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Perspective: Using Information on Somatic Mutations to Direct Management of Neurological Disorders

Key findings

  • Next-generation sequencing technologies and bioinformatic pipelines have made it possible to identify somatic variants in brain tissue biopsies and surgical resection samples
  • Somatic mutations in the MTOR gene are now known to cause focal cortical dysplasia and hemimegalencephaly, and mTOR inhibitors are promising medical therapies for those congenital syndromes
  • Similarly, somatic mutations in genes comprising the MAPK pathway are associated with mesial temporal lobe epilepsy, and somatic mutations in the KRAS gene have been implicated in arteriovenous malformations; agents already exist to target both pathways
  • Neurosurgeons are creating innovative approaches to obtaining tissue samples during common clinical procedures, such as acquiring DNA from stereo-electroencephalography electrodes or, someday, from the electrodes used for deep-brain stimulation

For years, somatic mutations—acquired genomic alterations present in some body cells and not others—have been analyzed in tissue obtained from surgical biopsies or resections of brain tumors. The information gained led to a revolution in prognostication and personalized treatments in neuro-oncology.

Now, somatic mutations are increasingly being implicated in neurological disorders beyond cancer. Most studies have relied on post-mortem brain samples, but DNA and RNA can degrade after death. Samples from other tissues, such as blood, are also non-optimal because variants specific to brain cells may not be present.

In a Perspectives article in Science, Kristopher T. Kahle, MD, PhD, director of Pediatric Neurosurgery in the Massachusetts General Hospital Department of Neurosurgery, along with colleagues Eduardo Maury, PhD and Christopher Walsh, MD, PhD, from Boston Children’s Hospital, explained that neurosurgeons are now identifying somatic mutations relevant to non-oncologic neurological disease from fresh brain tissue collected in the operating room.

The resulting insights may lead to "molecular scalpels"—pharmacotherapy and gene therapies that could help some patients avoid highly morbid surgeries.

Congenital Focal Cortical Dysplasia Syndromes

Next-generation sequencing technologies and bioinformatic pipelines have made it possible to identify somatic variants in neurosurgically resected samples from children with focal cortical dysplasia (FCD) or hemimegalencephaly (HMG). Using that approach, scientists identified somatic mutations in the mechanistic target of the rapamycin (MTOR) gene that increase mTOR pathway activity and cause those disorders.

Therefore, orally available inhibitors of the mTOR pathway represent promising treatment options for patients with FCD or HMG, whether as monotherapies or adjuncts to surgical resection. These inhibitors include drugs already approved by the FDA: sirolimus, everolimus, and duvelisib.


Somatic mutations have also been implicated in mesial temporal lobe epilepsy. A study of 105 hippocampal samples resected from patients with that type of epilepsy, published in JAMA Neurology, detected pathogenic somatic variants in multiple genes known or predicted to activate the mitogen-activated protein kinase (MAPK) signaling pathway. Certain established anticancer agents target that pathway and might become adjuncts to neurosurgery or a primary treatment option.

Arteriovenous Malformations

Research into somatic mutations in arteriovenous malformations (AVMs) has revealed activating mutations in the KRAS gene that can be therapeutically targeted.

In one such study, which appeared in NEJM, pathogenic somatic mutations in KRAS were enriched in brain endothelial cells from 26 patients with AVMs. Applying MAPK kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) inhibitors to the cells downregulated the KRAS signaling pathway.

Innovative Tissue Sampling

Neurosurgeons are creating innovative approaches to obtaining tissue samples during common procedures. A current example is acquiring DNA from electrodes used to identify the source of epileptogenic activity, once they have been removed from the brain.

Approaches that are still theoretical include:

  • Endovascular sampling of blood vessel lumens during diagnostic cerebral angiography; this approach could also allow for surgical planning based on the molecular profile of the vascular pathology
  • Sampling tissue along the path of deep-brain stimulation electrodes in Parkinson's disease and other neurodegenerative disorders
  • Biopsies of the insertion site when implanting a ventricular shunt in a patient with normal-pressure hydrocephalus

Neurosurgeons who are leading innovation in tissue sampling and data analysis are focused on maximizing not only how much can be learned from patients but also how the findings can be translated into better outcomes.

Learn more about the Department of Neurosurgery

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