Angelman Syndrome

Angelman Syndrome

Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by the loss of function of the maternally inherited UBE3A gene, a crucial E3-ubiquitin ligase involved in neuronal development. The condition is a classic example of genomic imprinting, where only the maternal copy of the gene is expressed in the brain, while the paternal copy is silenced.

 

Genetics and Diagnosis

The aetiology of Angelman syndrome is primarily genetic, with four main mechanisms leading to the loss of UBE3A function:

  • Maternal 15q11-q13 deletion (70%): The most common cause, involving a deletion of the maternal chromosome 15q11.2-q13 region, which includes the UBE3A gene.

  • Paternal Uniparental Disomy (UPD) (3-7%): The child inherits two copies of chromosome 15 from the father and none from the mother.

  • Imprinting Centre Defect (ICD) (3%): A mutation in the regulatory region that controls the expression of the UBE3A gene.

  • UBE3A gene mutation (10-15%): A point mutation in the maternal UBE3A gene.

Diagnosis is typically confirmed with a blood test. The first-line investigation is a methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) test which detects methylation abnormalities in the 15q11-q13 region and can diagnose deletion, UPD, and ICD cases. Further testing, such as gene sequencing, is required to identify UBE3A mutations if the methylation test is normal.

 

Clinical Features

Clinical suspicion for Angelman syndrome should arise in children with severe developmental delay and a movement disorder. While the antenatal period is often normal, signs and symptoms become apparent from 6-12 months of age.

Key features include:

  • Developmental: Severe global developmental delay is a consistent feature, with walking often delayed until 3-4 years of age. Most individuals will have little or no spoken language.

  • Behavioural: A consistently happy demeanour with frequent smiling, laughter, and an excitable personality. Hand-flapping is common, as is a fascination with water.

  • Neurological:

    • Movement Disorder: This is a hallmark of the syndrome and includes ataxia (uncoordinated, unsteady gait), limb tremor, and hypermotoric behaviour.

    • Seizures: Epilepsy is present in up to 90% of cases, typically starting between 1-3 years of age. Seizures can be difficult to control and may include atypical absence, myoclonic, or atonic seizures.

    • Sleep: Sleep disturbances, including a reduced need for sleep and a fragmented sleep cycle, are very common.

  • Physical:

    • Microcephaly: Disproportionately small head circumference, often apparent by two years of age.

    • Craniofacial features: Can include a wide mouth, prominent chin, and a flat occiput.

    • Ophthalmology: Strabismus is common.

 

Clinical Management and Recent Developments

Management is multidisciplinary and focuses on symptom control to improve quality of life. Paediatric care guidelines in the UK, often informed by international standards, recommend a team approach involving:

  • Physiotherapy and Occupational Therapy: To address gross motor delay and movement disorders.

  • Speech and Language Therapy: With a strong emphasis on augmentative and alternative communication (AAC) strategies, such as sign language, picture cards, and communication devices.

  • Neurology: For seizure management. Pharmacotherapy often requires a combination of anticonvulsants, with sodium valproate and clonazepam being effective, while carbamazepine is often less so.

  • Sleep Medicine: Melatonin and behavioural strategies are often used to manage sleep disturbances.

  • Gastroenterology: To manage feeding difficulties, gastro-oesophageal reflux, and constipation.

Recent Developments in Therapeutics

The last few years have seen significant progress in the development of disease-modifying therapies that target the root cause of Angelman syndrome. These treatments aim to either reactivate the silent paternal UBE3A allele or replace the non-functional maternal gene.

  • Antisense Oligonucleotides (ASOs): This is a leading therapeutic approach. ASOs like GTX-102 and ION582 are designed to bind to and inhibit the UBE3A antisense transcript (UBE3A-ATS), which naturally silences the paternal UBE3A gene in the brain. By unsilencing this paternal copy, the brain can produce functional UBE3A protein. Both GTX-102 and ION582 have recently entered pivotal Phase 3 clinical trials, representing a major step toward a potential cure.

  • Gene Therapy: This involves using a viral vector (e.g., AAV) to deliver a functional copy of the UBE3A gene directly into the central nervous system. Research is ongoing to improve delivery and efficacy, with clinical trials in earlier phases exploring this approach.