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.
• 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.
• 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, dismorfic facies, seizures and/or deletion in chromosome 15, 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

Common risk factors in the development of [disease name] are [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].

Natural History

• The majority of patients with [disease name] remain asymptomatic for [duration/years].
• Early clinical features include [manifestation 1], [manifestation 2], and [manifestation 3].
• If left untreated, [#%] of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].
• Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].
• Prognosis is generally [excellent/good/poor], and the [1/5/10­year mortality/survival rate] of patients with [disease name] is approximately [#%].

Natural history

Pregnancy and delivery are usually uneventful but the babies tend to weigh 200 to 300 g less than their sibs on average. They are often miserable babies and feeding problems are a common cause for concern. Jerky movements become apparent during the first few months and motor delay is obvious by 9 months of age. Seizures begin around 2 years and remain a problem until 7 or 8 years when they decrease in frequency and may cease altogether. Hyperactivity and sleep disturbance, which are common in childhood, improve with age. The facial features are not usually apparent in infancy but evolve over the first five years of life. Language does not develop, most patients having only one or two words, in spite of having reasonable comprehension of simple commands and sentences. Some patients can communicate using Makaton sign language or other gestures. Most patients remain ambulant into adulthood if kept mobile to prevent contractures developing in the hypertonic limbs. General health is good. Scoliosis occurs in 10% patients. This is an infantile type of scoliosis, apparent before the age of 5 years but progressive, particularly during the adolescent years. Cardiorespiratory difficulties may arise if it is left untreated. Patients with AS can acquire some simple skills, such as eating with a knife or spoon and fork, dressing and washing with help, and performing simple household tasks; 80% become toilet trained by day. None acquires sufficient skills to be able to live independently.

Prognosis

Note that the severity of the symptoms associated with AS varies significantly across the population of affected persons. Some speech and a greater degree of self-care are possible among the least profoundly affected. Unfortunately, walking and the use of simple sign language may be beyond the reach of the more profoundly affected. Early and continued participation in physical, occupational (related to the development of fine-motor control skills), and communication (speech) therapies are believed to improve significantly the prognosis (in the areas of cognition and communication) of individuals affected by AS. Further, the specific genetic mechanism underlying the condition is thought to correlate to the general prognosis of the affected person. On one end of the spectrum, a mutation to the UBE3A gene is thought to correlate to the least affected, whereas larger deletions on chromosome 15 are thought to correspond to the most affected.

The clinical features of Angelman syndrome alter with age. As adulthood approaches, hyperactivity and poor sleep patterns improve. The seizures decrease in frequency and often cease altogether and the EEG abnormalities are less obvious. Medication is typically advisable to those with seizure disorders. Often overlooked is the contribution of the poor sleep patterns to the frequency and/or severity of the seizures. Medication may be worthwhile in order to help deal with this issue and improve the prognosis with respect to seizures and sleep. Also noteworthy are the reports that the frequency and severity of seizures temporarily escalate in pubescent AS girls but do not seem to affect long-term health.

The facial features remain recognizable but many adults with AS look remarkably youthful for their age.

Puberty and menstruation begin at around the normal time. Sexual development is thought to be normal, as evidenced by a single reported case of a woman with Angelman syndrome conceiving a female child who also had Angelman syndrome.

The majority of those with AS achieve continence by day and some by night.

Dressing skills are variable and usually limited to items of clothing without buttons or zippers. Most adults are able to eat with a knife or spoon and fork and can learn to perform simple household tasks. General health is fairly good and life-span near normal. Particular problems which have arisen in adults are a tendency to obesity (more in females), and worsening of scoliosis if it is present. The affectionate nature which is also a positive aspect in the younger children may also persist into adult life where it can pose a problem socially, but this problem is not insurmountable.

Diagnosis

Diagnostic Criteria

• The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met:

• [criterion 1]
• [criterion 2]
• [criterion 3]
• [criterion 4]

Symptoms

• [Disease name] is usually asymptomatic.
• Symptoms of [disease name] may include the following:

• [symptom 1]
• [symptom 2]
• [symptom 3]
• [symptom 4]
• [symptom 5]
• [symptom 6]

Physical Examination

• Patients with Angelman syndrome usually appear dysmorphic.
• The most common physical examination finding are:

• Flat occiput
• Small 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

• There are no specific laboratory findings associated with [disease name].

• A [positive/negative] [test name] is diagnostic of [disease name].
• An [elevated/reduced] concentration of [serum/blood/urinary/CSF/other] [lab test] is diagnostic of [disease name].
• Other laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].

Imaging Findings

• There are no [imaging study] findings associated with [disease name].

• [Imaging study 1] is the imaging modality of choice for [disease name].
• On [imaging study 1], [disease name] is characterized by [finding 1], [finding 2], and [finding 3].
• [Imaging study 2] may demonstrate [finding 1], [finding 2], and [finding 3].

Other Diagnostic Studies

• [Disease name] may also be diagnosed using [diagnostic study name].
• Findings on [diagnostic study name] include [finding 1], [finding 2], and [finding 3].

The diagnosis of Angelman syndrome is based on:

• A history of delayed motor milestones and then later a delay in general development, especially of speech
• Unusual movements including fine tremors, jerky limb movements, hand flapping and a wide-based, stiff-legged gait.
• Characteristic facial appearance (but not in all cases).
• A history of epilepsy and an abnormal EEG tracing.
• A happy disposition with frequent laughter
• A deletion on chromosome 15

The Angelman Syndrome Foundation defined criteria for diagnosis in 1995,, and updated these criteria in 2005.

Features

• Feeding problems during infancy (poor suck and poor weight gain) in 75%
• Delay in sitting and walking
• Absent or little speech (not in all cases - some children have a vocabulary of up to 50 words)
• Receptive and non-verbal communication skills higher than verbal ones
• Poor attention span and hyperactivity
• Severe learning disabilities
• Epilepsy (80%) and an abnormal EEG
• Unusual movements (fine tremors, hand flapping, jerking movements)
• Affectionate nature and frequent laughter
• Wide-based stiff-legged gait, with tendency to hold arms up and flexed while walking.
• Below average head size, often with flattening at the back
• Subtle, but sometimes characteristic facial features (wide mouth, widely spaced teeth, prominent chin, tendency to tongue thrust)
• Poor sleeping pattern
• Strabismus (Squint - crossed eye/s) in 40%
• Scoliosis (abnormal curvature of the spine) in 10%
• Increased sensitivity to heat
• Attraction to/fascination with water

EEG

The most common 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

• There is no treatment for [disease name]; the mainstay of therapy is supportive care.

• The mainstay of therapy for [disease name] is [medical therapy 1] and [medical therapy 2].
• [Medical therapy 1] acts by [mechanism of action 1].
• Response to [medical therapy 1] can be monitored with [test/physical finding/imaging] every [frequency/duration].

Surgery

• Surgery is the mainstay of therapy for [disease name].
• [Surgical procedure] in conjunction with [chemotherapy/radiation] is the most common approach to the treatment of [disease name].
• [Surgical procedure] can only be performed for patients with [disease stage] [disease name].

Prevention

• There are no primary preventive measures available for [disease name].

• Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].

• Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].

Because Angelman syndrome is not an illness, but a genetic condition, there is no currently available cure for AS. The epilepsy can be controlled by the use of one or more types of anticonvulsant medications. However, there are difficulties in ascertaining the levels and types of anticonvulsant medications needed to establish control, because AS is usually associated with having multiple varieties of seizures, rather than just the one as is normal cases of epilepsy. Many families use melatonin to promote sleep in a condition which often affects sleep patterns. Many individuals with Angelman Syndrome sleep for a maximum of 5 hours at any one time. Mild laxatives are also used frequently to encourage regular bowel movements and early intervention with physiotherapy is important to encourage joint mobility and prevent stiffening of the joints. Occupational therapy, speech therapy, hydrotherapy and music therapy are also used in the management of this condition.

Living with Angelman syndrome

Although a diagnosis of AS 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. AS 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. Most afflicted individuals will not develop more than 5-10 words, if at all.

See also

• Epigenetics

External links

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

References

Template:WikiDoc Sources