Angelman Syndrome: Common Misdiagnoses
Angelman syndrome (AS) is commonly diagnosed at one to two years of age. Prior to the diagnosis of AS, some individuals may receive other diagnoses due to overlapping symptoms.
Why and How Does Angelman Syndrome Get Misdiagnosed?
The initial symptoms of Angelman syndrome, primarily developmental delays, are common across various genetic conditions and other health issues. Because Angelman syndrome is rare, these symptoms are more commonly associated with other conditions. Consequently, children, especially babies, living with AS may initially receive an incorrect diagnosis.
As children grow and exhibit AS-specific traits such as balance difficulties, frequent laughing, and speech problems, genetic testing is often performed to confirm the diagnosis.
The Role of Genetic Testing in Diagnosing Angelman Syndrome
Unlike some conditions that are diagnosed through clinical observations, AS is typically confirmed through genetic testing using a blood or saliva sample. Genetic testing for AS can identify a clear genetic difference in most people living with AS, ensuring an accurate diagnosis and preventing prolonged misdiagnoses.
Autism vs. Angelman Syndrome
Autism is diagnosed based on observed behaviors, including social interaction and communication difficulties, repetitive behaviors, and restricted interests. Since individuals living with AS may not use verbal speech and may exhibit repetitive behaviors, there can be diagnostic confusion.
Is Angelman Syndrome part of the Autism Spectrum?
No. While AS and autism share some behavioral similarities, they are distinct conditions. Angelman syndrome is a specific genetic condition caused by absence of UBE3A, whereas autism is a broader neurodevelopmental diagnosis.
A person living with AS can meet the educational eligibility criteria for autism. In the U.S., these criteria vary from state to state and may differ from medical diagnostic standards. The educational eligibility criteria for autism primarily determine school service eligibility.
Can Angelman Syndrome Be Misdiagnosed as Autism?
Yes. Autism is typically diagnosed around 2 or 3 years of age, and at that time, most individuals living with AS have more AS-specific symptoms. However, sometimes a person living with AS may be diagnosed with autism first, usually because that individual has speech and social delays as the primary early symptoms.
Cerebral Palsy vs. Angelman Syndrome
Cerebral palsy (CP) is a group of conditions affecting movement and posture, typically caused by brain damage before birth. Since CP symptoms, including developmental delays and muscle stiffness, overlap with AS, misdiagnoses can occur.
Why Is Angelman Syndrome Sometimes Diagnosed as Cerebral Palsy?
Because CP is significantly more common than AS, infants showing motor delays and muscle tone differences may be initially diagnosed with CP. However, genetic testing can later reveal an AS diagnosis.
The Importance of Genetic Testing for Cerebral Palsy
A recent study suggests that around 35% of individuals diagnosed with CP have an underlying genetic condition. Families with a diagnosis of CP should talk to their doctors about genetic testing to explore other potential underlying genetic causes.
Prader-Willi Syndrome vs. Angelman Syndrome
Prader-Willi syndrome (PWS) is a genetic condition characterized by low muscle tone (hypotonia) and feeding difficulties in infancy, followed by excessive hunger and obesity in childhood. Like AS, PWS is caused by genetic differences affecting chromosome 15.
What Chromosome Is Affected in Angelman and Prader-Willi Syndromes?
Both Angelman syndrome and Prader-Willi syndrome are caused by differences in chromosome 15 (15q11.2-q13.1). The key difference lies in inheritance, or which parent the chromosome was inherited from:
A maternal deletion causes Angelman syndrome.
A paternal deletion causes Prader-Willi syndrome.
Similarly, uniparental disomy (UPD, having two copies of a chromosome from one parent instead of the usual one chromosome copy from mom and one chromosome copy from dad) of chromosome 15 can result in either AS (two paternal copies) or PWS (two maternal copies).
What Is So Significant About Prader-Willi and Angelman Syndrome?
The significance of these conditions lies in the unique imprinting of chromosome 15. Imprinting is a method for controlling which genes are on or off based on whether the gene was inherited from the mother or the father.
Genetic testing like chromosomal microarray can identify a deletion or UPD but is not able to tell if the deletion or UPD was maternally or paternally inherited. Further testing, specifically methylation analysis, is needed to determine whether the maternal or the paternal chromosomes were affected.
In that time between the identification of the deletion (or UPD) and getting the methylation results, healthcare providers and families may not know if the child has AS or PWS. If the baby has hypotonia or difficulties feeding, occasionally the assumption is made that the baby has PWS. Methylation analysis can accurately determine whether the person is living with AS or PWS.
Angelman Syndrome vs. Prader-Willi Syndrome Characteristics
Other Misdiagnoses for Angelman Syndrome
Many other genetic conditions share characteristics with AS. Genetic testing such as whole exome or whole genome sequencing has reduced misdiagnoses, but in the past, conditions with overlapping features were sometimes confused with AS.
Conditions Once Mistaken for Angelman Syndrome:
Rett syndrome (predominantly affects females)
Phelan-McDermid syndrome
Mowat-Wilson syndrome
Smith-Magenis syndrome
Pitt-Hopkins syndrome
Other Single Gene Disorders That Cause Characteristics That May Mimic Angelman Syndrome:
HERC2
SLC9A6
MECP2 duplication syndrome
ATRX
EHMT1
Importance of Updated Genetic Testing
If a loved one has a clinical diagnosis of AS but has not had genetic testing in the past decade (or ever), seeking updated genetic testing may provide clarity. For assistance, reach out to FAST’s genetic counselor, Niki Armstrong, at niki@cureangelman.org.
Sources
Center for Disease Control (CDC). 2024. Autism Spectrum Disorder Page. Retrieved from https://www.cdc.gov/autism/hcp/diagnosis/index.html.
Bird, L. M. (2014). Angelman syndrome: review of clinical and molecular aspects. *The Application of Clinical Genetics, 7*, 93-104.
Dagli AI, Mathews J, Williams CA. Angelman Syndrome. 1998 Sep 15 [Updated 2021 Apr 22]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1144/
Driscoll DJ, Miller JL, Cassidy SB. Prader-Willi Syndrome. 1998 Oct 6 [Updated 2024 Dec 5]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1330/
Prader-Willi Syndrome Association (USA). (2023). Understanding Prader-Willi Syndrome. Retrieved from https://www.pwsausa.org
Autism Society. (2023). Autism and Related Conditions. Retrieved from https://www.autism-society.org
National Institute of Neurological Disorders and Stroke (NINDS). (2022). Cerebral Palsy Information Page. Retrieved from https://www.ninds.nih.gov