UCLA researchers seeking alternative to radical brain surgery

UCLA and UCSD researchers are searching for an alternate treatment for a rare but severe brain disorder, which occurs in infancy: hemimegalencephaly. Infants suffering from this disorder have a malformed brain in which the abnormal side is much larger than the other. Currently, the only available treatment is a radical surgical procedure: the surgical disconnection of the abnormal side of the brain. The researchers have conducted genetic research that may lead to an alternate treatment for the affliction. They published their findings online on June 24 in the journal Nature Genetics.

The investigators have discovered that mutations in three genes, which are involved in the regulation of cell size and proliferation (cell multiplication), are likely responsible for the disorder. They caution, however, that other genes might also be involved. The three mutations that have been identified are known as de novo somatic mutations: genetic changes in the cells of the brain. “De novo” refers to a spontaneous new mutation; because they are in non-sex organs, the mutations are not transmitted to the child by either parent. The researchers note that the discovery of these mutated genes may lead to the development of new medications that can dampen the signals from them; thus, reducing the severity of the disorder.

The research was a collaboration between: Dr. Gary W. Mathern, co-senior author and a professor of neurosurgery at Mattel Children’s Hospital UCLA; Dr. Joseph G. Gleeson, co-senior author and a professor of neurosciences and pediatrics at the UC San Diego School of Medicine and Rady Children’s Hospital–San Diego; researchers from the Howard Hughes Medical Institute; and other colleagues. Dr. Mathern is one of a handful of pediatric neurosurgeons in the nation who specialize in hemispherectomy surgery (the removal of half the brain) to treat intractable epilepsy. He supplied brain tissue samples from 20 hemimegalencephaly patients for the study. Because of the rarity of the condition, it took nearly a decade to collect samples from enough patients.

Dr. Gleeson then analyzed and compared DNA sequences from the brain tissue supplied by Dr. Mathern with DNA from the patients’ blood and saliva. He explained, “Dr. Mathern had reported a family with identical twins in which one had hemimegalencephaly and one did not. Since such twins share all inherited DNA, we got to thinking that there may be a new mutation that arose in the diseased brain that causes the condition.” Realizing that they shared the same theories regarding potential causes of the disorder, the two physicians set out to evaluate it with new exome sequencing technology, which allows for the sequencing of all the protein-coding exons of the genome at the same time. (An exon is a nucleic acid sequence found in DNA.)

The three mutated genes referenced in the study were only found only in the brain samples supplied by Dr. Mathern. All three mutated genes had previously been linked to cancers. Dr. Gleeson explained, “We found mutations in a high percentage of the cells in genes regulating the cellular growth pathways in hemimegalencephaly. These same mutations have been found in various solid malignancies, including breast and pancreatic cancer. For reasons we do not yet understand, our patients do not develop cancer but rather this unusual brain condition. Either there are other mutations required for cancer propagation that are missing in these patients, or neurons are not capable of forming these types of cancers.”

Because the mutations were found in 30% of the patients studied, this indicated that other factors are involved. Despite this, the researchers have begun investigating potential treatments that address the known gene mutations, with the clear goal of finding a way to avoid the need for surgery.

Although disconnecting half of the brain is an extremely radical procedure, the developing brain of a child possesses a remarkable ability to compensate for the loss. Dr. Mathern explained, “Although counterintuitive, hemimegalencephaly patients are far better off following the functional disconnection and removal of the enlarged hemisphere. Prior to the surgery, most patients have devastating epilepsy, with hundreds of seizures per day, completely resistant to even our most powerful anti-seizure medications. The surgery disconnects the affected hemisphere from the rest of the brain, stopping the seizures. If performed at a young age and with appropriate rehabilitation, most children suffer less language or cognitive delay, due to the neural plasticity of the remaining hemisphere.”

Despite, the benefits of a hemispherectomy for these patients, medical treatment of the disorder may prove to be a far better alternative. “We know that certain already-approved medications can ‘turn down’ the signaling pathway used by the mutated genes in hemimegalencephaly,” noted lead author and former UC San Diego postdoctoral researcher Jeong Ho Lee. He added, “We would like to know if future patients might benefit from such a treatment. Wouldn’t it be wonderful if our results could prevent the need for such radical procedures in these children?”