Metabolism of autism reveals developmental origins

New insights have been provided by researchers at the University of California San Diego School of Medicine into the metabolic changes that take place between birth and the later onset of autism spectrum disorder (ASD) in children. The majority of these changes can be attributed to a limited number of metabolic pathways, according to the researchers’ findings, which may guide the development of novel methods of early autism identification and prevention.

Robert Naviaux, M.D., Ph.D., professor in the Departments of Medicine, Pediatrics, and Pathology at UC San Diego School of Medicine, said, “We’re starting to learn about the governing dynamics that regulate the transition from risk to the actual appearance of the first symptoms of ASD. Early diagnosis opens the possibility of early intervention and optimal outcomes.”

In addition to the well-established genetic risk factors for autism, environmental variables can contribute to the onset and severity of ASD. Scientists are finding that the dynamic interplay of these different elements controls the course of autism development. Through research on the developmental biology of metabolism and its variations in autism, new understandings of ASD and other complex developmental diseases are being gained.

Robert Naviaux, M.D., Ph.D., a professor in the Departments of Medicine, Pediatrics, and Pathology at UC San Diego School of Medicine, said, “Behavior and metabolism are linked—you cannot separate them.”

Scientists looked at two kid cohorts to gain additional insight into the early metabolic alterations that take place in autistic children. One group included infants who were too young to have autism. Five-year-old children, some of whom had received an autism diagnosis, made up the second cohort. They discovered startling discrepancies between the metabolic profiles of youngsters in the cohort who were subsequently diagnosed with autism and those who developed neurotypically. Just 14 of the 50 distinct biochemical pathways that scientists looked into account for 80% of the metabolic effects of autism.

The cell danger response, a typical and universal cellular response to damage or metabolic stress, is associated with the pathways that saw the most significant alteration. Biochemical defenses in the body allow cells to stop responding to danger once it has passed. According to Naviaux, autism arises when these defenses don’t function properly. The outcome is increased sensitivity to outside stimuli, which exacerbates sensory sensitivity and other symptoms linked to autism.

Naviaux said, “Metabolism is the language that the brain, gut, and immune system use to communicate, and autism occurs when the communication between these systems is changed.”

The body’s chemical energy currency, adenosine triphosphate (ATP), controls the cell’s danger response. Despite the abnormal development of these ATP-signaling pathways in autism, they might be partially restored by currently available pharmaceutical treatments. The only medication authorized for use in humans that can target ATP signaling and is typically used to treat African sleeping sickness, suramin, was the subject of early clinical research that Naviaux and his team finished in 2017. Now, by identifying the precise ATP-related pathways that are disrupted in autism, the researchers hope that their findings can aid in the development of more medications that target these pathways to treat the symptoms of ASD.

Scientists noted, “Suramin is just one drug that targets the cell danger response. Now that we’re closely interrogating how metabolism changes in ASD, we could be at the beginning of a drug renaissance that will create new options for treatment that never existed before.”

Journal Reference:

1. Lingampelly, S.S., Naviaux, J.C., Heuer, L.S. et al. Metabolic network analysis of pre-ASD newborns and 5-year-old children with autism spectrum disorder. Commun Biol 7, 536 (2024). DOI: 10.1038/s42003-024-06102-y