Mitochondrial Dysfunction and Myoclonic Epilepsy

Recently, I reported 2 cases of infantile-onset myoclonic epilepsy characteristic of Dravet syndrome. ¹ Both cases possessed mutations in mitochondrial deoxyribonucleic acid (DNA) that have been associated with Leber’s hereditary optic neuropathy and did not manifest mutations within the α subunit of the sodium channel (SCN1A) gene—the most commonly known cause of Dravet syndrome. In the recent correspondence titled “Dravet Syndrome and Mitochondrial Dysfunction,” Castro-Gago et al ² point out that they previously postulated the involvement of mitochondrial dysfunction in Dravet syndrome in case reports in 1995 ³ and 1997. ⁴ Although Castro-Gago and colleagues did indeed report this association in these 2 case reports, it should be noted that infantile-onset myoclonic epilepsy was associated with mitochondrial disorders previous to their reports, first in this journal in 1991 ⁵ and 2 years later in 1993 by Mak et al. ⁶ These studies further support the notion that mitochondrial dysfunction can cause infantile-onset myoclonic epilepsy with characteristics of Dravet syndrome as hypothesized in my report. ¹

I reported the presence of mitochondrial mutations that are known to cause mitochondrial disease, ¹ whereas the reports of Castro-Gago and colleagues ^3,4,7 relied on biochemical markers of mitochondrial dysfunction to make the diagnosis of a mitochondrial disorder. This is an important distinction as mitochondrial dysfunction can be secondary to many pathophysiological processes. Some of these same pathophysiological processes can both cause and result from seizure activity. Indeed, inflammation and oxidative stress, 2 pathophysiological processes involved in both the pathogenesis and propagation of seizures, ^8–10 can result in mitochondrial dysfunction. For example, increased reactive oxygen species ^11,12 and elevated concentrations of tumor necrosis factor (TNF)–α, a proinflammatory cytokine, ^13–15 can impair mitochondrial function.

A specific connection between seizures and mitochondrial dysfunction that may be very pertinent to the cases reported by Castro-Gago and colleagues ^3,4,7 involves TNF-α. TNF-α is elevated during periods of seizures as compared to seizure-free periods ¹⁶ and has been shown to be important in the pathogenesis of epilepsy. ¹⁷ TNF-α has been shown to reduce oxidative phosphorylation by inhibiting complex IV function. ¹³ This suggests that persistent seizures could cause progressive inhibition of complex IV over time. Interestingly, this is consistent with the cases reported by Castro-Gago and colleagues ^3,4,7 and the additional case by Fernández-Jaén et al ¹⁸ referenced in their letter. Indeed, all of these cases demonstrated complex IV deficiencies. In fact, the second case that Castro-Gago and colleagues reported ⁴ suggests that complex IV deficiency developed over time after increased seizure frequency ⁷ —a notion that would support that the complex IV deficiency was acquired, not congenital. In addition, mutations in the mitochondrial polymerase γ gene, mentioned in the case by Bolszak et al ¹⁹ in the correspondence of Castro-Gago et al, ² is associated with complex IV deficiency in patients with severe myoclonic epilepsy and valproic acid–induced liver failure. ²⁰ Interestingly, other forms of myoclonic epilepsy have also been associated with complex IV deficiency. ^21,22 For example, myoclonic epilepsy with ragged red fibers (MERRF) is characterized by complex IV depletion despite the mitochondrial DNA mutation causing MERRF affecting the mitochondrial transfer ribonucleic acid genes, not complex IV genes.

The cases discussed by Castro-Gago and colleagues ² in their correspondence point to the involvement of complex IV deficiency in myoclonic epilepsy. Additional research supports this notion. However, it is critical to recognize that biochemical markers of mitochondrial dysfunction, including respiratory chain complex deficiencies, may be secondary to other pathophysiological processes. Individuals suspected of having a mitochondrial disorder should have a comprehensive evaluation with sequencing of mitochondrial DNA and targeted nuclear gene sequencing as necessary to determine whether the mitochondrial dysfunction is being caused by a primary mitochondrial disease or is secondary to another pathophysiological process. ²³ Determining the cause of the mitochondrial dysfunction can lead to specifically tailored therapy, especially if a secondary cause for the mitochondrial dysfunction is found. Although few efficacious therapies exist for primary mitochondrial disease, active research programs are starting to identify therapies. For example, recently a promising clinical trial has demonstrated the efficacy of idebenone in a subgroup of patients with Leber’s hereditary optic neuropathy. ²⁴ Mitochondrial medicine is a relatively new and evolving field. As we learn more about the connections between mitochondrial dysfunction and pathological processes, we will be better able to diagnose and treat neurological disease.

Richard E. Frye, MD, PhD Department of Pediatrics Division of Child and Adolescent Neurology and the Children’s Learning Institute, University of Texas Health Science Center, Houston, TX, USA