The Energy-Deficit Hypothesis of Autism

This hypothesis paper proposes that autism spectrum disorder (ASD) is fundamentally an immune-metabolic disorder characterized by TNF-α-mediated mitochondrial dysfunction. The resulting cerebral energy deficit impairs two critical processes: (1) synaptic pruning during neurodevelopment, and (2) real-time social cognition including gaze processing and emotion recognition. I synthesize evidence showing that parental autoimmune diseases—psoriasis (OR 1.59), type 1 diabetes (OR 1.49-2.36), and rheumatoid arthritis (OR 1.51)—all TNF-α-mediated conditions—significantly increase offspring autism risk. Based on this framework, I propose a novel, testable prediction: parents with normal-tension glaucoma (NTG), another TNF-α-mediated neurodegenerative condition, will show elevated prevalence of autistic offspring. To my knowledge, no published study has examined this association. This unified "energy-deficit hypothesis" explains core autism symptoms from a mechanistic perspective and suggests potential therapeutic targets including anti-TNF interventions and mitochondrial support.