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This is a rare genetic disorder first described in 1965 by Harry Angelman (1915-1996), an English physician. The behavioural features of Angelman's syndrome (AS) include a happy demeanour, easily provoked laughter, short attention span, hypermotoric behaviour, mouthing of objects, sleep disturbance and an affinity for water.

  • AS is caused by a lack of expression of the maternally inherited UBE3A gene in the brain.
  • This can be due to:[1]
    • Deletion of the AS critical region on maternal chromosome 15q11-q13 (the most common type).
    • Paternal uniparental disomy (UPD) for chromosome 15.
    • An imprinting defect causing lack of expression of the maternal copy of UBE3A.
    • Mutations in the maternally inherited copy of UBE3A.
  • UBE3A is one of a small subset of human genes that are imprinted. This means that it is expressed, depending on parent of origin, in a tissue-specific manner.[2]
  • In the brain, the paternally derived UBE3A gene is silenced, and only the maternally inherited copy is active.
  • However, there is a subgroup of patients with a clinical diagnosis of AS for whom no abnormality of UBE3A can be identified.[1]
  • In most cases the recurrence is extremely rare - less than 1%.
  • However, some deletions are familial and carry a 50% risk of recurrence.
  • When the UBE3A mutations are inherited from the mother's paternally acquired allele then the recurrence risk is also 50%.[3]


  • Its prevalence ranges from 1:10,000 to 1:40,000.[4]
  • Diagnosis is commonly made at age 3-7 years, when the clinical features and behaviours become apparent.


  • The prenatal course and birth are normal.
  • There is normal head circumference at birth and there are no major birth defects.
  • Developmental delay is apparent by 6 months.
  • There is forward progression with no loss of skills once acquired.

Consistent features

Motor signs

  • Functionally severe developmental delay.
  • Gross motor milestones are delayed:
    • Sitting occurs by 12 months; walking at 3-4 years.
    • 10% fail to walk.
  • Legs are wide-spaced and feet are flat and turned out.
  • There are disorders of movement and balance with ataxia, and tremulous movement of limbs.
  • There is jitteriness from 6 months with irregular, coarse movements that prevent walking, feeding and reaching for objects.
  • There may be toe-walking or a mild prancing gait.
  • They tend to lean forward or lurch when they run.


  • There is speech impairment with no or minimal use of words.
  • Receptive and non-verbal communication skills are better.
  • Even in the highest-functioning cases conversation does not develop.
  • Cases caused by UPD are clinically less severe, with a vocabulary of up to 30 words reported.


  • There are unique behaviours - a combination of laughter and smiling, an apparent happy demeanour and excitable personality.
  • Laughter is an expressive motor event and most stimuli will produce it.
  • Hand-flapping is common, as is hyper-motor behaviour and short attention span, impairing social interaction.
  • There is a tendency to pinch, grab and bite in older children.

Frequent features


  • Delayed disproportionate head circumference growth.
  • Absolute or relative microcephaly by age 2 years; 34-88% have absolute as defined as within the lowest 2.5% centile.


  • Epilepsy occurs in around 90% of cases and may present with multiple seizure types, including non-convulsive status epilepticus.[6]
  • Seizures are often intractable and typically require broad-spectrum antiepileptic medications.
  • The electroencephalography (EEG) shows high amplitude, bilateral spike and wave activity, which is symmetrical, synchronous and monorhythmic, having a slow wave component at two cycles per second.


  • Sleep disorders are also common, often characterised by abnormal sleep-wake cycles.[6]
  • The sleep disorders may be related to abnormal serum melatonin profiles.[7]
  • Poor sleep does not significantly interfere with daytime alertness.
  • Sleep problems commonly diminish by late childhood, with continuing improvement through adolescence and adulthood.

Associated features


  • Strabismus is present in 30-60%.
  • Increased tendon reflexes.
  • Uplifted, flexed arms when walking.
  • Tongue thrusting and swallowing problems (leading to feeding problems in infancy).
  • Movement disorders are nearly universal in those with AS, most frequently presenting with ataxia and tremor.[6]


  • Hypopigmentation of the eyes and skin, typically in deletion-caused cases - sun-sensitive.
  • Prominent mandible with a wide mouth and wide-spaced teeth.
  • Flat occiput.


  • Frequent drooling.
  • Excess chewing/mouthing.
  • Increased sensitivity to heat, and fascination with water.
  • The brain is structurally normal on CT or MRI scan. However, if there is any abnormality it is usually mild cortical atrophy and/or mildly decreased myelination.
  • In the presence of normal chemical, haematological, metabolic tests and normal brain imaging, high-resolution chromosome analysis, including material from both parents, is undertaken.
  • Fluorescence in situ hybridisation (FISH) is able to detect 80-85% of all deletions.
  • DNA methylation testing increases pick-up rate.


Suggested interventions include:

  • Behaviour modification programmes
  • Speech therapy
  • Occupational therapy
  • Physiotherapy
  • Parental training

Behavioral treatment may be a reasonable way to address sleep problems in some children with AS.[8]

Parents of children with AS have an increased risk of high levels of stress and mental health problems.[9]These need to be addressed and managed appropriately.


The most common preschool education programme used is 'Portage'.[10] This provides particular help with language, socialisation, self-help skills and cognitive and motor skills in a step-wise fashion at home.

A statement of special educational need will be required for specialist provision after 5 years.


  • It is common that a combination of treatment with anticonvulsants is needed to control seizures.[1]
  • Sodium valproate and clonazepam are the most effective medications and carbamazepine is one of the least effective.[6]
  • Sleep patterns may be helped by melatonin.

They have good general health and a normal lifespan.

  • Clinical features alter with age:
    • As adults there is improvement in sleep patterns and hyperactivity.
    • Frequency of seizures also diminishes and may stop.
    • Females can tend to become obese.
  • There is normal sexual development.

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Further reading and references

  1. Bird LM; Angelman syndrome: review of clinical and molecular aspects. Appl Clin Genet. 2014 May 167:93-104. doi: 10.2147/TACG.S57386. eCollection 2014.

  2. Chamberlain SJ; RNAs of the human chromosome 15q11-q13 imprinted region. Wiley Interdiscip Rev RNA. 2013 Mar-Apr4(2):155-66. doi: 10.1002/wrna.1150. Epub 2012 Dec 3.

  3. Van Buggenhout G, Fryns JP; Angelman syndrome (AS, MIM 105830). Eur J Hum Genet. 2009 Nov17(11):1367-73. doi: 10.1038/ejhg.2009.67. Epub 2009 May 20.

  4. Leyser M, Penna PS, de Almeida AC, et al; Revisiting epilepsy and the electroencephalogram patterns in Angelman syndrome. Neurol Sci. 2014 May35(5):701-5. doi: 10.1007/s10072-013-1586-3. Epub 2014 Jan 7.

  5. Williams CA, Beaudet AL, Clayton-Smith J, et al; Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet A. 2006 Mar 1140(5):413-8.

  6. Thibert RL, Larson AM, Hsieh DT, et al; Neurologic manifestations of Angelman syndrome. Pediatr Neurol. 2013 Apr48(4):271-9. doi: 10.1016/j.pediatrneurol.2012.09.015.

  7. Takaesu Y, Komada Y, Inoue Y; Melatonin profile and its relation to circadian rhythm sleep disorders in Angelman syndrome patients. Sleep Med. 2012 Oct13(9):1164-70. doi: 10.1016/j.sleep.2012.06.015. Epub 2012 Jul 28.

  8. Allen KD, Kuhn BR, DeHaai KA, et al; Evaluation of a behavioral treatment package to reduce sleep problems in children with Angelman Syndrome. Res Dev Disabil. 2013 Jan34(1):676-86. doi: 10.1016/j.ridd.2012.10.001. Epub 2012 Nov 1.

  9. Griffith GM, Hastings RP, Oliver C, et al; Psychological well-being in parents of children with Angelman, Cornelia de Lange and Cri du Chat syndromes. J Intellect Disabil Res. 2011 Apr55(4):397-410. doi: 10.1111/j.1365-2788.2011.01386.x. Epub 2011 Feb 15.

  10. National Portage Association