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:
- 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.
- 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.
- 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%.
- Its prevalence ranges from 1:10,000 to 1:40,000.
- 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.
Consensus criteria for clinical features
- 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.
- 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.
- 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.
- The sleep disorders may be related to abnormal serum melatonin profiles.
- Poor sleep does not significantly interfere with daytime alertness.
- Sleep problems commonly diminish by late childhood, with continuing improvement through adolescence and adulthood.
- 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.
- 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.
- There are several characteristics shared with autism. Many are given a secondary diagnosis of autism. However, children with AS tend to be highly sociable in contrast to typical autistic peers.
- There is significant overlap with Rett’s syndrome.
- Swallowing and feeding problems may lead cases to present with failure to thrive, lactose intolerance or gastro-oesophageal reflux.
- 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
- Parental training
Behavioral treatment may be a reasonable way to address sleep problems in some children with AS.
Parents of children with AS have an increased risk of high levels of stress and mental health problems.]These need to be addressed and managed appropriately.
The most common preschool education programme used is ‘Portage’. 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.
- Sodium valproate and clonazepam are the most effective medications and carbamazepine is one of the least effective.
- 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.