Angelman Syndrome is a rare neurodevelopmental genetic disorder affecting approximately 1 in 15,000 to 20,000 live births. This condition primarily affects the nervous system, leading to various physical and developmental challenges. While Angelman Syndrome typically involves genetic changes present in all cells, “mosaicism” is a distinct and less common genetic presentation where only some cells carry the genetic change.
What is Angelman Syndrome and Mosaicism?
Angelman Syndrome is a neurodevelopmental disorder caused by the absence or reduced function of the UBE3A gene. This gene is located on chromosome 15 and plays a role in brain development and function, influencing learning, motor coordination, and communication. Normally, individuals inherit two copies of the UBE3A gene, one from each parent. However, due to a process called imprinting, only the maternal copy of UBE3A is active in brain cells. If the maternal UBE3A copy is missing or not working properly, the brain lacks the necessary functional protein, leading to the symptoms of Angelman Syndrome.
Genetic mosaicism is a condition where an individual has two or more populations of cells with different genetic compositions. This differs from typical genetic conditions where all cells share the same genetic makeup. In the context of Angelman Syndrome, mosaicism means that some cells in the body contain a functional UBE3A gene, while others do not. This mixture of cell types can result in a spectrum of symptom severity, as the proportion of cells with the functional gene can vary.
How Mosaic Angelman Syndrome Develops
Mosaic Angelman Syndrome arises from genetic changes that occur after fertilization. Unlike typical Angelman Syndrome where the genetic alteration is present from conception, in mosaic cases, the mutation in the UBE3A gene happens during early embryonic development. This means that as cells divide and multiply, some cells will inherit the genetic change affecting UBE3A, while others will retain their original, functional genetic information.
The mechanisms can involve a post-zygotic mutation within the UBE3A gene, or a post-zygotic loss of the paternal UBE3A allele with duplication of the maternal allele. This uneven distribution of genetic material across different cell populations results in varying levels of UBE3A protein production throughout the body. The occurrence of mosaicism after conception means the chance of it reoccurring in future pregnancies is very low.
Identifying Characteristics and Diagnosis
Individuals with Angelman Syndrome exhibit a range of characteristics, including severe developmental delay, significant speech impairment, and challenges with movement and balance. Other common features include a happy demeanor with frequent laughter, hyperactivity, microcephaly, and seizures. Developmental delays become noticeable between 6 and 12 months of age, though the more distinct features of Angelman Syndrome may appear after one year.
The mosaic nature of Angelman Syndrome can lead to a broader range of symptom severity. Individuals with mosaic Angelman Syndrome may experience milder symptoms, such as fewer seizures, improved ambulation, and some verbal communication. The degree of mosaicism, the percentage of cells with functional UBE3A, directly influences the clinical presentation. For example, individuals with 1-5% UBE3A expression may have few to no seizures and be ambulatory with some speech, while 20% expression might lead to no seizures and speech in sentences.
Diagnosing mosaic Angelman Syndrome requires specialized genetic testing. Standard genetic tests might miss mosaic mutations if the percentage of affected cells is below their detection threshold. Initial testing involves DNA methylation analysis, which screens for abnormal parental DNA methylation patterns in the 15q11.2-q13 region and can identify approximately 80% of individuals with Angelman Syndrome. If methylation analysis is normal but Angelman Syndrome is still suspected, UBE3A gene sequencing is performed to look for specific mutations in the maternal gene. Other tests like chromosomal microarray (CMA) or fluorescence in situ hybridization (FISH) can detect larger deletions.
Support and Outlook
Managing mosaic Angelman Syndrome involves a multidisciplinary approach to addressing individual symptoms and developmental needs. Therapies play a central role, including physical therapy to improve walking and movement, occupational therapy to enhance daily living skills, and speech therapy using nonverbal communication methods like picture cards or sign language. Behavioral therapy is also beneficial for managing hyperactivity or attention challenges.
Medical interventions are necessary for associated conditions such as seizures, managed with anti-seizure medications. Addressing sleep issues with medicines or sleep training, and managing feeding difficulties or constipation through diet changes and medication, are also common aspects of care. Early intervention across all therapeutic areas is encouraged to maximize developmental progress.
While there is currently no cure for Angelman Syndrome, research is actively exploring potential treatments, including gene therapies to activate the dormant paternal UBE3A gene. The long-term outlook for individuals with mosaic Angelman Syndrome can vary significantly based on the degree of mosaicism, with those having a higher percentage of functional UBE3A cells showing milder symptoms and better functional outcomes. Many individuals with Angelman Syndrome have a typical life expectancy, with complications from severe seizures or falls as concerns managed by their care team.