Angelman syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Moises Romo, M.D.

Angelman Syndrome
ICD-10	Q93.5
ICD-9	759.89
OMIM	105830
DiseasesDB	712
MeSH	D017204

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

Phenotype	Gene	Location
Angelman syndrome	UBE3A	15q11-15q13

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:

Diseases	Type of motor abnormality				Clinical findings	Laboratory findings and diagnostic tests	Radiographic findings
	Spasticity	Hypotonia	Ataxia	Dystonia
Leigh syndrome	-	-	+	+	Progressive psychomotor regression Seizures External ophthalmoplegia Lactic acidosis Vomiting	Increased lactate levels in blood and CSF Genetic testing	MRI: abnormal white matter signal in the putamen, basal ganglia, and brainstem on T2 images
Niemann-Pick disease type C	-	-	+	+	Progressive neurodegeneration Hepatosplenomegaly Systemic involvement of liver, spleen, or lung preceedes neurologic symptoms	Abnormal liver function tests Fibroblast cell culture with filipin staining	MRI: Cerebral and cerebellar atrophy Thinning of the corpus callosum
Infantile Refsum disease	-	+	+	-	Abnormalities of the optic nerve and disc Retinitis pigmentosa Sensorineural hearing loss Hepatomegaly and cirrhosis Neurologic deterioration is slower than in Zellweger syndrome or ALD	Elevated plasma VLCFA levels	--
Adrenoleukodystrophy	+	-	-	-	Cognitive and behavioral abnormalities Adrenal insufficiency Hyperpigmented skin Gonadal dysfunction Neurologic deterioration progresses at a variable rate	Elevated plasma VLCFA levels Molecular genetic testing for mutations in the ABCD1 gene	--
Zellweger syndrome	-	+	-	-	Craniofacial dysmorphism Hepatomegaly Neonatal seizures Profound developmental delay MRI findings include cortical and white matter abnormalities Neurologic deterioration is rapid and infants rarely survive beyond six months of age	Elevated plasma VLCFA levels Elevated levels of phytanic acid, pristanic acid, and pipecolic acid in plasma and fibroblasts Reduced plasmalogen in erythrocytes Molecular genetic testing for mutations in the PEX1 or PEX6 genes	--
Pyruvate dehydrogenase deficiency	+	+	+	-	Lactic acidosis Seizures Intellectual disability	Elevated lactate and pyruvate levels in blood and CSF Abnormal PDH enzymatic activity in cultured fibroblasts	--
Arginase deficiency	+	-	-	-	Hyperammonemia Encephalopathy Respiratory alkalosis	Elevated ammonia level Elevated arginine level	--
Holocarboxylase synthetase deficiency	-	+	-	-	Ketoacidosis Dermatitis Alopecia Seizures Developmental delay	Elevated levels of: Beta-hydroxyisovalerate Beta-methylcrotonylglycine Beta-hydroxypropionate Methylcitrate Tiglylglycine	--
Glutaric aciduria type 1	-	-	-	+	Episodes of metabolic decompensation and encephalopathy often precipitated by infection and fever Rarely presents in the newborn period Microencephalic macrocephaly Seizures (approximately 20 percent) Cognitive function is preserved	Elevated levels of: glutaric acid 3-hydroxyglutaric acid	MRI: Frontal and temporal atrophy
Ataxia telangiectasia	-	-	+	-	Progressive cerebellar ataxia Abnormal eye movements Oculocutaneous telangiectasias Immune deficiency Increased risk of malignancy	Elevated serum alpha-fetoprotein level Low IgA and IgG levels Lymphopenia Genetic testing for mutation in the ATM gene	--
Pontocerebellar hypoplasias	-	+	-	-	Progressive muscle atrophy Microcephaly Developmental delay	Genetic testing for PCH gene mutations	MRI : Small cerebellum and brainstem including the pons
Metachromatic leukodystrophy	-	+	+	-	Regression of motor skills Seizures Optic atrophy Reduced or absent deep tendon reflexes Intellectual disability	Deficient arylsulfatase A enzyme activity in leukocytes or cultured skin fibroblasts	--
Pelizaeus-Merzbacher	+	-	+	-	Nystagmus Cognitive impairment Onset in infancy Slowly progressive Language development may be normal	Genetic testing for mutations in PLP1 gene	MRI: White matter abnormalities
Angelman syndrome	-	-	+	-	Profound intellectual disability Postnatal microcephaly Typical abnormal behaviors (paroxysmal laughter, easily excitable)	Methylation studies and chromosome microarray to detect chromosome 15 anomalies and UBE3A mutations	--
Rett syndrome	+	-	-	+	Occurs almost exclusively in females Normal development during first six months followed by regression and loss of milestones Loss of speech capability Stereotypic hand movements Seizures Autistic features	Clinical diagnosis Genetic testing for MECP2 mutations	--
Lesch-Nyhan syndrome	+	-	-	+	Self-mutilating behavior Urinary stones due to hyperuricemia	Elevated uric acid level Abnormal enzymatic activity of HPRT in cultured fibroblasts Genetic testing for HPRT gene mutations	--
Miller-Dieker lissencephaly	+	+	-	-	Lissencephaly Microcephaly Dysmorphic features Seizures Failure to thrive	Cytogenetic testing for 17p13.3 microdeletion	--
Dopa-responsive dystonia	+	-	-	+	Onset in early childhood Symptoms worsen with fatigue and exercise	Positive response to a trial of levodopa	--

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 acquiere 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 2–3 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:
  1. Mitigate gross and fine motor delays.
  2. Improve communication with non-verbal methods (eg. use of communication devices, implement a sign language, exchange of image cards).
  3. 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.

See also

• Epigenetics

External links

• Template:Dmoz
• Angelman Syndrome at NIH/UW GeneTests
• Angelman Syndrome Foundation USA

References

Template:WikiDoc Sources