Angelman Syndrome

Angelman syndrome is a neurogenetic disorder due to loss of maternally inherited UBE3A function in the 15q11.2-q13 imprinted region, where UBE3A is expressed only from the maternal allele in neurons. Incidence is about 1 in 12,000 to 20,000. Mechanisms: maternal deletion 15q11-q13 (about 70%; the most severe phenotype), UBE3A pathogenic variants on the maternal allele (about 10 to 15%), paternal uniparental disomy 15 (about 3 to 7%), and imprinting defects (about 3%). About 10% have no identified molecular cause.

• Severe developmental delay evident by 6 to 12 months, and profound speech impairment (few or no words)
• Characteristic happy demeanour with frequent laughter, smiling, hand flapping and easy excitability
• Ataxia and a stiff, jerky gait with wide based stance, tremulousness
• Microcephaly (acquired by 2 years; in about 80%), wide mouth with widely spaced teeth, prognathism, tongue thrusting, and drooling
• Seizures (80 to 90%), onset usually before 3 years, including atypical absences, myoclonic, atonic and tonic clonic seizures, and non-convulsive status epilepticus; EEG shows high amplitude slow wave activity (delta), notched delta and rhythmic spike-and-wave patterns
• Sleep disturbance (reduced need for sleep, frequent waking), hypopigmentation (in deletion cases), strabismus, scoliosis, constipation, reflux, and obesity in older children
• Heat sensitivity and fascination with water

1. DNA methylation analysis of 15q11-q13 (SNRPN): detects deletion, UPD and imprinting defects (about 80%).
2. Chromosomal microarray, or UPD and imprinting centre studies as follow up.
3. UBE3A sequencing if methylation is normal and the clinical picture is typical (about 10 to 15%).
4. EEG, and MRI to exclude other causes (usually normal or mild delayed myelination).

There is no cure. Care is supportive and multidisciplinary.

• Seizures: valproate (20 to 40 mg/kg/day in divided doses), levetiracetam (20 to 60 mg/kg/day), lamotrigine (with slow titration to avoid rash), clobazam, topiramate, or ethosuximide for absence type seizures. Avoid carbamazepine, oxcarbazepine, phenytoin, tiagabine and vigabatrin, which can worsen seizures. A ketogenic diet is an option for refractory epilepsy. Rescue treatment: buccal midazolam 0.3 mg/kg.
• Sleep: sleep hygiene, melatonin 1 to 10 mg at night, and in refractory cases trazodone or clonidine.
• Communication: augmentative and alternative communication devices, sign language and picture systems, early speech and language therapy.
• Motor: physiotherapy, ankle foot orthoses, treatment of scoliosis (bracing or surgery), and occupational therapy.
• Gastrointestinal: constipation (polyethylene glycol 3350 0.4 to 0.8 g/kg/day) and reflux (proton pump inhibitors).
• Feeding and weight: dietitian input, especially in UPD and imprinting cases where obesity occurs.
• Behaviour and education: structured programmes, behavioural support.
• Genetic counselling: recurrence risk depends on mechanism (below 1% for sporadic deletion, up to 50% for UBE3A variants in a mother carrying a pathogenic variant, and up to 50% for imprinting centre deletions).
• Investigational: antisense oligonucleotides that unsilence paternal UBE3A (gtx-102, ION582) are in phase 3 trials.