The Energy-Deficit Hypothesis of Autism: Linking Parental TNF-α-Mediated Diseases to Offspring Autism Risk via Mitochondrial Dysfunction

Background: Autism spectrum disorder (ASD) affects approximately 1-2% of children worldwide, yet its etiology remains incompletely understood. Emerging evidence suggests that parental autoimmune diseases significantly increase offspring autism risk, with psoriasis (OR 1.59), type 1 diabetes (OR 1.49-2.36), and rheumatoid arthritis (OR 1.51) showing particularly strong associations. Hypothesis: I propose that autism is fundamentally an immune-metabolic disorder characterized by TNF-α-mediated mitochondrial dysfunction leading to cerebral energy deficiency. This energy deficit impairs two critical processes: (1) synaptic pruning during neurodevelopment, and (2) real-time social cognition including gaze processing and emotion recognition. The primary mechanism involves TNF-α pathway dysregulation—through genetic inheritance from parents with autoimmune diseases and/or through direct fetal exposure to elevated maternal TNF-α during pregnancy. Additionally, for cases without parental autoimmune history, I propose a speculative secondary mechanism: mitonuclear immune conflict, where paternal immune genes may partially recognize maternal mitochondria as non-self, generating endogenous TNF-α. Novel Prediction: Based on this framework, I predict that parents with normal-tension glaucoma (NTG)—another TNF-α-mediated condition characterized by neurodegeneration independent of intraocular pressure—will show elevated prevalence of autistic offspring. This prediction has not been tested in any published study. Implications: This hypothesis unifies disparate observations about autism pathophysiology and suggests that anti-inflammatory interventions targeting the TNF-α pathway may have therapeutic potential, particularly when administered early in neurodevelopment.