Researchers at the UC San Diego School of Medicine have come across a biochemical reaction hypothesized to be responsible for the development of autism spectrum disorder in early childhood. In a recent study, researchers identified several biochemical pathways where a change in metabolism occurs, which could lead to the early detection of ASD in children. 

ASD is a developmental disorder that affects an individual’s ability to communicate and socialize. Autism can be diagnosed at any age, but symptoms are often apparent in the first two years after birth.

Robert Naviaux, professor in the departments of medicine, pediatrics, and pathology at the UC San Diego School of Medicine, has spent the last 10 years testing his theory that ASD is a metabolic condition. He and other researchers are finding evidence that both genetic and environmental risk factors influence the development of ASD. 

“At birth, the physical appearance and behavior of a child who will develop autism over the next few years are indistinguishable from that of a neurotypical child. Indeed, in most cases the fate of the child with regard to autism is not set at birth,” Naviaux said. 

Children whose neurological development does not contain any abnormalities are considered neurotypical, while those whose neurological development differs from what is considered standard are neurodivergent. 

“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,” Naviaux said.

The study consisted of two cohorts: one that analyzed the newborn dried blood samples of children ages three to 10 and the other that analyzed the biochemical pathways of five-year-old children. Both cohorts consisted of a group of children who had been diagnosed with ASD and a control group of neurotypical children.

“It was because we knew which children would develop ASD later that we were able to call one group ‘pre-ASD.’ The other group we knew would not develop ASD because they were neurotypical when they reached three to 10 years of age,” said Naviaux.

To analyze the metabolic profiles of the newborn blood, researchers studied the metabolites of the children closely using a method known as mass spectrometry.

“We used a laboratory technique called mass spectrometry to measure about 450 natural chemicals in the blood. Just as genomics studies many genes, metabolomics studies many metabolites and how they interact,” said Naviaux.

Upon comparing the dried blood of children in the newborn cohort who were eventually diagnosed with ASD with those of neurotypical children, researchers identified 14 biochemical pathways responsible for the metabolism of autism. 

“We used a laboratory technique called mass spectrometry to measure about 450 natural chemicals in the blood,” he explained. “These chemicals were grouped into 50 different biochemical pathways. Of all the pathways studied, the pathway called purine metabolism was most changed during child development.”

The purine metabolism pathway is involved in activating the cell danger response, which protects cells from external threats. The purine network revealed a metabolic process in typically developing children, but not in children who developed ASD. Safeguards are produced in response to sensory overexcitation. Naviaux believes that the dysfunction in the development of these safeguards is responsible for autism. 

“During development of neurotypical children, the newborn pattern of excitatory purine connections is reversed to a pattern that has more inhibitory than excitatory connections by five years of age,” he said. “These excitatory connections in ASD cause what is called sensory over-responsivity.”

Naviaux hypothesizes that sensory over-responsivity is what causes children with ASD to have intense responses to everyday stimuli.

“Because the newborn pattern of excess excitatory ATP-related connections persisted in children with ASD, they were not able to dampen spikes in calcium release that are part of many kinds of sensory stimulation,” he said. “The new metabolic network methods allowed us to visualize the pathways that drive sensory over-responsivity, and lead to persistent activation of the cell danger response in many children with ASD.”

The persistent activation of the CDR can cause cells to become stuck in a defensive state, which Naviaux attributes to the cause of autism.

“When cells are injured, stressed, or perceive a threat, the cell danger response is triggered. Cells behave like countries at war,” he explains. “They harden their borders. They don’t trust their neighbors. But without constant communication with the outside, cells begin to function differently.”

Regarding the symptoms of ASD, Naviaux links metabolism with behavior. The chemicals of metabolism that cells use to communicate are used by all the cells in the body. When changes in metabolism occur and the cell danger response is continually activated, cells communicate to the body to remain in a state of overexcitation to external stimuli. The communication between cells and how they respond to each other will reflect in children’s behavior.

“Metabolism is the language that the brain, gut, and immune system use to communicate. These systems are linked,” he said. “You can’t change one without changing the others.”

Now that the biochemical pathways that alter autism have been identified, Naviaux and other scientists have begun to work on testing drugs with therapeutic potential for reducing symptoms of ASD. Naviaux has tested the drug Suramin, which targets the CDR and induces cells to retreat from their defensive states. Initial tests have shown positive results of the drug’s effectiveness in reducing symptoms of autism.