Hurley, Dan

doi: 10.1097/01.NT.0000521715.10826.a9

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Isaac Marin-Valencia, MD, recipient of an AAN Clinical Research Training Scholarship, is studying clinical and molecular aspects of pontocerebellar hypoplasia, a brain metabolism disorder so rare it is virtually unseen in the United States. Here, he discusses his research.

BOSTONFrom the Canary Islands to New York by way of Spain and Texas, Isaac Marin-Valencia, MD, has dedicated his career to investigating pediatric neurologic diseases as exotic as his homeland.

The recipient of an AAN Clinical Research Training Scholarship, Dr. Marin-Valencia is studying clinical and molecular aspects of pontocerebellar hypoplasia, a brain metabolism disorder so rare it is virtually unseen in the United States.

All our patients are in the Middle East, because of the high rates of consanguinity, Dr. Marin-Valencia said during a break from the AAN Annual Meeting here in April. I've been to Cairo, to work with collaborators in hospitals there.

Born and raised in the Canary Islands, the Spanish archipelago off the coast of Morocco, Dr. Marin-Valencia grew up with a younger brother, Abimael, who had autism and epilepsy. He decided when he was six to become a doctor to help Abimael.

He was the reason for my career path, Dr. Marin-Valencia said. He's the inspiration for me to continue working on brain disorders that don't have treatments.

After graduating from medical school at the University of Las Palmas de Gran Canaria, he completed his four-year residency in pediatrics at Sant Joan de Deu Hospital of Barcelona. It was there he met Juan Pascual, MD, PhD, a pediatric neurologist who became his mentor.

I was very impressed by his knowledge and expertise is in brain metabolism disorders, Dr. Marin-Valencia said.

It was in Barcelona that he first began seeing young patients with the disorders that Dr. Pascual specialized in treating. I learned a lot about biochemistry and got fascinated, he said.

In 2008, he moved to the University of Texas-Southwestern Medical Center, to pursue postdoctoral research in pediatric neurology. Three years later, a poster of his won a grand prize at the university's postdoctoral research symposium, becoming the basis of a paper, published in the journal Cell Metabolism, that overturned 50 years of scientific dogma.

The so-called Warburg effect, named after Nobel Prize winner Otto Warburg, had been based on his in vitro observation that cancer cells preferentially metabolize glucose to lactate, even in the presence of sufficient oxygen in the mitochondria.

Dr. Marin-Valencia and colleagues disproved the long-held assumption that the same process holds true in vivo, using human glioblastomas implanted into the mouse brain to show that the cells' mitochondria oxidize glucose.

Determined to get back to his primary interest in metabolic disorders of the brain, he moved to Rockefeller University in 2015 to study human genetics and developmental neurobiology.

My background until then was in biochemistry and electrophysiology, Dr. Marin-Valencia said. I was missing two important pieces of the puzzle. Most of these metabolic disorders are genetic, and therefore they affect development of the brain. Learning these two areas have helped me to have a global picture about these disorders. If you're an expert in just one thing, you're going to miss other important facets that could be essential to understand and improve the diseases. Making more connections, meeting other investigators, associating with other laboratories all of that enriches my knowledge and way of thinking.

Under the mentorship of Joseph Gleeson, MD, a pediatric neurologist and neurogeneticist at University of California, San Diego, who has identified some 200 genetic mutations linked to brain disorders, Dr. Marin-Valencia is now looking for genes associated with pontocerebellar hypoplasia.

We use zebrafish and mice, Dr. Marin-Valencia said. We knock out or knock down genes and then see if there is a problem in the development of the brain. From the developmental standpoint, we want to replicate the disease in the animal model, to see what kind of cells are compromised and when the problem is first manifested. Then we go down to the cell and molecular level to localize where the gene is expressed and what the product of the gene is, where the protein is located in the cell and what its role is. Once we know all that, once we sort out the mechanism, we try to development new therapies.

Asked if he has yet identified a particular gene associated with pontocerebellar hypoplasia, he paused and said, I cannot tell you. It's not published yet.

Ultimately, his goal is to identify treatments for diseases that are now untreatable, something Dr. Gleeson's research has already done for a number of pediatric brain diseases.

One of the major problems we have in neurology is that we have few treatments for these devastating diseases that kill children at a very early age, Dr. Marin-Valencia said. There are things we can do to alleviate pain, to alleviate suffering, to provide a better quality of life. But from the biochemical and genetic standpoint, we cannot do much to change the outcome of many of these diseases.

Might his research into pontocerebellar hypoplasia one day lead to a treatment? It's a long way, Dr. Marin-Valencia said, but we are working to get there.

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At the Bench: Inspired by a Brother, AAN Scholarship Awardee Investigates Brain Metabolism Disorders - LWW Journals