Ketogenic Diet as an Epigenetic Therapy in SETD1B ‐Related Epilepsy

Histone lysine methyltransferases such as SETD1B regulate chromatin structure and gene transcription. Ketone bodies, including butyrate, act as histone deacetylase inhibitors. We report a 4‐year‐old boy with SETD1B ‐related absence epilepsy, refractory to conventional medications, who achieved sustained > 90% seizure reduction on the Modified Atkins ketogenic diet. Single‐cell RNA sequencing of 25,159 peripheral mononuclear cells across 3 samples: baseline, 3 months on‐diet and age‐matched control, revealed widespread dysregulation of the patient's chromatin, ribosomal, immune and mitochondrial pathways at baseline, which were reversed with ketogenic therapy. These findings suggest that the ketogenic diet can improve gene regulation in chromatin‐mediated brain disorders.