from 'Happy Puppet' to Angelman syndrome by Williams and Frias.
|-style="width:100%"
|'''1987'''
|Discovery of a genetic marker for AS – an absent genetic code on maternally derived chromosome 15.
|-style="width:100%"
|'''1997'''
|The cause of AS discovered by Dr. Joseph Wagstaff and Dr. Arthur Beaudet – mutation or deletion in the UBE3A gene.
|-style="width:100%"
|'''1998'''
|Transgenic mice with absent maternal UBE3A created to illustrate motor and learning deficits in addition to seizures.<ref name="PMID9808466"><pubmed>9808466</pubmed></ref>
|-style="width:100%"
|'''2007'''
|AS mouse model shows that neurological deficits can be reversed by decreasing levels of alphaCaMKII inhibitory phosphorylation.<ref><pubmed>17259980</pubmed></ref>
|-style="width:100%"
|'''Current'''
|Four different genetic abnormalities for AS confirmed by genetic testing.
|-style="width:100%"
|}

==Epidemiology==

'''Incidence'''
: The current population of people diagnosed with AS is unknown but studies have estimated the number to be around 1/10,000<ref name="PMID7573182" /> and 1/20,000<ref name="PMID8703225" />.

'''Gender'''
: Males appeared to be at higher risk for some aspects of early developmental delays in comparison to females with AS.<ref><pubmed>17019625</pubmed></ref>

'''Demography'''
: Denmark- 1:10,000<ref name="PMID7573182" />
: Estonia- 1:52,000<ref><pubmed>16906556</pubmed></ref>
: Sweden- 1:20,000<ref name="PMID8703225" />
: Western Australia- 1:40,000<ref><pubmed>16492624</pubmed></ref>

==Aetiology==

[[File:Chromosome 15 Deletion of 15q11.2 to 15q13.jpg|thumb|100px|Chromosome 15 - The deletion occurs at 15q11.2-15q13.]]

Different genetic mechanisms lead to different clinical phenotypes of AS. The most common genetic mechanism leading to AS is the deletion or re-arrangement of maternal chromosome at [[#Glossary | '''locus''']] 15q11.2-q13,as the chromosome image shows on the right, accounting for 70% of AS occurrences.<ref name="PMID8988171"><pubmed> 8988171</pubmed></ref> This leads to more severe clinical phenotypes of microcephaly, motor difficulties, seizures and impaired speech development. The next most common genetic mechanism is mutation in the ''UBE3A'' gene responsible for 10% of AS cases and paternal uniparental disomy and mutation in the imprinting centre (IC), both accounting for 2-5% of AS observed.<ref><pubmed>19455185</pubmed></ref>

AS is caused by the 4 major genetic mechanisms mentioned above and are thus divided into Classes I to IV based on their underlying genetic mechanism. AS patients with the clinical features of AS but no [[#Glossary | '''cytogenetic''']] or molecular abnormality in Chromosome 15q11.2-13 are grouped under Class V (summarised in table below).<ref name="PMID8988171" /><ref><pubmed>10364509</pubmed></ref>

{| style="width:100%; height:25px"
|-bgcolor="lightpink"
| Class
| Mechanism
| Diagnostic Tests
| Frequency
|-style="width:100%; height:25px"
| '''Ia'''
| [[#Glossary | '''De novo''']] deletion
| High resolution cytogenetics [[#Glossary | '''FISH''']]
| 70%
|-style="width:100%; height:25px"
| '''Ib'''
| Deletion due to chromosome rearrangement
| High resolution cytogenetics FISH
| <1%
|-style="width:100%; height:25px"
| '''II'''
| Paternal uniparental disomy
| [[#Glossary | '''RFLP''']] analysis
| 2%
|-style="width:100%; height:25px"
| '''IIIa'''
| Imprinting defect with IC mutation
| Screening of [[#Glossary | '''IC''']] for mutations is positive
| 2%
|-style="width:100%; height:25px"
| '''IIIb'''
| Imprinting defect withouth IC mutation
| Screening of IC for mutations is negative
| 2%
|-style="width:100%; height:25px"
| '''IIIc'''
| Mosaic imprinting defect
| Screening of IC for mutations is usually negative
| ?
|-style="width:100%; height:25px"
| '''IV'''
| ''UBE3A'' mutation
| Screening of ''UBE3A'' for mutations
| 5-10%
|-style="width:100%; height:25px"
| '''V'''
| No identifiable genetic abnormality
| Consider other diagnoses
| 5-26%
|}

==Pathogenesis==

Chromosome 15 became associated with AS in the 1980s after the observation of many AS patients harboring [[#Glossary | '''microdeletions''']] of 15q11.2-15q13.<ref><pubmed>15668046</pubmed></ref> The last decade has shed even more light in the aetiology of AS,as Kishino and Matsuura first identified UBE3A as the causative gene for AS in 1997.<ref name="PMID:8988171"><pubmed>8988171</pubmed></ref><ref><pubmed>8988172</pubmed></ref>

'''Normal gene product: E6-AP ubiquitin ligase'''

The function of UBE3A is to encode for E6-AP ubiquitin ligase, however its function in the development of the nervous system and the process of UBE3A mutation leading to cognitive impairment in AS patients is still vague.<ref name="PMID:20211139><pubmed>20211139</pubmed></ref> Past and current research has elucidated that E6-AP ubiquitin ligase is involved in the degradation of four proteins, listed below, but currently, no protein with a direct role in long-term potentiation (LTP) as a target of E6-AP, has been identified.<ref><pubmed>12684449</pubmed></ref> The identification of such target proteins would be a landmark discovery in further understanding of the pathogenesis, aetiology and prospective treatment strategies of AS, as LTP defects is one of the major neurological impairments of AS.

* p53 tumor suppressor protein
* yeast DNA repair protein Rad23
* multicopy maintenance protein 7 subunit
* E6-AP

'''Abnormal gene product'''

Disruption to the gene,UBE3A, interferes with the normal functioning of the gene, which is its crucial role in UBE3A ubiquitylation. Problems involving this pathway can lead to various diseases either from the loss or gain of function.<ref name="PMID:9857172"><pubmed>9857172</pubmed></ref> In the case of AS, E6-AP is affected, leading to detrimental cognitive impairment in addition to other deficits.<ref name="PMID:9857172"><pubmed>9857172</pubmed></ref>

'''Regional functioning of UBE3A'''

Despite the uncertain progression of UBE3A mutation and the neurological abnormalities characteristic of AS, animal models have illustrated the vital role of UBE3A in the normal functioning of the brain. This can be exemplified by a study which utilized a mouse model with target inactivation of the gene UBE3A resulting in the manifestation of classical features of AS.<ref><pubmed>11895368</pubmed></ref> In addition, the fact that imprinting of UBE3A takes place only in specific brain regions (cerebellum, olfactory tracts and the hippocampus) confirms the hypothesis that the loss of this gene would be detrimental in the cognitive development.<ref><pubmed>20398390</pubmed></ref> Most genes are inherited in copies of two, one paternal and the other maternal; however, some genes, such as UBE3A only have one functional copy as the other is silenced, coined 'imprinting'. Imprinting of the paternal copy of UBE3A takes place in some cell populations, such as the hippocampal neurons and Purkinje cells in the cerebellum.<ref><pubmed>9288101</pubmed></ref> This means only the maternal UBE3A is functionally expressed in these particular brain regions. Thus a de novo mutation in the maternal copy of the gene will result in the complete absence of functional E6-AP in the associated brain areas.<ref><pubmed>9288088</pubmed></ref>

It is also known that UBE3A plays an important role in synaptic transmission, but exactly how it does so is still not completely understood.<ref name="PMID:9808466"><pubmed>9808466</pubmed></ref>

'''UBE3A ubiquitylation'''

As briefly mentioned above, UBE3A is a member of the E3 ubiquitin ligase family of enzymes, responsible for the addition of ubiquitin to the target protein for degradation of the ubiquitinated protein, as illustrated in the diagram below. These processes are required for normal human cognitive function.<ref name="PMID:9808466"><pubmed>9808466</pubmed></ref> In this way synaptic protein [[#Glossary | '''Arc''']](activity-regulated cytoskeleton-associated protein) is degraded to control synaptic function. Arc is a target protein of UBE3A in dendritic spines found in the hippocampal neurons.<ref name="PMID:20668179"><pubmed>20668179</pubmed></ref> Deletion of UBE3A leads to the accumulation of Arc in neurons leading to trafficking of [[#Glossary | '''AMPA''']] receptors, resulting in impaired cognitive functions.<ref name="PMID:20211139"><pubmed>20211139</pubmed></ref> [[File:UBE3A Ubiquitylation Pathway.png|thumb|350px|right|UBE3A Ubiquitylation Pathway]]

UBE3A ubiquitylation consists of:
# Activation of ubiquitin by E1 enzyme
# E1 ezyme transfers ubiquitin to E2 enzyme
# E2 enzyme transfers ubiquitin to UBE3A
# UBE3A attaches activated ubiquitin to target protein which is then polyubiquitylated
# Target protein is then degraded by 26S proteosome.<ref name="PMID:20668179"><pubmed>20668179</pubmed></ref>

'''Phenotype-Genotype correlations'''

[[File:Extent of microcephaly in 20 AS patients with deletion and without deletion.png|thumb|250px|right|Extent of microcephaly in 20 AS patients with deletion and without deletion-http://www.nature.com/ejhg/index.html/ European Journal of Human Genetics]]

All AS patients show differing extents of cognitive impairment, movement disorder, characteristic behaviours and difficulty in speech and language.<ref name="PMID:11748306"><pubmed>11748306</pubmed></ref> However, there seems to be some phenotype-genotype correlations:

- 5-7Mb deletions result in the most severe phenotypes such as microcephaly, more sever epilepsy and seizures, motor difficulties and language impairment.<ref><pubmed>9546330</pubmed></ref><ref name="PMID20445456"><pubmed>20445456</pubmed></ref> AS patients with large deletions also present with clinical hypopigmentation, light hair and eye colour due to the close association of OCA2 gene with UBE3A.<ref name="PMID16470747"><pubmed>16470747</pubmed></ref> Individuals under this category have in general no increased BMI<ref name="PMID:15253756"><pubmed>15253756</pubmed></ref> This is indicated by the graph on the left, which shows more cases of AS patients with deletions having larger deviations from the mean head circumference measurement than non-deletion AS patients.

- AS patients with uniparental disomy (UPD) have better physical growth, fewer motor deficits and lower seizure occurrences.<ref><pubmed>16023557</pubmed></ref>

- Individuals with AS resulting from imprinting defects have the least debilitating features, such as higher developmental and language ability than AS caused by other mechanisms.<ref name="PMID:11748306"><pubmed>11748306</pubmed></ref>

- The Body Mass Index (BMI) of 33% of the UBE3A mutation patients, and 47–64% of the patients from the classes II (UPD) and III (Imprinting defect) is above the 95th centile.<ref name="PMID:15253756"><pubmed>15253756</pubmed></ref>

'''Animal models'''

* '''Drosophila'''

Drosophila is an excellent model to use for better understanding of genetic diseases in humans as they are highly homologous to human UBE3A (hUBE3A), illustrating a high evolutionary conservation. Studies using the Drosophila model have shown that the functional absence of UBE3A resulted in decreased morphogenesis of dendritic branches. This is of interest as dendritic branches cover over 90% of the neuronal surface where synapse between neurons occur. Proper formation and maturation of dendritic spines is also required so they come in contact with other neurons for effective transmission of neuronal signals. Thus proper formation of dendritic branching is pivitol for effective neuronal function and hence cognitive function.<ref><pubmed>18996915</pubmed></ref> Interestingly, overexpression of dUBE3A also gave the same result, consisting of abnormal locomotion and decreased dendritic branching in sensory neurons.<ref><pubmed>18701717</pubmed></ref> This suggests a possible research field for some forms of autism where the region containing UBE3A is duplicated, leading to delayed motor skills and seizures.<ref><pubmed>16433693</pubmed></ref>[[File:Normal and AS mice performance on the Rotarod apparatus.jpg|thumb|250px|right|Normal and AS mice performance on the Rotarod apparatus]]

* '''Mice'''

Absence of UBE3A in mice manifest similar phenotype to human AS, as illustrated by motor and learning deficits with inducible seizures.<ref><pubmed>21235769</pubmed></ref> It has been shown through various mice model studies that larger deletions, ie. from UBE3A to GABRB3, more closely mirrors the large 6Mb deletions seen in human AS patients. Numerous tests, such as the Rotarod (for motor coordination and learning ability), Morris water maze test (for spatial learning and memory) and EEG (electroencephalography), were carried out on UBE3A null mutants, which showed the results to be abnormal or impaired.<ref><pubmed>20808828</pubmed></ref> Other studies using mouse models have also outlined the obesity observed in 15% of AS children, albeit it is not the major characterisitics of AS.<ref><pubmed>17259980</pubmed></ref> The diagram on the right clearly highlights the results obtained from such mouse model studies of AS, where the absence of UBE3A accumulated in deficits of motor function and obesity. In addition, excessive drooling and feeding difficulties were also highlighted by mice models with inactivated UBE3A, reflected by defects in fluid consumption and licking.<ref><pubmed>18413322</pubmed></ref>

===Pathophysiology===

'''Cognitive defects'''

[[File:Role of UBE3A in dendritic spine neuronal synapses.png|thumb|250px|right|Role of UBE3A in dendritic spine neuronal synapses]]

AS patients present with abnormally high UBE3A, leading to neurological impairment. Recent identification of key target proteins of Ephexin-58 (Eph-5) and Arc (Activity-Regulated Cytoskeleton-associated protein) have aided in better understanding of the progression of UBE3A to cognitive defects. These two proteins are vital in the understanding of AS as Eph-5 determines synapse numbers and Arc contributes to plasticity and synapse function.<ref><pubmed>21164477</pubmed></ref> Studies utilizing mice models have illustrated that UBE3A null mice could not ubiquitinate Eph-5, thus increasing its levels and limiting the growth of dendritic spines by the activation of RhoA. This subsequent activation of RhoA inhibits synapse formation and results in neuronal defects.

In contrast, mice with normally functioning UBE3A showed phosphorylated Eph-5, resulting from the interaction of two neurons via the activation of EphB signalling receptor.<ref><pubmed>21029865</pubmed></ref> Phosphorylation of Eph-5 allows UBE3A to ubiquitinate and degrade it. This degradation of Eph-5 permits new synaptic connections to form with cells they come into contact with. However, in AS, the absence of UBE3A means Eph-5 cannot be degraded, so RhoA activity is prolonged to reduce synaptic formation.

As mentioned previously, Arc plays a pivitol role in synapse function as it removes synaptic receptors that respond to glutamate, a neurotransmitter.<ref><pubmed>17088211</pubmed></ref> In UBE3A present neurons, UBE3A ubiquitinates Arc, leading to it degradation as illustrated by the diagram on the left. However, in UBE3A deficient neurons, Arc accumulates and prevents the proper synaptic communications essential for normal cognitive functions.<ref name="PMID20211139"><pubmed>20211139</pubmed></ref>

==Signs and Symptoms==

Angelman Syndrome presents a variety of different Phenotypes, and the presented symptoms may vary at different ages.<ref><pubmed>7625442</pubmed></ref>
In 1995 Williams et al embraced the observed clinical features of AS in a consensus statement, in order to present an appliance for clinicians. These diagnostic criteria were updated in 2005.<ref name="PMID16470747" /> The following table shows the most frequent occurring characteristics in AS patients:

'''4 characteristics appear in 100% of the cases:'''

*Delayed development: becoming apperant by the age of 6 to 12 months. 2.
*Motion and or balance malfunction
*Behavior patterns like unmotivated laughter, frequent excitement; often including body movements, Hypermotoric behavior
*Impairment of speech

'''3 characteristics appear in more than 80% of the cases:'''

*Abnormalities in head circumference, microcephaly
*Seizures
*EEG shows specific pattern<ref name="PMID20445456" /><ref name="PMID16470747" />

Angelman Syndrome individuals show the most distinct disease pattern from 2 to 16 years of age.
In most cases at least 8 of the symptom traits are shown.<ref><pubmed>7625442</pubmed></ref>

[[File:A 12 year old PWS patient and a 4 year old AS patient.jpg|thumb|200px|A 12 year old PWS patient and a 4 year old AS patient.]]

'''Behavioural Characteristics'''

A range of substantial characteristics appear in all AS cases, regardless of the genetic mechanisms, and are often responsible for diagnosing the syndrome. According to the original name, Happy Puppet Syndrome, is a happy demeanor, with frequent laughter or smiling that can easily be triggered.<ref name="PMID12566516"><pubmed>12566516</pubmed></ref> This behaviour can already be observed in 1 to 3 month old infants.<ref><pubmed>20981772</pubmed></ref> Uplifted hand flapping or waving motions are associated with laughter and excitement. Other characteristics manifesting in early childhood are sleep abnormalities with reduced sleep demand, and feeding problems. Breast and bottle feeding can be difficult due to non efficient attachment to the breast, tongue thrusting and uncoordinated sucking. Furthermore, there is affection to crinkly and reflective surfaces, like some papers or plastic materials, and especially water.<ref name="PMID16470747" /><ref name="PMID12566516 "/>

'''Communication Skills'''

Communication is challenging for AS patients due to the fact, that speech impairment is invariable in all people relevant. In the majority of affected people a lack of speech development is present. Only some of them have a minimal vocabulary of two or three words, and some patients use gestures to articulate themselfes. A few can speak in basic sentences. The Picture Exchange Communication System (PECS) or sign languages such as Makaton can be used for communicating interactions by a minority. Simple demands regarding their everyday occurrence can be understood by most patients.<ref name="PMID16470747" /><ref name="PMID12566516 "/>

'''Clinical and External Characteristics'''

Developmental delays are present in all patients. Motor milestones are delayed, and children with the syndrome manage to sit unsupported with about 12 months and crawl or bottom shuffle at the age of 18- 24 months. The average age for walking is 4 years, however the range is from 18 months to 7 years.
The gait is characterized as slow, and flapping hands are a common trait. The legs remain stiff during walking, arms are inflected at the wrists and elbows. The movements can appear ataxic, jerky or lurching. The muscle tone shows abnormalities with truncal hypotonia and hypertonicity of the limbs and alert reflexes.<ref name="PMID16470747" /><ref name="PMID12566516 "/>

The most striking external traites that might be present in patients include broad- spaced teeth, and a wide mouth, light hair and eye colour, hypopigmented skin, deep set eyes, and a flat occiput.<ref name="PMID16470747" />

'''Seizures in Angelman Syndrome'''

85% of AS patients suffer from epileptic seizures during their first three years. The first appearance can be within one month to 20 year old patients. In infants with AS, epilepsy manifests with febrile convulsions, and is hard to manage in childhood.
The most common type of seizure within 25% of patients are [[#Glossary | '''myoclonic seizures''']], followed by [[#Glossary | '''atonic seizures''']] as the next occurring seizure, then 21% experience generalised [[#Glossary | '''tonic clonic seizures''']] and lastly [[#Glossary | '''atypical absences''']] occur in 12% of patients.<ref><pubmed>20398390</pubmed></ref>

'''Angelman Syndrome in adults'''

Patients with Angelman syndrome posses normal secondary sexual characteristics, and puberty sets in at a usual time. Limb hypertonicity, and [[#Glossary | '''thoracic scoliosis''']] leads to decreasing mobility. Oesophageas reflux might lead to severe problems, which the majority suffer from obesity. Facial traits such as a prominent lower lip, [[#Glossary | '''macrostomia''']], and [[#Glossary | '''mandibular prognathism''']] manifest in adults. Frustration, particular regarding communication, leads to aggressive behaviour in some adults.
Whit age, patients gain a higher concentration span, and the behaviour becomes more quiet.<ref name="PMID16470747" />

===Complications===
'''Hypopigmentation and Ocular albinism'''

OCA2 gene, also known as the P gene, is closely located to the UBE3A gene. It encodes a protein vital to tyrosine metabolism, which plays a role in pigmentation development of skin, hair and eyes. However, AS caused by the large deletion of UBE3A leads to haploinsufficiency of OCA2 gene, resulting in hypopigmentation of the skin and the eyes. In some children with severe hypopigmentation, some form of alibinism is suspected.<ref><pubmed>12749060</pubmed></ref> When AS is caused by another mechanism, no abnormality of the skin and eye pigmentation is observed. However, not all AS children with OCA2 gene deletion will present with obvious hypopigmentation, they may just exhibit lighter skin colour than their parents.<ref><pubmed>8302318</pubmed></ref>

==Diagnosis==

'''Prenatal Diagnosis'''

Prenatal detection of deletions of 15q11.2-q13, Paternal UPD (Uniparental Disomy), Imprinting defects and UBE3A mutations are done through DNA/chromosome/FISH analysis of fetal cells obtained by either chronic villus sampling (CVS) or amniocentesis<ref name="PMID20445456" />.
DNA methylation analysis using amniocytes is usually the first test carried out in molecular diagnosis of AS. An abnormal result is followed up by either a FISH or array CGH analysis to search for a deletion on chromosome 15. If they produce a normal result, then UPD testing using DNA polymorphysims is carried out. If there is no evidence of UPD, other DNA analysis tests are used search for an imprinting centre deletion<ref><pubmed>9792887</pubmed></ref>. A normal DNA methylation analysis is followed by a UBE3A sequence analysis. In addition, a parent of origin test is also done to determine if the genetic disruption is of maternal origin or paternal origin. If it is maternally derived the fetus is diagnosed with AS (a paternally derived genetic disruption is indicative of Prader-Willi Syndrome).

The flow chart summarizes the normal procedure used for prenatal diagnosis of AS.

[[File:Angelman Syndrome Prenatal Diagnosis.jpg]]

*''DNA Methylation Analysis''

Identifies approximately 80% of AS affected individuals and is usually the first test to be ordered. Molecular disruptions such as deletions, paternal UPD and imprinting defects on chromosome 15 all demonstrate abnormal methylation patterns by either southern blot analysis or PCR amplification of bisulphate-treated DNA<ref name="PMID20445456" />. An affected individual will only have an unmethylated (paternal) SNRPN (small nuclear ribonuclear protein-associated polypeptide N) allele compared with an unaffected individual who will have both a methylated and an unmethylated SNRPN allele.

*''FISH (Fluorescent in situ hybridization)''

[[File:Critical_region_of_Angelman_Syndrome_on_chromosome_15.png‎|thumb|250px|right|Critical region of Angelman Syndrome on chromosome 15]]

FISH analysis detects 5-7 Mb deletions in approximately 68% of affected individuals using detecting probes such as D15S10 and/or SNRPN. It is also able to distinguish UPD from micro-deletions and imprinting defects. In plain terms the FISH analysis involves the binding of a fluorescent probe to a specific part of chromosome 15 and the detection of deletions. FISH analysis is much more accurate in deletion detection compared to other high-resolution cytogenetics in the diagnosis of AS patients<ref><pubmed>1511093</pubmed></ref>.
Array-based CGH is an advanced type of cytogenetic testing that can also be used to detect deletions.

*''UPD (Uniparental Disomy) detection''

DNA Polymorphism testing detects paternal UPD in approximately 7% of affected AS individuals. It is also able to distinguish between UPD and an Imprinting defect. Requires a DNA sample from the proband and from both parents. A homologous or non-homologous whole-arm translocation of the long arms of chromosome 15 is a sound indication for the need for prenatal UPD testing.<ref><pubmed>18059071</pubmed></ref>

*''Imprinting Center Analysis''

This type of analysis is used when individuals have an abnormal DNA methylation pattern but show normal results for FISH, array CGH study and UPD analysis. It is used to differentiate between the Imprinting defects caused by either microdeletions in the AS imprinting centre or by epigenetic mutations (that occur in maternal oogenesis or early embryogenesis).<ref><pubmed>9634532</pubmed></ref>.

*''Cytogenetic testing''

Is used to detect a chromosomal rearrangement (translocation or inversion) at locus 15q11.2-q13 which occurs in less than 1% of affected individuals.

*''UBE3A Sequence Analysis''

Sequence analysis for multiexonic (10 major coding exons) or whole gene deletions of UBE3A gene in individuals who produces a normal DNA methylation result but has characteristic clinical features of AS.<ref><pubmed>9792887</pubmed></ref>
This is recommended as a prenatal diagnostic tool in families that include multiple AS affected individuals because the imprinted pattern can be inherited from distant relatives.

'''Postnatal Diagnosis'''

[[File:Subtle Finger tremors-Angelman Syndrome.jpg|left|thumb|250px|Subtle Finger Tremors-Angelman Syndrome]]

Postnatal diagnosis is made though a combination common clinical features of AS and UBESA gene sequence analysis. The clinical features of AS include unsteady or shaky movements, muscle hypotonia and developmental delay that become apparent between 6 months to 2 years of age. Thus early infancy diagnosis of AS is difficult because the clinical indicators of the syndrome takes time to manifest and characteristic features such as finger and hand tremors and excessive smiling are overlooked during infancy.

'''Differential Diagnosis'''

*Rett Syndrome

Some children with the clinical diagnosis of AS but no underlying genetic mechanism show mutations in ''MECP2'' gene, corresponding to Rett Syndrome. This should be suspected in AS test negative girls in the first few years of life.<ref><pubmed>17980307</pubmed></ref>

*Mowat-Wilson Syndrome

Genetic mechanism is heterozygous deletion or truncation in ''ZFHX1B'' (''SIP1'') gene on 2q22. This presents with clinical features of severe intellectual disability, micrcephaly and seizures.<ref><pubmed>17958891</pubmed></ref>

*X-linked alpha-thalassemia/mental retardation syndrome (ATR-X)

This arises from mutations in ''XNP'' gene on Xq13. ATR-X presents with severe intellectual disability, no speech development and seizures are common.<ref><pubmed>11449489</pubmed></ref>

*Phelan-McDermid Syndrome/22q13 deletion syndrome

Deletions are usually submicroscopic and thus requires special molecular cytogenetic methods to confirm this deletion. Patients show moderate to profound intellectual disability and delay in speech development.<ref><pubmed>18505557</pubmed></ref>

'''Related Disease'''

*Prader-Willi Syndrome(PWS)

PWS is a result from the absence of paternally expressed 15q11-q13 gene as a corollary of de novo deletion, maternal uniparental disomy of chromosome 15 or an imprinting defect on paternal chromosome 15 leading to the silencing of paternal alleles.<ref name="PMID:20668179 "/> It is characterized by hyperphagia, obesity in later infancy and early childhood and difficulty in feeding during early infancy.<ref name="PMID:20668179 "/> There is also cognitive impairment to some extent, though some PWS patients may exhibit intelligence in the normal IQ range. Behavioral phenotypes include stubbornness, manipulative tendency, obsessive compulsive characteristics.<ref name="PMID:20668179 "/>

==Treatment and Management==

{| style="height:50px"
|-bgcolor="lightpink"
| Problems encountered
| Treatment and Management
|-style="height:50px"
| Difficulty in feeding newborn AS babies
| Use of special nipples may improve feeding
|-style="height:50px"
| Gastroesophageal reflux
| Special motility medications requiried or upright positioning
|-style="height:50px"
| Seizures
| Anticonvulsant medications
|-style="height:50px"
| Ocular problems
| Visual assessment is vital to encourage interactions and minimize chances of self-harm and autism development
|-style="height:50px"
| Drooling in developmental delayed AS patients
| Difficult to treat, but new surgical procedure on salivary duct reimplantation seems to be a promising alternative
|-style="height:50px"
| Unstable children
| Physical Therapy
|-style="height:50px"
| AS patients become less active with increasing age
| Activity schedules to prevent scoliosis and obesity. Occupational Therapy to stimulate fine motor and oral-motor control skills in conjunction to speech therapy
|-style="height:50px"
| Sleeping difficulty
| Sedative medication in severe cases. Melatonin may be used to promote sleeping but some studies have found that it loses its therapeutic effects after several weeks in most AS patients <ref><pubmed>19379289</pubmed></ref>
|-
|-
|colspan="4" |From Buggenhout GV, ''et al''. Angelman syndrome (AS, MIM 105830). ''EJHG'' 2009; '''17''': 1367-1373., unless otherwise noted
|}

==Prognosis==

Life expectancy of AS patients seems to be normal<ref><pubmed>19455185</pubmed></ref>, but there is still a high degree of developmental delay and limited expressive language skills.<ref><pubmed>17019625</pubmed></ref> This problem arises prominently in the assessment of the severity of coincidental medical conditions due to difficulties in communication. A visit to the dentist can become difficult if good communication is not conveyed between the parents, the dentist, and the child.<ref><pubmed>18271768</pubmed></ref> Some problems require extreme measures, such as the procedure of lens implantation was performed in both eyes of a person diagnosed with AS, due to the inability to wear spectacles.<ref><pubmed>20656169</pubmed></ref>

During adulthood, menstruation and puberty begin at around average age evidenced by females with Angelman syndrome that are fully capable of conceiving children.<ref><pubmed>11258627</pubmed></ref> Most adult patients can feed themselves, but needed help with many other daily activities. Main troubles which have shown in adults are a tendency to become obese and start developing thoracic scoliosis, which some adults with AS begin wheelchair bounded.<ref><pubmed>9072912</pubmed></ref>

==Genetic Counselling==

{| style="width:100%; height:25px"
|-bgcolor="lightpink"
| Class
| Mechanism
| Risk to siblings
|-style="width:100%; height:25px"
| Ia
| De novo deletion
| <1%
|-style="width:100%; height:25px"
| Ib
| Deletion due to chromosome rearrangement
| Up to 50%
|-style="width:100%; height:25px"
| II
| Paternal uniparental disomy
| <1%
|-style="width:100%; height:25px"
| IIIa
| Imprinting defect with IC mutation
| Close to 100% if father has 15;15 Robertsonian translocation
|-style="width:100%; height:25px"
| IIIb
| Imprinting defect withouth IC mutation
| Up to 50% (if mother has IC deletion)
|-style="width:100%; height:25px"
| IIIc
| Mosaic imprinting defect
| <1%
|-style="width:100%; height:25px"
| IV
| ''UBE3A'' mutation
| Up to 50% (is mother has mutation)
|-style="width:100%; height:25px"
| V
| No identifiable genetic abnormality
| ? <ref><pubmed>20459762</pubmed></ref>
|}

==Current and Future Research==

Currently there is no cure for the treatment of AS, so much research is being carried out for therapeutic interventions. Findings in the last five years have suggested through various mice and fruit fly models that the absence of maternal UBE3A results in the same human AS features of neurological defects and seizures. However, more recently, studies have outlined that the symptoms of AS can be improved by modifying other gene products. In addition, restoring of a functional UBE3A protein into adult mice neurons have shown to reduce motor and neurological deficits and balance disorders. This shows promising research prospects in that improvements may be possible in human AS patients by restoring functional UBE3A proteins into their neurons.

'''Possible treatment pathways for...'''

* Cognitive and physical impairment

Although everyone is born with two copies of the gene UBE3A, one maternal and one paternal copy, it is only the maternal UBE3A that is used in the brain. Most AS patients have a genetic mutation on the maternal chromosome 15 that results in dysfunctional UBE3A.<ref>http://www.cureangelman.org/what-hope.html</ref> The above research focused on turning on the father's copy of UBE3A to restore its functions. Furthermore, mouse models were utilized to show that CaMKII could be increased to compensate the loss of UBBE3A and restore compromised mental and physical abilities. However, this finding still requires much more research <ref><pubmed>17259980</pubmed></ref>

* Epilepsy

There is research being done on improving certain conditions that are involved in AS by nutritional benefits. The use of corticosteroids<ref><pubmed>19666884</pubmed></ref>,valproateor<ref><pubmed>19453717</pubmed></ref> and clonazepam<ref><pubmed>19605773</pubmed></ref> and having a ketogenic diet<ref><pubmed>20880305</pubmed></ref> has all been shown to aid in the treatment of epilepsy. They have also been reported to be efficient in the treatment of other conditions such as behavioral disorders, reduction in seizures, muscle twitches, sleep patterns, and developmental progress and sleep disturbances. Levetiracetam<ref><pubmed>17326790</pubmed></ref> could be used in such a situation, especially when the patient has an intolerance to valproate and clonazepam.

==Glossary==

'''allele''': Dissimilar variant of one gene. Organisms have two alleles for each gene inherited from their parents, one from each of them.

'''AMPA''': (2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl)propanoic acid) Compound that binds to the AMPA receptor to imitate glutamate neurotransmitter.

'''arc''': Activity-Regulated Cytoskeleton-associated protein; involved in learning and memory.

'''ataxia''': Lack of coordination in muscle movements.

'''atonic seizures''': A abrupt loss of muscle tone, this can lead to the limbs loosing strength, or the head may drop to the side. The patient remains conscious during this kind of epileptic seizure.

'''atypical absences''': Seizure leads to unconsciousness in most cases.

'''chromosome''': Structure consisting of coiled DNA with DNA associated proteins such as histones.

'''congenital''': Present at birth, but does not always result from genetics.

'''cytogenetics''': Study of the structure, function and abnormality of the cell, especially the chromosome.

'''deletion''': Lack of a part of the DNA (deoxyribonucleic acid is a nucleic acid containing information for protein synthesis), can vary form a single base to a hole gene.

'''de novo mutation''': Change in a gene of a family member for the first time due to a mutation in the egg or sperm of the parents or in the fertilized egg (zygote).

'''disorder''': A mental or physical health disturbance or dysfunction.

'''EEG''': Electroencephalography is a means of measuring electrical activity along the scalp by measuring the total electrical charges fired by thousands or millions of neurons.

'''epilepsy''': Neurological disorder characterised by recurrent impairment of brain function that can cause seizures or unconsciousness.

'''E6-AP''': E6AP ubiquitin-protein ligase is an enzyme encoded by UBE3A which adds ubiquitin chain to target proteins to be degraded by proteasomes.

'''febrile convulsions''': The occurrence of high fiver, especially in children.

'''FISH''': Fluorescent in situ hybridization is a technique used to identify and localize the presence or absence of DNA sequences on the chromosome. This is achieved by using fluorescently labelled DNA sequences which then binds to complementary DNA sequence on the chromosome. After hybridization (attachment), chromosome of interest will fluoresce under the microscope.

'''hypermotoric''': Sudden appearance of uncontrolled movements such as kicking or striking.

'''hypertonicity''': Increase of muscle tension and a disability to stretch leading to an impairment of motor activity.

'''hypopigmented''': A lack of melanin pigments or melanocytes affecting the colour of the skin, hair and iris. This features appear light coloured.

'''hypotonia''': Decrease in the ability to stretch passively, due to a low muscle tone.

'''imprinting''': This is a process to describe the modification of a maternally or paternally derived chromosome, which consequently influences the expression of certain genes on the altered chromosome.

'''infant''': Human offspring from birth up to 12 months of age.

'''locus''': Location of a gene on a chromosome(loci: plural for locus).

'''LTP''': Long-term potentiation shares common features with long term memory. It strengthens and enhances signal transmission between neurons by improving the communication between two neurons.

'''macrostomia''': A wide- spaced mouth.

'''Makaton''': Language programme using symbols and signs to support speaking.

'''mandibular prognathism''': The mandible referres to the lower jaw, prognathism means abnormal protrusion of the jaw.

'''maxillary hypoplasia''': Hypoplasia means a tissue or organ is underdevelopt, the maxilla is the upper jaw.

'''microcephaly''': The circumference of the head is less than average due to abnormalities of the nervous system. This abnormality can be present at birth or emerge during the first few years of life and reduces both life expectancy and the cognitive functions of the individual affected.

'''mutation''': Event that changes the DNA (deoxyribonucleic acid is a nucleic acid, containing information for protein synthesis) or RNA (ribonucleic acid is a type of nucleic acid transmitting the information from the DNA to the proteins ) of a gene permanently.

'''myoclonic seizures''': A quick jerk of the skeletal muscle, due to a irregular brain activity.

'''neurogenetic''': Genetic basis of the nervous system.

'''neurotransmitter''': Transmits neuronal signals to a target cell. They are first packaged in vesicles just beneath the membrane of presynaptic axon terminals and released into the synaptic cleft (space between the two interacting neurons) and enter the postsynaptic dendrite.

'''occiput''': Referres to the back of the head.

'''oesophagus reflux''': Impairment of a sphincter in the lower end of the oesophagus leads to the back flow of stomach acid into the oesophagus. Heartburn is a typical symptom.

'''paediatrician''': Physicians that concentrate at on infants, children and adolescents.

'''phenotype''': Visible traites of an organism determined by genetic and environmental factors.

'''Picture Exchange Communication System (PECS)''': Individuals communicate using images instead of words. It is frequently used by children with autism, to articulate their needs and wishes or to make comments about something.

'''Robertsonian translocation''': Rearrangement of the chromosome, occurs in 5 chromosome including 13,14,15,21 and 22. This type of mutation occurs in chromosomes with the centromere not at the centre, resulting in long and short arm chromosomes. Translocation breaks the chromosome at the centromere so the long arm attaches to the other long arm, and the same for the short arm happens. Cell division will result in the loss of the short arms as they do not contain important genes.

'''seizure''': Abnormal electrical activity in the brain that can result in a variety of physical symptoms like convulsion, body shaking, loss of consciousness, confusion, mood changes, and many more.

'''symptom''': Subjective evidence of a desease, illness or condition, only expirienced the patient.

'''synapse''': Allows transmission of signal between neurons for effective neuronal function.

'''synaptic plasticity''': One of the most important theory behind learning and memory. Ability of a synapse between two neurons to change in strength due to the use or disuse of transmission.

'''syndrome''': Signs, symptoms or traits that appear together.

'''thoracic scoliosis''': The spine is curved lateral(means to the side).

'''tonic clonic seizures''': This type of seizure is associated with unconsciousness due to electrical discharges in a big proportion of the brain.

==External Links==

: http://www.angelmansyndrome.org/research.html
: http://www.angelman.org/
: http://rarediseasesnetwork.epi.usf.edu/arpwsc/
: http://www.rarediseases.org/rare-disease-information/rare-diseases/byID/411/viewAbstract
: http://www.epilepsyfoundation.org/
: http://www.kumc.edu/gec/support/angelman.html

==References==

<references />