Epilepsies are chronic neurological disorders in which large groups of neurons firing at the same time generate electrical activity that causes seizures and involuntary movements. They are one of the most common brain diseases in children and, in almost a quarter of cases, patients do not respond to standard medical treatments. Life-threatening treatment-resistant epilepsy often results from tissue that was damaged or developed abnormally during prenatal brain formation, known as malformations of cortical development (MCD).
Epilepsy resulting from MCD is a rare but serious condition. Although some types of epilepsy run in families, the genetic cause of MCD is unclear. New research funded by the National Institute of Mental Health (NIMH), National Institute of Neurological Disorders and Stroke, and National Institute on Aging sheds light on genetic mutations that may play a key role in the development of epilepsies. The study provides insights that could lead to improved diagnosis and treatment of diseases with origins in early brain development.
Led by Joseph Gleeson, M.D., at the University of California San Diego and the Rady Children’s Institute for Genomic Medicine, the study was a multicenter international collaboration. The researchers looked for mutations in the brain that may contribute to MCD. They performed genetic profiling of tissue using advanced detection techniques and best practice guidelines from the Brain Somatic Mosaicism Network—an NIMH-supported network of investigative teams working together to study mutations present in a small subset of brain cells.
Almost 300 children with diverse forms of MCD provided brain tissue through the Focal Cortical Dysplasia Neurogenetics Consortium. Brain samples were collected as part of surgery to treat epilepsy. For each person, paired blood or saliva samples were also collected, as were parental samples when available. The researchers included brain tissue from a small sample of people without neurological conditions for comparison and validated a subset of identified genes via patient biopsies and in mice.
Comprehensive screening to identify genetic causes of MCD proceeded in three phases:
- Targeted examination of genes in the mTOR pathway, which regulates cell growth, proliferation, and metabolism and shows excessive signaling in the brains of people with epilepsy
- Unbiased gene discovery to identify new genes that may be associated with MCD
- Independent testing in a new sample to confirm the genes identified in the first two phases
Additional analyses looked for networks of genes with related functions involved in brain development and at links between identified genes and clinical and behavioral features of the disease.
This study identified 69 mutated genes associated with MCD. Of these, 60 were genes linked to MCD for the first time. Twelve of the mutated genes were recurrently mutated, meaning they were identified in at least two different patient brain samples, giving more confidence that they contribute to MCD. Among the recurrently mutated genes were two genes linked to MCD for the first time and another three genes identified in prior studies. These data suggest that researchers have only scratched the surface of the number of genes involved in epilepsy and may identify more genes in future studies.
The results also confirmed the critical role of the mTOR pathway. This pathway is dysregulated in several human diseases, including cancer and diabetes. As such, the mutations could have implications for risk for any number of diseases and disorders.
To test the function of the mutations, the researchers introduced mutated or non-mutated forms of the identified MCD genes into a small region of the brain in developing mice. Introduction of the mutated genes led to the development of brain abnormalities similar to those seen in humans with MCD, indicating that many of the mutated genes likely contribute to features of the disease. Further analyses revealed four major networks into which the mutated genes clustered, all of which play critical roles during early brain development. These groups of genes correlated with clinical features of the disease. Together, the results showed that the mutated genes are vital to cortical development and related to patient outcomes later in life.
The findings of this study have important implications for treatment-resistant epilepsy and related diseases, as well as for human brain development. The identified genes could offer potential drug targets, help inform new clinical classifications and diagnoses, and ultimately lead to personalized treatments or early interventions for a range of mental and physical health conditions.
The current sample size was larger than in previous studies, leading to the discovery of many new genes. The researchers’ use of state-of-the-art methods and independent validation of genes also enhanced confidence in the results. However, confirming the current set of genes and identifying new MCD-related genes will require replication in larger samples. Future research taking advantage of this study’s innovative roadmap for studying rare genetic variants will also help answer important questions, such as the contribution of environmental versus genetic factors in disease.