2011 Group Project 7

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Angelman Syndrome

--Mark Hill 13:42, 8 September 2011 (EST) Good overall layout in terms of sub-headings, but still feeling very incomplete.

  • History - which version are you using text or table? don't have the same content twice.
  • Epidemiology - very poor content. Who was doing this section?
  • Aetiology - chromosome image is useful here. If you include tables, you need to refer to them within the text and why is the table reference in this section?
  • Pathogenesis - a good section, ext could be simplified in structure. Includes a student drawn image, though no description to what each of the blocks and orange blobs are meant to represent.
  • Animal models - fix the numbered formatting. Text reads like it has come directly from a paper.
  • Signs and Symptoms - seems out of place located here and the content is a little jumbled about.
  • Complications
  • Differential Diagnosis - should this be a sub-heading of Diagnosis?
  • Genetic Counselling - same comment as for first table. How is this adapted it looks pretty much the same to me.
  • Current and Future Research - nothing in this section.
  • Notable people with Angelman Syndrome - is this relevant as a sub-heading?
  • Glossary - incomplete and does not include any acronyms.


Introduction

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. [1] It is caused by maternal 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.[2] [3] [4]

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]

Currently, there is no cure for the syndrome, and current research does rather focus at improving life quality of patients with Angelman syndrome than finding a cure. [7]

History

Timeline

1965: First reported by Dr Harry Angelman- Initially called this disorder “Happy Puppet Syndrome”

1980’s: First reports of AS reaches US and research into the disorder begin at the University of Florisa under the direction of Dr. Charles Williams.

1987: Discovery of a genetic marker for AS – an absent genetic code on chromosome 15

1997: The cause of AS discovered by Dr. Joseph Wagstaff and Dr. Arthur Beaudet – mutation or deletion in the UBE3A gene.

Current:: Four different genetic abnormalities for AS confirmed by genetic testing; Deletion, Uniparental Disomy (UPD), Imprinting and UBE3A mutation. [8]


Year Notes
1965 First reported by Dr Harry Angelman- Initially called this disorder “Happy Puppet Syndrome”
1980s First reports of AS reaches US and research into the disorder being at the University of Florisa under the direction of Dr. Charles Williams.
1987 Discovery of a genetic marker for AS – an absent genetic code on chromosome 15
1997 The cause of AS discovered by Dr. Joseph Wagstaff and Dr. Arthur Beaudet – mutation or deletion in the UBE3A gene.
Current Four different genetic abnormalities for AS confirmed by genetic testing; Deletion, Uniparental Disomy (UPD), Imprinting and UBE3A mutation.

Epidemiology

Incidence

The current population of people diagnosed with AS is unknown but studies have estimated the number to be around 1/10 000[9] and 1/20 000[10].

Age

Gender

Demography

Ethnicity


Aetiology

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 60-75% of AS occurrences.[11] 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.[12]

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 cytogenetic or molecular abnormality in Chromosome 15q11.2-13 are grouped under Class V (summarised in table below). [13]


Class Mechanism Diagnostic Tests Frequency
Ia De novo deletion High resolution cytogenetics FISH 60-75%
Ib Deletion due to chromosome rearrangement High resolution cytogenetics FISH <1%
II Paternal uniparental disomy RFLP analysis 2%
IIIa Imprinting defect with IC mutation Screening of IC for mutations is positive 2%
IIIb Imprinting defect withouth IC mutation Screening of IC for mutations is negative 2%
IIIc Mosaic imprinting defect Screening of IC for mutations is usually negative ?
IV UBE3A mutation Screening of UBE3A for mutations 5-10%
V No identifiable genetic abnormality Consider other diagnoses 5-26%
Adapted from Smith JC, et al. Angelman syndrome: a review of the clinical and genetic aspects. J Med Genet 2003;40:87-95


Pathogenesis

Chromosome 15 became associated with AS in the 1980s after the observation of many AS patients harboring microdeletions of 15q11.2-15q13. [14] 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. [15] [16] 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. [17] 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. [18] In addition, the fact that imprinting of UBE3A takes place on ly 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. [19] It is also known that UBE3A plays an important role in synaptic transmission, but exactly how it does so is still not completely understood.[20]

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. These processes are required for normal human cognitive function.[21] 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.[22] Deletion UBE3A leads to the accumulation of Arc in neurons leading to trafficking of AMPA receptors, resulting in impaired cognitive functions.[23]

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
  4. UBE3A attaches activated ubiquitin to target protein which is then polyubiquitylated
  5. Target protein is then degraded by 26S proteosome. [24]

File:UBE3A Ubiquitination Pathway.png

Phenotype-Genotype correlation

All AS patients show differing extents of cognitive impairment, movement disorder, characteristic behaviours and difficulty in speech and language. [25] However, there seems to be some phenotype-genotype correlations as 5-7Mb deletions result in the most severe phenotypes such as microcephaly, more sever epilepsy and seizures, motor difficulties and language impairment.[26] [27] AS patients with large deletions also present with clinical hypopigmentation, whereas AS patients with uniparental disomy have better physical growth, fewer motor deficits and lower seizure occurrences. [28] The underlying mechanism for AS which gives the least debilitating phenotype is imprinting defects, resulting in higher developmental and language ability than AS caused by other mechanisms. [29] The Body Mass Index (BMI) of 33% of the UBE3A mutation patients, and 47–64% of the patients from the classes II and III is above the 95th centile. Patients with a deletion have in general no increased BMI. [30] Traits observed only in patients with deletions include light hair and eye colour, and hypopigmented skin. [31]

Animal models

  1. 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. [32] 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. [33] Interestingly, overexpression of dUBE3A also gave the same result, consisting of abnormal locomotiona dn decreased dendritic branching in sensory neurons. [34] 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. [35]


  1. Mice

Absence of UBE3A in mice manifest similar phenotype to human AS, as illustrated by motor and learning deficits with inducible seizures. [36] 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. [37] In addition, excessive drooling and feeding difficulties were also highlighted by mice models with inactivated UBE3A, reflected by defects in fluid consumption and licking. [38]

Signs and Symptoms

Angelman Syndrome presents a variety of different Phenotypes, and the presented symptoms may vary at different ages. [39] 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. [40] The following table shows the most frequent occurring characteristics in AS patients.


4 characteristics appear in 100% of the cases 3 characteristics appear in more than 80% of the cases
Delayed development: becoming apparant by the age of 6 to 12 months. [41] Abnormalities in head circumference, microcephaly
Motion and or balance malfunction Seizures
Behavior patterns like unmotivated laughter, frequent excitement; often including body movements, Hypermotoric behavior EEG shows specific pattern
Impairment of speech
Adapted from Smith JC, et al. Angelman syndrome: a review of the clinical and genetic aspects. J Med Genet 2003;40:87-95

Adapted from Williams CA, et al Angelman syndrome: consensus for diagnostic criteria. J Med Genet 1995;56:237–8

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. [42]


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.[43] This behaviour can already be observed in 1 to 3 month old infants. [44] 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. [45] [46]


A 12 year old PWS patient and a 4 year old AS patient.

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. [47] [48]


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.[49] [50]

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. [51]


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 seizures within 25% of patients are myoclonic seizures, atonic seizures are the second most frequent ones, followed by generalized tonic clonic seizures occurring in 21% and atypical absences 12% of patients.[52]


Angelman Syndrome in adults

Patients with Angelman syndrome posses normal secondary sexual characteristics, and puberty sets in at a usual time. Limb hypertonicity, and thoracic scoliosis leads to decreasing mobility. Oesophageas reflux might lead to severe problems, and the majority suffers from obeseness. Facial traits such as a prominent lower lip, macrostomia, and 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.[53]

Complications

Hypopigmentation and Ocular albinism

OCA2 gene, also known as P gene, is closely located to the UBE3A gene. It encodes a protein vital in tyrosine metabolism, which plays a role in pigmentation development of skin, hair and irides. 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. [54] 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. [55]

Diagnosis

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. [56]However, unsteady or shaky movements before walking can be an early indicator of AS. [57]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. [58]

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 hybridisaton 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.[59]

Differential Diagnosis

  • Prader-Willi Syndrome

Results from a deletion on Chromosome 15q11.2-q13 that is inherited paternally, rather than AS that is inherited maternally.[60]

  • 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.[61]

  • 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.[62]

  • 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.[63]

  • 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. [64]

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.[65] It is characterized by hyperphagia, obesity in later infancy and early childhood and difficulty in feeding during early infancy.[66] 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. [67]


Prognosis

Life expectancy of AS patients seems to be normal.[68]

Treatment and Management

Problems encountered Treatment and Management
Difficulty in feeding newborn AS babies Use of special nipples may improve feeding
Gastroesophageal reflux Special motility medications requiried or upright positioning
Seizures Anticonvulsant medications
Ocular problems Visual assessment is vital to encourage interactions and minimize chances of self-harm and autism development
Drooling in mentally retarded AS patients Difficult to treat, but new surgical procedure on salivary duct reimplantation seems to be a promising alternative
Unstable children Physical Therapy
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
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 [69]
From Buggenhout GV, et al. Angelman syndrome (AS, MIM 105830). EJHG 2009; 17: 1367-1373., unless otherwise noted


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%
IIIa Imprinting defect with IC mutation Close to 100% if father has 15;15 Robertsonian translocation
IIIb Imprinting defect withouth IC mutation Up to 50% (if mother has IC deletion)
IIIc Mosaic imprinting defect <1%
IV UBE3A mutation Up to 50% (is mother has mutation)
V No identifiable genetic abnormality ?
Adapted from Williams CA, et al. Clinical and genetic aspects of Angelman syndrome. Genetics in Medicine 2010;12:385-395.



Current and Future Research

Notable people with Angelman Syndrome

Glossary

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

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.

disorder: A mental or physical health disturbance or dysfunction.

hypermotoric: Suddenly appearing uncontrolled movements such as kicking or stricking

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

Makaton: Is a language programme using symbols and signs to support speaking

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 usually, this abnormality can be present at birth or emerge during the first few years of life

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.

neurogenetic: Genetic basis of the nervous system

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

phenotyp: 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.

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.

syndrome: Signs, symptoms or traits that appear together.

External links

http://www.angelmansyndrome.org/research.html

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