Drug-Resistant Epilepsy Caused by DNMT1-Associated Neurodegenerative Syndrome: A Mitochondrial Disease Mimic

Background: DNMT1 gene-related neurodegenerative disorder is a rare autosomal dominant condition associated with progressive neurological decline, typically involving sensory predominant neuropathy, sensorineural hearing loss, seizure, cerebellar ataxia, and cognitive impairment. The responsible enzyme is deoxyribonucleic acid (DNA) methyltransferase 1, one of the important enzymes for methylation during DNA replication and repair. Case Report: A 61-year-old man with no comorbidities presented with a longstanding neurological illness spanning more than 40 years. He had drug-resistant generalized tonic–clonic seizures of unknown onset, gradually progressive hearing loss, gradually progressive symmetric vision loss, gait difficulty, left-sided retrocollis, and spasmodic dysarthria. Family history was positive for sudden cardiac arrest in mother and walking difficulty in maternal cousin. He was initially considered to have mitochondrial cytopathy, because of elevated cerebrospinal fluid lactate levels, positive maternal family history, optic neuropathy, progressive gait difficulty, and myopathic features. Over time, his condition gradually worsened, with recurrent seizures, bilateral optic atrophy, profound sensorineural hearing loss, progressive dystonia, psychosis, hallucinations, and significant functional decline. Over the years, serial investigations including magnetic resonance imaging scans, electrophysiological studies, metabolic workup, and muscle biopsy, pointed toward a possible mitochondrial or other neurodegenerative process. However, definitive diagnosis was established only after genetic testing confirmed a DNMT1 mutation (c.4795G>A p.Gly1599Arg). The patient has been on treatment with levetiracetam, oxcarbazepine, and clobazam along with medications for dystonia and mitochondrial cocktail with stabilization of the disease course over 8 years. Discussion: This case highlights the considerable clinical overlap between DNMT1-related disorders and mitochondrial diseases. As DNMT1 plays a role in DNA methylation, including epigenetic regulation that can influence mitochondrial function, mutations in DNMT1 may produce clinical features that resemble mitochondrial disorders. Publication History Article published online: 15 July 2026 © 2026. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Thieme Medical and Scientific Publishers Private Limited A-13A, Graphix Tower 1, 6th floor, Sector 62, Noida 201309, Uttar Pradesh, India