• Last Updated: 12/23/94

ANGELMAN SYNDROME

• DEFINITION:

A chromosomal disorder resulting in a syndrome characterized by :

*** dysmorphic facial features

with neurological and behavioural manifestations.

• EPIDEMIOLOGY:

• incidence: 1/20,000
• age of onset:
• first year of life (gross motor delay & microbrachycephaly)

• risk factors:
• maternally-derived de novo deletion of chromosome 15q11-13
• M= F

PATHOGENESIS:

1. Historical Perspectives

• first reported in 1965 by Harry Angelman, an English general Paediatrician, in 3 children - called "puppet children" (Dev. Med. Child. Neurol. 7:681 [1965])
• called "Happy Puppet Syndrome" by Bower and Jeavons (Arch. Dis. Child. 43: 298 [1967])

2. Genetic Defect

1. Cytogentic Findings (Anomaly (%))

• interstitial deletion (maternally-derived de novo deletion of chromosome 15q11-13)- 75-80%
• no cytogenetic anomaly found (10-15%)
• rearrangement of maternal chromosome 15 (5%)
• uniparental disomy (both chromosome 15's from father) - 3%

CLINICAL FEATURES:

1. Neurological Manifestations

• gross motor developmental delay (100%)
• severe mental retardation (100%)
• ataxia +/- wide-based stiff gait (100%)
• absent speech (98%)
• truncal hypotonia (90%)
• limb hypertonia +/- flexion contractures (85%)
• hyperreflexia (85%)
• seizures (begin in infancy to 2nd year of life and tend to occur in clusters) - 80%

2. Facial Dysmorphisms*

• pointed chin +/- prognathism (95%)
• brachycephaly with flattened occiput (90%)
• blue eyes (88%)
• macrostomia (large mouth) - 75%
• tongue protrusion (70%)
• blond hair (65%)
• widely-spaced teeth (60%)
• strabismus (40%)
• occipital groove (35%)
• bowed primary dentation (35%)
• Others: head circumference <25th%, thin upper lip, mid- facial hypoplasia, deep set eyes, decreased pigment of choroid and iris

* absent at birth but become evident by 5 years of age

3. Behavioural Manifestations

• jerky movements (develop by 1 year of age)
• tongue thrusting and mouthing
• hand flapping
• hyperactivity & hypermotor behaviours
• sleep disturbances
• miserable babies
• paroxysms of laughter (develop at 3-4 years of age)

4. Musculoskeletal Manifestations

• scoliosis (10%) - onset by 5 years of age and progressive
• arms flexed at the elbows and upheld
• small hands and feet

5. Other Manifestations

• skin hypopigmentation
• feeding problems (75%)

INVESTIGATIONS:

1. Imaging Studies

1. CT/MRI

• mild cortical atrophy
• mild generalized ventricular enlargement

2. EEG

• large amplitude slow wave activity (4-6 cycles/sec) which persists and is unrelated to drowsiness
• very large amplitude slow wave activity (2-3 cycles/sec) occurring in runs and more prominent anteriorly - spikes or sharp waves mixed with large amplitude 3-4 cycles /sec components seen posteriorly and usually on passive eye closure
• findings less evident with age

MANAGEMENT:

1. Supportive

• no treatment for underlying disease
• multidisciplinary approach
• Paediatrics, Neurology, Orthopedics
• physiotherapy and adaptive devices
• non-speaking methods of communication
• surgery for flexion contractures
• genetic counselling

2. Prognosis

• most reach adulthood
• basic self-care skills are needed throughout adulthood
• severity of seizures tends to decrease with age

ADDITIONAL REFERENCES:

1. J. Med. Gen 29:412 (1992)

2. Angelman Syndrome Support Group of Canada

3. Am. J. of Med. Gen. 35:314 (1990)

INTERNET LINKS:

Angelman Syndrome: A Parent's Guide
Angelman Syndrome Foundation, USA
Angels Among Us

National Institutes of Health, Bethesda, Maryland 20892

Written September 1997

ANGELMAN SYNDROME

• What is Angelman Syndrome?
• Is there any treatment?
• What is the prognosis?
• What research is being done?
• Where can I find more information? (last updated November 19,1998)

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Boyd, S, et al. "The EEG in Early Diagnosis of the Angelman (Happy Puppet) Syndrome." European Journal of Pediatrics, 147; 508-513 (1988).

Clayton-Smith, J. "Clinical Research on Angelman Syndrome in the United Kingdom: Observations on 82 Affected Individuals." American Journal of Medical Genetics, 46; 12-15 (1993).

Robb, S, et al. "The ‘Happy Puppet’ Syndrome of Angelman: Review of the Clinical Features." Archives of Disease in Childhood, 64; 83-86 (1989).

Zori, R, et al. "Angelman Syndrome: Clinical Profile." Journal of Child Neurology, 7; 270-280 (July 1992).

PROFILE A - Z GENETIC CONDITIONS

Reprinted From the AGSA Newsletter with the permission of The Association

of Genetic Support of Australia

ANGELMAN SYNDROME

Angleman Syndrome is a neurological disorder associated with mental delay

and characteristic facial appearance and behaviour. It affects

approximately 1 in 20,000 individuals. In 1965, Dr Harry Angelman, an

English physician, first reported his f1ndings on three children with

similar characteristics now known as Angelman Syndrome.

Angelman Syndrome is most often diagnosed by a paediatric neurologist or

geneticist. It is diff1cult to diagnose a child with Angelman Syndrome

under 12 months of age. Som individuals have not been diagnosed until late

childhood or adulthood.

The main characteristics of Angelman Syndrome include:

* mental retardation

* speech impairment - little or no speech and limited communication skills

* movement or balance disorder - children with Angelman Syndrome usually

have an unsteady, stiff gait with legs wide and arms uplifted. Balance

improves in some individuals with age. Hand tremulousness is also common

* happy, smiling disposition children will laugh easily

* epilepsy

* hyperactivity

* flattened back of the head

* drooling and excessive chewing

* hypopigmented skin - light hair and eye colour

* small widely spaced teeth

* wide mouth, protruding tongue with prominent jaw.

Not all characteristics need to be present to obtain a positive diagnosis

of Angelman Syndrome.

Genetics

Angleman Syndrome is caused by a deleted or missing segment in the proximal

portion of the long arm of chromosome 15. Every person has two number 15

chromosomes, one inherited from each parent. In many children with Angelman

Syndrome an abnormality can be demonstrated by either directly examining

the number 15 chromosome under a microscope or by using molecular

diagnostic methods to examine the chromosomes - DNA. In a small percentage

of individuals two chromosome 15's have been inherited from the father and

none from the mother thus causing Angelman Syndrome.

Hovever in 10-20% of Angelman Syndrome children, no abnormality has yet to

be found on their chromosome 15, but the abnormality may be too small to

identify with present technology. Thus a normal or negative study does not

necessarily mean that a child does not have Angelman Syndrome.

Maternal But Not Paternal Transmission of 15q11-13-Linked Nondeletion Angelman Syndrome Leads to Phenotypic Expression

J. Wagstaff J, J.H. Knoll, K.A. Glatt, Y.Y. Shugart, A. Sommer, M. Lalande

Nature Genetics 1(4), 291--294 (1992 Jul)

Abstract

Angelman syndrome (AS) may result from either maternally inherited deletions of chromosome 15q11-13 or from paternal uniparental disomy for chromosome 15. This is in contrast to Prader-Willi syndrome (PWS), which is caused by either paternal deletion of this region or maternal disomy for chromosome 15. However, 40% of AS patients inherit an apparently intact copy of chromosome 15 from each parent. We now describe a family in which three sisters have given birth to four AS offspring who have no evidence of deletion or paternal disomy. We show that AS in this family is caused by a mutation in 15q11-13 that results in AS when transmitted from mother to child, but no phenotype when transmitted paternally. These results suggest that the loci responsible for AS and PWS, although closely linked, are distinct.