This is a congenital chromosome disorder first described in 1965 by Harry Angelman (1915-1996), an English physician. A few cases were also described in the USA in the 1980s but the rarity of the condition provoked queries as to its existence for several years.

Bower and Jeavons coined the term ' happy puppet', although this may now be seen as derogatory by many.

Genetics

There are several mechanisms of genetic disruption in Angelman's syndrome:

• Fluorescence in situ hybridisation (FISH) has shown a small deleted area on chromosome 15. This could contain several genes and is found in 70% of cases.¹
• It is inherited from the mother. Similar genetic changes on the chromosome 15 of paternal origin produce Prader-Willi syndrome.²
• Whether the deletion is active depends on the origin of the chromosome. This is known as genetic imprinting.
• A gene located in the Angelman's syndrome region is called UBE3A.³ This is found to have mutated in 50% of cases. It codes for a protein called ubiquitin protein ligase. This is believed to be the causative gene.
• Another cause is uniparental disomy (UPD) which occurs in 2-3%. This is where both copies of chromosome 15 are from the father. Therefore the child still has no active UBE3A gene.
• The cause is unknown in approximately 15% of cases.
• Chromosome deletion is spontaneous in 70-75 % of cases. It is associated with a greater level of disability in the phenotype.⁴ In these cases recurrence is extremely rare - less than 1%.
• Depending on the causative genetic mechanism for the first child, recurrence risk is predictable by a genetic specialist with particular knowledge of Angelman's syndrome.

Epidemiology

Prevalence

• Approximately 1 in 25,000.
• Diagnosis is commonly made at age 3-7 years, when the clinical features and behaviours become apparent.

Since 2002, a series of reports have suggested an increased risk of imprinting disorders such as Beckwith-Wiedemann syndrome and Angelman's syndrome, in children conceived by assisted reproduction techniques (ARTs). Based on current evidence, the absolute risk of imprinting disorders after ART remains small and does not warrant routine screening.⁵

Presentation

Symptoms

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

Consensus criteria for clinical features⁶

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.
  • Disorders of movement and balance with ataxia, and tremulous movement of limbs.
  • 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.
• Communication:
  • Speech impairment with no or minimal use of words.
  • Receptive and nonverbal communication skills are better.
  • Even in the highest functioning cases conversation does not develop.
  • Cases caused by uniparental disomy (UPD) are clinically less severe, with a vocabulary of up to 30 words reported.
• Behaviour:
  • 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 - impairs social interaction.
  • There is a tendency to pinch, grab and bite in older children.

Frequent features

• Growth:
  • 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:
  • Epilepsy predominates in childhood but may persist or reappear in adulthood.⁷
  • 90% have seizures, most with onset by 3 years of age.
  • Many different seizure types may occur - atypical absences and myoclonic seizures being particularly prevalent.
  • The electroencephalography (EEG) shows high amplitude, bilateral spike and wave activity, which is symmetrical, synchronous and mono-rhythmic, having a slow wave component at 2 cycles per second.
  • Angelman's syndrome patients with a deletion of chromosome 15q11-13 have more prominent EEG abnormalities than patients with other genetic disturbances of the chromosome 15 region.⁸ There is no difference in EEG findings in Angelman's syndrome patients with or without epileptic seizures.
• Sleep:
  • Disrupted sleep patterns include sleep initiation, sleep duration, being awakened by loud noises and being disoriented when roused.⁹
  • Reduced rapid eye movement (REM) sleep and periodic leg movements may also be seen.¹⁰
  • 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

• Motor:
  • 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).
• Phenotype:
  • 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.
• Behaviour:
  • Frequent drooling.
  • Excess chewing/mouthing.
  • Increased sensitivity to heat, and fascination with water.¹¹

Differential diagnosis

• There are several characteristics shared with autism. Many are given a secondary diagnosis of autism. However, children with Angelman's syndrome tend to be highly sociable in contrast to typical autistic peers.
• There is significant overlap with Rett's syndrome.¹²
• Swallowing and feeding problems may lead cases to present as failure to thrive, milk intolerance or gastro-oesophageal reflux.

Investigations

• 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.

Management

General

Suggested interventions include:

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

Education

The most common preschool education programme used is 'Portage'.¹³ 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.

Pharmacological

• The region of chromosome 15 which is affected contains several genes that code for gamma-aminobutyric acid type A (GABA-A) receptor subunits.
• GABA-A is the most common GABA receptor in the brain.
• In Angelman's syndrome it is thought that the lack of GABA-A influence increases the excitability of the central nervous syndrome.
• This creates the muscle-twitching activity seen in cases. This can be significantly reduced with piracetam.¹⁴
• Anticonvulsant medication tends to be with valproate, topiramate, carbamazepine, clonazepam and ethosuximide rather than phenytoin, phenobarbital or adrenocorticotropic hormone (ACTH).
• Multiple medications are common and there is a risk of over-medication because of the tendency to abnormal twitching movements.
• Sleep patterns may be helped by melatonin 0.3 mg, 1 hour before bedtime.

Prognosis

They have good general health and a normal lifespan.

• Clinical features alter with age:
  • As adults there is improvement in sleep patterns and hyperactivity.
  • Fit frequency also diminishes and may stop.¹⁵
  • Females can tend to become obese.
• There is normal sexual development.
• None has lived independently to date. A recent report from Australia highlighted the level of medical care often needed by individuals with Angelman's syndrome, especially those with epilepsy.¹⁶

Document references

1. Jiang Y et al; The Genetics of Angelman Syndrome. Am J Hum Genet. 1999 July; 65(1): 1–6
2. Scheimann A; Prader-Willi syndrome, eMedicine, Jul 2009
3. Angelman Syndrome, Online Mendelian Inheritance in Man (OMIM)
4. Williams CA; Neurological aspects of the Angelman syndrome. Brain Dev. 2005 Mar;27(2):88-94. [abstract]
5. Owen CM, Segars JH Jr; Imprinting disorders and assisted reproductive technology. Semin Reprod Med. 2009 Sep;27(5):417-28. Epub 2009 Aug 26. [abstract]
6. Williams CA, Beaudet AL, Clayton-Smith J, et al; Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet A. 2006 Mar 1;140(5):413-8. [abstract]
7. Pelc K, Boyd SG, Cheron G, et al; Epilepsy in Angelman syndrome. Seizure. 2008 Apr;17(3):211-7. Epub 2007 Sep 29. [abstract]
8. Laan LA, Vein AA; Angelman syndrome: is there a characteristic EEG? Brain Dev. 2005 Mar;27(2):80-7. [abstract]
9. Walz NC, Beebe D, Byars K; Sleep in individuals with Angelman syndrome: parent perceptions of patterns and problems. Am J Ment Retard. 2005 Jul;110(4):243-52. [abstract]
10. Pelc K, Cheron G, Boyd SG, et al; Are there distinctive sleep problems in Angelman syndrome? Sleep Med. 2007 Aug 30. [abstract]
11. Didden R, Korzilius H, Sturmey P, et al; Preference for water-related items in Angelman syndrome, Down syndrome and non-specific intellectual disability. J Intellect Dev Disabil. 2008 Mar;33(1):59-64. [abstract]
12. Jedele KB; The overlapping spectrum of rett and angelman syndromes: a clinical review. Semin Pediatr Neurol. 2007 Sep;14(3):108-17. [abstract]
13. National Portage Association; Home page
14. Guerrini R, Carrozzo R, Rinaldi R, et al; Angelman syndrome: etiology, clinical features, diagnosis, and management of Paediatr Drugs. 2003;5(10):647-61. [abstract]
15. Valente KD, Koiffmann CP, Fridman C, et al; Epilepsy in patients with angelman syndrome caused by deletion of the chromosome 15q11-13. Arch Neurol. 2006 Jan;63(1):122-8. [abstract]
16. Thomson AK, Glasson EJ, Bittles AH; A long-term population-based clinical and morbidity profile of Angelman syndrome in Western Australia: 1953-2003. Disabil Rehabil. 2006 Mar 15;28(5):299-305. [abstract]

Acknowledgements