By: Clare Logan
Phelan-McDermid Syndrome and Epilepsy
What is Phelan-McDermid Syndrome?
Phelan-McDermid Syndrome (PMS) is a rare neurodevelopmental disorder most often caused by changes in the SHANK3 gene. This gene plays a crucial role in how brain cells connect and communicate. When the SHANK3 gene does not function properly, connections between nerve cells weaken, affecting brain development and function. Individuals with PMS often experience developmental delays, low muscle tone, intellectual disabilities, limited or absent speech, and features of autism spectrum disorder. While these symptoms vary, PMS is widely recognized as a disorder of brain development and communication.
Phelan-McDermid Syndrome and Epilepsy
One of the more serious health challenges for some individuals with PMS is epilepsy or repeated seizures. Although not everyone with PMS will develop seizures, research suggests that anywhere between 20% to 40% of people with PMS experience them. While the types of seizures individuals experience vary, the most commonly reported is an atypical absence seizure, which involves a temporary loss of awareness and changes in muscle tone, such as slumping or jerking. Seizures in PMS affect both the individual’s development and the burden on caregivers. Studies show that children with PMS who develop seizures may have more challenges with learning and daily living skills, and in some cases, may experience regression, meaning they lose abilities they had previously gained. This makes it important to identify and treat seizures early in people with PMS.
Research and Treatment
At this time, there is no single treatment specifically for PMS-related epilepsy. As with other types of epilepsy, medical professionals typically use the same anti-seizure medications. For some people, these medications help reduce seizures, but others may find seizures remain difficult to control, even with more than one medication. Researchers are now investigating treatments that target the underlying biology of PMS. One promising study examined AMO-01, a drug that targets the Ras-ERK signaling pathway in the brain, which is believed to play a role in PMS-related seizures. In a small pilot study, participants with PMS who received AMO-01 showed a reduction in seizure frequency and tolerated the treatment safely, without serious adverse events. While this is only an early step, it provides hope that future treatments could be designed specifically for PMS-related seizures.
Updated clinical guidelines now recommend that families and doctors remain especially alert for signs of epilepsy in PMS, using electroencephalograms (EEGs) and brain imaging when necessary, and adjusting treatments as the child grows. Ongoing research aims to better understand how the size and type of genetic change in PMS relate to seizure risk, which may one day help guide more individualized treatments. In conclusion, PMS is a complex condition that affects brain development and function. In combination, epilepsy is a common and often difficult complication that typically causes a significant impact on the quality of life of the affected individual and their caregivers. While current treatments are limited, research into therapies tailored to PMS is beginning to offer new possibilities. With greater awareness, collaboration, and scientific progress, families affected by PMS-related epilepsy may see more effective treatment options in the future.
Resources:
de Coo, I. F. M., et al. (2023). Consensus recommendations on epilepsy in Phelan-McDermid syndrome. European Journal of Medical Genetics, 66(3), 104547. https://doi.org/10.1016/j.ejmg.2023.104547
Jain, L., Oberman, L. M., Beamer, L., Cascio, L., May, M., Srikanth, S., Skinner, C., Jones, K., Allen, B., Rogers, C., Phelan, K., Kaufmann, W. E., DuPont, B., Sarasua, S. M., & Boccuto, L. (2022). Genetic and metabolic profiling of individuals with Phelan-McDermid syndrome presenting with seizures. Clinical genetics, 101(1), 87–100. https://doi.org/10.1111/cge.14074
Levy, T., Gluckman, J., Siper, P.M. et al. Clinical, genetic, and cognitive correlates of seizure occurrences in Phelan-McDermid syndrome. J Neurodevelop Disord 16, 25 (2024). https://doi.org/10.1186/s11689-024-09541-0
Levy, T., et al. (2025). An open-label study evaluating the safety and efficacy of AMO-01 for the treatment of seizures in Phelan-McDermid syndrome. Seizure, 74, 1-7. https://doi.org/10.1016/j.seizure.2024.12.003
Phelan-McDermid Syndrome Foundation. (2023). Epilepsy and seizure update. https://pmsf.org/epilepsy-and-seizure-update/
Reierson, G., Bernstein, J., Froehlich-Santino, W., Urban, A., Purmann, C., Berquist, S., Jordan, J., O’Hara, R., & Hallmayer, J. (2017). Characterizing regression in Phelan McDermid Syndrome (22q13 deletion syndrome). Journal of psychiatric research, 91, 139–144. https://doi.org/10.1016/j.jpsychires.2017.03.010
U.S. National Library of Medicine. (2024). SHANK3 gene. MedlinePlus. https://medlineplus.gov/genetics/gene/shank3/#conditions
