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Purpose: Complete oocyte lysis in in vitro fertilization (IVF) is a rare event, but one against which we remain helpless. The recurrence of this phenomenon in some women in each of their IVF attempts, regardless of treatment, together with the results of animal experiments led us to investigate the possible involvement of the genes encoding for the glycoproteins constituting the zona pellucida (ZP). Patients & methods: Over the last ten years, during which we treated over 500 women each year, three women suffered recurrent oocyte lysis during their IVF attempts in our Centre for Reproductive Biology. For each of these three cases, we sequenced the four genes and promoter sequences encoding the glycoproteins of the ZP. The sequence variations likely to cause a change in protein expression or structure, were investigated in a control group of 35 women who underwent IVF without oocyte lysis and with normal rates of fertilization. Results & conclusion: We found no mutations in the ZP genes sequenced. Only some polymorphisms present in the control group and in the general population were detected, excluding their specific involvement in the phenotype observed. Thus, although we suspected that complete oocyte lysis was due to a genetic cause, it did not seem possible to directly incriminate the genes encoding the proteins of the ZP in the observed phenotype. Further study of the genes involved in the processing and organization of ZP glycoproteins may allow elucidation of the mechanism underlying recurrent oocyte lysis during in vitro fertilization. [ABSTRACT FROM AUTHOR]

Abstract: The OPA1 gene, encoding a dynamin-like mitochondrial GTPase, is involved in autosomal dominant optic atrophy (ADOA, OMIM #165500). ADOA, also known as Kjer''s optic atrophy, affects retinal ganglion cells and the axons forming the optic nerve, leading to progressive visual loss. OPA1 gene sequencing in patients with hereditary optic neuropathies indicates that the clinical spectrum of ADOA is larger than previously thought. Specific OPA1 mutations are responsible for several distinct clinical presentations, such as ADOA with deafness (ADOAD), and severe multi-systemic syndromes, the so-called “ADOA plus” disorders, which involve neurological and neuromuscular symptoms similar to those due to mitochondrial oxidative phosphorylation defects or mitochondrial DNA instability. The study of the various clinical presentations of ADOA in conjunction with the investigation of OPA1 mutations in fibroblasts from patients with optic atrophy provides new insights into the pathophysiological mechanisms of the disease while underscoring the multiple physiological roles played by OPA1 in energetic metabolism, mitochondrial structure and maintenance, and cell death. Finally, OPA1 represents an important new paradigm for emerging neurodegenerative diseases affecting mitochondrial structure, plasticity and functions. [Copyright &y& Elsevier]

Objective: The objective of this study was to evaluate the implementation of NGS within the French mitochondrial network, MitoDiag, from targeted gene panels to whole exome sequencing (WES) or whole genome sequencing (WGS) focusing on mitochondrial nuclear‐encoded genes. Methods: Over 2000 patients suspected of Primary Mitochondrial Diseases (PMD) were sequenced by either targeted gene panels, WES or WGS within MitoDiag. We described the clinical, biochemical, and molecular data of 397 genetically confirmed patients, comprising 294 children and 103 adults, carrying pathogenic or likely pathogenic variants in nuclear‐encoded genes. Results: The cohort exhibited a large genetic heterogeneity, with the identification of 172 distinct genes and 253 novel variants. Among children, a notable prevalence of pathogenic variants in genes associated with oxidative phosphorylation (OXPHOS) functions and mitochondrial translation was observed. In adults, pathogenic variants were primarily identified in genes linked to mtDNA maintenance. Additionally, a substantial proportion of patients (54% (42/78) and 48% (13/27) in children and adults, respectively), undergoing WES or WGS testing displayed PMD mimics, representing pathologies that clinically resemble mitochondrial diseases. Interpretation: We reported the largest French cohort of patients suspected of PMD with pathogenic variants in nuclear genes. We have emphasized the clinical complexity of PMD and the challenges associated with recognizing and distinguishing them from other pathologies, particularly neuromuscular disorders. We confirmed that WES/WGS, instead of panel approach, was more valuable to identify the genetic basis in patients with "possible" PMD and we provided a genetic testing flowchart to guide physicians in their diagnostic strategy. [ABSTRACT FROM AUTHOR]

Background: The pathophysiology of toxico-nutritional optic neuropathies remains debated, with no clear understanding of the respective roles played by the direct alcohol toxicity, smoking and the often associated vitamin deficiencies, which are risk factors for optic neuropathy. Our aim was to investigate genetic susceptibility in patients with bilateral infraclinical optic neuropathy associated with chronic alcohol use disorder. Methods: This retrospective cohort study included 102 visually asymptomatic patients with documented alcohol use disorder from a French reference center. Optic neuropathy was identified with optical coherence tomography (OCT), after which genetic susceptibility in the group of affected patients was investigated. Genetic testing was performed using panel sequencing of 87 nuclear genes and complete mitochondrial DNA sequencing. Results: Optic neuropathy was detected in 36% (37/102) of the included patients. Genetic testing of affected patients disclosed two patients (2/30, 6.7%) with optic neuropathy associated with pathogenic variants affecting the SPG7 gene and five patients (5/30, 16.7%) who harbored variants of uncertain significance close to probable pathogenicity in the genes WFS1, LOXL1, MMP19, NR2F1 and PMPCA. No pathogenic mitochondrial DNA variants were found in this group. Conclusions: OCT can detect presence of asymptomatic optic neuropathy in patients with chronic alcohol use disorder. Furthermore, genetic susceptibility to optic neuropathy in this setting is found in almost a quarter of affected patients. Further studies may clarify the role of preventative measures in patients who might be predisposed to avoidable visual loss and blindness. [ABSTRACT FROM AUTHOR]

: PurposeTo examine the involvement of the optic atrophy 1 (OPA1) gene in optic atrophy associated with moderate deafness.: DesignObservational case report.: MethodThe entire coding sequence of the OPA1 gene was directly sequenced in the case of a patient suffering from optic atrophy associated with moderate deafness.: ResultsA de novo heterozygous mutation R445H in the OPA1 gene was found. No similar mutation was detected in either of the patient’s parents or in the 100 chromosome controls.: ConclusionThe R445H mutation in OPA1 might be the cause of the association between dominant optic atrophy and moderate deafness, a phenotype that may be currently underdiagnosed. [Copyright &y& Elsevier]

Hereditary optic neuropathies are caused by the degeneration of retinal ganglion cells whose axons form the optic nerves, with a consistent genetic heterogeneity. As part of our diagnostic activity, we retrospectively evaluated the combination of Leber hereditary optic neuropathy mutations testing with the exon sequencing of 87 nuclear genes on 2,186 patients referred for suspected hereditary optic neuropathies. The positive diagnosis rate in individuals referred for Leber hereditary optic neuropathy testing was 18% (199/1,126 index cases), with 92% (184/199) carrying one of the three main pathogenic variants of mitochondrial DNA (m.11778G > A, 66.5%; m.3460G > A, 15% and m.14484T > C, 11%). The positive diagnosis rate in individuals referred for autosomal dominant or recessive optic neuropathies was 27% (451/1,680 index cases), with 10 genes accounting together for 96% of this cohort. This represents an overall positive diagnostic rate of 30%. The identified top 10 nuclear genes included OPA1, WFS1, ACO2, SPG7, MFN2, AFG3L2, RTN4IP1, TMEM126A, NR2F1 and FDXR. Eleven additional genes, each accounting for less than 1% of cases, were identified in 17 individuals. Our results show that 10 major genes account for more than 96% of the cases diagnosed with our nuclear gene panel. [ABSTRACT FROM AUTHOR]

Leber's hereditary optic neuropathy (MIM#535000), the commonest mitochondrial DNA-related disease, is caused by mutations affecting mitochondrial complex I. The clinical expression of the disorder, usually occurring in young adults, is typically characterized by subacute, usually sequential, bilateral visual loss, resulting from the degeneration of retinal ganglion cells. As the precise action of mitochondrial DNA mutations on the overall cell metabolism in Leber's hereditary optic neuropathy is unknown, we investigated the metabolomic profile of the disease. High performance liquid chromatography coupled with tandem mass spectrometry was used to quantify 188 metabolites in fibroblasts from 16 patients with Leber's hereditary optic neuropathy and eight healthy control subjects. Latent variable-based statistical methods were used to identify discriminating metabolites. One hundred and twenty-four of the metabolites were considered to be accurately quantified. A supervised orthogonal partial least squares discriminant analysis model separating patients with Leber's hereditary optic neuropathy from control subjects showed good predictive capability (Q 2cumulated = 0.57). Thirty-eight metabolites appeared to be the most significant variables, defining a Leber's hereditary optic neuropathy metabolic signature that revealed decreased concentrations of all proteinogenic amino acids, spermidine, putrescine, isovaleryl-carnitine, propionyl-carnitine and five sphingomyelin species, together with increased concentrations of 10 phosphatidylcholine species. This signature was not reproduced by the inhibition of complex I with rotenone or piericidin A in control fibroblasts. The importance of sphingomyelins and phosphatidylcholines in the Leber's hereditary optic neuropathy signature, together with the decreased amino acid pool, suggested an involvement of the endoplasmic reticulum. This was confirmed by the significantly increased phosphorylation of PERK and eIF2α, as well as the greater expression of C/EBP homologous protein and the increased XBP1 splicing, in fibroblasts from affected patients, all these changes being reversed by the endoplasmic reticulum stress inhibitor, TUDCA (tauroursodeoxycholic acid). Thus, our metabolomic analysis reveals a pharmacologically-reversible endoplasmic reticulum stress in complex I-related Leber's hereditary optic neuropathy fibroblasts, a finding that may open up new therapeutic perspectives for the treatment of Leber's hereditary optic neuropathy with endoplasmic reticulum-targeting drugs. [ABSTRACT FROM AUTHOR]

Mitochondrial cytopathies, among which the Leigh syndrome (LS), are caused by variants either in the mitochondrial or the nuclear genome, affecting the oxidative phosphorylation process. The aim of the present study consisted in defining the molecular diagnosis of a group of Tunisian patients with LS. Six children, belonging to five Tunisian families, with clinical and imaging presentations suggestive of LS were recruited. Whole mitochondrial DNA and targeted next-generation sequencing of a panel of 281 nuclear genes involved in mitochondrial physiology were performed. Bioinformatic analyses were achieved in order to identify deleterious variations. A single m.10197G>A (p.Ala47Thr) variant was found in the mitochondrial MT-ND3 gene in one patient, while the others were related to autosomal homozygous variants: two c.1412delA (p.Gln471ArgfsTer42) and c.1264A>G (p.Thr422Ala) in SLC19A3, one c.454C>G (p.Pro152Ala) in SLC25A19 and one c.122G>A (p.Gly41Asp) in ETHE1. Our findings demonstrate the usefulness of genomic investigations to improve LS diagnosis in consanguineous populations and further allow for treating the patients harboring variants in SLC19A3 and SLC25A19 that contribute to thiamine transport, by thiamine and biotin supplementation. Considering the Tunisian genetic background, the newly identified variants could be screened in patients with similar clinical presentation in related populations. [ABSTRACT FROM AUTHOR]

Mutations in the Optic Atrophy 1 gene ( OPA1 ) were first identified in 2000 as the main cause of Dominant Optic Atrophy, a disease specifically affecting the retinal ganglion cells and the optic nerve. Since then, an increasing number of symptoms involving the central, peripheral and autonomous nervous systems, with considerable variations of age of onset and severity, have been reported in OPA1 patients. This variety of phenotypes is attributed to differences in the effects of OPA1 mutations, to the mode of inheritance, which may be mono- or bi-allelic, and eventually to somatic mitochondrial DNA mutations. The diversity of the pathophysiological mechanisms involved in OPA1 -related disorders is linked to the crucial role played by OPA1 in the maintenance of mitochondrial structure, genome and function. The neurological expression of these disorders highlights the importance of mitochondrial dynamics in neuronal processes such as dendritogenesis, axonal transport, and neuronal survival. Thus, OPA1 -related disorders may serve as a paradigm in the wider context of neurodegenerative syndromes, particularly for the development of novel therapeutic strategies against these diseases. [ABSTRACT FROM AUTHOR]

Dominant Optic Atrophy (DOA) is one of the most common inherited mitochondrial diseases, leading to blindness. It is caused by the chronic degeneration of the retinal ganglion cells (RGCs) and their axons forming the optic nerve. Until now, DOA has been mainly associated with genes encoding proteins involved in mitochondrial network dynamics. Using next-generation and exome sequencing, we identified for the first time heterozygous PMPCA variants having a causative role in the pathology of late-onset primary DOA in five patients. PMPCA encodes an α subunit of the mitochondrial peptidase (MPP), responsible for the cleavage and maturation of the mitochondrial precursor proteins imported from the cytoplasm into mitochondria. Recently, PMPCA has been identified as the gene responsible for Autosomal Recessive Cerebellar Ataxia type 2 (SCAR2) and another severe recessive mitochondrial disease. In this study, four PMPCA variants were identified, two are frameshifts (c.309delA and c.820delG) classified as pathogenic and two are missenses (c.1363G>A and c.1547G>A) classified with uncertain pathological significance. Functional assays on patients' fibroblasts show a hyperconnection of the mitochondrial network and revealed that frameshift variants reduced α-MPP levels, while not significantly affecting the respiratory machinery. These results suggest that alterations in mitochondrial peptidase function can affect the fusion-fission balance, a key element in maintaining the physiology of retinal ganglion cells, and consequently lead to their progressive degeneration. [ABSTRACT FROM AUTHOR]

A new c.740G>A (R247H) mutation in OPA1 alternate spliced exon 5b was found in a patient presenting with bilateral optic neuropathy followed by partial, spontaneous visual recovery. R247H fibroblasts from the patient and his unaffected father presented unusual highly tubular mitochondrial network, significant increased susceptibility to apoptosis, oxidative phosphorylation uncoupling, and altered OPA1 protein profile, supporting the pathogenicity of this mutation. These results suggest that the clinical spectrum of the OPA1-associated optic neuropathies may be larger than previously described, and that spontaneous recovery may occur in cases harboring an exon 5b mutation. Ann Neurol 2008 [ABSTRACT FROM AUTHOR]

Inherited optic neuropathies are the most common mitochondrial diseases, leading to neurodegeneration involving the irreversible loss of retinal ganglion cells, optic nerve degeneration and central visual loss. Importantly, properly regulated mitochondrial dynamics are critical for maintaining cellular homeostasis, and are further regulated by MIEF1 (mitochondrial elongation factor 1) which encodes for MID51 (mitochondrial dynamics protein 51), an outer mitochondrial membrane protein that acts as an adaptor protein to regulate mitochondrial fission. However, dominant mutations in MIEF1 have not been previously linked to any human disease. Using targeted sequencing of genes involved in mitochondrial dynamics, we report the first heterozygous variants in MIEF1 linked to disease, which cause an unusual form of late-onset progressive optic neuropathy characterized by the initial loss of peripheral visual fields. Pathogenic MIEF1 variants linked to optic neuropathy do not disrupt MID51's localization to the outer mitochondrial membrane or its oligomerization, but rather, significantly disrupt mitochondrial network dynamics compared to wild-type MID51 in high spatial and temporal resolution confocal microscopy live imaging studies. Together, our study identifies dominant MIEF1 mutations as a cause for optic neuropathy and further highlights the important role of properly regulated mitochondrial dynamics in neurodegeneration. [ABSTRACT FROM AUTHOR]

Background:FOXL2 is the gene involved in blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES). There have been few single case reports of growth hormone deficiency (GHD) with this syndrome, and Foxl2 is known to be involved in pituitary development in mice. Our aim was to analyze the prevalence of FOXL2 gene alteration in a series of patients with congenital hypopituitarism and eyelid anomalies. Methods:FOXL2 was analyzed in 10 patients with hypopituitarism (ranging from isolated GHD to complete pituitary hormone deficiency) and eyelid anomalies (typical BPES in 4 patients and milder anomalies in 6 patients). In patients with an FOXL2 mutation, we ruled out other possible molecular explanations by analyzing a panel of 20 genes known to be associated with hypopituitarism, and a candidate gene approach was used for patients without an FOXL2mutation. Results: Three patients had an FOXL2mutation. All 3 had typical BPES. Their pituitary phenotype varied from GHD to complete pituitary hormone deficiency and their pituitary morphology ranged from normal to an interrupted pituitary stalk. No mutations were found in genes previously associated with hypopituitarism. Conclusion: Our study shows that some patients with BPES have hypopituitarism with no molecular explanation other than FOXL2 mutation. This points toward an involvement of FOXL2 in human pituitary development. [ABSTRACT FROM AUTHOR]

Due to its pivotal role in NADH oxidation and ATP synthesis, mitochondrial complex I (CI) emerged as a crucial regulator of cellular metabolism. A functional CI relies on the sequential assembly of nuclear- and mtDNA-encoded subunits; however, whether CI assembly status is involved in the metabolic adaptations in CI deficiency still remains largely unknown. Here, we investigated the relationship between CI functions, its structure and the cellular metabolism in 29 patient fibroblasts representative of most CI mitochondrial diseases. Our results show that, contrary to the generally accepted view, a complex I deficiency does not necessarily lead to a glycolytic switch, i.e. the so-called Warburg effect, but that this particular metabolic adaptation is a feature of CI assembly defect. By contrast, a CI functional defect without disassembly induces a higher catabolism to sustain the oxidative metabolism. Mechanistically, we demonstrate that reactive oxygen species overproduction by CI assembly intermediates and subsequent AMPK-dependent Pyruvate Dehydrogenase inactivation are key players of this metabolic reprogramming. Thus, this study provides a two-way-model of metabolic responses to CI deficiencies that are central not only in defining therapeutic strategies for mitochondrial diseases, but also in all pathophysiological conditions involving a CI deficiency. Unlabelled Image • Complex I functional vs structural defects lead to different metabolic adaptations. • Complex I intermediates impair pyruvate oxidation in a ROS/AMPK dependent pathway. • Complex I disassembly drives metabolic reprogramming towards aerobic glycolysis. [ABSTRACT FROM AUTHOR]

Abstract Introduction Mitochondrial diseases are a group of disorders caused mainly by the impairment of the mitochondrial oxidative phosphorylation process, due to mutations either in the mitochondrial or nuclear genome. Among them, the mitochondrial neuro-gastrointestinal encephalo-myopathy (MNGIE) syndrome affects adolescents or young adults, and is mostly caused by TYMP mutations encoding a cytosolic thymidine phosphorylase (TP). Patients and methods The present study reports the molecular investigation by next-generation re-sequencing of 281 nuclear genes, encoding mitochondrial proteins, of consanguineous family including two individuals with MNGIE syndrome associated to optic atrophy. Bioinformatic analysis was also performed in addition to mtDNA deletion screening and mtDNA copy number quantification in blood of the two patients which were carried out by solf clipping program and qPCR respectively. Results Next-generation re-sequencing revealed a novel homozygous c.2391G > T POLG mutation (p.M797I) co-occurring with the hypomorphic c.1311A > G OPA1 variant (p.I437M). Analysis of the mitochondrial genome in the two patients disclosed mtDNA depletion in blood, but no deletion. Bio-informatics investigations supported the pathogenicity of the novel POLG mutation that is located in the C-terminal subdomain and might change POLG 3D structure, stability and function. Conclusion The novel homozygous p.M797I POLG mutation is responsible for MNGIE combined to optic atrophy and mtDNA depletion in the two patients. Highlights • We reported 2 patients with MNGIE syndrome plus optic atrophy. • Novel homozygous POLG c.2391 G > T variation was reported. • The heterozygous OPA1 c.1311 A > G variation was reported. • mtDNA depletion was revealed in the two patients. [ABSTRACT FROM AUTHOR]

Dominant optic atrophy is a blinding disease due to the degeneration of the retinal ganglion cells, the axons of which form the optic nerves. In most cases, the disease is caused by mutations in OPA1, a gene encoding a mitochondrial large GTPase involved in cristae structure and mitochondrial network fusion. Using exome sequencing, we identified dominant mutations in DNM1L on chromosome 12p11.21 in three large families with isolated optic atrophy, including the two families that defined the OPA5 locus on chromosome 19q12.1-13.1, the existence of which is denied by the present study. Analyses of patient fibroblasts revealed physiological abundance and homo-polymerization of DNM1L, forming aggregates in the cytoplasm and on highly tubulated mitochondrial network, whereas neither structural difference of the peroxisome network, nor alteration of the respiratory machinery was noticed. Fluorescence microscopy of wild-type mouse retina disclosed a strong DNM1L expression in the ganglion cell layer and axons, and comparison between 3-month-old wild-type and Dnm1l+/- mice revealed increased mitochondrial length in retinal ganglion cell soma and axon, but no degeneration. Thus, our results disclose that in addition to OPA1, OPA3, MFN2, AFG3L2 and SPG7, dominant mutations in DNM1L jeopardize the integrity of the optic nerve, suggesting that alterations of the opposing forces governing mitochondrial fusion and fission, similarly affect retinal ganglion cell survival. [ABSTRACT FROM AUTHOR]

Ketogenic Diet used to treat refractory epilepsy for almost a century may represent a treatment option for mitochondrial disorders for which effective treatments are still lacking. Mitochondrial complex I deficiencies are involved in a broad spectrum of inherited diseases including Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes syndrome leading to recurrent cerebral insults resembling strokes and associated with a severe complex I deficiency caused by mitochondrial DNA (mtDNA) mutations. The analysis of MELAS neuronal cybrid cells carrying the almost homoplasmic m.3243A > G mutation revealed a metabolic switch towards glycolysis with the production of lactic acid, severe defects in respiratory chain activity and complex I disassembly with an accumulation of assembly intermediates. Metabolites, NADH/NAD + ratio, mitochondrial enzyme activities, oxygen consumption and BN-PAGE analysis were evaluated in mutant compared to control cells. A severe complex I enzymatic deficiency was identified associated with a major complex I disassembly with an accumulation of assembly intermediates of 400 kDa. We showed that Ketone Bodies (KB) exposure for 4 weeks associated with glucose deprivation significantly restored complex I stability and activity, increased ATP synthesis and reduced the NADH/NAD + ratio, a key component of mitochondrial metabolism. In addition, without changing the mutant load, mtDNA copy number was significantly increased with KB, indicating that the absolute amount of wild type mtDNA copy number was higher in treated mutant cells. Therefore KB may constitute an alternative and promising therapy for MELAS syndrome, and could be beneficial for other mitochondrial diseases caused by complex I deficiency. [ABSTRACT FROM AUTHOR]

Via whole-exome sequencing, we identified rare autosomal-recessive variants in UBA5 in five children from four unrelated families affected with a similar pattern of severe intellectual deficiency, microcephaly, movement disorders, and/or early-onset intractable epilepsy. UBA5 encodes the E1-activating enzyme of ubiquitin-fold modifier 1 (UFM1), a recently identified ubiquitin-like protein. Biochemical studies of mutant UBA5 proteins and studies in fibroblasts from affected individuals revealed that UBA5 mutations impair the process of ufmylation, resulting in an abnormal endoplasmic reticulum structure. In Caenorhabditis elegans , knockout of uba-5 and of human orthologous genes in the UFM1 cascade alter cholinergic, but not glutamatergic, neurotransmission. In addition, uba5 silencing in zebrafish decreased motility while inducing abnormal movements suggestive of seizures. These clinical, biochemical, and experimental findings support our finding of UBA5 mutations as a pathophysiological cause for early-onset encephalopathies due to abnormal protein ufmylation. [ABSTRACT FROM AUTHOR]

Autosomal-recessive optic neuropathies are rare blinding conditions related to retinal ganglion cell (RGC) and optic-nerve degeneration, for which only mutations in TMEM126A and ACO2 are known. In four families with early-onset recessive optic neuropathy, we identified mutations in RTN4IP1 , which encodes a mitochondrial ubiquinol oxydo-reductase. RTN4IP1 is a partner of RTN4 (also known as NOGO), and its ortholog Rad8 in C. elegans is involved in UV light response. Analysis of fibroblasts from affected individuals with a RTN4IP1 mutation showed loss of the altered protein, a deficit of mitochondrial respiratory complex I and IV activities, and increased susceptibility to UV light. Silencing of RTN4IP1 altered the number and morphogenesis of mouse RGC dendrites in vitro and the eye size, neuro-retinal development, and swimming behavior in zebrafish in vivo. Altogether, these data point to a pathophysiological mechanism responsible for RGC early degeneration and optic neuropathy and linking RTN4IP1 functions to mitochondrial physiology, response to UV light, and dendrite growth during eye maturation. [ABSTRACT FROM AUTHOR]

Complex I (CI) deficiency is the most common respiratory chain defect representing more than 30% of mitochondrial diseases. CI is an L-shaped multi-subunit complex with a peripheral arm protruding into the mitochondrial matrix and a membrane arm. CI sequentially assembled into main assembly intermediates: the P (pumping), Q (Quinone) and N (NADH dehydrogenase) modules. In this study, we analyzed 11 fibroblast cell lines derived from patients with inherited CI deficiency resulting from mutations in the nuclear or mitochondrial DNA and impacting these different modules. In patient cells carrying a mutation located in the matrix arm of CI, blue native-polyacrylamide gel electrophoresis (BN-PAGE) revealed a significant reduction of fully assembled CI enzyme and an accumulation of intermediates of the N module. In these cell lines with an assembly defect, NADH dehydrogenase activity was partly functional, even though CI was not fully assembled. We further demonstrated that this functional N module was responsible for ROS production through the reduced flavin mononucleotide. Due to the assembly defect, the FMN site was not re-oxidized leading to a significant oxidative stress in cell lines with an assembly defect. These findings not only highlight the relationship between CI assembly and oxidative stress, but also show the suitability of BN-PAGE analysis in evaluating the consequences of CI dysfunction. Moreover, these data suggest that the use of antioxidants may be particularly relevant for patients displaying a CI assembly defect. [ABSTRACT FROM AUTHOR]

Objective OPA1 mutations are responsible for more than half of autosomal dominant optic atrophy (ADOA), a blinding disease affecting the retinal ganglion neurons. In most patients the clinical presentation is restricted to the optic nerve degeneration, albeit in 20% of them, additional neuro-sensorial symptoms might be associated to the loss of vision, as frequently encountered in mitochondrial diseases. This study describes clinical and neuroradiological features of OPA1 patients. Methods Twenty two patients from 17 families with decreased visual acuity related to optic atrophy and carrying an OPA1 mutation were enrolled. Patients underwent neuro-ophthalmological examinations. Brain magnetic resonance imaging (T1, T2 and flair sequences) was performed on a 1.5-Tesla MR Unit. Twenty patients underwent 2-D proton spectroscopic imaging. Results Brain imaging disclosed abnormalities in 12 patients. Cerebellar atrophy mainly involving the vermis was observed in almost a quarter of the patients; other abnormalities included unspecific white matter hypersignal, hemispheric cortical atrophy, and lactate peak. Neurological examination disclosed one patient with a transient right hand motor deficit and ENT examination revealed hearing impairment in 6 patients. Patients with abnormal MRI were characterized by: (i) an older age (ii) more severe visual impairment with chronic visual acuity deterioration, and (iii) more frequent associated deafness. Conclusions Our results demonstrate that brain imaging abnormalities are common in OPA1 patients, even in those with normal neurological examination. Lactate peak, cerebellar and cortical atrophies are consistent with the mitochondrial dysfunction related to OPA1 mutations and might result from widespread neuronal degeneration. [ABSTRACT FROM AUTHOR]

Purpose: Inherited retinal dystrophies (IRDs) and inherited optic neuropathies (IONs) are rare diseases defined by specific clinical and molecular features. The relative prevalence of these conditions was determined in Southern France. Methods: Patients recruited from a specialized outpatient clinic over a 21-year period underwent extensive clinical investigations and 107 genes were screened by polymerase chain reaction/sequencing. Results: There were 1957 IRD cases (1481 families) distributed in 70% of pigmentary retinopathy cases (56% non-syndromic, 14% syndromic), 20% maculopathies and 7% stationary conditions. Patients with retinitis pigmentosa were the most frequent (47%) followed by Usher syndrome (10.8%). Among non-syndromic pigmentary retinopathy patients, 84% had rod-cone dystrophy, 8% cone-rod dystrophy and 5% Leber congenital amaurosis. Macular dystrophies were encountered in 398 cases (30% had Stargardt disease and 11% had Best disease). There were 184 ION cases (127 families) distributed in 51% with dominant optic neuropathies, 33% with recessive/sporadic forms and 16% with Leber hereditary optic neuropathy. Positive molecular results were obtained in 417/609 families with IRDs (68.5%) and in 27/58 with IONs (46.5%). The sequencing of 5 genes ( ABCA4, USH2A, MYO7A, RPGR and PRPH2) provided a positive molecular result in 48% of 417 families with IRDs. Except for autosomal retinitis pigmentosa, in which less than half the families had positive molecular results, about 75% of families with other forms of retinal conditions had a positive molecular diagnosis. Conclusions: Although gene discovery considerably improved molecular diagnosis in many subgroups of IRDs and IONs, retinitis pigmentosa, accounting for almost half of IRDs, remains only partly molecularly defined. [ABSTRACT FROM AUTHOR]

Abstract: Mitochondria form dynamic tubular networks through processes of fission and fusion. Defect in mitochondrial dynamics lead to various pathologies, including several common and some rare neurodegenerative disorders. OPA1 and MFN2 are two key players in mitochondrial fusion associated with Autosomal Dominant Optic Atrophy and Charcot Marie Tooth neuropathy type 2A respectively. We used micropatterned coverslips to standardize the visualization of mitochondrial distribution in skin fibroblasts. In fibroblasts from affected patients, mutations in the OPA1 and MFN2 genes were found to affect the volume and cellular distribution of mitochondria. In G1/S cell cycle phase, mitochondria emerging from the microtubule organizing centre may be crucial to mitochondrial biogenesis since it appeared to be protected against mitochondrial fragmentation induced by OPA1 mutations. The standardized quantitative analysis of the mitochondrial network and the description of mitochondrial subcellular distribution should lead to better diagnostic criteria for mitochondrial diseases and yield new insights into mitochondrial dysfunction in disease and aging. [Copyright &y& Elsevier]

Abstract: The m.3243A>G variant in the mitochondrial tRNALeu(UUR) gene is a common mitochondrial DNA (mtDNA) mutation. Phenotypic manifestations depend mainly on the heteroplasmy, i.e. the ratio of mutant to normal mtDNA copies. A high percentage of mutant mtDNA is associated with a severe, life-threatening neurological syndrome known as MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). MELAS is described as a neurovascular disorder primarily affecting the brain and blood vessels, but the pathophysiology of the disease is poorly understood. We developed a series of cybrid cell lines at two different mutant loads: 70% and 100% in the nuclear background of a neuroblastoma cell line (SH-SY5Y). We investigated the impact of the mutation on the metabolism and mitochondrial respiratory chain activity of the cybrids. The m.3243A>G mitochondrial mutation induced a metabolic switch towards glycolysis in the neuronal cells and produced severe defects in respiratory chain assembly and activity. We used two strategies to compensate for the biochemical defects in the mutant cells: one consisted of lowering the glucose content in the culture medium, and the other involved the addition of l-arginine. The reduction of glucose significantly shifted the 100% mutant cells towards the wild-type, reaching a 90% mutant level and restoring respiratory chain complex assembly. The addition of l-arginine, a nitric oxide (NO) donor, improved complex I activity in the mutant cells in which the defective NO metabolism had led to a relative shortage of NO. Thus, metabolically induced heteroplasmy shifting and l-arginine therapy may constitute promising therapeutic strategies against MELAS. [Copyright &y& Elsevier]

Definition of the disease: Dominant Optic Atrophy (DOA) is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing insidious visual loss, typically starting during the first decade of life. The disease affects primary the retinal ganglion cells (RGC) and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the lateral geniculus in the brain. Epidemiology: The prevalence of the disease varies from 1/10000 in Denmark due to a founder effect, to 1/30000 in the rest of the world. Clinical description: DOA patients usually suffer of moderate visual loss, associated with central or paracentral visual field deficits and color vision defects. The severity of the disease is highly variable, the visual acuity ranging from normal to legal blindness. The ophthalmic examination discloses on fundoscopy isolated optic disc pallor oratrophy, related to the RGC death. About 20% of DOA patients harbour extraocular multi-systemic features, including neurosensory hearing loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts.Aetiology: Two genes (OPA1, OPA3) encoding inner mitochondrial membrane proteins and three loci (OPA4, OPA5, OPA8) are currently known for DOA. Additional loci and genes (OPA2, OPA6 and OPA7) are responsible for X-linked or recessive optic atrophy. All OPA genes yet identified encode mitochondrial proteins embedded in the inner membrane and ubiquitously expressed, as are the proteins mutated in the Leber Hereditary Optic Neuropathy. OPA1 mutations affect mitochondrial fusion, energy metabolism, control of apoptosis, calcium clearance and maintenance of mitochondrial genome integrity. OPA3 mutations only affect the energy metabolism and the control of apoptosis.Diagnosis: Patients are usually diagnosed during their early childhood, because of bilateral, mild, otherwise unexplained visual loss related to optic discs pallor or atrophy, and typically occurring in the context of a family history of DOA. Optical Coherence Tomography further discloses non-specific thinning of retinal nerve fiber layer, but a normal morphology of the photoreceptors layers. Abnormal visual evoked potentials and pattern ERG may also reflect the dysfunction of the RGCs and their axons. Molecular diagnosis is provided by the identification of a mutation in the OPA1 gene (75% of DOA patients) or in the OPA3 gene (1% of patients). Prognosis: Visual loss in DOA may progress during puberty until adulthood, with very slow subsequent chronic progression in most of the cases. On the opposite, in DOA patients with associated extra-ocular features, the visual loss may be more severe over time. Management: To date, there is no preventative or curative treatment in DOA; severely visually impaired patients may benefit from low vision aids. Genetic counseling is commonly offered and patients are advised to avoid alcohol and tobacco consumption, as well as the use of medications that may interfere with mitochondrial metabolism. Gene and pharmacological therapies for DOA are currently under investigation. [ABSTRACT FROM AUTHOR]

Charcot-Marie-Tooth disease type 2A (CMT2A) is an autosomal dominant axonal form of peripheral neuropathy caused by mutations in the mitofusin 2 gene (MFN2), which encodes a mitochondrial outer membrane protein that promotes mitochondrial fusion. Emerging evidence also points to a role of MFN2 in the regulation of mitochondrial metabolism. To examine whether mitochondrial dysfunction is a feature of CMT2A, we used a transgenic mouse model expressing in neurons a mutated R94Q form of human MFN2 shown to induce a CMT2A phenotype. Oxygraphic and enzymatic measurements both revealed a combined defect of mitochondrial complexes II and V (40 and 30% decrease, respectively) in the brain of Tg-R94 mice, leading to a drastic decrease of ATP synthesis. These deficiencies were reversed by the mitochondrial ATP-sensitive potassium channel (mKATP) inhibitor 5-hydroxydecanoate. Conversely, in controls and wild-type human MFN2 mice, the mKATP activator diazoxide mimicked the deficiency observed with the R94Q mutation. The physical links between complexes II and V, previously proposed as part of mKATP, were reinforced in Tg-R94Q mice. Our results show that the R94Q MFN2 mutation induces a combined defect of complexes II and V linked to the opening of mKATP, which could participate in the pathophysiology of the disease. [ABSTRACT FROM AUTHOR]

Abstract: Hereditary spastic paraplegia refers to a genetically heterogeneous syndrome. We identified five members of a family suffering from a late-onset spastic paraplegia-like disorder, carrying the homoplasmic m.9176T>C mutation in the mitochondrial ATP6 gene. The clinical severity of the disease observed in the family was correlated with the biochemical and assembly defects of the ATP synthase. The m.9176T>C mutation has been previously associated to Leigh syndrome or familial bilateral striatal necrosis. Other factors such as modifying genes may be involved in the phenotypic expression of the disease. The family belongs to the mitochondrial haplogroup J, previously shown to play a role in modulating the phenotype of mitochondrial diseases and be associated with longevity. Moreover other nuclear modifying genes or environmental factors may contribute to the disease phenotype. This finding extends the genetic heterogeneity of the hereditary spastic paraplegia together with the clinical spectrum of mutations of the ATP6 gene. [ABSTRACT FROM AUTHOR]

Abstract: Charcot–Marie–Tooth (CMT) disease represents a large group of clinically and genetically heterogeneous disorders leading to inherited peripheral neuropathies affecting motor and sensory neurons. Mutations in the ganglioside-induced differentiation-associated-protein 1 gene (GDAP1), which encodes a protein anchored to the mitochondrial outer membrane, are usually associated with the recessive forms of CMT disease and only rarely with the autosomal dominant forms. The function of GDAP1 is not fully understood but it plays a role in mitochondrial dynamics by promoting fission events. We present an overview of GDAP1 and the corresponding protein together with the complete spectrum of the 41 gene mutations described so far. We examine the relationship between the genotype and the phenotype in the various forms of CMT disease related to GDAP1 mutations, and discuss the pathophysiological hypotheses that link peripheral neuropathies to mitochondrial dysfunction and GDAP1 mutations. The meta-analysis of the literature reveals the great heterogeneity of phenotypic presentations and shows that the recessive forms of CMT disease, i.e. CMT4A and AR-CMT2, are far more severe than the dominant form, i.e. CMT2K. Among patients with recessive forms of the disease, those carrying truncating mutations are more seriously affected, often becoming wheelchair-bound before the end of the third decade. At the neuronal level, GDAP1 mutations may lead to perturbed axonal transport and impaired energy production as in other neurodegenerative diseases due to mutations in genes involved in mitochondrial dynamics. [ABSTRACT FROM AUTHOR]

Abstract: Ethambutol (EMB), widely used in the treatment of tuberculosis, has been reported to cause Leber’s hereditary optic neuropathy in patients carrying mitochondrial DNA mutations. We study the effect of EMB on mitochondrial metabolism in fibroblasts from controls and from a man carrying an OPA1 mutation, in whom the drug induced the development of autosomal dominant optic atrophy (ADOA). EMB produced a mitochondrial coupling defect together with a 25% reduction in complex IV activity. EMB induced the formation of vacuoles associated with decreased mitochondrial membrane potential and increased fragmentation of the mitochondrial network. Mitochondrial genetic variations may therefore be predisposing factors in EMB-induced ocular injury. [Copyright &y& Elsevier]

Hereditary optic neuropathies are heterogeneous diseases characterized by the degeneration of retinal ganglion cells leading to optic nerve atrophy and impairment of central vision. We found a common coupling defect of oxidative phosphorylation in fibroblasts of patients affected by autosomal dominant optic atrophy (mutations of OPA1), autosomal dominant optic atrophy associated with cataract (mutations of OPA3), and Leber's hereditary optic neuropathy, a disorder associated with point mutations of mitochondrial DNA complex I genes. Interestingly, the energetic defect was significantly more pronounced in Leber's hereditary optic neuropathy and autosomal dominant optic atrophy patients with a more complex phenotype, the so-called plus phenotype. Ann Neurol 2008 [ABSTRACT FROM AUTHOR]

Mitochondrial DNA (mtDNA) mutations have been implicated in non-syndromic hearing loss either as primary or as predisposing factors. As only a part of the mitochondrial genome is usually explored in deafness, its prevalence is probably under-estimated. Among 1350 families with non-syndromic sensorineural hearing loss collected through a French collaborative network, we selected 29 large families with a clear maternal lineage and screened them for known mtDNA mutations in 12S rRNA, tRNASer(UCN) and tRNALeu(UUR) genes. When no mutation could be identified, a whole mitochondrial genome screening was performed, using a microarray resequencing chip: the MitoChip version 2.0 developed by Affymetrix Inc. Known mtDNA mutations was found in nine of the 29 families, which are described in the article: five with A1555G, two with the T7511C, one with 7472insC and one with A3243G mutation. In the remaining 20 families, the resequencing Mitochip detected 258 mitochondrial homoplasmic variants and 107 potentially heteroplasmic variants. Controls were made by direct sequencing on selected fragments and showed a high sensibility of the MitoChip but a low specificity, especially for heteroplasmic variations. An original analysis on the basis of species conservation, frequency and phylogenetic investigation was performed to select the more probably pathogenic variants. The entire genome analysis allowed us to identify five additional families with a putatively pathogenic mitochondrial variant: T669C, C1537T, G8078A, G12236A and G15077A. These results indicate that the new MitoChip platform is a rapid and valuable tool for identification of new mtDNA mutations in deafness.European Journal of Human Genetics (2007) 15, 1145–1155; doi:10.1038/sj.ejhg.5201891; published online 18 July 2007 [ABSTRACT FROM AUTHOR]

To characterize the molecular links between type-1 autosomal dominant optic atrophy (ADOA) and OPA1 dysfunctions, the effects of pathogenic alleles of this dynamin on mitochondrial morphology and apoptosis were analyzed, either in fibroblasts from affected individuals, or in HeLa cells transfected with similar mutants. The alleles were missense substitutions in the GTPase domain (OPA1G300E and OPA1R290Q) or deletion of the GTPase effector domain (OPA1Δ58). Fragmentation of mitochondria and apoptosis increased in OPA1R290Q fibroblasts and in OPA1G300E transfected HeLa cells. OPA1Δ58 did not influence mitochondrial morphology, but increased the sensitivity to staurosporine of fibroblasts. In these cells, the amount of OPA1 protein was half of that in control fibroblasts. We conclude that GTPase mutants exert a dominant negative effect by competing with wild-type alleles to integrate into fusion-competent complexes, whereas C-terminal truncated alleles act by haplo-insufficiency. We present a model where antagonistic fusion and fission forces maintain the mitochondrial network, within morphological limits that are compatible with cellular functions. In the retinal ganglion cells (RGCs) of patients suffering from type-1 ADOA, OPA1-driven fusion cannot adequately oppose fission, thereby rendering them more sensitive to apoptotic stimuli and eventually leading to optic nerve degeneration. J. Cell. Physiol. 211: 423–430, 2007. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract: The mitochondria are dynamic organelles that constantly fuse and divide. An equilibrium between fusion and fission controls the morphology of the mitochondria, which appear as dots or elongated tubules depending the prevailing force. Characterization of the components of the fission and fusion machineries has progressed considerably, and the emerging question now is what role mitochondrial dynamics play in mitochondrial and cellular functions. Its importance has been highlighted by the discovery that two human diseases are caused by mutations in the two mitochondrial pro-fusion genes, MFN2 and OPA1. This review will focus on data concerning the function of OPA1, mutations in which cause optic atrophy, with respect to the underlying pathophysiological processes. [Copyright &y& Elsevier]

Purpose: To present detailed clinical findings of a Turkish family from central Anatolia with a hereditary form of optic atrophy. Design: Observational case series. Material and methods: A detailed family history of a patient with optic atrophy revealed similarly affected family members. Nine members of this consanguineous family were evaluated. The OPA1 gene of seven of the nine individuals was screened for mutations using direct DNA sequencing. Results: No mutation was found in the OPA1 gene. Four females were clinically affected, two of whom had previous diagnoses of glaucoma. Affected family members demonstrated abnormal findings in at least one of the following: optic disk, visual field, or color vision. Myopia, oblique insertion of the optic nerve, marginal pigmentation of the optic nerve head, and entry and exit anomalies of central retinal vessels were additional findings. Conclusion: This family demonstrates a highly variable expression of a form of hereditary optic atrophy, ranging from asymptomatic involvement to legal blindness. It is important for doctors to look for subtle but typical optic disk, visual field, and color vision anomalies in asymptomatic members when screening such families. [ABSTRACT FROM AUTHOR]

Background: The dysfunction of OPA1, a dynamin GTPase involved in mitochondrial fusion, is responsible for a large spectrum of neurological disorders, each of which includes optic neuropathy. The database dedicated to OPA1 ( https://www.lovd.nl/OPA1 ), created in 2005, has now evolved towards a centralized and more reliable database using the Global Variome shared Leiden Open-source Variation Database (LOVD) installation.Results: The updated OPA1 database, which registers all the patients from our center as well as those reported in the literature, now covers a total of 831 patients: 697 with isolated dominant optic atrophy (DOA), 47 with DOA "plus", and 83 with asymptomatic or unclassified DOA. It comprises 516 unique OPA1 variants, of which more than 80% (414) are considered pathogenic. Full clinical data for 118 patients are documented using the Human Phenotype Ontology, a standard vocabulary for referencing phenotypic abnormalities. Contributors may now make online submissions of phenotypes related to OPA1 mutations, giving clinical and molecular descriptions together with detailed ophthalmological and neurological data, according to an international thesaurus.Conclusions: The evolution of the OPA1 database towards the LOVD, using unified nomenclature, should ensure its interoperability with other databases and prove useful for molecular diagnoses based on gene-panel sequencing, large-scale mutation statistics, and genotype-phenotype correlations. [ABSTRACT FROM AUTHOR]

OPA1 (Optic Atrophy 1) is a multi-isoform dynamin GTPase involved in the regulation of mitochondrial fusion and organization of the cristae structure of the mitochondrial inner membrane. Pathogenic OPA1 variants lead to a large spectrum of disorders associated with visual impairment due to optic nerve neuropathy. The aim of this study was to investigate the metabolomic consequences of complete OPA1 disruption in Opa1−/− mouse embryonic fibroblasts (MEFs) compared to their Opa1+/+ counterparts. Our non-targeted metabolomics approach revealed significant modifications of the concentration of several mitochondrial substrates, i.e. a decrease of aspartate, glutamate and α-ketoglutaric acid, and an increase of asparagine, glutamine and adenosine-5′-monophosphate, all related to aspartate metabolism. The signature further highlighted the altered metabolism of nucleotides and NAD together with deficient mitochondrial bioenergetics, reflected by the decrease of creatine/creatine phosphate and pantothenic acid, and the increase in pyruvate and glutathione. Interestingly, we recently reported significant variations of five of these molecules, including aspartate and glutamate, in the plasma of individuals carrying pathogenic OPA1 variants. Our findings show that the disruption of OPA1 leads to a remodelling of bioenergetic pathways with the central role being played by aspartate and related metabolites. [ABSTRACT FROM AUTHOR]

Backrground: Evaluation of the efficacy of oral cyclosporine A as a prophylactic agent in preventing second-eye involvement in Leber's hereditary optic neuropathy (LHON) in a prospective, open-label, non-randomized, multicenter pilot study. Only LHON patients aged 18 years or more, with confirmed primary mitochondrial DNA mutations and strictly unilateral optic neuropathy occurring within 6 months prior to enrolment, were included in the study. All these patients, receiving treatment with oral cyclosporine (Neoral®, Novartis) at 2.5 mg/kg/day, were examined at three-month intervals for a year. The primary endpoint was the best corrected visual acuity in the unaffected eye; the secondary endpoints were the best corrected visual acuity in the first eye affected, the mean visual field defect on automated perimetry, the thickness of the perifoveal retinal ganglion cell inner plexiform layer, and the thickness of the peripapillary retinal nerve fiber layer in both eyes.Results: Among the 24 patients referred to our institution with genetically confirmed LHON, between July 2011 and April 2014, only five patients, four males and one female, fulfilled the inclusion criteria. Age at enrolment ranged from 19 to 42 years (mean: 27.2 years; median: 26 years), four patients harbored the m.11778G > A pathogenic variant, and one the m.14484 T > C pathogenic variant. The time-interval between the onset of symptoms and inclusion in the study ranged from 7 to 17 weeks (mean: 11.8 weeks; median: 9 weeks). Despite treatment with oral cyclosporine A, all patients eventually experienced bilateral eye involvement, occurring within 11-65 weeks after the initiation of treatment. Over the study time period, the average best corrected visual acuity worsened in the first eye affected; by the end of the study, both eyes were equally affected.Conclusions: Oral cyclosporine, at 2.5 mg/kg/day, did not prevent second-eye involvement in patients with strictly unilateral Leber's hereditary optic neuropathy.Trial Registration: ClinicalTrials.gov Identifier: NCT02176733 . Registrated June 25, 2014. [ABSTRACT FROM AUTHOR]

Unlabelled: DEFINITION OF THE DISEASE: Dominant Optic Atrophy (DOA) is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing insidious visual loss, typically starting during the first decade of life. The disease affects primary the retinal ganglion cells (RGC) and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the lateral geniculus in the brain.Epidemiology: The prevalence of the disease varies from 1/10000 in Denmark due to a founder effect, to 1/30000 in the rest of the world.Clinical Description: DOA patients usually suffer of moderate visual loss, associated with central or paracentral visual field deficits and color vision defects. The severity of the disease is highly variable, the visual acuity ranging from normal to legal blindness. The ophthalmic examination discloses on fundoscopy isolated optic disc pallor or atrophy, related to the RGC death. About 20% of DOA patients harbour extraocular multi-systemic features, including neurosensory hearing loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts.Aetiology: Two genes (OPA1, OPA3) encoding inner mitochondrial membrane proteins and three loci (OPA4, OPA5, OPA8) are currently known for DOA. Additional loci and genes (OPA2, OPA6 and OPA7) are responsible for X-linked or recessive optic atrophy. All OPA genes yet identified encode mitochondrial proteins embedded in the inner membrane and ubiquitously expressed, as are the proteins mutated in the Leber Hereditary Optic Neuropathy. OPA1 mutations affect mitochondrial fusion, energy metabolism, control of apoptosis, calcium clearance and maintenance of mitochondrial genome integrity. OPA3 mutations only affect the energy metabolism and the control of apoptosis.Diagnosis: Patients are usually diagnosed during their early childhood, because of bilateral, mild, otherwise unexplained visual loss related to optic discs pallor or atrophy, and typically occurring in the context of a family history of DOA. Optical Coherence Tomography further discloses non-specific thinning of retinal nerve fiber layer, but a normal morphology of the photoreceptors layers. Abnormal visual evoked potentials and pattern ERG may also reflect the dysfunction of the RGCs and their axons. Molecular diagnosis is provided by the identification of a mutation in the OPA1 gene (75% of DOA patients) or in the OPA3 gene (1% of patients).Prognosis: Visual loss in DOA may progress during puberty until adulthood, with very slow subsequent chronic progression in most of the cases. On the opposite, in DOA patients with associated extra-ocular features, the visual loss may be more severe over time.Management: To date, there is no preventative or curative treatment in DOA; severely visually impaired patients may benefit from low vision aids. Genetic counseling is commonly offered and patients are advised to avoid alcohol and tobacco consumption, as well as the use of medications that may interfere with mitochondrial metabolism. Gene and pharmacological therapies for DOA are currently under investigation. [ABSTRACT FROM AUTHOR]