AFG3L2 and ACO2-Linked Dominant Optic Atrophy: Genotype-Phenotype Characterization Compared to OPA1 Patients.

PURPOSE: Heterozygous mutations in the AFG3L2 gene (encoding a mitochondrial protease indirectly reflecting on OPA1 cleavage) and ACO2 gene (encoding the mitochondrial enzyme aconitase) are associated with isolated forms of Dominant Optic Atrophy (DOA). We aimed at describing their neuro-ophthalmological phenotype as compared with classic OPA1-related DOA. DESIGN: Cross-sectional study. METHODS: The following neuro-ophthalmological parameters were collected: logMAR visual acuity (VA), color vision, mean deviation and foveal threshold at visual fields, average and sectorial retinal nerve fiber layer (RNFL), and ganglion cell layer (GCL) thickness on optical coherence tomography. ACO2 and AFG3L2 patients were compared with an age- and sex-matched group of OPA1 patients with a 1:2 ratio. All eyes were analyzed using a clustered Wilcoxon rank sum test with the Rosner-Glynn-Lee method. RESULTS: A total of 44 eyes from 23 ACO2 patients and 26 eyes from 13 AFG3L2 patients were compared with 143 eyes from 72 OPA1 patients. All cases presented with bilateral temporal-predominant optic atrophy with various degree of visual impairment. Comparison between AFG3L2 and OPA1 failed to reveal any significant difference. ACO2 patients compared to both AFG3L2 and OPA1 presented overall higher values of nasal RNFL thickness (P = .029, P = .023), average thickness (P = .012, P = .0007), and sectorial GCL thickness. These results were confirmed also comparing separately affected and subclinical patients. CONCLUSIONS: Clinically, DOA remains a fairly homogeneous entity despite the growing genetic heterogeneity. ACO2 seems to be associated with an overall better preservation of retinal ganglion cells, probably depending on the different pathogenic mechanism involving mtDNA maintenance, as opposed to AFG3L2, which is involved in OPA1 processing and is virtually indistinguishable from classic OPA1-DOA.

Idebenone increases chance of stabilization/recovery of visual acuity in OPA1-dominant optic atrophy.

We previously documented that idebenone treatment in OPA1-Dominant Optic Atrophy (OPA1-DOA) led to some degrees of visual improvement in seven patients. We here present the results of a cohort study, which investigated the effect of off-label idebenone administration in a larger OPA1-DOA group compared with untreated patients. Inclusion criteria were: OPA1-DOA clinical and molecular diagnosis, baseline visual acuity (VA) greater than/equal to counting fingers and treatment duration greater than 7 months. We found a significant difference between the last visit and baseline VA in favor of stabilization/recovery in idebenone-treated as compared to untreated patients. This effect was retained after controlling for confounders.

Intrafamilial "DOA-plus" phenotype variability related to different OMI/HTRA2 expression.

Dominant Optic Atrophy and Deafness (DOAD) may be associated with one or more of the following disorders such as myopathy, progressive external ophthalmoplegia, peripheral neuropathy, and cerebellar atrophy ("DOA-plus"). Intra- and interfamilial variability of the "DOA-plus" phenotype is frequently observed in the majority of the patients carrying the same mutation in the OPA1 gene. We are describing two familial cases of "DOA-plus" carrying the same c.1334G>A (p.Arg445His) mutation in OPA1 and disclosing different clinical, pathological and biochemical features. The two patients showed different expression levels of the mitochondrial OMI/HTRA2 molecule, which acts as a mitochondrial stress sensor and has been described to interplay with OPA1 in in vitro studies. Our data offer the cue to inquire the role of OMI/HTRA2 as a modifier gene in determining the "DOAplus" phenotype variability.

Autosomal dominant optic atrophy with OPA1 gene mutations accompanied by auditory neuropathy and other systemic complications in a Japanese cohort.

Purpose: This study aimed to describe the genetic and clinical characteristics of four Japanese patients with autosomal dominant optic atrophy (DOA) accompanied by auditory neuropathy and other systemic complications (i.e., DOA-plus disease). Methods: Four patients from four independent families underwent comprehensive ophthalmic and auditory examinations and were diagnosed with DOA-plus disease. The disease-causing gene variants in the OPA1 gene were identified by direct sequencing. The genetic and clinical data of 48 DOA patients without systemic complications-that is, with simple DOA-were compared to those of DOA-plus patients. Results: DOA-plus patients noticed a decrease in vision before the age of 14 and hearing impairment 3 to 13 years after the development of visual symptoms. Two patients had progressive external ophthalmoplegia, and one patient had vestibular dysfunction and ataxia. The DOA-plus phenotypes accounted for 13.3% (4/30) of the families with the OPA1 gene mutations. Each DOA-plus patient harbored one of the monoallelic mutations in the OPA1 gene: c.1334G>A, p.R445H, c.1618A>C, p.T540P, and c.892A>C, p.S298R. Missense mutations accounted for 100% (4/4) of the DOA-plus families and only 11.5% (3/26) of the families with simple DOA. Conclusions: All the patients with the DOA-plus phenotype carried one of the missense mutations in the OPA1 gene. They all had typical ocular symptoms and signs of DOA in their first or second decade, and other systemic complications-such as auditory neuropathy, vestibular dysfunction, and ataxia-followed the ocular symptoms. We should consider the occurrence of extraocular complications in cases with DOA, especially when they carry the missense mutations in the OPA1 gene.

Derivation of a human DOA iPSC line, IISHDOi006-A, with a mutation in the ACO2 gene: c.1999G>A; p.Glu667Lys.

Human iPSC line, IISHDOi006-A, was obtained from fibroblasts of a patient with Dominant Optic Atrophy (DOA) carrying a heterozygous mutation in the gene ACO2: c.1999G>A; p.Glu667Lys. Reprogramming factors Oct3/4, Sox2, Klf4, and c-Myc were delivered using a non-integrative methodology that involves the use of Sendai virus.

Mitochondrial pathophysiology beyond the retinal ganglion cell: occipital GABA is decreased in autosomal dominant optic neuropathy.

PURPOSE: It has remained a mystery why some genetic mitochondrial disorders affect predominantly specific cell types such as the retinal ganglion cell. This is particularly intriguing concerning retinal and cortical function since they are tightly linked in health and disease. Autosomal dominant optic neuropathy (ADOA) is a mitochondrial disease that affects the ganglion cell. However, it is unknown whether alterations are also present in the visual cortex, namely in excitation/inhibition balance. METHODS: In this study, we performed in vivo structural and biochemical proton magnetic resonance imaging in 14 ADOA and 11 age-matched control participants focusing on the visual cortex, with the aim of establishing whether in this genetically determined disease an independent cortical neurochemical phenotype could be established irrespective of a putative structural phenotype. Cortical thickness of anatomically defined visual areas was estimated, and a voxel-based morphometry approach was used to assess occipital volumetric changes in ADOA. Neurochemical measurements were focused on γ-aminobutyric acid (GABA) and glutamate, as indicators of the local excitatory/inhibitory balance. RESULTS: We found evidence for reduced visual cortical GABA and preserved glutamate concentrations in the absence of cortical or subcortical atrophy. These changes in GABA levels were explained by neither structural nor functional measures of visual loss, suggesting a developmental origin. CONCLUSIONS: These results suggest that mitochondrial disorders that were previously believed to only affect retinal function may also affect cortical physiology, especially the GABAergic system, suggesting reduced brain inhibition vs. excitation. This GABA phenotype, independent of sensory loss or cortical atrophy and in the presence of preserved glutamate levels, suggests a neurochemical developmental change at the cortical level, leading to a pathophysiological excitation/inhibition imbalance.

Thickness mapping of individual retinal layers and sectors by Spectralis SD-OCT in Autosomal Dominant Optic Atrophy.

PURPOSE: To assess layer- and location-specific retinal thickness deficits in autosomal dominant optic atrophy (ADOA) using Spectralis SD-OCT. METHODS: This cross-sectional study included 41 ADOA patients with OPA1 exon 28 (2826delT) mutation [age, 8.6-83.5 years; best-corrected visual acuity (BCVA), 8-89 Early Treatment Diabetic Retinopathy Study (ETDRS) letters] and 55 mutation-free first-degree relatives as healthy controls (age, 8.9-68.7; BCVA, 80-99). Participants underwent routine examination and optical coherence tomography (OCT) with segmentation of the whole retina, inner retinal layers (IRL) and outer retinal layers (ORL). Individual segmentation was performed of the perifoveal retinal nerve fibre layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), retinal pigment epithelium (RPE) and the peripapillary RNFL. Combinations of layers and sectors were tested for their diagnostic significance. Only right eye data are presented. Statistical analysis was adjusted for age, gender, spherical equivalent, axial length and family clustering in a mixed model analysis. RESULTS: The perifoveal RNFL, GCL, IPL and the peripapillary RNFL were all significantly thinner in ADOA patients than in healthy controls (p < 0.0001). No statistical difference was found for other layers. The most prominent and diagnostically most valuable deficit was found in the GCL (-49.9%) in the 'nasal inner macula' (NIM) sector (-63%). Attenuation of the peripapillary RNFL was most significant in the temporal sector (-58.4%). CONCLUSION: In ADOA, retinal ganglion cells are most prominently reduced in the nasal perifoveal area of the GCL, which together with the temporal peripapillary RNFL area serves as the strongest diagnostic OCT marker.

Genotype-phenotype and OCT correlations in Autosomal Dominant Optic Atrophy related to OPA1 gene mutations: Report of 13 Italian families.

Mutations in OPA1 are responsible of 32-89% cases of Autosomal Dominant Optic Atrophy (ADOA). OPA1 ADOA usually presents in childhood with bilateral, progressive visual loss due to retinal ganglion cells neurodegeneration, but environmental factors are supposed to influence onset and phenotype. Sixty Italian OPA1 mutations carriers (fifty-two symptomatic), belonging to thirteen families, underwent neuro-ophthalmologic evaluation. Visual acuity (n=60) and Optical Coherence Tomography (OCT) (n=12) were compared in missense mutations (OPA-M) versus haploinsufficiency-inducing mutations (OPA-H) and correlated with age. Presence of plus phenotypes was investigated. We found four known mutations, the most common being missense c.1034G>A, and a new missense mutation, c1193A>C, the latter in a 54-yrs old female with late-onset phenotype. Visual acuity, colour sensitivity, and optic disc atrophy were sensitive indicators of disease. OCT RNFL thickness was reduced in OPA1 compared to controls. OPA-M showed worst visual acuity than OPA-H, but not more frequent plus-phenotype, observed only in four OPA-H patients. In both groups, visual acuity worsened with age. Our data confirm worst vision in OPA-M, but not increased plus-phenotype. Since most patients belonged to nine families from south-eastern Sicily (a famous region for the cult of St. Lucy, patron of the blinds) local genetic and environmental factors might have accounted for the low occurrence of plus-phenotypes.

Dominant Optic Atrophy and Leber's Hereditary Optic Neuropathy: Update on Clinical Features and Current Therapeutic Approaches.

Dominant optic atrophy (DOA) and Leber hereditary optic neuropathy (LHON) are the two most common inherited optic neuropathies encountered in clinical practice. This review provides a summary of recent advances in the understanding of the clinical manifestations, current treatments, and ongoing clinical trials of these two optic neuropathies. Substantial progress has been made in the understanding of the clinical, genetic, and pathophysiological basis of DOA and LHON. Pathogenic OPA1 gene mutations in DOA and 3 primary mutations of mitochondrial DNA in LHON-induced mitochondrial dysfunction, which in turn leads to increased reactive oxygen species levels in mitochondria and possibly insufficient ATP production. The pathologic hallmark of these inherited optic neuropathies is primary degeneration of retinal ganglion cells, preferentially in the papillomacular bundle, which results in temporal optic disc pallor and central or cecocentral visual loss. There are no effective treatments for patients with LHON and DOA, although clinical trials are underway for the former. Translational research for these diseases is entering an accelerated phase with the availability of animal models, and a variety of pharmacological and genetic therapies are being developed.

Assessment of the retinal posterior pole in dominant optic atrophy by spectral-domain optical coherence tomography and microperimetry.

BACKGROUND: To assess posterior pole (PP) retinal structure in patients with genetically confirmed autosomal dominant optic atrophy (ADOA) using new spectral domain optical coherence tomography (SD-OCT) segmentation technology. To analyze retinal PP thickness in relation to retinal sensitivity data from microperimetry (MP) in ADOA patients. METHODS AND FINDINGS: This prospective cross-sectional study included 11 patients with ADOA and 11 age-matched healthy subjects. All participants underwent both a "Posterior Pole" and "peripapillary RNFL (pRNFL)" scanning protocol using SD-OCT. Functional mapping of the PP was also performed using MP. A customized program was implemented in order to achieve accurate superimposition of MP sensitivity map onto SD-OCT map. The thickness of the PP different retinal layers and pRNFL was obtained and measured for each eye. Mean retinal sensitivity values and fixation stability were obtained and compared between ADOA patients and healthy subjects. Correlation analysis was performed on a point-to-point basis to evaluate the association between mean thickness and retinal sensitivity of each retinal layer. Total retinal thickness (TRT), Retinal Nerve Fiber Layer (RNFL), Ganglion Cell Layer (GCL), Inner Plexiform Layer (IPL), Inner Nuclear Layer (INL) and Inner Retinal Layers (IRL) at the posterior pole as well as pRNFL were significantly thinner in ADOA patients (P < 0.0001). On the contrary, the Outer Plexiform Layer (OPL) and the Outer Nuclear Layer (ONL) were significantly thicker in the ADOA group (P < 0.001). No significant differences were found in Retinal Pigment Epithelium (RPE) and Outer Retinal Layers (ORL) thickness between ADOA and controls. The average PP retinal sensitivity was significantly reduced in ADOA patients compared with controls (P < 0.001), as measured by microperimeter Nidek MP-1 (MP1). Fixation stability was significantly worse in the ADOA group (P = 0.01). The most severe sensitivity defects in ADOA patients were found at the level of the papillo-macular bundle (PMB). CONCLUSIONS: Inner retinal layers showed pathological changes in ADOA patients. In addition, the whole retinal PP (not only the PMB) was significantly altered in ADOA, both in terms of retinal thickness and sensitivity.

The Pattern of Retinal Ganglion Cell Loss in OPA1-Related Autosomal Dominant Optic Atrophy Inferred From Temporal, Spatial, and Chromatic Sensitivity Losses.

Purpose: Progressive retinal ganglion cell (RGC) loss is the pathological hallmark of autosomal dominant optic atrophy (DOA) caused by pathogenic OPA1 mutations. The aim of this study was to conduct an in-depth psychophysical study of the visual losses in DOA and to infer any selective vulnerability of visual pathways subserved by different RGC subtypes. Methods: We recruited 25 patients carrying pathogenic OPA1 mutations and age-matched healthy individuals. Spatial contrast sensitivity functions (SCSFs) and chromatic contrast sensitivity were quantified, the latter using the Cambridge Colour Test. In 11 patients, long (L) and short (S) wavelength-sensitive cone temporal acuities were measured as a function of target illuminance, and L-cone temporal contrast sensitivity (TCSF) as a function of temporal frequency. Results: Spatial contrast sensitivity functions were abnormal, with the loss of sensitivity increasing with spatial frequency. Further, the highest L-cone temporal acuity fell on average by 10 Hz and the TCSFs by 0.66 log10 unit. Chromatic thresholds along the protan, deutan, and tritan axes were 8, 9, and 14 times higher than normal, respectively, with losses increasing with age and S-cone temporal acuity showing the most significant age-related decline. Conclusions: Losses of midget parvocellular, parasol magnocellular, and bistratified koniocellular RGCs could account for the losses of high spatial frequency sensitivity and protan and deutan sensitivities, high temporal frequency sensitivity, and S-cone temporal and tritan sensitivities, respectively. The S-cone-related losses showed a significant deterioration with increasing patient age and could therefore prove useful biomarkers of disease progression in DOA.

A Review of Mitochondrial Optic Neuropathies: From Inherited to Acquired Forms.

In recent years, the term mitochondrial optic neuropathy (MON) has increasingly been used within the literature to describe a group of optic neuropathies that exhibit mitochondrial dysfunction in retinal ganglion cells (RGCs). Interestingly, MONs include genetic aetiologies, such as Leber hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA), as well as acquired aetiologies resulting from drugs, nutritional deficiencies, and mixed aetiologies. Regardless of an inherited or acquired cause, patients exhibit the same clinical manifestations with selective loss of the RGCs due to mitochondrial dysfunction. Various novel therapies are being explored to reverse or limit damage to the RGCs. Here we review the pathophysiology, clinical manifestations, differential diagnosis, current treatment, and promising therapeutic targets of MON.

[Differential diagnosis of juvenile normal pressure glaucoma]. / Differenzialdiagnose juveniles Normaldruckglaukom.

The case of a 50-year-old female patient with autosomal dominant optic atrophy is described, which was initially misinterpreted and treated as normal pressure glaucoma. Bilateral partial optic atrophy can be diagnosed by chance with mild manifestation of symptoms and can initially be misinterpreted as glaucoma. Taking a detailed medical history and performing a thorough optic nerve head examination can raise the suspicion of hereditary optic atrophy. The reliable detection of autosomal dominant optic atrophy by genetic investigations should be strived for in such cases.

The reduction of temporal optic nerve head microcirculation in autosomal dominant optic atrophy.

PURPOSE: To evaluate the optic nerve head (ONH) microcirculation in autosomal dominant optic atrophy (ADOA) patients. METHODS: This study comprised 22 eyes of 12 ADOA patients, diagnosed according to clinical findings including family history and the presence of mutations in the OPA1 gene. Twenty-four normal eyes of 24 age-matched subjects, with either the right or left eye randomly selected for use, served as controls. Circumpapillary retinal nerve fibre layer thickness (cpRNFLT) and mean blur rate (MBR) in the ONH were determined with optical coherence tomography (OCT) and laser speckle flowgraphy (LSFG), respectively. For each ONH quadrant (superior, temporal, inferior and nasal), the MBR and cpRNFLT ratio was also calculated by dividing tissue MBR in that quadrant by tissue MBR in the entire ONH and by dividing cpRNFLT in that quadrant by cpRNFLT in the entire ONH respectively. RESULTS: Mean blur rate (MBR) in all quadrants was significantly lower in the ADOA patients than in the controls (p < 0.001 in each). The MBR ratio was significantly lower in the ADOA patients only in the temporal quadrant (p < 0.001). Similarly, cpRNFLT was lower in the ADOA patients in all quadrants (p < 0.001 in each), and the cpRNFLT ratio was lower in the temporal quadrant (p < 0.001). CONCLUSION: Reduced blood flow in the temporal optic disc in ADOA patients is associated with reduced temporal cpRNFLT, suggesting that both are caused by damage to the papillomacular bundle. The anatomical characteristics of the papillomacular bundle may make it especially susceptible to mitochondrial dysfunction-induced damage, which occurs in ADOA.

OPA1-related disorders: Diversity of clinical expression, modes of inheritance and pathophysiology.

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.

Electrophysiological ON and OFF Responses in Autosomal Dominant Optic Atrophy.

PURPOSE: To assess the effect of autosomal dominant optic atrophy (ADOA) on ON and OFF retinal ganglion cell (RGC) function by evaluating the ON and OFF components of the photopic negative response (PhNR). METHODS: Twelve participants from six families with OPA1 ADOA and 16 age-matched controls were recruited. Electrophysiological assessment involved pattern ERGs (PERGs), focal (20°) and full-field long-duration (250 ms) flash ERGs using a red light-emitting diode flash on a rod-saturating blue background, and full-field brief (300 µs) xenon flash ERGs using a red filter over a continuous rod saturating blue background. Amplitudes and implicit times of the ERG components were analyzed and the diagnostic potential of each electrophysiological technique was determined by generating receiver operating characteristic (ROC) curves. RESULTS: Mean amplitudes of the N95 and all PhNRs, except the full-field PhNRON, were significantly reduced in participants with ADOA (P < 0.01). Subtraction of the group-averaged focal ERG of ADOA participants from that of controls showed an equal loss in the focal PhNRON and PhNROFF components, whereas in the full-field ERG the loss in the PhNROFF was greater than that in the PhNRON component. The areas under the ROC curve (AUC) for the focal PhNRON (0.92), focal PhNROFF (0.95), and full-field PhNROFF (0.83), were not significantly different from that of the PERG N95 (0.99). CONCLUSIONS: In patients with ADOA, the PhNRON and PhNROFF components are nearly symmetrically reduced in the long-duration ERG, suggesting that ON- and OFF-RGC pathways may be equally affected.

A novel OPA1 mutation causing variable age of onset autosomal dominant optic atrophy plus in an Australian family.

Pathogenic mutations in the OPA1 gene can be associated with Autosomal Dominant Optic Atrophy (ADOA). In approximately 20 % of patients with OPA1 mutations, a more complex neurodegenerative disorder with extraocular manifestations, known as ADOA Plus, can arise. 12 members of a multigenerational family were assessed clinically and screened for a genetic mutation in OPA1. Eight family members displayed manifestations consistent with ADOA Plus and four did not. Affected members of the oldest available generation displayed the most severe phenotype, which included severe optic atrophy, deafness, ptosis, ophthalmoplegia, proximal myopathy, neuropathy and ataxia. The next generation was less severely affected but several members displayed manifestations only after the fifth decade. Genetic analysis revealed a heterozygous variant in the OPA1 gene (c.1053T>A, p.Asp351Glu) that segregated with disease. The affected family members described here exhibited visual loss later than is typical for OPA1-related disease, as well as later onset of other neurological abnormalities in the fifth or sixth decades of life that progressed to severe neurological disability by the seventh decade. These findings expand the clinical spectrum of OPA1-related disease associated with a novel OPA1 mutation.