Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder most commonly caused by a deletion involving chromosome 22q13.3 and SHANK3, or by a pathogenic variant in SHANK3. Epilepsy occurs in a substantial subset but is not present in everyone.
Core features
PMS commonly causes developmental delay, intellectual disability, severe speech impairment, hypotonia and autism-spectrum or behavioural features.
Other medical problems can include sleep disturbance, reduced perspiration, gastrointestinal problems and decreased perception of pain.
SHANK3
SHANK3 encodes a synaptic scaffolding protein important for excitatory synapse structure and signalling.
Loss of SHANK3 function is central to the neurodevelopmental phenotype in most cases.
How PMS is caused
The most common mechanism is a terminal or interstitial 22q13 deletion that includes SHANK3.
Pathogenic SHANK3 sequence variants and more complex chromosome rearrangements can also cause the syndrome.
Epilepsy
Epilepsy is variable. People can have focal seizures, generalised seizures or mixed seizure types.
Some individuals never develop epilepsy.
EEG
EEG abnormalities are common but are not always accompanied by clinical seizures.
European consensus recommendations emphasise interpreting EEG together with the clinical event rather than treating EEG findings in isolation.
MRI
Brain MRI can be normal or show non-specific structural abnormalities.
MRI is particularly relevant when seizures are focal or when neurological examination suggests an additional structural problem.
Regression
Some people with PMS experience loss of previously acquired skills, especially during adolescence or adulthood.
Regression should prompt assessment for seizures, non-convulsive status, sleep disorder, psychiatric illness, catatonia, pain and other medical causes rather than automatically being attributed to the syndrome.
Behaviour and psychiatric features
Autism spectrum features, anxiety, mood disturbance and episodes of severe behavioural change can occur.
These can overlap clinically with seizure-related changes, so careful assessment is important.
Treatment
There is no PMS-specific antiseizure medicine proven superior for all patients.
Medication choice follows seizure type and individual response.
When treatment is necessary
EEG abnormalities without convincing clinical seizures do not automatically require antiseizure treatment.
Consensus recommendations support integrating clinical history, EEG and MRI when deciding whether therapy is needed.
Drug resistance
A subset of people have drug-resistant epilepsy, while others achieve good control or have only occasional seizures.
Outcome is heterogeneous.
Genetic testing
Testing should be able to detect both SHANK3 sequence variants and larger 22q13 deletions or rearrangements.
Chromosomal microarray, genome sequencing and targeted testing may therefore play complementary roles.
Genetic counselling
Most cases are de novo, but inherited chromosome rearrangements can affect recurrence risk.
Parental chromosome studies may be appropriate when a deletion or rearrangement is identified.
Care beyond epilepsy
Communication support, physiotherapy, occupational therapy, behavioural care, sleep management and psychiatric assessment can be major parts of treatment.
Epilepsy should be managed within the broader neurodevelopmental condition.
Worldwide access
Comprehensive diagnosis may require both molecular and chromosome-level testing.
Access to autism services, augmentative communication and specialist epilepsy care differs greatly between countries.
The central point
Phelan-McDermid syndrome is not an epilepsy syndrome. It is a broader SHANK3-related neurodevelopmental disorder in which epilepsy is common enough to require structured surveillance but not universal.
Related reading
Genetics & Epilepsy →
Genetic Testing in Epilepsy →
Sources
Medical note: developmental regression or behavioural change in PMS has many possible causes and should not automatically be assumed to be epilepsy.
Evidence checked: September 2026.