Epileptic phenotypes associated with mitochondrial disorders

Canafoglia, Laura; Franceschetti, Silvana; Antozzi, Carlo; Carrara, Franco; Farina, Laura; Granata, Tiziana; Lamantea, Eleonora; Savoiardo, M.; Uziel, Graziella; Villani, Flavio; Zeviani, Massimo; Avanzini, Giulio

doi:10.1212/wnl.56.10.1340

Cited by 141 publications

(174 citation statements)

References 30 publications

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“…One of mitochondrial disorders is the myoclonus epilepsy with ragged red fibers (MERRF) syndrome that is linked to point mutations in the mitochondrial tRNALys gene [42, 43]. Partial seizures are also frequently noticed in mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, which is associated with mutations in the mitochondrial tRNALeu gene [44, 45]. …”

Section: Signalling Roles Of Ca2+ and Rosmentioning

confidence: 99%

The Role of Reactive Species in Epileptogenesis and Influence of Antiepileptic Drug Therapy on Oxidative Stress

Martinc

Grabnar²,

Vovk³

2012

Current Neuropharmacology

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Epilepsy is considered one of the most common neurological disorders. The focus of this review is the acquired form of epilepsy, with the development process consisting of three major phases, the acute injury phase, the latency epileptogenesis phase, and the phase of spontaneous recurrent seizures. Nowadays, an increasing attention is paid to the possible interrelationship between oxidative stress resulting in disturbance of physiological signalling roles of calcium and free radicals in neuronal cells and mitochondrial dysfunction, cell damage, and epilepsy. The positive stimulation of mitochondrial calcium signals by reactive oxygen species and increased reactive oxygen species generation resulting from increased mitochondrial calcium can lead to a positive feedback loop. We propose that calcium can pose both, physiological and pathological effects of mitochondrial function, which can lead in neuronal cell death and consequent epileptic seizures. Various antiepileptic drugs may impair the endogenous antioxidative ability to prevent oxidative stress. Therefore, some antiepileptic drugs, especially from the older generation, may trigger oxygen-dependent tissue injury. The prooxidative effects of these antiepileptic drugs might lead to enhancement of seizure activity, resulting in loss of their efficacy or apparent functional tolerance and undesired adverse effects. Additionally, various reactive metabolites of antiepileptic drugs are capable of covalent binding to macromolecules which may lead to deterioration of the epileptic seizures and systemic toxicity. Since neuronal loss seems to be one of the major neurobiological abnormalities in the epileptic brain, the ability of antioxidants to attenuate seizure generation and the accompanying changes in oxidative burden, further support an important role of antioxidants as having a putative antiepileptic potential.

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Section: Signalling Roles Of Ca2+ and Rosmentioning

confidence: 99%

The Role of Reactive Species in Epileptogenesis and Influence of Antiepileptic Drug Therapy on Oxidative Stress

Martinc

Grabnar²,

Vovk³

2012

Current Neuropharmacology

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“…In the series of 73 children, seizures were observed in 25 patients (34%) 1 and in 61% of cases in another cohort of 38 children with mitochondrial encephalopathies. 2 Focal epilepsy seems to be predominant in adults, 3 whereas pediatric series report a great predominance of generalized epilepsy syndromes. 2,4,5 Epilepsy of mitochondrial origin is often associated with other symptoms.…”

Section: Introductionmentioning

confidence: 99%

Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency

et al. 2012

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We report two children, born from consanguineous parents, who presented with early-onset refractory epilepsy associated with psychomotor delay, failure to thrive, blindness and deafness. Polarographic and spectrophotometric analyses in fibroblasts and liver revealed a respiratory chain (RC) dysfunction. Surprisingly, we identified a homozygous nonsense mutation in the GM3 synthase gene by using exome sequencing. GM3 synthase catalyzes the formation of GM3 ganglioside from lactosylceramide, which is the first step in the synthesis of complex ganglioside species. Mass spectrometry analysis revealed that the complete absence of GM3 ganglioside and its biosynthetic derivatives was associated with an upregulation of the alternative globoside pathway in fibroblasts. The accumulation of Gb3 and Gb4 globosides likely has a role in RC dysfunction and in the decrease of mitochondrial membrane potential leading to apoptosis, which we observed in fibroblasts. We show for the first time that GM3 synthase deficiency, responsible for early-onset epilepsy syndrome, leads to a secondary RC dysfunction. Our study highlights the role of secondary mitochondrial disorders that can interfere with the diagnosis and the evolution of other metabolic diseases.

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“…This mutation is associated with a broad spectrum of clinical manifestations, including mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodic syndrome (MELAS) and maternally inherited diabetes and deafness syndrome (MIDD) [4,8,15,21]. Diabetes mellitus and exocrine insufficiency are the most common pancreatic features of mitochondriopathy.…”

Section: Discussionmentioning

confidence: 99%

“…MELAS, which forms a major clinical subgroup of the mitochondrial encephalomyopathies, is caused by any of several different single base replacements in the mt tRNA Leu(UUR) gene, which is responsible for the translation of UUR (R = A or G) leucine codons in mitochondrial genes [1][2][3][4][5]. It has been reported that 15% of patients with mitochondriopathies have symptoms of digestive disorders [3,7,14].…”

Section: Communicating Authormentioning

confidence: 99%

Application of molecular imaging combined with genetic screening in diagnosing MELAS, diabetes and recurrent pancreatitis

Wang

Li²,

Zhou³

et al. 2016

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Epileptic phenotypes associated with mitochondrial disorders

Cited by 141 publications

References 30 publications

The Role of Reactive Species in Epileptogenesis and Influence of Antiepileptic Drug Therapy on Oxidative Stress

The Role of Reactive Species in Epileptogenesis and Influence of Antiepileptic Drug Therapy on Oxidative Stress

Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency

Application of molecular imaging combined with genetic screening in diagnosing MELAS, diabetes and recurrent pancreatitis

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