Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of function of the maternally inherited copy of the UBE3A gene located on chromosome 15q11-q13. It is classified as Q93.51 in ICD-10-CM.
Along with Prader-Willi syndrome, it is known as a classic example of a genomic imprinting disorder. Genomic imprinting is a phenomenon in which one copy of a gene is silenced by methylation, and only the unmethylated copy is expressed.
The estimated prevalence is 1 in 12,000 to 24,000 people. There is no sex difference, and it is usually diagnosed in early childhood. The actual prevalence may be higher due to undiagnosed cases and underreporting.
Both diseases are caused by abnormalities in the chromosomal region 15q11-q13. AS is caused by loss of function of maternally derived UBE3A, while Prader-Willi syndrome is caused by loss of function of paternally derived genes. Although they are imprinting abnormalities in the same chromosomal region, their clinical features are markedly different.
Most patients with Angelman syndrome have severe intellectual disability, making it difficult for them to report subjective symptoms. The main signs noticed by caregivers are as follows.
Ophthalmic findings are observed in 20–80% of patients.
Common Findings
Strabismus: The most common ophthalmic finding in Angelman syndrome. Primarily horizontal deviation.
Hypopigmentation of the iris: Likely involves the P gene on chromosome 15. Observed as a pale blue iris.
Refractive error: Myopia, hyperopia, and astigmatism are observed. Astigmatism may be more common.
Less common findings
Nystagmus: Often horizontal.
Brushfield spots: White spots on the iris surface.
Optic atrophy: Rarely reported.
Ocular motor dysfunction: Including ocular motor apraxia.
The P gene is located on chromosome 15 and is involved in the production of an important membrane protein of melanosomes. Therefore, patients with a deletion of 15q11-q13 may exhibit hypopigmentation similar to oculocutaneous albinism.
It may be present from birth, but can also develop later in childhood. It presents with varying degrees, from intermittent to constant. Regular ophthalmologic follow-up is important.
Angelman syndrome is caused by loss of function of the maternal copy of the UBE3A gene. UBE3A encodes an E3 ubiquitin ligase enzyme, which plays a key role in protein degradation and synaptic plasticity.
Loss of function occurs through the following four mechanisms.
| Mechanism | Frequency |
|---|---|
| Maternal deletion (de novo deletion) | Approximately 70% |
| UBE3A gene mutation | Approximately 10% |
| Paternal uniparental disomy | Approximately 5% |
| Imprinting defect | Approximately 5% |
Maternal deletion is the most common, accounting for about 70% of cases. It is caused by a de novo deletion of the maternal chromosome 15q11-q13 region.
Paternal uniparental disomy (UPD) occurs when both copies of chromosome 15 are inherited from the father. This leads to the absence of maternal UBE3A, causing the condition.
Imprinting abnormalities disrupt the DNA methylation pattern on the maternal allele, suppressing UBE3A expression.
The diagnosis of Angelman syndrome is based on clinical features, genetic testing, and neuroimaging. Since clinical features overlap with autism spectrum disorder and other conditions, genetic testing is essential for an accurate diagnosis.
The following core features provide diagnostic clues.
MRI or CT may show structural abnormalities in the cerebellum or cerebrum. However, imaging findings are often interpreted as normal.
It is usually diagnosed in early childhood. Developmental delay, epilepsy, and characteristic behavioral patterns are often the triggers. Genetic testing provides a definitive diagnosis.
There is currently no curative treatment for Angelman syndrome. The mainstay of management is multidisciplinary symptomatic treatment and early intervention for neurodevelopmental and behavioral symptoms.
In a review by Chang (2020), surgical outcomes for strabismus in children with cerebral visual impairment reported that 56% were corrected to a horizontal deviation of 10 prism diopters (PD) or less, 28% had an eye position of 11–24 PD, and 16% had poor results with 25 PD or more1). Surgery is recommended in cases with good visual improvement, stable eye position, and controlled neurological comorbidities.
The UBE3A gene encodes an E3 ubiquitin ligase. This enzyme regulates protein degradation via the ubiquitin-proteasome system and plays an important role in maintaining synaptic plasticity.
In brain neurons, the paternal UBE3A is suppressed by imprinting. Therefore, loss of function of the maternal copy means a complete absence of UBE3A protein in neurons.
The pathophysiology caused by loss of UBE3A function is as follows.
The pathophysiological mechanisms of ophthalmic complications are not fully understood. For strabismus, abnormalities in visual system development and impairment of neural circuits involved in eye movement control are presumed. Hypopigmentation is explained by reduced melanin production due to loss of one allele of the P gene (OCA2 gene) included in the 15q11-q13 deletion.
Research is progressing on gene therapy to deliver a functional copy of UBE3A to affected neurons. Approaches using adeno-associated virus (AAV) vectors are being studied in animal models.
Paternal UBE3A is normally suppressed in the brain by antisense RNA transcription. ASO therapy aims to degrade this antisense RNA and restore expression of paternal UBE3A. Clinical trials are ongoing.
Research is underway to identify drugs that enhance synaptic plasticity or modulate downstream targets of the UBE3A signaling pathway.
