ubiquinone and Optic-Atrophy

Coenzyme Q10 was administered under placebo controlled blinded crossover conditions to six subjects suffering from type 3 3-methylglutaconic aciduria ('optic atrophy plus'), following a report of benefit. Despite attainment of high plasma levels of coenzyme Q10, no clinical benefit was observed and there was no diminution of urinary excretion of 3-methylglutaconic acid.

Topics: Administration, Oral; Adolescent; Adult; Child; Coenzymes; Cross-Over Studies; Female; Glutarates; Humans; Male; Movement Disorders; Neuromuscular Diseases; Optic Atrophy; Single-Blind Method; Treatment Failure; Ubiquinone; Visual Acuity

To describe a case of primary coenzyme Q. Clinical presentation and workup including visual fields, electroretinogram, and optical coherence tomography are presented. Genetic testing was performed.. An eight-year-old female with nephropathy requiring renal transplantation subsequently developed progressive cone-rod dystrophy and optic atrophy. The patient had negative results on a targeted next-generation sequencing retinal dystrophy panel but whole-exome sequencing revealed two variants in. Primary coenzyme Q

Topics: Child; Electroretinography; Female; Genetic Testing; Humans; Mutation; Optic Atrophy; Retinal Dystrophies; Tomography, Optical Coherence; Ubiquinone; Visual Fields

To investigate mitophagy in 5 patients with severe dominantly inherited optic atrophy (DOA), caused by depletion of OPA1 (a protein that is essential for mitochondrial fusion), compared with healthy controls.. Patients with severe DOA (DOA plus) had peripheral neuropathy, cognitive regression, and epilepsy in addition to loss of vision. We quantified mitophagy in dermal fibroblasts, using 2 high throughput imaging systems, by visualizing colocalization of mitochondrial fragments with engulfing autophagosomes.. Fibroblasts from 3 biallelic OPA1(-/-) patients with severe DOA had increased mitochondrial fragmentation and mitochondrial DNA (mtDNA)-depleted cells due to decreased levels of OPA1 protein. Similarly, in siRNA-treated control fibroblasts, profound OPA1 knockdown caused mitochondrial fragmentation, loss of mtDNA, impaired mitochondrial function, and mitochondrial mislocalization. Compared to controls, basal mitophagy (abundance of autophagosomes colocalizing with mitochondria) was increased in (1) biallelic patients, (2) monoallelic patients with DOA plus, and (3) OPA1 siRNA-treated control cultures. Mitophagic flux was also increased. Genetic knockdown of the mitophagy protein ATG7 confirmed this by eliminating differences between patient and control fibroblasts.. We demonstrated increased mitophagy and excessive mitochondrial fragmentation in primary human cultures associated with DOA plus due to biallelic OPA1 mutations. We previously found that increased mitophagy (mitochondrial recycling) was associated with visual loss in another mitochondrial optic neuropathy, Leber hereditary optic neuropathy (LHON). Combined with our LHON findings, this implicates excessive mitochondrial fragmentation, dysregulated mitophagy, and impaired response to energetic stress in the pathogenesis of mitochondrial optic neuropathies, potentially linked with mitochondrial mislocalization and mtDNA depletion.

Topics: Antioxidants; Cells, Cultured; Cognition Disorders; DNA Mutational Analysis; DNA, Mitochondrial; Family Health; Female; Fibroblasts; GTP Phosphohydrolases; Humans; Male; Membrane Potential, Mitochondrial; Mitochondrial Proteins; Mitophagy; Mutation; Optic Atrophy; Pedigree; Protein Kinases; RNA, Small Interfering; Transfection; Ubiquinone; Ubiquitin-Protein Ligases

Topics: Antioxidants; Humans; Male; Optic Atrophy; Optic Disk; Ubiquinone; Visual Fields; Wolfram Syndrome; Young Adult

Mitochondrial myopathies are regulated by two genomes: the nuclear DNA, and the mitochondrial DNA. While, so far, most studies have dealt with mitochondrial myopathies due to deletions or point mutations in the mitochondrial DNA, a new field of investigation is that of syndromes due to mutations in the nuclear DNA. These latter disorders have mendelian inheritance.. Three representative cases have been selected: one with COX deficiency and a Leigh syndrome due to a SURF1 gene mutation, one due to a defect of Coenzyme Q synthesis and one with dominant optic atrophy due to a mutation in the OPA1 gene.. Future developments will show that many neurodegenerative disorders are due to mutations of nuclear genes controlling mitochondrial function, fusion and fission.

Topics: Cell Nucleus; Child; DNA; Female; Genome; GTP Phosphohydrolases; Humans; Infant; Leigh Disease; Male; Membrane Proteins; Middle Aged; Mitochondrial Diseases; Mitochondrial Proteins; Mutation; Optic Atrophy; Prostaglandin-Endoperoxide Synthases; Ubiquinone