A form of partial epilepsy associated with auditory and other sensory hallucinations has been linked to the disruption of brain development during early childhood. The new findings focus on the development of synapses, the connections between brain cells.
“During early childhood – roughly between the ages of one and five – the brain undergoes a period of major circuit remodeling,” explains Matthew Anderson, MD, PhD, a principal investigator in the Departments of Neurology and Pathology at BIDMC, who lead researchers in a study at Beth Israel Deaconess Medical Center. “Our discovery that a familial form of temporal lobe epilepsy can develop at this point demonstrates the fragility of the brain during this critical period.”
Anderson, who is also an Assistant Professor of Neurology and Pathology at Harvard Medical School, explains: “At birth, the brain is loaded with excitatory synapses which help make nerve cells ‘fire.’ However, if these excess synapses are not adequately ‘pruned,’ they can overgrow, leading to excessive transmission of excitatory signals and the development of pathological conditions, including learning disabilities and autism in addition to epilepsy.”
Using a genetically engineered mouse model created in his laboratory, together with brain slice patch-clamp electrophysiology techniques, Anderson and his scientific team found that a mutant form of the LGI1 (leucine-rich glioma-inactivated 1) gene was preventing the normal brain development. (According to Wikipedia, since its earliest discovery, the LGI1 gene has been implicated in the control of cancer metastasis and in a predisposition to epilepsy.)
“The first clue was our discovery that LGI1 is not expressed until the exact time when excitatory synapses are matured,” said Anderson. “We subsequently learned that the mLGI1 gene was indeed prohibiting excitatory synapses from being adequately pruned, leading to an increased excitability of circuits in the brain which left it prone to excessive synchronous discharges that are characteristic of epilepsy.”
Autosomal dominant lateral temporal lobe epilepsy (ADLTE) is characterized by frequent partial seizures (two to five per month) that are associated with auditory or other sensory auras. Tonic-clonic seizures also occur in the majority of ADLTE patients, but are infrequent, developing only about once a year.
“These partial seizures can have a significant impact on a patient’s quality of life,” notes Anderson. “Because patients can be disoriented and excessively tired following a seizure event, their day-to-day lives can sometimes be seriously disrupted. And when it comes to driving and other activities, there is still a real danger associated with this condition.
“One important reason to identify genetic causes of epilepsy is the hope that these discoveries will eventually lead to new therapies,” he adds. “By identifying this new pathway, we may have found a new target for future drug development.”
Study coauthors include BIDMC investigators Yu-Dong Zhou (first author), Sanghoon Lee, Zhe Jin and Stephen E.P. Smith, and Moriah Wright of Tufts University School of Medicine.
Parents can read more at Epilepsy.com, the US National Institute of Neurological Disorders and Stroke, People Against Childhood Epilepsy, and Charlie Foundation to Help Cure Pediatric Epilepsy.