ANA2022 Plenary Session Spotlight: Annapurna Poduri, MD, MPH, and Sattar Khoshkoo, MD | Somatic Mutations in Neurological Disease

Mutations Under the Radar: A Patchwork of Somatic Variation May Drive Neurologic Disease

The ANA2022 plenary session, “Emerging Role of Somatic Mutations in Neurology,” will take place Monday, October 24, 2022, from 8:45 to 10:45 a.m. Register now to attend the Annual Meeting in Chicago!

New treatment pathways for disorders like epilepsy are coming into view thanks to a revolution in genomics. A novel area of genomics involves somatic mutations: post-zygotic genetic changes that result in genetic variants that may be present in only part of the body or brain. Somatic mutation is the subject of an ANA2022 plenary session highlighting its role in the genesis of non-cancer neurological disorders, including both neurodevelopmental and neurodegenerative disease. 

We spoke with plenary chair Annapurna Poduri, MD, MPH, Director of the Epilepsy Genetics Program at Boston Children’s Hospital, and co-chair Sattar Khoshkoo, MD, Instructor in Neurology at Brigham and Women’s Hospital.

How does emerging knowledge about somatic mutation change how we understand neurological disease?

Annapurna Poduri: Most physicians think somatic mutation equals cancer. Yet the same phenomenon of genetic mutation leading to variants located in the brain can give you non-cancer developmental abnormalities, brain malformations, and changes later in life. 

When we started looking at brain tissue from children with epilepsy compared to, for example, their blood, we found some really big genetic differences. We’ve found that the same phenomenon that happens in cancer has happened early in the brain: a mutation during development leads to abnormal, variant-positive cells in a region of the brain, which becomes seizure-generating. The cancer-meets-neurology part is new.

Sattar Khoshkoo: Somatic mutations actually allow for diseases that are sporadic and focal in the brain such as some epilepsies to have genetic etiologies. Any mutation that arises beyond the zygote’s first division is a somatic mutation. The later it occurs, the smaller the percentage of your cells that have the resulting variant. For example, with the focal epilepsies that Dr. Poduri studies, somatic variants are often not present outside the brain tissue—and as few as 1–5% of cells in the brain may carry it. Epilepsy is the first neurologic disorder aside from brain tumors in which we’ve identified a role for somatic mutation, but I suspect that we’ll identify many more roles in neurologic disease.

How could this be relevant for adult diseases?

Poduri: Something we’ve learned in the last decade is that even when you look at control brains of older people who didn’t have any neurodevelopmental conditions, you realize that we are all just mosaic patchwork quilts that are the results of post-zygotic events—although most of them are little changes that aren’t causing disease. 

Khoshkoo: As an adult epileptologist, I still believe a lot of “adult” epilepsy is the result of somatic mutations occurring either during gestation or maybe during the first couple years of life, but which don’t manifest until later in life. 

In addition, the older you get, individual neurons or cells that are terminally differentiated are going to also develop more somatic mutations. These so-called private mutations may have a role in causing neurodegenerative disease. For example, individuals with Alzheimer’s disease have a much higher rate of these private mutations in the neurons in the brain. 

How might this symposium affect attendees’ research and clinical practice?

Poduri: We have had this amazing opportunity to do a lot of discovery science. Our job now as clinician-scientists is to get it back to the patients. My hope is that everybody who sees a patient with any of these focal disorders will stop and think: Is this a somatic mutation? What should I do to work it up? And that every basic scientist in the audience will think, wow, this is something I want to work on and help move things forward.

Khoshkoo: We are fortunate as epileptologists that the disease we clinically treat happens to be one of the first where the connection between somatic mutations and disease is being worked out. Yet very little of that has made it into the clinic and affected actual patient care and diagnostics. We finally have a cause for the disease, so ideally in the future we will have the ability to make the diagnosis without taking a whole chunk of the brain out. We should have treatments that specifically target the molecular reason why the seizures are happening, and avoid years of unsuccessful treatment and also the potential sequelae of large brain surgeries. That, ultimately, is the goal.