Angelman Syndrome affects approximately 1 in 12,000 to 20,000 live births globally. While the condition occurs across all ethnicities and affects males and females with equal frequency, its prevalence may be underestimated due to misdiagnoses, often being mistaken for other neurodevelopmental disorders such as autism spectrum disorder, cerebral palsy, and Prader-Willi syndrome. Most cases are sporadic, meaning they occur without a family history of the disorder. Because of its rarity and complex genetic origins, many cases may go undiagnosed or initially misdiagnosed. 

AS results from a lack of functional UBE3A protein in the brain. The maternal copy of the UBE3A gene, located on chromosome 15q11-q13, is usually active in certain brain regions, while the paternal copy remains silenced due to genomic imprinting. AS can be caused by one of 4 different molecular mechanisms that cause disruptions to the maternal UBE3A gene: deletions (~75% of cases), mutations (10-20% of cases), uniparental disomy (inheritance of two paternal chromosomes 15, 3-5% of cases), or imprinting defects (3-5% of cases). The UBE3A gene provides instructions for making a protein called ubiquitin protein ligase E3A, which plays a crucial role in protein breakdown at the junctions between nerve cells (synapses). When the gene is not functioning properly, it disrupts the normal function of synaptic connections in the brain, leading to the characteristic neurological and developmental features of the syndrome. There is ongoing research into the mechanisms and how it relates to the development of AS and other neurodevelopmental disorders. 

Angelman Syndrome presents with a wide range of neurological and developmental symptoms:

• Developmental Delays: Evident by 6-12 months, delays in reaching milestones such as sitting, crawling, or walking.

• Speech Impairments: Minimal to absent verbal communication, with stronger receptive language abilities than expressive ones.

• Motor and Balance Issues: Ataxia (movement coordination problems), tremors, and a stiff or jerky gait.

• Behavioral Features: Frequent laughter, smiling, hyperactivity, short attention span, and an easily excited emotional state. 

• Other Symptoms: Seizures (beginning between 1-3 years of age) occur in >80% of individuals, microcephaly (small head size), distinctive facial features, sleep disturbances, and feeding difficulties in infancy.

AS is diagnosed through a combination of clinical evaluation and genetic testing. Early recognition enables access to therapeutic interventions that can improve developmental outcomes.

Diagnostic Tests

• Clinical Assessment: Based on developmental history, physical and behavioral characteristics.

• Genetic Testing:

  • Methylation Test: Detects imprinting defects and maternal deletions.

  • Gene Sequencing: Identifies point mutations in the UBE3A gene, if negative then likely not AS, but a similar disorder. 

  • Fluorescent in situ hybridization (FISH) or Comparative genomic hybridization (CGH): Detects deletions on chromosome 15.

  • DNA Marker Analysis: Identifies inheritance of two paternal chromosome 15 copies to determine if the cause is uniparental disomy. 

Although there is no cure for AS, treatment focuses on symptom management and enhancing quality of life through a multidisciplinary approach:

• Behavioral and Educational Therapies: Individualized developmental programs, including speech, physical, and occupational therapy, help improve motor skills, communication, and social interactions.

• Assistive Devices: Augmentative and alternative communication (AAC) tools to support nonverbal individuals in expressing themselves.

• Medications for seizure management: Anticonvulsant medications to control epilepsy, regular neurological monitoring, and individualized seizure treatment plans. 

• Supportive Care: Nutritional support for feeding difficulties, sleep management strategies, and interventions to address mobility challenges.

Although individuals with AS face significant developmental challenges, they generally have normal life expectancy. Many symptoms such as sleep disturbances and seizures tend to become less severe or less frequent as individuals get older. Individuals with AS will require lifelong care but with comprehensive care and early interventions, many can achieve improved functional outcomes and enjoy a good quality of life.

There are promising developments in gene therapy, protein reactivation, and other therapeutics. For more information, please visit the Angelman Syndrome Foundation: https://www.angelman.org/for-parents/angelman-therapies/.

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