Epilepsy and Respiratory Chain Defects in Children with Mitochondrial Encephalopathies

Khurana, Divya S.; Salganicoff, Leon; Melvin, Joseph J.; Hobdell, Elizabeth F.; Valencia, Ignacio; Hardison, H. Huntley; Marks, Harold G.; Grover, Warren D.; Legido, Agustín

doi:10.1055/s-2008-1076737

Cited by 64 publications

(75 citation statements)

References 28 publications

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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%

“…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. Among 56 children with RC disorders and epileptic phenotypes, seizures were associated with failure to thrive, psychomotor delay, ataxia or mutisystemic dysfunction in 82.5% of cases.…”

Section: Introductionmentioning

confidence: 99%

“…5 Epilepsy is always difficult to control and the occurrence of intractable seizures is consistently associated with severe neurologic deterioration. 2 Nevertheless, diagnosis of RC disorders remains challenging for several reasons. First, technical problems can give rise to artifactually low enzyme activities.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency

et al. 2012

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“…38,39 These so-called 'mitochondrial epilepsies' are clinically and genetically heterogeneous diseases; disease-causing mutations have been reported in many of the 37 mitochondrially encoded genes and at least 31 nuclear genes (reviewed in Rahman 40 ). Mutated genes encode different subunits of the respiratory chain or proteins that have a role in mitochondrial genome maintenance, translation and replication, as well as enzymes involved in the biosynthesis of coenzyme Q10 or the mitochondrial glutamate carrier SLC25A22 (reviewed in Rahman 40 ).…”

Section: Discussionmentioning

confidence: 99%

West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1

et al. 2015

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West syndrome (WS), defined by the triad of infantile spasms, pathognomonic hypsarrhythmia and developmental regression, is a rare epileptic disease affecting about 1:3500 live births. To get better insights on the genetic of this pathology, we exomesequenced the members of a consanguineous family affected with isolated WS. We identified a homozygous variant (c.1825G4T/p.(Ala609Ser)) in the GUF1 gene in the three affected siblings. GUF1 encodes a protein essential in conditions that counteract faithful protein synthesis: it is able to remobilize stuck ribosomes and transiently inhibit the elongation process to optimize protein synthesis. The variant identified in the WS family changes an alanine residue conserved in all eukaryotic organisms and positioned within the tRNA-binding moiety of this nuclear genome-encoded mitochondrial translational elongation factor. Yeast complementation assays show that the activity of GUF1 A609S is modified in suboptimal environments. We suggest a new link between improper assembly of respiratory chain complexes and WS.

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“…50 Seizures are reported to occur in 35% -60% of infants, children and adolescents with biochemically or genetically confirmed disease. [50][51][52][53] The prevalence in adults is potentially lower with one study reporting a general prevalence of 23%;…”

Section: Epilepsymentioning

confidence: 99%

Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society

Parikh

Goldstein

Karaa

et al. 2017

Genetics in Medicine

204

208

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Purpose The purpose of this statement is to provide consensus-based recommendations for optimal management and care for patients with primary mitochondrial disease. This statement is intended for physicians who are engaged in the diagnosis and management of these patients.Methods Working Group members were appointed by the Mitochondrial Medicine Society. The panel included members with several different areas of expertise. The panel members utilized surveys and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve.

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Epilepsy and Respiratory Chain Defects in Children with Mitochondrial Encephalopathies

Abstract: Epilepsy is an important component of ME. The higher incidence of complex I defects in patients with epilepsy suggests a possible relationship between mitochondrial oxidative stress dysfunction and epileptogenic process.

Cited by 64 publications

References 28 publications

Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency

Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency

West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1

Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society

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