A 3-hit metabolic signaling model for the core symptoms of autism spectrum disorder

A 3-hit metabolic signaling model of the causes of autism spectrum disorder (ASD) is described. The 3-hits required for ASD are: 1) inheritance of a genotype that sensitizes mitochondria and/or eATP-stimulated, intracellular calcium signaling to environmental change, 2) early exposure to environmental triggers that activate the metabolic features of the cell danger response (CDR), and 3) recurrent or persistent exposure to CDR-activating triggers for at least 3-6 months during the critical neurodevelopmental window from the late 1st trimester of pregnancy to the first 18-36 months of life. The three hits associated with an increased risk of ASD can be functionally classified as primers, triggers, and amplifiers of the CDR, respectively. Since the CDR is maintained by metabolic signaling, this new model creates a unified intellectual framework for understanding how the diverse features of ASD are connected. The example of phenylketonuria (PKU) is given to show that even disorders with very strong genetic predispositions can follow this 3-hit developmental paradigm and still be treatable using the principles of metabolic signaling. Since the 2nd and 3rd hits are modifiable, this model predicts that if the children at greatest risk can be diagnosed and treated before symptoms occur, as many as 40-50 % of these children may never develop ASD, and if diagnosed after symptoms occur, the core symptoms that are most disabling can be decreased significantly. Lay summary. A 3-hit developmental model for autism spectrum disorder is described. New methods in systems biology have identified a pattern of changes in mitochondrial function and metabolism that underlie the core symptoms of ASD. The metabolic features of the cell danger response (CDR), maintained by abnormalities in ATP-related purinergic signaling, have emerged as a common denominator for each of the genetic and environmental causes of ASD studied to date.