ABSTRACT Objective Super‐Refractory Status Epilepticus (SRSE) is a rare, life‐threatening neurological emergency with unclear etiology in many cases. Mitochondrial dysfunction, often due to disease‐causing genetic variants, is increasingly recognized as a cause, with each gene producing distinct pathophysiological mechanisms. Methods We describe the detailed clinical, neurophysiological, neuroimaging, and molecular findings of a 19‐year‐old female with SRSE associated with compound heterozygous variants in OPA1 , a key gene for mitochondrial inner membrane fusion and cristae maintenance. In addition, a literature review was performed, identifying 16 previously published cases reporting one or both of the variants observed in the present case. Results Despite a longstanding history of generalized hypotonia, celiac disease, optic atrophy, cerebellar ataxia, and progressive motor decline, the proband had no prior history of seizures. She developed super‐refractory status epilepticus with occipital‐predominant epileptiform activity and MRI showing transient diffusion restriction in the right parieto‐occipital cortex and cerebellum. Genetic testing revealed a frameshift variant (p.Val903GlyfsTer3) and a missense variant (p.Ile382Met) in the GTPase domain, known to impair mitochondrial fusion. Unlike POLG or MELAS‐associated seizures, typically driven by severe mtDNA depletion and respiratory chain failure, OPA1 dysfunction usually spares mtDNA copy number but disrupts mitochondrial dynamics. In severe biallelic loss‐of‐function, a “second‐hit” stressor may trigger a diffuse energy crisis and catastrophic seizures. Interpretation This case of mitochondrial SRSE in a patient with no known infectious, autoimmune, or structural cause emphasizes the possible role of genetic background and mitochondrial disorders in the development of the disease. This case highlights a rare mitochondrial subtype of RSE, emphasizing the need to consider energy metabolism defects in unexplained refractory status epilepticus.
Mohammadi et al. (Wed,) studied this question.