Mitochondrial Epilepsy, a Challenge for Neurologists

Abstract

Primary mitochondrial diseases are relatively common inborn errors of energy metabolism, with a combined prevalence of 1 in 4300. These disorders typically affect tissues with high energy requirements, including the brain. Epilepsy affects >1% of the worldwide population, making it one of the most common neurological illnesses; it may be the presenting feature of a mitochondrial disease, but is often part of a multisystem clinical presentation. The major genetic causes of mitochondrial epilepsy are mutations in mitochondrial DNA and in the nuclear-encoded gene POLG. Treatment of mitochondrial epilepsy may be challenging, often representing a poor prognostic feature. This narrative review will cover the most recent advances in the field of mitochondrial epilepsy, from pathophysiology and genetic etiologies to phenotype and treatment options.

Characterization of the zebrafishgabra1sa43718/sa43718germline loss of function allele confirms a function for Gabra1 in motility and nervous system development

“…Furthermore, we identified downregulation of proteins implicated in mitochondrial complex I deficiency, including NADH:ubiquinone oxidoreductase core subunit S2 and NADH:ubiquinone oxidoreductase core subunit A10. Remarkably, mutations in the genes encoding these proteins are associated with Leigh syndrome, one of the most common mitochondrial diseases, in which epilepsy is a primary phenotype [33], [34]. Interestingly, mutation of GABRA1 in humans have been prematurely diagnosed as a primary mitochondrial disorder prior to exome sequencing [23].…”

“…and NADH:ubiquinone oxidoreductase core subunit A10. Remarkably, mutations in the genes encoding these proteins are associated with Leigh syndrome, one of the most common mitochondrial diseases, in which epilepsy is a primary phenotype 31,32 . Interestingly, mutation of GABRA1 in humans was prematurely diagnosed as a primary mitochondrial disorder prior to exome sequencing 24 .…”

Astrocyte mitochondria: Potential therapeutic targets for epilepsy

“…Remarkably, in almost 20 % of patients with primary mitochondrial diseases, epilepsy is the first symptom, which can manifest as any type of seizure. SE in primary mitochondrial disease often coexists with stroke-like seizures, resulting in poor prognosis and high mortality due to its treatment resistance [ 67 ]. Moreover, after feeding valproic acid (VPA) to rats for 75 days, Ponchaut et al discovered that the decrease in mitochondrial respiration induced by VPA was attributed to the depletion of mitochondrial cytochrome aa 3, resulting in a nearly 30 % reduction [ 68 ].…”

Delineating mechanisms underlying parvalbumin neuron impairment in different neurological and neurodegenerative disorders: the emerging role of mitochondrial dysfunction

“…mixed mutated and wild-type mtDNAs in the tissues), threshold effect and genetic bottleneck [ 49 ]. Neurological manifestations are prevalent in PMDs, and may include cerebellar ataxia [ 50 ], extra-pyramidal movement disorders, progressive cognitive impairment [ 51 ], stroke-like episodes [ 52 ] and epileptic seizures [ 53 ], which are reported to affect up to 60% of paediatric and ∼23% of adult patients [ 54 , 55 ]. Status epilepticus in PMDs is often refractory or super-refractory to ASMs, including general anaesthetic agents, and intriguingly often demonstrate an occipital lobe predilection [ 52 , 56–58 ].…”