Angelman Syndrome

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 80s 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 be seen as derogatory by many.

There are several mechanisms of genetic disruption in Angelman syndrome (AS):

• FISH (Fluorescence In Situ Hybridization) 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 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 causative genetic mechanism for first child, recurrence risk is predictable by genetic specialist with particular knowledge of Angelman syndrome.

Prevalence

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

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.

Consistent (100%)

Frequent (80% or more)

Associated (20-80%)

• There are several characteristics shared with autism, and many are given a secondary diagnosis of autism. However, children with Angelman syndrome tend to be highly sociable in contrast to typical autistic peers.
• There is significant overlap with Rett syndrome.¹¹
• Swallowing and feeding problems may lead cases to present as failure to thrive, milk intolerance or gastro-oesophageal reflux.

• The brain is structurally normal on CT or MRI. However, if there is any abnormality it is usually mild cortical atrophy and/or mildly decreased myelination.
• In presence of normal chemical, haematological, metabolic tests and normal brain imaging, high resolution chromosome analysis, including material from both parents is undertaken.
• FISH is able to detect 80-85% of all deletions.
• DNA methylation testing increases pick up rate.

General

Suggested interventions include:

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

Education

The most common pre-school education programme used is PORTAGE.¹² 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 that is affected contains several genes that code for GABA-A receptor subunits.
• GABA-A is the most common GABA receptor in the brain.
• In Angelman syndrome it is thought that the lack of GABA-A influence increases the excitability of the CNS.
• This creates the muscle-twitching activity seen in cases. This can be significantly reduced with piracetam.¹³
• Anti-convulsant medication tends to be with valproate, topiramate, carbamazepine, clonazepam and ethosuximide rather than phenytoin, phenobarbitone or 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.

They have good general health and a normal life-span.

• Clinical features alter with age:
  • As adults there is improvement in sleep patterns and hyperactivity.
  • Fit frequency also diminishes and may stop.¹⁴
  • Females can tend to become obese.
• There is normal sexual development.
• None have lived independently to-date. A recent report from Australia highlighted the level of medical care often needed by individuals with AS, especially those with epilepsy.¹⁵