Angelman syndrome

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

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

Overview

Angelman syndrome is a neuro-genetic disorder named after a British pediatrician, Dr. Harry Angelman, who first described the syndrome in 1965. AS is characterized by intellectual and developmental delay, speech impediment, sleep disturbance, unstable jerky gait, seizures, hand flapping movements, frequent laughter/smiling and usually a happy demeanour. AS is a classic example of genetic imprinting caused by deletion or inactivation of critical genes on the maternally inherited chromosome 15. The sister syndrome is called Prader-Willi syndrome, and is caused by loss of paternal genes.

An older, alternative term for Angelman syndrome, happy puppet syndrome, is generally considered pejorative and stigmatizing so it is no longer used, though it remains useful as a diagnostic heuristic.

Historical Perspective

Dr. Harry Angelman, a pediatrician working in Warrington (then in Lancashire) first reported three children with this condition in 1965. It was initially incorrectly presumed to be rare.

In 1987, it was first noted that around half of the children with Angelman syndrome have a small piece of chromosome 15 missing (chromosome 15q partial deletion).

Dr. Angelman stated this painting led him to write his seminal paper in 1965;

"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."

Pathophysiology

Angelman syndrome is caused by the loss of the normal maternal contribution to a region of chromosome 15, most commonly by deletion of a segment of that chromosome.

Other causes include uniparental disomy, translocation, or single gene mutation in that region.

A healthy person receives two copies of chromosome 15, one from mother, the other from father. However, in the region of the chromosome that is critical for Angelman syndrome, the maternal and paternal contribution express certain genes very differently. This is due to sex-related epigenetic imprinting; the biochemical mechanism is DNA methylation.

In a normal individual, the maternal allele is expressed and the paternal allele is silenced. If the maternal contribution is lost or mutated, the result is Angelman syndrome. (When the paternal contribution is lost, by similar mechanisms, the result is Prader-Willi syndrome.)

Please note that the methylation test that is performed for Angelman syndrome (a defect in UBE3A) is actually looking for the gene's neighbor SNRPN (which has the opposite pattern of methylation).

Angelman syndrome can also be the result of mutation of a single gene. This gene (UBE3A, part of the ubiquitin pathway) is present on both the maternal and paternal chromosomes, but differs in the pattern of methylation (Imprinting). The paternal silencing of the UBE3A gene occurs in a brain region-specific manner; the maternal allele is active almost exclusively in the hippocampus and cerebellum.

The most common genetic defect leading to Angelman syndrome is an ~4Mb (mega base) maternal deletion in chromosomal region 15q11-13 causing an absence of UBE3A expression in the maternally imprinted brain regions.

UBE3A codes for an E6-AP ubiquitin ligase, which chooses its substrates very selectively and the four identified E6-AP substrates have shed little light on the possible molecular mechanisms underlying the human Angelman syndrome mental retardation state.

Initial studies of mice that do not express maternal UBE3A show severe impairments in hippocampal memory formation. Most notably, there is a deficit in a learning paradigm that involves hippocampus-dependent contextual fear conditioning. In addition, maintenance of long-term synaptic plasticity in hippocampal area CA1 in vitro is disrupted in Ube3a^-/- mice. These results provide links amongst hippocampal synaptic plasticity in vitro, formation of hippocampus-dependent memory in vitro, and the molecular pathology of Angelman syndrome.

Epidemiology and Demographics

Prevalence

Though the prevalance of Angelman syndrome is not precisely known, there are some estimates. The best data available is from studies of school age children, ages 6-13 years, living in Sweden and from Denmark where the diagnosis of AS children in medical clinics was compared to an 8 year period of about 45,000 births. The Swedish study showed an AS prevalence of about 1/20,000 and the Danish study showed a minimum AS prevalence of about 1/10,000. Note that it is desirable to use the term prevalence, since estimates of AS diagnosis have been made in relatively small cohorts of children over various periods of time.

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

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

Differential diagnosis

Angelman syndrome must be differentiated from other diseases that cause neurological manifestations in infants.

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	--

Treatment

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