Poster Presentation AUS-oMicS 2025

Cerebrospinal fluid metabolomics in autistic regression reveals dysregulation of sphingolipids and decreased β-hydroxybutyrate (120594)

Jinni Yan 1 2 , Velda X Han 3 , Timothy A Couttas 4 , Russell C Dale 2
  1. Faculty of Science, University of Technology Sydney, Ultimo, NSW, Australia
  2. Clinical School, Faculty of Medicine and Health, University of Sydney, Westmead, NSW, Australia
  3. Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  4. Neuroscience Research Australia, Randwick, NSW, Australia

Autism is highly heritable, however actionable genetic findings are only found in a minority of patients. Many people with autism suffer loss of neurodevelopmental skills, known as autistic regression. The cause of regression is poorly understood, and the diagnostic and therapeutic pathways are lacking. Metabolomics has emerged as a promising tool to explore underlying biochemical disruptions and to discover novel biomarkers for neurodevelopmental disorders. We performed untargeted followed by targeted CSF metabolomics to discover biomarkers in children with autistic regression, with the aim to provide insights into disease mechanisms, and potential future therapeutic opportunities.

Untargeted metabolomics using a UPLC-Q-Exactive-HFx Mass Spectrometry examined cerebrospinal fluid from twenty-two patients with autistic regression compared to sixteen controls with neurodevelopmental disorders and thirty-four controls with other neurological disease. Untargeted case-control studies revealed good separation of patients from controls using multivariate analysis. β-hydroxybutyrate was significantly decreased in patients with autistic regression, and the findings were validated using a targeted β-hydroxybutyrate assay. In the discovery case-control studies, sphingolipid metabolism pathways were also significantly dysregulated. We therefore developed a targeted metabolite assay of forty sphingolipids. After FDR correction, 21 of the 40 sphingolipids were significantly dysregulated (pFDR<0.05) in autistic regression compared to the neurodevelopmental controls, and 26 of the 40 sphingolipids were significantly dysregulated in autistic regression compared to other neurological controls.

There are very few studies comparing alterations in CSF metabolite profiles in autism spectrum disorders and the literature in autistic regression is even more scarce. The reproducibility of CSF metabolomics findings in our discovery and targeted studies provides insight into the pathophysiology of autistic regression, with the potential for clinical and therapeutic translation.