A new review by Dr. John Jay Gargus MD-PhD, Founding Scientist/Chief Scientific Officer of NeuroQure and Founding Director of the Center for Autism Research and Translation at the University of California, Irvine, offers a unifying framework for understanding the biological underpinnings of autism spectrum disorder (ASD) through the lens of energy metabolism and calcium signaling.

Published in GENES, "Genetic Dissection of Energy Deficiency in Autism Spectrum Disorder," integrates decades of work in human genetics, neurobiology, and evolutionary physiology to show that autism's core features may arise from subtle failures in the brain's energy-production machinery, reflecting vulnerabilities that trace back to the rapid evolutionary expansion of the human brain.

The Evolutionary Perspective

Dr. Gargus's review traces how the human brain, long similar in size to a chimp's, underwent a sudden tripling in size about 70,000 years ago during the coldest part of the Ice Age. In a small group of survivors, likely sustained by coastal shellfish, the higher association cortex rapidly expanded; an evolution driven by fast-changing DNA regions called human accelerated regions (HARs). This leap gave rise to language, art, and culture, but it may also have created a hidden weakness: a brain highly dependent on energy. That vulnerability, seen today as mitochondrial dysfunction and disrupted calcium signaling, may help explain the biological roots of autism.

"The human brain's accomplishments from new extraordinary energy requirements were a triumph of evolution, but that very triumph may also represent its Achilles' heel. When the delicate coupling between calcium signaling and mitochondrial energy production falters, the result is a brain under metabolic stress, which is precisely where we see it in autism."

Dr. John Jay Gargus, Founding Scientist/Chief Scientific Officer, NeuroQure

Linking Cellular Energy to Autism

Dr. Gargus's review links autism to disruptions in cellular energy regulation, showing that individuals with ASD often have mitochondrial dysfunction and oxidative stress tied to faulty calcium signaling. His team has identified defects in the ITPR calcium channel as a key driver that impairs communication between energy-producing structures in cells and reduces ATP levels in brain regions vital for social and sensory function.

The paper also spotlights the BTBR mouse model, which carries a mutation in the Itpr3 gene that may mirror these same energy deficits, pointing to a promising new direction for research targeting calcium signaling in autism.

A New Era of Autism Research

The review concludes that restoring metabolic resilience and calcium-signal integrity could open new diagnostic and therapeutic avenues for ASD.

"We're entering a new era of autism research. By integrating genetics, metabolism, and neurodevelopment, we can begin to identify biomarkers and interventions that truly address the disorder's cellular foundations."

Dr. John Jay Gargus