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Pathophysiology of mitochondrial disease causing epilepsy and status epilepticus Shamima Rahman ⁎ Mitochondrial Research Group, Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK Metabolic Unit, Great Ormond Street Hospital, London, UK

a r t i c l e

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Article history: Accepted 1 May 2015 Available online xxxx Keywords: Mitochondrial disease Epilepsy Seizure Neuronal energy depletion Oxidative stress Coenzyme Q10 Cerebral folate deficiency L-arginine Immune dysfunction Calcium homeostasis and signaling

a b s t r a c t 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”.

1. Mitochondrial function and dysfunction The mitochondria are subcellular organelles present inside virtually all human cells as dynamic networks. They are often described as ‘powerstations’, since they are responsible for producing the majority of adenosine triphosphate (ATP), the universal cellular energy currency. The mitochondria have diverse functions in addition to energy generation, including calcium homeostasis, cellular signaling via the generation of reactive oxygen species (ROS), and regulation of apoptotic cell death. Inside the mitochondria, ATP is generated through the process of oxidative phosphorylation (OXPHOS) by the concerted action of five multisubunit enzyme complexes (I–V) embedded in the mitochondrial inner membrane. Electrons are passed from NADH and FADH2 to complexes I and II respectively, then sequentially to complexes III and IV via two mobile electron carriers (coenzyme Q10 (CoQ10) and cytochrome c), and then from complex IV to molecular oxygen to produce water. Complexes I, III, and IV also act as proton pumps, generating an electrochemical gradient across the inner mitochondrial membrane that is ultimately harnessed by complex V (ATP synthase) to produce ATP from ADP and inorganic phosphate. In the brain, the mitochondria are responsible for providing ATP for neurotransmission, reactive oxygen species (ROS) signaling at synapses, ⁎ UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. Tel.: +44 7905 2608; fax: +44 7404 6191. E-mail address: [email protected]

© 2015 Elsevier Inc. All rights reserved.

and regulating pre- and postsynaptic calcium concentrations [1]. Epileptogenesis is characterized by neuronal hyperexcitability that may be triggered by multiple molecular and physiological changes [2]. These changes include increased glucose utilization, reduced activity of mitochondrial respiratory chain complex I, impaired ATP production, generation of ROS, and excessive calcium fluxes [2,3]. It is, therefore, not surprising that mitochondrial dysfunction and epilepsy have been intertwined in the literature for many years [4]. However, the precise pathogenic mechanisms responsible for mitochondrial epilepsy remain enigmatic and are the subject of this review. The situation is further complicated by differences in mitochondrial function between neurons and astrocytes, between different types of neurons, and in different brain regions [5].

2. Genetic basis of primary mitochondrial disorders associated with epilepsy Mitochondrial dysfunction leads to disease, with heterogeneous clinical presentations that can affect any tissue or organ system in the body in any combination at any age [6]. Primary mitochondrial diseases are inherited disorders that may arise from mutation of the mitochondrial DNA (mtDNA), a dedicated ~ 16.5 kb genome located within the mitochondria, or from mutations in hundreds of nuclear encoded genes. These nuclear genes include genes encoding subunits and assembly factors of the OXPHOS complexes and genes coding for 1525-5050/© 2015 Elsevier Inc. All rights reserved.

Please cite this article as: Rahman S, Pathophysiology of mitochondrial disease causing epilepsy and status epilepticus, Epilepsy Behav (2015),


S. Rahman / Epilepsy & Behavior xxx (2015) xxx–xxx

Fig. 1. Nuclear gene defects linked to mitochondrial epilepsy. Nuclear genes with mutations linked to mitochondrial disease, grouped by pathological mechanism (oxidative phosphorylation (OXPHOS) subunits; OXPHOS assembly factors; mitochondrial DNA (mtDNA) maintenance factors; mitochondrial translation factors; biosynthesis of cofactors including coenzyme CoQ10 (CoQ10), lipoic acid and iron–sulfur (FeS) clusters; and membrane function and import). Gene defects highlighted in red have been linked to epilepsy.

mitochondrial translation factors, import proteins, and enzymes required for biosynthesis of cofactors and mitochondrial membrane lipids (Fig. 1). The brain is frequently involved in mitochondrial disease, because of its high energy demands, and up to 40% of children with primary mitochondrial disease may experience seizures [4,7]. In 80% of cases of mitochondrial epilepsy, seizures are preceded by other clinical features [8], including feeding difficulties, faltering growth, developmental delay and/or regression, impairment of hearing and/or vision, cardiomyopathy, renal tubulopathy, anemia, hormone deficiencies, muscle weakness, and peripheral neuropathy. Epilepsy phenotypes observed in mitochondrial disease include neonatal refractory status, neonatal myoclonic epilepsy, infantile spasms, refractory or recurrent status epilepticus, epilepsia partialis continua, and myoclonic epilepsy [8]. However, frequently, it is only when multisystem features are present that clinical suspicion of mitochondrial disease is triggered [4]. 3. Disease mechanisms underlying mitochondrial epilepsy 3.1. Cerebral energy deficiency and epilepsy Since a primary function of the mitochondria is to generate the majority of cellular ATP, for decades, it has been assumed that epilepsy in mitochondrial disorders is a consequence of neuronal energy depletion. If this were the sole mechanism underlying ‘mitochondrial epilepsy’, then it would be logical to assume that all genetic mitochondrial disease would be associated with epilepsy. However, this is far from the case. Theoretically, each of the N250 mutations reported in the mtDNA ( should be equally likely to cause epilepsy. Yet, this is not what is observed in clinical practice; rather, there are specific ‘hot spots’ within the mitochondrial genome that appear to be particularly associated with epilepsy phenotypes. These hot spots include the m.3243ANG mutation present in ~ 80% of patients with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) [9] and the m.8344ANG mutation associated with the myoclonic epilepsy, ragged red fibers (MERRF) syndrome [10].

Other hot spots include the MTND5 gene encoding a subunit of complex I [11] and the MTATP6 gene encoding a subunit of the ATP synthase (complex V) [12]. Mutations in both of these genes are associated with Leigh syndrome (subacute necrotizing encephalomyelopathy) presenting with infantile spasms [13]. In addition, MTND5 mutations are another cause of MELAS [11]. Furthermore, only a fraction of the N200 nuclear gene defects linked to human disease are associated with epilepsy (Fig. 1). These observations argue against neuronal energy depletion being the unifying cause of all mitochondrial epilepsy. Other mechanisms need to be invoked. 3.2. Oxidative stress and epilepsy It has been suggested that ROS are integral to the pathogenesis of epilepsy both in primary mitochondrial diseases and in acquired epilepsy [14]. Furthermore, production of superoxide preceded ATP depletion in an astrocyte model in which the respiratory chain was partially inhibited by nitric oxide, suggesting that ROS generation may be more important than disruption of energy metabolism in the development of mitochondrial disease [15]. Natural antioxidant defense mechanisms present inside the mitochondria include CoQ10, ascorbate, and manganese superoxide dismutase (MnSOD). The group led by Manisha Patel has shown that overexpression of the Sod2 gene encoding MnSOD can protect mice against kainic acid-induced seizures, while mice with partial knockdown of Sod2 were more susceptible to developing seizures following kainic acid administration [16]. Recently, the same group has shown that pharmacologically scavenging ROS can attenuate seizures in mice with a forebrain specific conditional deletion of Sod2 and that ROS production drives mitochondrial bioenergetic dysfunction in isolated hippocampal synaptosomes from a rat model treated with kainic acid [2]. Further evidence linking oxidative stress to epilepsy comes from studies of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, a disorder of mitochondrial valine degradation. Mutations in HIBCH lead to a severe neurodegenerative disorder, often with prominent seizures, which may be associated with multiple OXPHOS enzyme deficiencies

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[17]. The pathomechanism of this disorder appears to be via oxidation of critical cysteine residues in multiple OXPHOS enzymes and other mitochondrial proteins by the highly toxic metabolite 3-methacrylyl-CoA that accumulates in HIBCH deficiency [17]. Another conundrum has been whether mitochondrial dysfunction is primary or secondary in idiopathic epilepsy. Recently, using live cell imaging in glioneuronal cultures, Kovac et al. demonstrated that prolonged seizure-like activity led to calcium-independent ROS production by NADPH oxidase and xanthine oxidase in the plasma membrane through NMDA receptor activation [18]. This suggests that, at least in some circumstances, mitochondrial dysfunction appears to be secondary to seizures in acquired epilepsy.

3.3. Role of calcium sensing, signaling, and homeostasis? The mitochondria play a central role in calcium homeostasis by sequestering calcium, which is an important signaling molecule participating in several cellular pathways under physiological conditions [19]. Aberrant calcium signaling in astrocytes and neurons is likely to be a factor in epileptogenesis, probably by causing excessive synchronization of neurons [3]. There is evidence that impaired calcium handling resulting from mitochondrial dysfunction can increase neuronal excitability, leading to seizures [5,20]. The precise mechanism by which the mitochondria import calcium remained obscure for many decades, but in recent years, an integrative genomics approach has led to the identification of the calcium uniporter MCU and its regulatory subunits MICU1, MICU2, and EMRE [21]. No mutations have been reported in MCU, but MICU1 mutations were recently identified in 15 children with proximal myopathy, learning difficulties, and a progressive extrapyramidal movement disorder [22]. Surprisingly, the phenotype did not include epilepsy. A final consideration supporting a role for calcium in mitochondrial epilepsy is that levetiracetam, which acts at least in part by modulating intracellular calcium influx [23], appears to be one of the more effective anticonvulsant drugs in mitochondrial epilepsy [24].

3.4. Immune mechanisms and mitochondrial epilepsy Mutations in POLG, encoding the catalytic subunit of DNA polymerase gamma, the DNA polymerase responsible for replicating mtDNA, are the most frequent cause of mitochondrial epilepsy [4]. Several of the phenotypes associated with POLG mutations have prominent seizures: Alpers– Huttenlocher syndrome, mitochondrial recessive ataxia syndrome (MIRAS), spinocerebellar ataxia with epilepsy (SCAE), and myoclonic epilepsy, myopathy, and sensory ataxia (MEMSA). However, POLG disease is extremely heterogeneous, with phenotypes ranging from a fatal infantile hepatocerebral syndrome to late-onset ophthalmoplegia and parkinsonism. Remarkably, enormous clinical variability has been observed in association with homozygosity for a single common missense mutation, A467T [25]. This suggests that other factors, which may be genetic, epigenetic, or environmental, are important in modulating the pathogenesis of POLG mutations. Autoantibodies have been detected in the blood and CSF of children with POLG mutations [26, 27]. Furthermore, one patient with compound heterozygous known pathogenic POLG mutations had neuropathological features of acute disseminated encephalomyelitis (ADEM) [27]. These observations suggest that mitochondrial disease may lead to immune dysfunction, although it is possible that the converse is also true, that immune dysfunction may be an unrecognized cause of mitochondrial disease. Of note, proven viral illness has been shown to precede initial decompensation in Alpers– Huttenlocher syndrome [28] and other mitochondrial disorders [29], and immunopathogenic mechanisms coupled to energy-dependent processes have been suggested in the etiology of both febrile infectionrelated epilepsy syndrome (FIRES) and Rasmussen encephalitis [30].


3.5. Role of vitamin, cofactor, and metabolite deficiency states? 3.5.1. Cerebral folate deficiency Epilepsy has been reported in association with cerebral folate deficiency (CFD) in Kearns–Sayre syndrome (KSS) and AlpersHuttenlocher syndrome [26,31]. Patients with KSS appear to be particularly susceptible to developing CFD, possibly because the choroid plexus is disrupted in this condition [32]. The relationship between CFD and seizures does not appear to be straightforward. Although epilepsy appears to be a constant feature of CFD caused by mutations in FOLR1 (encoding folate receptor alpha) or DHFR (encoding dihydrofolate reductase) [33], not all patients with KSS and CFD have epilepsy. Treatment with oral folinic acid is associated with improvements in clinical and neuroimaging features [31,34], suggesting an etiological relationship between CFD and the mitochondrial phenotype in these patients. 3.5.2. Defective biosynthesis of coenzyme Q10 The complex pathway of coenzyme Q10 biosynthesis has not yet been fully delineated in humans, but eight genetic defects of CoQ10 synthesis have been described, six of which are associated with epilepsy [35–37]. Patients with ADCK3 mutations have seizures associated with autosomal recessive cerebellar ataxia [38,39], while those with COQ6 mutations present with nephrotic syndrome which may or may not be associated with seizures [40]. In other patients, CoQ10 deficiency is associated with a complex multisystem disorder that may include seizures [35]. The only patient reported to have mutations in COQ9 had intractable epilepsy, in addition to severe global developmental delay, hypertrophic cardiomyopathy, and renal tubulopathy [41,42]. Secondary CoQ10 deficiency has also been reported in various mitochondrial disorders [37]. The relationship between CoQ10 status and development of seizures is not clear, since seizures do not appear to be a universal feature of CoQ10 deficiency [35]. Furthermore, supplementation with exogenous CoQ10 does not improve seizures in all cases, despite biochemical correction of the CoQ10 deficiency [39,41,42]. 3.5.3. Glutamate transporter mutations Mutations in SLC25A22 encoding a mitochondrial inner membrane glutamate carrier have been reported in several families with severe epilepsy syndromes, presenting as early myoclonic epilepsy with burst suppression or migrating partial seizures of infancy [43–46]. The SLC25A22 glutamate/H+ symporter is particularly abundant in astrocytes; thus, possible disease mechanisms include accumulation of glutamate in astrocytes, dysregulation of extracellular glutamate levels, and abnormal neurotransmission following activation of extrasynaptic glutamate receptors [43]. Glutamate can overactivate NMDA receptors, causing an excessive influx of calcium, leading to epileptogenesis [3]. Patients with mutations in another mitochondrial glutamate transporter gene SLC25A12, encoding the mitochondrial aspartate–glutamate carrier isoform 1 (AGC1 or aralar), develop seizures from a few months of age [47,48]. Normal activities of respiratory chain complexes I to IV were observed in biopsied muscle from the first reported case with AGC1 mutations, but there was severely reduced ATP production, particularly when using glutamate + succinate or glutamate + malate as substrates [48]. Aspartate–glutamate carrier isoform 1 is an essential component of the neuronal malate aspartate shuttle that is responsible for transferring NADH reducing equivalents from the cytosol to the mitochondria for use in OXPHOS. Another contributory factor to disease pathogenesis with both SLC25A22 and SLC25A12 mutations may be the lack of intramitochondrial glutamate for anaplerosis in the Krebs cycle, which would also decrease the availability of reducing equivalents for OXPHOS [47]. 3.5.4. Depletion of L-arginine and/or L-citrulline In patients with MELAS syndrome, the stroke-like episodes may be heralded by focal epilepsy [11]. The etiology of stroke-like episodes in MELAS is not completely understood, but endothelial dysfunction

Please cite this article as: Rahman S, Pathophysiology of mitochondrial disease causing epilepsy and status epilepticus, Epilepsy Behav (2015),


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caused by relative nitric oxide insufficiency has been proposed as a potential disease mechanism [49]. The amino acid L-arginine is required for nitric oxide synthesis, and it is thought that relative L-arginine depletion predisposes to nitric oxide insufficiency and, thus, to stroke-like episodes in MELAS. Accordingly, L-arginine supplementation has been shown to attenuate the severity and reduce the frequency of strokelike episodes in Japanese patients with MELAS caused by the common mtDNA point mutation m.3243ANG in the MTTL1 gene [49]. Low levels of another amino acid precursor of nitric oxide, L-citrulline, have been reported in patients with MELAS [50], and it has been suggested that L-citrulline supplementation exerts a greater protective effect than L-arginine supplementation in MELAS [51]. Low L-citrulline has also been observed in patients with Leigh syndrome caused by the m.8993TNG mutation in the MTATP6 gene [52].

Acknowledgments The author is supported by Great Ormond Street Hospital Children's Charity (V1260) and her group currently receives research grant funding from The Wellcome Trust, The Lily Foundation, and Vitaflo International Ltd. Conflict of interest statement The author declares that she has received grant support from Vitaflo International Ltd., but the funder played no role in the preparation of this manuscript.

References +

3.5.5. Role of cellular NAD depletion? Recently, evidence has begun to accumulate suggesting that depletion of nicotinamide adenine dinucleotide (NAD+) may be a critical factor in mitochondrial disease pathogenesis [53]. Nicotinamide adenine dinucleotide plays a key role in transferring electrons to the respiratory chain; thus, its depletion could impair electron transport and the mitochondrion's ability to maintain its membrane potential and generate ATP. Although NAD+ depletion has not been directly demonstrated in mitochondrial epilepsy syndromes, clinical improvement was observed in two mouse models of mitochondrial disease following therapy with nicotinamide riboside, a biologically available form of NAD+ [54, 55]. These studies provide indirect evidence that NAD+ depletion may be a pathogenic mechanism underlying mitochondrial disease. 4. Conclusions In conclusion, heterogeneous mechanisms impairing mitochondrial dysfunction have now been linked to epilepsy, including neuronal energy depletion, oxidative stress, and impaired calcium signaling (Fig. 2), as well as immune mechanisms, and deficiencies of vitamins, cofactors, amino acids, reducing equivalents and other metabolites. Different factors are likely to be predominant in different causes of mitochondrial epilepsy, and the relative contributions of these mechanisms now need to be studied systematically in cell and animal models of mitochondrial disease. The complexity of these disorders creates unique challenges in developing effective treatments, and better understanding of the underlying pathomechanisms is crucial in order to develop rational therapeutic strategies for mitochondrial epilepsy.

Fig. 2. Disease mechanisms in mitochondrial epilepsy. There is a complex interrelationship between mitochondrial dysfunction, seizures, and cell death. Key molecular mechanisms mediating epileptogenesis include neuronal ATP depletion, reactive oxygen species (ROS) generation, and abnormal calcium signaling. Complex molecular cascades are established, each feeding back on other components of the cascades, leading to a vicious spiral of mitochondrial dysfunction, seizure generation, and cell death.

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Please cite this article as: Rahman S, Pathophysiology of mitochondrial disease causing epilepsy and status epilepticus, Epilepsy Behav (2015),

Pathophysiology of mitochondrial disease causing epilepsy and status epilepticus.

Epilepsy is part of the clinical phenotype in nearly 40% of children with mitochondrial disease, yet the underlying molecular mechanisms remain poorly...
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