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Angelman Syndrome

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 mentally challenged children.

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 chanfe 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.[1] [2] [3]

The syndrome is sometimes incorrectly referred to as "happy puppet" syndrome, due to frequent laughter and excitement. [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]

Up to now 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 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. [8]



Incidence

Incidence of AS is estimated to be around 1/10 000 and 1/20 000.

Aetiology

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-q13, accounting 60-75% of AS occurrences. 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 disoomy and mutation in the imprinting centre (IC), both accounting 2-5% of AS observed.

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 15q11-13 are grouped under Class V (summarised in table below).


Class Mechanism Diagnotstic 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


Pathophysiology

Symptoms

Angelman syndrome causes a variety of symptoms, and the presented symptoms may vary at different ages. [9]


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. [10]

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 showen. [11]

4 characteristics appear in 100% of the cases:

Delayed development: becoming apperant by the age of 6 to 12 months. [12]

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


Furthermore, there is a range of major and minor traits in patients with Angelman Syndrome:[13]

Physical appearance

Behavioural appearance

Differences between patients with deletions and mutations

Diagnosis

Diagnosis of AS during early infancy is difficult as clinical deatures such as developmental delay, muscle hypotonia usually appear between 6 months to 2 years of age. However, unsteady or shaky movements before walking can be an early indicator of AS. Diagnosis can also be made on the basis of EGG patterns, as AS patients most typically sho 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.

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

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

Molecular testing – Inolves 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-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 critial area on the chromosome 15 important for Angelman Syndrome. If there is a deletion on the chromosome, the region will not light up, indicating wether 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.[14]

Differential Diagnosis

1. 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.

2. Mowat-Wilson Syndrome

Genetic mechanism is heterozygous deletion or truncation in ZFHX1B (SIP1) gene on 2q22. This presents with clinical features of severe mental retardation, micrcephaly and seizures.

3. X-linked alpha-thalassemiz/mental retardation sundrome (ATR-X)

This arises from mutations in XNP gene on Xq13. ATR-X presents with severe mental retardation, no speech development and seizures are common.

4. Phelan-McDermid Syndrome/22q13 deletion syndrom

Deletions are usually submicroscopic and thus requires special molecular cytogenetic methods to confirm this deletion. Patients show moderate to profound mental retardation and delay in speech development.

Prognosis

Life expectancy of AS patients seems to be normal.

Related Diseases

Prader-Willi Syndrome

Treatment and Management

Problems encountered Management and Treatment
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 autistism 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 pomote sleeping but some studies have found that it loses its therapeutic effects after several weeks in most AS patients


Genetic Counselling

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, can vary form a single base to a hole gene.

disorder: A mental or physical health disturbance or disfunction.

mutation

neurogenetic: genetic basis of the nervous system

seizure

syndrome

External links

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

References