Angelman syndrome

# Overview
Angelman syndrome, formerly known as "happy puppet syndrome", is a genetic disorder characterized by intelectual and development delay, seizures, puppet-like movement, unprovoked laughter/smiling, and excessive socialization with strangers.

# Historical Perspective
- Angelman syndrome was first discovered by Dr. Harry Angelman, a British pediatrician, in 1965 during his seminar, where he described three children with the typical facies of the syndrome.
- In 1965,Dr. Angelman quoted in his seminal paper:
"I happened to see an oil painting...called... "a Boy with a Puppet". The boy's laughing face and the fact that my patients exhibited jerky movements gave me the idea of writing an article about the three children with a title of Puppet Children."
- In 1987, maternal allele deletion in chromosome 15 was first identified in the pathogenesis of Angelman syndrome.
- In 1994 point mutations in UBE3A gene was known to be the gene responsible for Angelman syndrome.

# Pathophysiology

## Modes of Inheritance
- In 70% of the cases, Angelman syndrome is caused by a sporadic (de novo) maternal deletion in chromosomal region 15q11-13 causing an absence of UBE3A gene, involving the ubiquitin pathway.  There is a lack of expression of the maternally-inherited UBE3A gene in the brain, while the paternally-inherited copy of UBE3A is silenced.
- Other causes include paternal uniparental disomy, impringting error, translocation, or single gene mutation in UBE3A.
- 3-5% of cases of Angelman syndrome can be inherited.
- Recurrence of Angelman syndrome in subsequent children when having a child with a de novo deletion is estimated around 1%.
- In approximately 10% of cases, no cause can be identified.

## Phenotype-Gene Relationships

# Clinical Features
Angelman syndrome is characterized by:
- Puppet-like movement
- Intelectual and development delay
- Seizures
- Unprovoked laughter/smiling
- Excessive socialization with strangers
- Speech impairment
Other less common features are:
- Delayed head circumference growth
- Suck/swallowing disorders
- Feeding problems
- Frequent drooling
- Excessive chewing
- Wide based gait
- Increased sensitivity to heat
- Diminished need for sleep
- Hydrophilia
- Fascination with crinkly things
- Abnormal feeding conducts
- Constipation

# Differentiating Angelman syndrome from Other Diseases
Angelman syndrome must be differentiated from other diseases that cause intelectual and development delay, dysmorphic facies, and seizures, such as:

# Epidemiology and Demographics
- The prevalence of Angelman syndrome is approximately 5-7 per 100,000 individuals worldwide.
- The exact incidence of Angelman syndrome is unknown, but its estimated to be between 6-7 per 100,000 births .

## Age
Full spectrum of the disease appears usually before 3 years of age.

## Gender
Angelman syndrome affects men and women equally.

## Race
There is no racial predilection for Angelman syndrome.

# Risk Factors
There are no risk factors for developing Angelman syndrome, since most of the cases occur due to a de novo deletion and there is a very small chance for this condition to be hereditary transmitted.

# Screening
Prenatal screening of 15q11.2-q13 region mutations is possible through DNA and/or chromosomal/FISH analysis of fetal cells acquired by chorionic villus sampling or amniocentesis.
Screening for Angelman syndrome-suspected patients can be made by the following tests:
- Karyotyping. Is warranted for any patient with suspected Angelman syndrome.
- Fluorescent in situ hybridization (FISH). May detect deletions, but not imprinting centers or uniparental disomy.
- Methylation test. May detect deletions, uniparental disomies, and imprinting mutations, but not UBE3A gene mutation.
- Paternal uniparental disomy (UPD) studies. Usually done after a normal FISH and methylation test.
- Ubiquitin-protein ligase E3A (UBE3A) mutations. Is performed in patients with clinical presentation of Angelman syndrome, but negative methylation test.
- Imprinting center (IC) mutations. Detects small deletions, but is only available in research centers.

# Natural History, Complications & Prognosis
- Newborns with Angelman syndrome usually weight less than averange when delivered.
- Motor delay and jerky movements usually appear before 1 year of age.
- Seizures could be present between 2 and 8 years of age.
- Dysmorphic facies and scoliosis are aparent after 5 years of age.
- Sexual developement begins and progresses at a normal time.
- Dressing skills and use of certain utensils may happen.
- Patients never develope proper language (5-10 learned word) and usually comunicate with signs.
- At the end, patients do not acquire enough abilities to live by there own.
- Prognosis will vary depending on the severity of symptoms and earliness of management.
- Patients may have a normal life span.
- The mortality rate of Angelman syndrome per 1000 patients/year was 15.84.

# Diagnosis

## Diagnostic Criteria
The Angelman Syndrome Foundation defined criteria for diagnosis in 1995, and updated his criteria in 2006.
The diagnosis of Angelman syndrome according to the Scientific Advisory Committee of the US Angelman syndrome Foundation (Williams et al 2006) is based on:
- Developement history. Normal birth, delayed motor milestones, with no loss of skills.
- Clinical findings. Clinical features (puppet-like movements, speech impairment, feeding dificulties, unprovoked laughter, etc.) previously described, dysmorphic facies, and behavioural uniqueness.
- Genetic testing. Deletion in chromosomal region 15q11-13 with absence of UBE3A gene.

## Symptoms
Angelman syndrome is usually asymptomatic.

## Physical Examination
- Patients with Angelman syndrome usually appear dysmorphic.
- The most common physical examination findings are:
- Flat occiput 
- Below average head size
- Occipital groove
- Protruding tongue
- Tongue thrusting
- Truncal hypotonia
- Prognathia
- Wide mouth
- Wide spaced teeth
- Strabismus
- Light color of skin,hair, and eyes
- Uplifted, flexed arm position during ambulation
- Valgus positioned ankles
- Obesity found in older child
- Scoliosis

## Laboratory Findings
- Hematologic, metabolic, and chemical laboratory findings in Angelman syndrome are usually normal.

## Imaging Findings
- Usually, MRI and CT scans demonstrate normal structural finidings; in some cases, there may be cortical atrophy or demyelinating lesions.

## EEG
- The most common EEG patern observed in Angelman syndrome are signals of high amplitude rhythmic 23 Hz activity (delta rythmicity) primarly over the frontal regions with superimposed interictal epileptiform discharges. Other patern found are rhythmic theta, and epileptiform spike-wave discharges.

# Treatment

## Medical Therapy
- Currently, there is no specific treatment for Angelman syndrome.
- Treatment is only supportive and is amied to:
Mitigate gross and fine motor delays.
Improve communication with non-verbal methods (eg. use of communication devices, implement a sign language, exchange of image cards).
Intervention for autism spectrum disorder, when present.
- Mitigate gross and fine motor delays.
- Improve communication with non-verbal methods (eg. use of communication devices, implement a sign language, exchange of image cards).
- Intervention for autism spectrum disorder, when present.
- Feeding in newborns may requiere special nipples due to poor sucking.
- Antiepileptics are used for seizures, but there hasn't been a consensus on wich medication is the most appropiate.
- Stimulants (methylphenidate) have been used to control hyperactivity behaviours.
- Physiotherapy may improve range of movements and prevents joint stiffness.
- Occupational therapy helps to ameliorate fine motor and oral-motor control.
- Use of low-potency sedatives may help with disruptive nighttime wakefulness.
- Orthopedic postures may be corrected with bracing.
- Dietary recomendations should be made in patients with constipation and/or obesity.

## Surgery
- Sometimes fundoplication may be requiered for reflux symptoms.
- Surgery may be needed to correct certain orthopedic problems (eg. severe scoliosis).
- Surgery for tongue protrusion has not found to be effective.

## Prevention
- There are no primary preventive measures available for Angelman syndrome.

# Living with Angelman syndrome
Although a diagnosis of Angelman syndrome is life-changing, it does not need to be life-destroying. Individuals with Angelman Syndrome are generally happy and contented individuals, who like human contact and play. Angelman syndrome individuals exhibit a profound desire for personal interaction with others. Communication can be difficult at first, but as an AS child develops, there is a definite character and ability to make themselves understood. It is widely accepted that their understanding of communication directed to them is much larger than their ability to return conversation.