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 living with AS may be given other diagnoses to explain their symptoms or characteristics.   

Why and How Does Angelman Syndrome Get Misdiagnosed?  

The initial symptoms of Angelman syndrome, primarily developmental delays, are common.  Developmental delays can be seen in many different genetic conditions and because of birth difficulties or other health issues.  Because other conditions that cause developmental delays are far more common than AS, a child, especially a baby, may receive an initial diagnosis of a different condition.  As the baby gets older and shows more AS-specific symptoms such as balance difficulties, frequent laughing, and speech problems, the diagnosis of AS is usually made.    

It is important to understand that many of the conditions that are “misdiagnosed” are made based on observation of behaviors or a physical exam.  AS, however, is typically diagnosed based on genetic testing, using a blood or saliva sample, identifying a clear genetic difference.  Genetic testing for AS enables the correct diagnosis to be made.  

Autism  

The diagnosis of autism is made based on the observation of long-term difficulties in social interactions and communication and behaviors that are repetitive and/or restricted.  There is not a specific genetic test or other blood test that can diagnose autism. Because individuals living with AS may not use verbal speech, this can be interpreted as a difficulty in communication.  In addition, repetitive behaviors like hand-flapping or restricted interests that are common in autism are also common in individuals living with neurodevelopmental disabilities like AS.    

A person living with AS can have a diagnosis of AS AND meet the educational eligibility criteria for  autism.  In the USA, the educational eligibility criteria are different than the criteria for a diagnosis and are meant to determine who is eligible for school services for autism. 

A person living with AS can also be misdiagnosed with autism before the AS diagnosis.   

Cerebral Palsy

Cerebral palsy (CP) is a group of conditions that affect movement and posture.  CP is variable, with some people having mild symptoms and others having serious medical concerns.  Some common symptoms of CP are developmental delays, muscle stiffness (spasticity or hypertonia), exaggerated reflexes, lack of balance (ataxia), and difficulties with speech or eating.  CP is caused by damage to the developing brain that typically happens before birth.  CP is diagnosed based on clinical assessment and observation of motor (muscle) development. It is a clinical diagnosis with no single diagnostic test.   

Because many symptoms of Angelman syndrome can overlap with the symptoms of CP, especially in very young children, and because CP is much more common, a child may be misdiagnosed with cerebral palsy.   As characteristics of Angelman syndrome become more apparent, genetic testing may be performed and diagnose AS.    

Recent studies suggest that all individuals living with CP should have genetic testing, since about 35% of individuals with a diagnosis of cerebral palsy will have a genetic diagnosis identified if detailed genetic testing like whole exome sequencing is performed. 

Prader Willi  

Prader-Willi syndrome (PWS) is a genetic condition that causes muscle weakness (hypotonia) and feeding difficulties in infancy, followed by excessive hunger and obesity in childhood, with an increased chance of developmental delays and behavioral issues. PWS has several possible causes but is most commonly caused by a deletion, a missing section of chromosome 15 at 15q11.2-q13.1.   

AS and PWS are sometimes confused because the exact SAME deletion can cause both conditions.  If the deletion is on the maternal chromosome 15 (the chromosome 15 from the egg), it causes AS.  If the deletion is on the paternal chromosome 15 (from the sperm), it causes PWS.   Similarly, uniparental disomy (UPD) of chromosome 15 can also be either PWS (two maternal chromosome 15s) or AS (two paternal chromosome 15s). 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.  

Other Misdiagnoses for Angelman Syndrome  

There are many other genetic conditions that have similar or overlapping characteristics.  Genetic testing such as chromosomal microarray and whole exome or whole genome sequencing can be used to diagnose these other conditions.  Many individuals who were initially found to have a “clinical diagnosis” of Angelman syndrome, meaning that they had clinical characteristics of AS but genetic testing was all negative (normal), have been found to have a different genetic condition once additional genetic testing was performed.   Several decades ago, genetic testing for many conditions was unavailable or difficult to obtain.  In addition, many neurogenetic conditions we know about now did not exist because the gene hadn’t been described yet. Consequently, people were often given a diagnosis based on meeting clinical criteria.   When conditions have very similar characteristics, people may have been inaccurately classified as having the wrong condition.   Conditions with similar characteristics that were occasionally confused with AS in the past: 

• Rett syndrome (almost exclusively affects females) 

• Phelan-McDermid syndrome 

• Mowat-Wilson 

• Smith-Magenis 

• Pitt-Hopkins syndrome 

The availability of extensive genetic testing has greatly reduced the likelihood of misdiagnosis and has identified many other rare single gene disorders that have similar characteristics.   Other single gene disorders that may mimic AS include: 

• HERC2 

• SLC9A6 

• MECP2 duplication syndrome  

• ATRX 

• EHMT1 

If your loved one has a clinical diagnosis of AS but has not had genetic testing in the last 10 years, consider talking to a genetics provider about additional genetic testing.  Having difficulty finding a genetics provider in your area? Reach out to FAST’s genetic counselor, Niki Armstrong at niki@cureangelman.org.