Skip to main content
Public beta This website is in public beta – please give your feedback.
Conditions

Angelman syndrome

Angelman syndrome is a genetic disorder that affects the nervous system. It is characterised by developmental delay, intellectual disability, severe speech impairment and ataxia.

Overview

Angelman syndrome is a genetic condition characterised by significant learning disabilities, seizures (with a characteristic EEG pattern), ataxic gait and a happy and excitable demeanour.

Clinical features

The main clinical features of Angelman syndrome are listed below.

  • Neonate and infant:
    • hypotonia manifesting as floppiness;
    • feeding problems in infancy due to poor sucking and/or swallowing; and
    • a normal head circumference at birth.
  • Childhood:
    • significant intellectual disability;
    • severe speech and language impairment;
    • progressive microcephaly;
    • seizures, usually starting before the age of three and often associated with characteristic low-amplitude slow-spike waves;
    • movement and balance problems manifesting with a broad-based gait (ataxia) and/or tremulous limbs;
    • unique behaviour, with sudden outbursts of laughter, an apparently happy demeanour, excitability, hand flapping and tongue protrusion; and
    • gastro-oesophageal reflux disease and constipation.
  • Facial features:
    • Many children with Angelman syndrome have recognisable facial features, including a wide mouth, widely spaced teeth, prognathia and hypopigmented skin and hair.

Genetics

Angelman syndrome is caused by the disruption of the maternal copy of the E3 ubiquitin ligase gene (UBE3A). UBE3A is located at chromosome 15q11.2-q13, the same region that can cause Prader-Willi syndrome. Disruption or loss of the maternal copy of UBE3A occurs through one of the following mechanisms:

  • abnormal methylation at 15q11.2 due to:
    • deletion of the maternal 15q11.2 region (65%–75% of cases);
    • uniparental disomy (UPD) of the paternal chromosome 15, where both copies of chromosome 15 are paternally inherited (3%–7% of cases); or
    • a 15q11.2 imprinting centre anomaly (3% of cases); or
  • a pathogenic variant in the maternal copy of UBE3A (11% of cases).

Chromosome microarray is often the first line of investigation for an intellectual disability and will detect those patients with a maternal chromosome 15q11.2 deletion. Methylation studies (MS-MLPA) will detect the 15q11.2 deletion, UPD and imprinting anomalies. If, after these investigations, there remains a high clinical suspicion of Angelman syndrome, UBE3A variant testing should be undertaken. Although these investigations identify about 80% of people with Angelman syndrome, about 20% remain without a genetic diagnosis.

For information about testing, see Presentation: Child with developmental delay or intellectual disability.

Inheritance and genomic counselling

The heritability of Angelman syndrome can be complex and depends upon the underlying genetic mechanism, as demonstrated in the table below.

Table 1: Genetics and recurrence risk of Angelman syndrome

Genetic mechanism Risk to siblings (recurrence risk), assuming parents are unaffected Comments
Maternal 15q11.2 deletion Less than 1% This is the constitutional (germline) mosaicism risk related to the deletion (residual risk that the deletion is present in some of the germline and undetectable through parental blood testing).
Paternal UPD 15 Less than 1% Note that this particular probability approaches 100% in the very rare situation in which a father has a 15;15 Robertsonian translocation, predisposing to the development of paternal UPD 15.
15q11.2 imprinting centre Less than 1% Note that this probability increases to 50% if the imprinting centre anomaly is caused by a maternally inherited deletion of the imprinting centre.
UBE3A mutation Up to 50% This is the probability if the mother also has the UBE3A mutation.

Management

Management of children with Angelman syndrome is complex and should be delivered via a multidisciplinary team; detailed suggested approaches have been published by several authors (see the resources list below).

Resources

For clinicians

References:

For patients

↑ Back to top
  • Last reviewed: 25/04/2023
  • Next review due: 25/04/2025
  • Authors: Dr Hassan Shakeel
  • Reviewers: Dr Ellie Hay, Professor Kate Tatton-Brown