Angelman syndrome

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Disease Entity


ICD-10-CM Q93.51 Angelman Syndrome


Angelman Syndrome (AS) is caused by the loss of function of the maternal copy of the UBE3A gene, which is located on chromosome 15q11-q13.[1] The majority of cases are maternal deletions, paternal disomy, or mutations directly to the maternal UBE3A gene.[1] Angelman syndrome, along with Prader-Willi syndrome, are classic examples of genomic imprinting: the phenomenon in which a single copy of a gene is silenced via methylation leaving the unmethylated copy to be expressed.[1]


Angelman Syndrome (AS) has an estimated prevalence of 1 in 12,000 to 24,000 individuals in the general population.[2] The disorder affects males and females equally and is typically diagnosed in early childhood. [1][2] It is possible that the true prevalence of the disorder may differ due to the potential for undiagnosed or underreported cases.[1]


Angelman syndrome (AS) is a neurodevelopmental disorder that is caused by the loss of function of the maternally inherited UBE3A gene.[3][4] This gene is located on chromosome 15q11-q13 and encodes for an E3 ubiquitin ligase enzyme that plays a crucial role in protein degradation and synaptic plasticity.[3][4] The loss of UBE3A function can occur through several mechanisms, including maternal deletion, paternal uniparental disomy, imprinting defects, and mutations in the UBE3A gene itself.[3][4]

Maternal deletions account for approximately 70% of AS cases and are typically caused by a de novo deletion on the maternally inherited chromosome 15q11-q13.[5] Paternal uniparental disomy (UPD) accounts for approximately 5% of cases and occurs when both copies of chromosome 15 are inherited from the father instead of one copy from each parent.[5] Imprinting defects account for approximately 5% of cases and occur when there is a disruption in the normal pattern of DNA methylation on the maternal allele.[5] Finally, mutations in the UBE3A gene itself account for approximately 10% of cases.[5]

The loss of UBE3A function leads to altered synaptic plasticity and impaired neuronal communication, which may underlie many of the clinical features observed in AS patients, including developmental delay, intellectual disability, ataxia, seizures, and characteristic behaviors such as frequent laughter and hand flapping.[6] While there is currently no cure for AS, several therapeutic approaches are being investigated to restore UBE3A function or compensate for its loss.[7] These include gene therapy approaches to deliver functional copies of UBE3A to affected neurons, pharmacological approaches to enhance synaptic plasticity or modulate downstream targets of UBE3A signaling pathways, and behavioral interventions to address specific symptoms associated with AS.[7]

Clinical Features

Systemic Manifestations

The most common systemic manifestations of AS include developmental delay, intellectual disability, ataxia, seizures, and characteristic behaviors such as frequent laughter and hand flapping. Developmental delay and intellectual disability are present in nearly all individuals with AS and can range from mild to severe.[8][9] Ataxia is also common in AS and can manifest as an unsteady gait, jerky arm movements, and tremors. Seizures are another common feature of AS that has been reported and are an important consideration in the development of pediatric patients with AS.[14] Seizure types can vary but may include generalized tonic-clonic seizures, absence seizures, myoclonic seizures, or atypical absence seizures.[16]

Characteristic behaviors such as frequent laughter and hand flapping that are common in AS may be mistaken for autism spectrum disorder or the two conditions may be comorbid.[7] Other behavioral features that have been reported in AS include hyperactivity, impulsivity, aggression, anxiety, and sleep disturbances.

In addition to these core features of AS, there are several other systemic manifestations that have been reported in the literature. These include abnormalities in muscle tone (hypotonia or hypertonia), abnormal electroencephalogram (EEG) findings (high-amplitude spikes and slow waves at 2-3 Hz noted anteriorly), abnormal head computed tomography (CT) scan (cerebral atrophy), facial dysmorphism (e.g., macrostomia, prognathism), sleep problems (e.g., difficulty falling asleep or staying asleep), scoliosis (abnormal curvature of the spine), childhood obesity, hypopigmentation (pale blue eyes or blond hair), and drooling/excessive chewing.

Ocular Manifestations

Ophthalmic signs may be present in Angelman syndrome (AS) and can include strabismus, nystagmus, and refractive errors.[9][10] While many nonspecific ophthalmic findings exist, strabismus and iris hypopigmentation are among the more common findings in AS and vary in prevalence from 20% up to 80% in affected individuals.[9][10] Strabismus may be present at birth or develop later in childhood and can be either intermittent or constant. Patients with AS also may present with features characteristic of oculocutaneous albinism due to the location of the P gene, which produces an important membrane protein in melanosomes, on chromosome 15.[11] While less common, tropias, nystagmus, Brushfield’s spots, and optic atrophy are among other ocular findings recorded in literature.[9] Ocular motility disorders and refractive errors, such as myopia, hyperopia, and astigmatism, are also seen in AS, although astigmatism may be more common among refractive errors[10]. Myopia and astigmatism are less common but have also been reported.[10]

The underlying mechanisms that lead to these ocular manifestations are not well understood but may be related to abnormalities in the development or function of the visual system. Early detection and treatment of ocular manifestations are important for optimizing visual outcomes for affected individuals. Treatment options may include corrective lenses for refractive errors and patching or surgery for strabismus. Ongoing monitoring by an ophthalmologist is recommended for individuals with AS to ensure timely detection and treatment of any ocular abnormalities that may arise over time.


The diagnosis of Angelman syndrome (AS) is typically made based on clinical features, genetic testing, and neuroimaging studies.[19] The clinical features of AS can be variable and may overlap with other neurodevelopmental disorders such as autism spectrum disorder, making accurate diagnosis challenging.

Genetic testing is an important tool for confirming the diagnosis of AS and identifying the underlying genetic mechanism. Chromosomal microarray analysis (CMA) can detect maternal deletions or paternal UPD while methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) can detect imprinting defects.[7][12] In cases where these tests are negative or inconclusive, sequencing of the UBE3A gene may be performed to identify mutations.[12]

Neuroimaging studies such as magnetic resonance imaging (MRI) or computed tomography (CT) scans may also be useful in the diagnosis of AS. These studies can reveal structural abnormalities in the brain that are characteristic of AS, such as cerebellar hypoplasia or cerebral atrophy.

The diagnostic criteria for AS have evolved over time as our understanding of the disorder has improved. An early and widely used diagnostic criterion was established by Holm et al. in 1993 and includes clinical features such as developmental delay, intellectual disability, ataxia, seizures, and characteristic behaviors such as frequent laughter and hand flapping.[20] However, these criteria have been revised over time to reflect new insights into the disorder and to improve diagnostic accuracy.


The management of Angelman syndrome (AS) is primarily focused on addressing the neurodevelopmental and behavioral symptoms associated with the disorder. Early intervention with therapies such as physical therapy, speech therapy, and behavioral interventions can improve outcomes for affected individuals.[17] Seizures are a common feature of AS and may require treatment with antiepileptic medications.[17] Behavioral symptoms such as hyperactivity, impulsivity, aggression, anxiety, and sleep disturbances can be managed with behavioral therapies such as applied behavior analysis (ABA) or cognitive-behavioral therapy (CBT).[17] Medications such as antipsychotics or antidepressants may also be used to manage specific symptoms.[17] Ongoing monitoring by a multidisciplinary team including a neurologist, developmental pediatrician, genetic counselor, and other specialists is recommended to ensure that affected individuals receive appropriate care throughout their lifespan.


The prognosis of Angelman syndrome (AS) varies depending on the underlying genetic mechanism and individual clinical features. While there is currently no cure for AS, early intervention with therapies such as physical therapy, speech therapy, and behavioral interventions may improve outcomes for affected individuals.[17]

Individuals with AS typically have a normal lifespan but may experience significant challenges related to their neurodevelopmental and behavioral symptoms, impacting their ability to perform self-care and activities of daily living.[13] Intellectual disability and developmental delay are nearly universal in AS and can impact an individual's ability to learn new skills and achieve independence. The combination of the aforementioned challenges these patients face may also contribute to increased anxiety and depression.[13][15] Seizures are also common in AS and can be difficult to control with medication.

Additional Resources


  1. Madaan M, Mendez MD. Angelman Syndrome. [Updated 2023 Jan 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from:
  2. Dagli AI, Mathews J, Williams CA. Angelman Syndrome. 1998 Sep 15 [Updated 2021 Apr 22]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from:
  3. Clayton-Smith, J., & Laan, L. (2003). Angelman syndrome: a review of the clinical and genetic aspects. Journal of medical genetics, 40(2), 87–95.
  4. Van Buggenhout, G., & Fryns, J. P. (2009). Angelman syndrome (AS, MIM 105830). European journal of human genetics: EJHG, 17(11), 1367–1373.
  5. Butler M.G. (2014). Prader-willi and angelman syndromes: examples of genomic imprinting. Murray M.F., & Babyatsky M.W., & Giovanni M.A., & Alkuraya F.S., & Stewart D.R.(Eds.), Clinical Genomics: Practical Applications in Adult Patient Care, 1e. McGraw Hill.
  6. Sun, J., Zhu, G., Liu, Y., Standley, S., Ji, A., Tunuguntla, R., Wang, Y., Claus, C., Luo, Y., Baudry, M., & Bi, X. (2015). UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis. Cell reports, 12(3), 449–461.
  7. Bird L. M. (2014). Angelman syndrome: review of clinical and molecular aspects. The application of clinical genetics, 7, 93–104.
  8. Smith, A., Marks, R., Haan, E., Dixon, J., & Trent, R. J. (1997). Clinical features in four patients with Angelman syndrome resulting from paternal uniparental disomy. Journal of medical genetics, 34(5), 426–429.
  9. Mah, M. L., Wallace, D. K., & Powell, C. M. (2000). Ophthalmic manifestations of Angelman syndrome. Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus, 4(4), 248–249.
  10. Michieletto, P., Bonanni, P., & Pensiero, S. (2011). Ophthalmic findings in Angelman syndrome. Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus, 15(2), 158–161.
  11. Fridman, C., Hosomi, N., Varela, M. C., Souza, A. H., Fukai, K., & Koiffmann, C. P. (2003). Angelman syndrome associated with oculocutaneous albinism due to an intragenic deletion of the P gene. American journal of medical genetics. Part A, 119A(2), 180–183.
  12. Ramsden, S. C., Clayton-Smith, J., Birch, R., & Buiting, K. (2010). Practice guidelines for the molecular analysis of Prader-Willi and Angelman syndromes. BMC medical genetics, 11, 70.
  13. Khan, N., Cabo, R., Burdine, R.D. et al. Health-related quality of life and medication use among individuals with Angelman syndrome. Qual Life Res (2023).
  14. Li, S., Ma, Y., Wang, T., Jin, H., Du, X., & Wang, Y. (2022). Epilepsy and Molecular Phenotype Affect the Neurodevelopment of Pediatric Angelman Syndrome Patients in China. Frontiers in psychiatry, 13, 886028.
  15. Grebe, S. C., Limon, D. L., McNeel, M. M., Guzick, A., Peters, S. U., Tan, W. H., Sadhwani, A., Bacino, C. A., Bird, L. M., Samaco, R. C., Berry, L. N., Goodman, W. K., Schneider, S. C., & Storch, E. A. (2022). Anxiety in Angelman Syndrome. American journal on intellectual and developmental disabilities, 127(1), 1–10.
  16. Cassater, D., Bustamante, M., Sach-Peltason, L., Rotenberg, A., Nespeca, M., Tan, W. H., Bird, L. M., & Hipp, J. F. (2021). Clinical Characterization of Epilepsy in Children With Angelman Syndrome. Pediatric neurology, 124, 42–50.
  17. Margolis, S. S., Sell, G. L., Zbinden, M. A., & Bird, L. M. (2015). Angelman Syndrome. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 12(3), 641–650.
  18. Bird L. M. (2014). Angelman syndrome: review of clinical and molecular aspects. The application of clinical genetics, 7, 93–104.
  19. Duca, D. G., Craiu, D., Boer, M., Chirieac, S. M., Arghir, A., Tutulan-Cunita, A., Barca, D., Iliescu, C., Lungeanu, A., Magureanu, S., & Budisteanu, M. (2013). Diagnostic approach of angelman syndrome. Maedica, 8(4), 321–327.
  20. Holm, V. A., Cassidy, S. B., Butler, M. G., Hanchett, J. M., Greenswag, L. R., Whitman, B. Y., & Greenberg, F. (1993). Prader-Willi syndrome: consensus diagnostic criteria. Pediatrics, 91(2), 398–402.
  21. Williams, C. A., Beaudet, A. L., Clayton-Smith, J., Knoll, J. H., Kyllerman, M., Laan, L. A., Magenis, R. E., Moncla, A., Schinzel, A. A., Summers, J. A., & Wagstaff, J. (2006). Angelman syndrome 2005: updated consensus for diagnostic criteria. American Journal of medical genetics. Part A, 140(5), 413–418.
  22. Cognitive and adaptive behavior profiles of children with Angelman syndrome. American journal of medical genetics. Part A, 128A(2), 110–113.
  23. Mertz, L. G., Christensen, R., Vogel, I., Hertz, J. M., Nielsen, K. B., Grønskov, K., & Østergaard, J. R. (2013). Angelman syndrome in Denmark. birth incidence, genetic findings, and age at diagnosis. American journal of medical genetics. Part A, 161A(9), 2197–2203.
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