EPILEPSY ASSOCIATED WITH A LHON MITOCHONDRIAL DNA MUTATION: STUDIES ON BIOENERGETIC MECHANISMS
Abstract number :
3.081
Submission category :
Year :
2002
Submission ID :
97
Source :
www.aesnet.org
Presentation date :
12/7/2002 12:00:00 AM
Published date :
Dec 1, 2002, 06:00 AM
Authors :
Stefan Vielhaber, Alexei Kudin, Dimitri Varlamov, Hans-Jochen Heinze, Christian E. Elger, Wolfram S. Kunz. Neurology, University of Magdeburg Medical Center, Magdeburg, Germany; Epileptology, University of Bonn Medical Center, Bonn, Germany
RATIONALE: There is accumulating evidence that mitochondrial DNA mutations can play an important role in the generation of epileptic seizures but the pathogenetic link between genotype and phenotype is not fully understood.
METHODS: To define the bioenergetic consequences of mitochondrial mutations in these disorders, we studied tissue preparations from muscle and brain from 6 patients carrying the three pathogenic homoplasmic Leber[ssquote]s hereditary optic neuropathy (LHON) mtDNA mutations C4640A/ND2 (a male with epilepsy and a female carrier), G11778A/ND4 (a male with blindness and a female carrier) and T14484C/ND6 (a male with blindness and a female carrier). Interestingly, upon preoperative Wada testing (unilateral infusion of amytal to evaluate the prospective outcome of the hippocampectomy) the patient with epilepsy and the mitochondrial ND2 mutation developed severe reversible visual loss. From this patient also brain tissue was available for further studies.
RESULTS: All mutations led in patients and non-affected carriers of the mutation to a similar decrease of citrate synthase-normalized activities of complex I being most severe for the ND6, less severe for ND4 and close to the detection limit for the ND2 mutation. This enzyme activity change was observed to be responsible for decreased respiration rates with NAD-dependent substrates detected in saponin-permeabilized muscle fibers, isolated skeletal muscle mitochondria and digitonin-treated brain homogenates (for the ND2 mutation). In addition, titrations of the activity of NADH:CoQ oxidoreductase with the complex I inhibitors amytal, rotenone and piericidin A revealed with all mutations no difference to controls indicating no alteration of kinetic properties of the CoQ reduction site by any of the investigated mutations.
CONCLUSIONS: Since all mutations led to a considerable increase of amytal sensitivity of mitochondrial respiratory chain our data are compatible with the concept that the investigated mutations lead to decreased quantities of the active NADH:CoQ oxidoreductase enzyme complex having in brain tissue more severe metabolic consequences.