Difference between revisions of "2011 Group Project 7"

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Angelman syndrome (AS) is a rare neurogenetic disorder, first described by Dr Harry Angelman in 1956. Dr Angelman was an English paediatrician who first diagnosed the disease in 3 children with a developmental delay. The syndrome is sometimes incorrectly referred to as "happy puppet" syndrome, due to frequent laughter and excitement. <ref>http://www.ncbi.nlm.nih.gov/books/NBK22221/</ref> It is caused by maternal [http://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_7#Glossary allele] disruptions of a single gene-UBE3A. Either mutations or deletions of UBE3A are liable for a variety of symptoms.  
AS presents with well known phenotypes during infancy and adulthood, such as microcephaly and maxillary hypoplasia. However, these features may change with advancing age due to  facial coarsening. Most frequent clinical features include delayed development, seizures, motion malfunction, 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>http://www.angelmansyndrome.org/home.html</ref>  

Revision as of 21:40, 15 September 2011

Angelman Syndrome




About 1 in 25,000 newborn babies are affected by this disorder. There appears to be no discrepancy in males and females affected by it, and persons with the syndrome have a normal life span. [5] [6]









Year Notes
1964 First observed by Dr Harry Angelman on three handicapped children
1998 Transgenic mice with absent maternal UBE3A created to illustrate motor and learning deficits in addition to seizures [8]
2007 AS mouse model shows that neurological deficits can be reversed by decreasing levels of alphaCaMKII inhibitory phosphorylation [9]
Current: Four different genetic abnormalities for AS confirmed by genetic testing



The current population of people diagnosed with AS is unknown but studies have estimated the number to be around 1/10 000[10] and 1/20 000[11].




Sweden- 1:12,000
Western Australia- 1:40,000 [13]
Estonia- 1:52,000 [14]


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 locus 15q11.2-q13, accounting 70% of AS occurrences. [15] 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 2-5% of AS observed.[16]


Class Mechanism Diagnostic Tests Frequency
Ia De novo deletion High resolution cytogenetics FISH 70% [18]
II Paternal uniparental disomy RFLP analysis 2%
IV UBE3A mutation Screening of UBE3A for mutations 5-10%
V No identifiable genetic abnormality Consider other diagnoses 5-26%


Imprinting Inheritance in Familial AS.jpeg


Chromosome 15 became associated with AS in the 1980s after the observation of many AS patients harboring microdeletions of 15q11.2-15q13. [19] 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. [20] [21] Although the function of UBE3A is known (encodes for a ubiuitin ligase enzyme),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. [22] 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. [23] 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. [24] It is also known that UBE3A plays an important role in synaptic transmission, but exactly how it does so is still not completely understood.[25]

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.[26] In this way synaptic protein 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.[27] Deletion of UBE3A leads to the accumulation of Arc in neurons leading to trafficking of AMPA receptors, resulting in impaired cognitive functions.[28]

UBE3A ubiquitylation consists of:

  1. Activation of ubiquitin by E1 enzyme
  2. E1 ezyme transfers ubiquitin to E2 enzyme
  3. E2 enzyme transfers ubiquitin to UBE3A
  5. Target protein is then degraded by 26S proteosome. [29]

UBE3A Ubiquitylation Pathway.png

Phenotype-Genotype correlations

All AS patients show differing extents of cognitive impairment, movement disorder, characteristic behaviours and difficulty in speech and language. [30] 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.[31] [32] 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.[33] Individuals under this category have in general no increased BMI [34]

Animal models

  • Drosophila

Drosophila is an excellent model to use for better understanding of genetic diseases in humans as they are highly homologous to humnan UBE3A (hUBE3A), illustrating a high evolutionary conservation. Drosophila UBE3A (dUBE3A) encodes a protein with 973 amino oacids where the C-terminal HECT domain of the gene shares 62% commonality with hUBE3A. [38] Studies using the Drosophila model have shown that the functional loss of UBE3A resulted in decreased morphogenesis of terminal dendritic branches. This is of interest as dendritic branches cover over 90% of the neuronal surface where synaptic input between neurons occur. Thus proper formation of dendritic branching is pivitol for proper neuronal function and hence cognitive function. [39] Interestingly, overexpression of dUBE3A also gave the same result, consisting of abnormal locomotiona dn decreased dendritic branching in sensory neurons. [40] 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. [41]

  • Mice

Absence of UBE3A in mice manifest similar phenotype to human AS, as illustrated by motor and learning deficits with inducible seizures. [42] 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 EGG, were carried out on UBE3A null mutants, which showed the results to be abnormal or impaired. [43] In addition, excessive drooling and feeding difficulties were also highlighted by mice models with inactivated UBE3A, reflected by defects in fluid consumption and licking. [44]

Signs and Symptoms

Angelman Syndrome presents a variety of different Phenotypes, and the presented symptoms may vary at different ages. [45] 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. [46] The following table shows the most frequent occurring characteristics in AS patients.

Delayed development: becoming apparant by the age of 6 to 12 months. [47] Abnormalities in head circumference, microcephaly
Motion and or balance malfunction Seizures
Impairment of speech




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.[49] This behaviour can already be observed in 1 to 3 month old infants. [50] 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. [51] [52]

Communication Skills


Clinical and External Characteristics



Seizures in Angelman Syndrome


Angelman Syndrome in adults



Hypopigmentation and Ocular albinism



Subtle Finger Tremors-Angelman Syndrome

Diagnosis of AS during early infancy is difficult as clinical features such as developmental delay, muscle hypotonia usually appear between 6 months to 2 years of age.[62] In addition, features such as finger and hand tremors, as illustrated by the image below, and smiling when still an infant are looked over without much worry, so do not act as effective diagnostic indicators [63]However, unsteady or shaky movements before walking can be an early indicator of AS. [64]Diagnosis can also be made on the basis of EGG patterns, as AS patients most typically show triphasic delta activity with a maximum over the frontal regions. The probability of this event increases with age and could help diagnose AS in mentally retarded people. [65]

Currently two main laboratory testing methods are being used to diagnose Angelman Syndrome:

Cytogenetic approach – Is used to detect a chromosomal rearrangement or deletion at locus 15q11.2-q13 region.

Molecular testing – Involves utilising the DNA etholation test to detect a deletion, UPD (Uniparental Disomy) or an imprinting centre defect to confirm the diagnosis. This is successful in about 78% of patients. Fluorescent in situ hybridisation studies (FISH) is also used to detect a 4-6 molecular base deletion of the 15q11.2-q13 region in about 70% of the patients by using a detecting probes such as D15S10 and/or SNRPN. The FISH test lights up or fluoresces a critical area on the chromosome 15 important for Angelman Syndrome. If there is a deletion on the chromosome, the region will not light up, indicating whether a deletion is present or not. Other molecular testing methods include sequence analysis of the UBE3A gene to detect mutations in about 10% of the patients.[66]

Differential Diagnosis

  • Rett Syndrome


  • Mowat-Wilson Syndrome




  • Phelan-McDermid Syndrome/22q13 deletion syndrome


Related Diseases

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.[71] It is characterized by hyperphagia, obesity in later infancy and early childhood and difficulty in feeding during early infancy.[72] 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. [73]

Treatment and Management

Problems encountered Treatment and Management
Gastroesophageal reflux Special motility medications requiried or upright positioning
Seizures Anticonvulsant medications
Unstable children Physical Therapy


Life expectancy of AS patients seems to be normal[75], but there is still a high degree of developmental delay and limited expressive language skills[76]. 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[77]. Some problems require extreme measures, as in the procedure of lens implantation was performed in both eyes of a person with AS due to the inability to wear spectatcles.[78]

During adulthood, menstruation and puberty begin at around average age evidenced by females with Angelman syndrome that are fully capable of conceiving children.[79] Most adult patients could feed themselves, but needed help with many daily activities. Main troubles which have shown in adults are a tendency to be obese and start developing scoliosis, which some adults with AS begin wheelchair-bounded.[80]

Genetic Counselling

Class Mechanism Risk to siblings
Ia De novo deletion <1%
Ib Deletion due to chromosome rearrangement Up to 50%
II Paternal uniparental disomy <1%
IIIc Mosaic imprinting defect <1%
V No identifiable genetic abnormality ? [81]

Current and Future Research



In addition, there is research being done on improving certain conditions that are involved in AS by nutritional benefits. The use of corticosteroids[84],valproateor[85] and clonazepam[86] and having a ketogenic diet[87] has all been shown to aid in the treatment of epilepsy and has 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[88] could be used in such a situation, especially when the patient has an intolerance to valproate and clonazepam.



ataxia: Muscular coordination failes.


atypical absences: Seizure leads to unconsciousness in most cases.


disorder: A mental or physical health disturbance or dysfunction.



hypermotoric: Suddenly appearing uncontrolled movements such as kicking or stricking





macrostomia: A wide- spaced mouth.







neurogenetic: Genetic basis of the nervous system

occiput: Referres to the back of the head.



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




syndrome: Signs, symptoms or traits that appear together.



External links



  1. http://www.ncbi.nlm.nih.gov/books/NBK22221/
  2. <pubmed>21592595</pubmed>
  3. <pubmed>21484597</pubmed>
  4. http://www.angelmansyndrome.org/home.html
  5. http://www.angelmansyndrome.org/home.html
  6. <pubmed>14510623</pubmed>
  7. http://www.bbc.co.uk/health/physical_health/conditions/angelman1.shtml
  8. <pubmed>9808466</pubmed>
  9. <pubmed>17259980</pubmed>
  10. <pubmed>7573182</pubmed>
  11. <pubmed>8703225</pubmed>
  12. <pubmed>17019625</pubmed>
  13. <pubmed>16492624</pubmed>
  14. <pubmed>16906556</pubmed>
  15. <pubmed> 8988171</pubmed>
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  17. <pubmed>10364509</pubmed>
  18. <pubmed>8988171</pubmed>
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  82. http://www.cureangelman.org/what-hope.html
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