Angelman's syndrome

What is Angelman's syndrome?¹

This is a rare genetic disorder first described in 1965 by Harry Angelman (1915-1996), an English physician.

Angelman syndrome is a neurodevelopmental disorder characterised by severe cognitive disability, motor dysfunction, speech impairment, hyperactivity, and frequent seizures.

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.

Genetics

Angelman syndrome is caused by disruption of the maternally expressed and paternally imprinted UBE3A, which encodes an E3 ubiquitin ligase. Four mechanisms that render the maternally inherited UBE3A non-functional are recognised:^{1 2}

• 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.³ 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.²

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%.⁴

Prevalence

• Its prevalence ranges from 1:12,000.⁵

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

Angelman's syndrome symptoms (presentation)⁶

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.

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.

Communication

• 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.

Behaviour

• 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

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.

Epilepsy⁷

Epilepsy occurs in around 90% of cases and may present with multiple seizure types, including non-convulsive status epilepticus.⁸

• The onset of epilepsy is most prevalent between 1 and 3 years of age. However, approximately 25% of patients develop epilepsy before one year of age.

• Various types of generalized seizures are most prevalent, with most common types are myoclonic and atypical absence.

• More than 95% of epilepsy patients may have daily seizures at least for a limited time during early childhood, and two-third patients develop disabling seizures. Fever provoked seizures, and frequent occurrence of nonconvulsive status epilepticus are two unique features.

• Seizures are frequently pharmacoresistant.
  

Sleep

• Sleep disorders are also common, often characterised by abnormal sleep-wake cycles.⁸

• The sleep disorders may be related to abnormal serum melatonin profiles.⁹

• 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).

• Movement disorders are nearly universal in those with AS, most frequently presenting with ataxia and tremor.⁸

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.

Differential diagnosis

• 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.

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.

Angelman's syndrome treatment and management

General

Suggested interventions include:

• Behaviour modification programmes.

• Speech therapy.

• Occupational therapy.

• Physiotherapy.

• Parental training.

Behavioural treatment may be a reasonable way to address sleep problems in some children with AS.¹⁰

Parents of children with AS have an increased risk of high levels of stress and mental health problems.¹¹ These need to be addressed and managed appropriately.

Education

The most common preschool 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

• It is common that a combination of treatment with anticonvulsants is needed to control seizures.²

• Sodium valproate and clonazepam are the most effective medications and carbamazepine is one of the least effective.⁸

• Sleep patterns may be helped by melatonin.

Prognosis

There is very variable severity from severe morbidity and early mortality to less severe clinical features and a much better prognosis. One study of adults with Angelman's syndrome (mean age 24 years, with range 16-50 years found:¹³

• Active seizures present in 41%.

• 72% had sleep dysfunction.

• Significant constipation was present in 85%.

• 32% were overweight or obese, with obesity disproportionately affecting women.

• Scoliosis affected 50% with a mean age at diagnosis of 12 years, and 24% of those diagnosed with scoliosis required surgery, an intervention disproportionately affecting men.

• 68% were able to walk independently.

• 13% were able to speak 5 or more words.

• Self-injury behaviour was exhibited in 52%.