Early metabolic changes linked to autism

Summary: Researchers have discovered significant metabolic changes that occur between birth and the onset of autism spectrum disorder (ASD) symptoms. This study reveals that a few biochemical pathways, largely linked to the body’s cellular response to danger, are responsible for the majority of these changes.

The results, which highlight the link between metabolism and the development of ASD, could pave the way for new early detection and intervention strategies. By identifying these metabolic differences at an early stage, the study opens the door to potential treatments targeting specific metabolic pathways, potentially modifying the course of ASD.

Highlights:

1. The study found that 14 of the 50 biochemical pathways studied account for 80% of autism-related metabolic changes, highlighting the cellular response to danger as a key area of ​​interest.
2. Early metabolic changes can be identified before ASD symptoms become apparent, providing a window for early intervention.
3. Researchers believe that targeting these specific metabolic pathways could lead to new treatments, such as the use of drugs like suramin that influence ATP signaling.

Source: UCSD

Researchers at the University of California San Diego School of Medicine have shed new light on the metabolic changes that occur between birth and the onset of autism spectrum disorder (ASD) later in childhood .

Researchers have found that a small number of biochemical pathways are responsible for the majority of these changes, which could help inform new strategies for early detection and prevention of autism.

“At birth, the physical appearance and behavior of a child who will develop autism over the next few years are indistinguishable from those of a neurotypical child. Indeed, in most cases, the child’s fate with respect to autism is not fixed at birth,” said Robert Naviaux, MD, Ph.D., professor in the Departments of Medicine, of Pediatrics and Pathology from the UC San Diego School of Medicine.

“We are beginning to learn more about the governing dynamics that regulate the transition from risk to the actual onset of early ASD symptoms. Early diagnosis opens the possibility of early intervention and optimal outcomes.

ASD is a developmental disorder characterized by difficulties with socialization and communication, as well as repetitive and/or restrictive behaviors. For the majority of people with ASD, this condition constitutes a significant disability, with only 10 to 20 percent of children diagnosed before age 5 able to live independently as adults.

Although autism is known to have strong genetic risk factors, there are also environmental risk factors that play a role in the development and severity of ASD. Naviaux and other researchers are discovering that the development of autism is governed by the real-time interaction of these various factors.

By studying the developmental biology of metabolism and its differences in autism, new knowledge is emerging about ASD and other complex developmental disorders.

“Behavior and metabolism are linked, we cannot separate them,” Naviaux added.

To learn more about the early metabolic changes that occur in children with autism, researchers studied two cohorts of children. One cohort consisted of newborns in whom autism cannot be detected. The second cohort consisted of 5-year-old children, some of whom had been diagnosed with autism.

Comparing the metabolic profiles of children in the cohort who were ultimately diagnosed with autism to those who developed neurotypically, they found striking differences. Of the 50 different biochemical pathways the researchers studied, just 14 were responsible for 80 percent of the metabolic impact of autism.

The pathways that were most altered were related to the cellular danger response, a natural and universal cellular reaction to injury or metabolic stress. The body has biochemical protections that can shut down the cellular response to danger once the threat has passed, and Naviaux hypothesizes that autism occurs when these protections do not develop normally.

The result is increased sensitivity to environmental stimuli, and this effect contributes to sensory sensitivities and other symptoms associated with autism.

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

The cellular response to danger is primarily regulated by adenosine triphosphate (ATP), the body’s chemical energy currency. Although these ATP signaling pathways do not develop normally in autism, they can be partially restored with existing pharmaceutical drugs.

In 2017, Naviaux and his team performed the first clinical tests on suramin, the only drug approved in humans capable of targeting ATP signaling and which is normally used to treat African sleeping sickness.

The researchers now hope that by revealing the specific ATP-related pathways that are impaired in autism, their work will help scientists develop more drugs targeting these pathways to manage ASD symptoms.

“Suramin is just one drug that targets the cellular response to danger,” he said. “Now that we are closely studying how metabolism changes in ASD, we could be at the start of a drug renaissance that will create new treatment options that never existed before.”

Study co-authors include: Sai Sachin Lingampelly, Jane C. Naviaux, Jonathan M. Monk, Kefeng Li and Lin Wang of UC San Diego School of Medicine and Luke S. Heuer, Lori Haapanen, Chelsea A. Kelland and Judy Van. of Water at the University of California Davis.

Funding: This work was supported, in part, by Autism Speaks (grant 7274), the National Center for Research Resources (grant UL1TR001442), and various philanthropic donations.

Robert Naviaux is a member of the scientific advisory board of The Autism Community in Action (TACA), the Open Medicine Foundation (OMF), Pannex Therapeutics, Yuva Biosciences, Kuzani, and PaxMedica.

About this autism research news

Author: Miles Martin
Source: UCSD
Contact: Miles Martin – UCSD
Picture: Image is credited to Neuroscience News

Original research: Free access.
“Analysis of metabolic networks of pre-ASD newborns and 5-year-old children with autism spectrum disorders” by Robert Naviaux et al. Communication biology

Abstract

Metabolic network analysis of pre-ASD newborns and 5-year-old children with autism spectrum disorders

Classic metabolomics methods and novel metabolic networks have been used to study the developmental characteristics of autism spectrum disorders (ASD) in newborns (not= 205) and children aged 5 (not= 53).

Eighty percent of the metabolic impact of ASD was due to 14 common biochemical pathways that led to a decrease in anti-inflammatory and antioxidant defenses, as well as an increase in physiological stress molecules like lactate, glycerol, cholesterol and ceramides. CIRCOS graphs and a new metabolic network parameter, 𝑉˙_netrevealed differences in the type and degree of network connectivity.

Among 50 biochemical pathways and 450 polar and lipid metabolites examined, the developmental regulation of the purine network was the most altered.

Purine network analysis revealed a 17-fold reversal in typically developing children. This reversal of the purine network did not occur in ASD cases.

These results revealed previously unknown metabolic phenotypes, identified novel developmental states of the metabolic correlation network, and highlighted the role of mitochondrial functional changes, purine metabolism, and purinergic signaling in autism spectrum disorders.