What is Angelman syndrome?

What is Angelman Syndrome

Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder caused by loss of function of the maternally inherited UBE3A gene on chromosome 15q11.2-q13, characterized by severe intellectual disability, absent speech, ataxia, seizures, microcephaly, and a distinctive happy demeanor with inappropriate laughter. 1, 2

Genetic Mechanisms

AS results from four distinct molecular mechanisms affecting the maternal chromosome 15:

• Maternal deletion of 15q11-q13 (approximately 70% of cases) - This is the most common mechanism and typically produces the most severe phenotype, likely due to co-deletion of GABA receptor genes 3, 2
• Paternal uniparental disomy (3-5% of cases) - The child inherits both copies of chromosome 15 from the father and none from the mother 3
• Imprinting defects (approximately 8% of remaining cases) - An abnormality in the genomic imprinting process prevents expression of the maternal UBE3A gene 3
• UBE3A gene mutations (10-15% of cases) - Direct mutations in the maternal UBE3A gene itself 2, 4
• Unknown mechanisms (15-20% of cases) - Some patients with clinical AS do not demonstrate any identifiable genetic abnormality with standard testing 3

Clinical Features

The cardinal features that define AS include:

• Severe developmental delay and intellectual disability - Cognitive developmental quotient averages around 40.5, with cognitive skills relatively stronger than language and motor abilities 5
• Profound speech impairment - Expressive language is more severely affected than receptive language, with most individuals remaining nonverbal 2, 5
• Movement and balance disorder (ataxia) - Affects nearly all ambulatory individuals, with characteristic gait abnormalities including crouched posture and tremor 2, 6
• Characteristic behavior - Easily excitable personality with inappropriately happy affect and paroxysms of laughter 2, 4

Additional common features include:

• Microcephaly - Small head circumference, particularly pronounced in deletion patients 2, 4
• Seizures and EEG abnormalities - Seizure activity varies by genotype, being most severe in deletion patients 2, 4
• Hypopigmentation - More common in deletion cases 4
• Sleep disturbances and hyperactivity 2
• Tongue protrusion 2

Genotype-Phenotype Correlations

The severity of AS manifestations correlates strongly with the underlying genetic mechanism:

• Deletion patients are most severely affected - They exhibit the most pronounced microcephaly, highest seizure frequency, lowest body mass index, and most severe developmental delays 5, 4
• UPD and imprinting defect patients are least severely affected - These two groups are clinically indistinguishable from each other and have milder phenotypes across all domains 4
• UBE3A mutation patients have intermediate severity 4
• Non-deletion patients (UPD, imprinting defects, UBE3A mutations) have better developmental outcomes - They demonstrate stronger motor and language skills compared to deletion patients 5

Diagnostic Approach

Methylation analysis should be the first-line diagnostic test, as it detects approximately 99% of cases regardless of genetic mechanism 7:

• If only paternal methylation pattern is present, AS is confirmed 3
• If biparental inheritance is identified, most identifiable causes of AS are ruled out 3
• Following positive methylation analysis, FISH and PCR studies determine whether the cause is deletion, UPD, or imprinting mutation for genetic counseling purposes 3

Clinical diagnosis in infants and young children can be challenging - Genetic testing is essential for verification, particularly in the first few years of life when clinical features may not be fully manifest 3, 2

If standard testing is negative but clinical suspicion remains high, referral to a clinician experienced in AS is indicated - Approximately 15-20% of cases do not demonstrate abnormal methylation patterns and require specialized molecular investigation 3

Important Clinical Considerations

The frequency of AS in newborns is estimated at approximately 1 in 12,000 to 20,000 individuals 2, 8

Recurrence risk varies by genetic mechanism:

• Deletion and UPD cases have low recurrence risk (approximately 1%) 7
• Imprinting mutations can have up to 50% recurrence risk 7
• UBE3A mutations carry significant familial recurrence risk 2

Current treatment is symptom-based only - Management focuses on controlling seizures, addressing feeding difficulties, and providing developmental support, as no curative therapies currently exist 2

AS is distinct from Prader-Willi syndrome despite sharing the same chromosomal region - PWS results from loss of paternally inherited genes in 15q11-q13, while AS results from loss of maternally inherited genes, producing completely different clinical phenotypes 3, 1