The Energy-Deficit Hypothesis of Autism: TNF-α-Mediated Mitochondrial Dysfunction as a Common Pathway from Parental Immune Dysregulation to Offspring Autism Risk

Background: Autism spectrum disorder (ASD) affects approximately 1-2% of childrenworldwide, yet its etiology remains incompletely understood. Emerging evidence suggeststhat offspring of parents with autoimmune diseases show elevated autism prevalence.Notably, children of parents with psoriasis (OR 1.59), type 1 diabetes (OR 1.49-2.36), andrheumatoid arthritis (OR 1.51) demonstrate particularly strong associations. Hypothesis: I propose that autism may be conceptualized as an immune-metabolic disorderin which TNF-α-mediated mitochondrial dysfunction contributes to cerebral energydeficiency. This energy deficit impairs three critical processes: (1) synaptic pruning duringneurodevelopment, (2) real-time social cognition including gaze processing and emotionrecognition, and (3) protein synthesis of critical synaptic scaffolding molecules.The proposed mechanism is TNF-α pathway dysregulation arising from inheritedinflammatory susceptibility and/or direct fetal exposure to elevated maternal TNF-α duringpregnancy.I further propose that the well-documented “firstborn effect” in autism reflects maternalimmune maladaptation during primigravid pregnancies. Additionally, for cases withoutparental autoimmune history, a speculative secondary mechanism is proposed: mitonuclearimmune conflict, where paternal immune genes may partially recognize maternalmitochondria as non-self, generating endogenous TNF-α.