Pathophysiology of mitochondrial disease causing epilepsy and status epilepticus

- Epilepsy is a frequent feature of mitochondrial disease.
- The molecular mechanisms underlying mitochondrial epilepsy are incompletely understood.
- Neuronal energy depletion, oxidative stress, and abnormal calcium signaling are key mechanisms.
- Immune mechanisms may also contribute to mitochondrial epilepsy.
- Vitamin, cofactor, and metabolite deficiencies are emerging as pathological mechanisms.

Epilepsy is part of the clinical phenotype in nearly 40% of children with mitochondrial disease, yet the underlying molecular mechanisms remain poorly understood. Energy depletion has been postulated as the cause of mitochondrial epilepsy, but if this were the case, then 100% of patients with mitochondrial disease would be expected to present with seizures. This review explores other potential disease mechanisms underlying mitochondrial epilepsy, including oxidative stress, impaired calcium homeostasis, immune dysfunction, and deficiency of vitamins, cofactors, reducing equivalents, and other metabolites. Different mechanisms are likely to predominate in different mitochondrial disorders, since mitochondrial function varies between neurons and astrocytes, between different types of neurons, and in different brain regions. Systematic studies in cell and animal models of mitochondrial disease are needed in order to develop effective therapies for mitochondrial epilepsy.This article is part of a Special Issue entitled “Status Epilepticus”.