bims-cytox1 2017-10-29 papers

Mitochondrion. 2017 Oct 17. pii: S1567-7249(17)30022-3. [Epub ahead of print]

Mitochondrial disorders of the retinal ganglion cells and the optic nerve.

Josef Finsterer, Michelangelo Mancuso, Davide Pareyson, Jean-Marc Burgunder, Thomas Klopstock.

OBJECTIVES: To summarise and discuss recent findings and future perspectives concerning mitochondrial disorders (MIDs) affecting the retinal ganglion cells and the optic nerve and (mitochondrial optic neuropathy. MON).
METHOD: Literature review.
RESULTS: MON in MIDs is more frequent than usually anticipated. MON may occur in specific as well as non-specific MIDs. In specific and non-specific MIDs, MON may be a prominent or non-prominent phenotypic feature and due to mutations in genes located either in the mitochondrial DNA (mtDNA) or the nuclear DNA (nDNA). Clinically, MON manifests with painless, bilateral or unilateral, slowly or rapidly progressive visual impairment and visual field defects. In some cases, visual impairment may spontaneously recover. The most frequent MIDs with MON include LHON due to mutations in mtDNA-located genes and autosomal dominant optic atrophy (ADOA) or autosomal recessive optic atrophy (AROA) due to mutations in nuclear genes. Instrumental investigations for diagnosing MON include fundoscopy, measurement of visual acuity, visual fields, and color vision, visually-evoked potentials, optical coherence tomography, fluorescein angiography, electroretinography, and MRI of the orbita and cerebrum. In non-prominent MON work-up of the muscle biopsy with transmission electron microscopy may indicate mitochondrial destruction. Treatment is mostly supportive but idebenone has been approved for LHON and experimental approaches are promising.
CONCLUSIONS: MON needs to be appreciated, requires extensive diagnostic work-up, and supportive treatment should be applied although loss of vision, as the most severe outcome, can often not be prevented.

Keywords: Mitochondrial; Optic nerve; Optic neuropathy; Oxidative phosphorylation; Respiratory chain; Second cranial nerve; mtDNA

DOI: https://doi.org/10.1016/j.mito.2017.10.003

Brain Dev. 2017 Oct 17. pii: S0387-7604(17)30267-X. [Epub ahead of print]

Is vatiquinone truly beneficial for Leigh syndrome?

Josef Finsterer, Sinda Zarrouk-Mahjoub.

Keywords: Antioxidant; Complex-1; Leigh syndrome; Mitochondrial; Respiratory chain; Treatment

DOI: https://doi.org/10.1016/j.braindev.2017.10.002

Biochem Biophys Res Commun. 2017 Oct 18. pii: S0006-291X(17)32044-2. [Epub ahead of print]

A 2 bp deletion in the mitochondrial ATP 6 gene responsible for the NARP (neuropathy, ataxia, and retinitis pigmentosa) syndrome.

Patrick Mordel, Stéphane Schaeffer, Quentin Dupas, Marie-Alice Laville, Marion Gérard, Françoise Chapon, S Allouche.

Mitochondrial (mt) DNA-associated NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) syndrome is due to mutation in the MT-ATP6 gene. We report the case of a 18-year-old man who presented with deafness, a myoclonic epilepsy, muscle weakness since the age of 10 and further developed a retinitis pigmentosa and ataxia. The whole mtDNA analysis by next-generation sequencing revealed the presence of the 2 bp microdeletion m.9127-9128 del AT in the ATP6 gene at 82% heteroplasmy in muscle and to a lower load in blood (10-20%) and fibroblasts (50%). Using the patient's fibroblasts, we demonstrated a 60% reduction of the oligomycin-sensitive ATPase hydrolytic activity, a 40% decrease in the ATP synthesis and determination of the mitochondrial membrane potential using the fluorescent probe tetramethylrhodamine, ethyl ester indicated a significant reduction in oligomycin sensitivity. In conclusion, we demonstrated that this novel AT deletion in the ATP6 gene is pathogenic and responsible for the NARP syndrome.

Keywords: ATP6 deletion; Complex V deficiency; Mitochondrial disease; NARP syndrome; Next generation sequencing

DOI: https://doi.org/10.1016/j.bbrc.2017.10.066