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.
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- National Portage Association
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