Autosomal Dominant Optic Atrophy Patients Research Articles

Genomic rearrangements in OPA1 are frequent in patients with autosomal dominant optic atrophy

Introduction:Autosomal dominant optic atrophy (ADOA) is considered as the most common form of hereditary optic neuropathy. Although genetic linkage studies point to the OPA1 locus on chromosome 3q28–q29 as by...

The natural history of OPA1-related autosomal dominant optic atrophy

Background/aims:Autosomal dominant optic atrophy (ADOA) is a genetically heterogenous disease. However, a large proportion of this disease is accounted for by mutations in OPA1. The aim of this longitudinal study...

Hereditary optic neuropathies share a common mitochondrial coupling defect

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.

Autosomal-dominant erbliche Optikusatrophie vs. Lebersche Optikusneuropathie – Wie kann man sie unterscheiden?

Patients with long-lasting bilateral optic atrophy showed typical clinical features of autosomal dominant optic atrophy (ADOA). Molecular genetic analysis identified them as atypical cases of Leber's hereditary optic neuropathy (LHON). Three patients with bilateral optic atrophy and central scotomas of their visual fields were clinically diagnosed with ADOA. Samples of lymphocytic genomic DNA were amplified with polymerase chain reaction, and analysis of the coding exons including the flanking intron/UTR sequences of the OPA-1 gene was performed. However, no ADOA-associated mutations were found. We therefore analysed the total lymphocyte mitochondrial DNA for all common LHON mutations in these patients. Three patients from three unrelated pedigrees (two men, one woman) who were clinically diagnosed as suffering from ADOA did not harbor any typical mutation of the OPA-1 gene. However, analysis of their mitochondrial DNA showed that they harbored the 3460, 11778, and 14484 LHON mutations. The patients were identified as atypical cases of LHON. The pedigrees of the patients fulfilled the criteria for both dominant and mitochondrial-maternal transmission in all cases. The clinical picture of LHON differed remarkably from the classic course of LHON. To identify atypical LHON patients with bilateral optic atrophy and central scotomas in the visual field and to distinguish them from ADOA patients, careful molecular genetic analysis is necessary. In these rare cases, only double examinations of both the genomic and the mitochondrial DNA will allow these patients to be adequately advised.

Reduction of Oscillatory Potentials and Photopic Negative Response in Patients with Autosomal Dominant Optic Atrophy withOPA1Mutations

To study the electroretinographic (ERG) findings in patients with autosomal dominant optic atrophy (ADOA) with OPA1 mutations. Eight ADOA patients (age range, 24-55 years; mean, 41 years) with OPA1 mutations were studied. In addition to routine ophthalmological tests, full-field ERGs including the rod response, mixed rod-cone response, oscillatory potentials (OPs), single-flash cone response, and photopic negative response (PhNR) were recorded and compared with those from 25 age-matched controls. The correlation between the ERG data and averaged retinal nerve fiber layer (RNFL) thickness around the optic disk measured by optical coherent tomography, mean deviation of the static perimetry (Humphrey 30-2 program), or corrected visual acuity was also examined. Amplitudes of the PhNR and OPs, both of which are believed to originate from inner retinal layers, were significantly smaller in ADOA patients than in control subjects (P < 0.01). Amplitudes of other ERG components were not statistically different in the two groups. OP amplitude was inversely correlated with the patient's age. The RNFL was thinner and the retinal sensitivities obtained by static perimetry were lower in ADOA patients, but these values were not correlated with the amplitude of PhNR or OPs. These results suggested that there are functional impairments not only in the ganglion cell layer but also in the inner nuclear and plexiform layers, including the amacrine cells of ADOA patients with OPA1 mutations.

A Novel OPA1 Mutation Responsible for Autosomal Dominant Optic Atrophy with High Frequency Hearing Loss in a Chinese Family

To investigate the genetic findings and phenotypic characters of autosomal dominant optic atrophy (ADOA). Case report and experimental study. Molecular genetic analysis and clinical examinations were performed in a Chinese family with ADOA. Mutations in OPA1 were detected by direct sequencing. Haplotypes were constructed and compared with the phenotypes in the family. Nine family members were diagnosed with ADOA and some of them were accompanied with hearing loss and/or high myopia. A novel heterozygous mutation, c.2848_2849delGA(p.Asp950CysfsX4), was detected in all ADOA patients. The mutation and the mutation bearing haplotype cosegregated with the nine affected members. One family member had high myopia without vision or hearing loss. This patient along with unaffected ones did not harbor the mutation. A novel mutation, c.2848_2849delGA in OPA1, was identified in a Chinese family with ADOA. This mutation is associated with hearing loss, but likely not high myopia.

Structural model of the OPA1 GTPase domain may explain the molecular consequences of a novel mutation in a family with autosomal dominant optic atrophy

Autosomal dominant optic atrophy (ADOA) is the most frequent hereditary optic neuropathy. Three loci have been reported for ADOA: a major locus, harboring all identified mutations to date, maps to 3q28 ( OPA1), a second locus is linked to 18q12.2–q12.3 ( OPA4) and a third locus on 22q12.1–q13.1 ( OPA5) has been reported recently. We describe a six-generation Iranian family in which optic atrophy runs as an autosomal dominant trait with an age of onset at 14–15 years. We performed linkage analysis with markers mapping to 3q28 and 18q12.2–q12.3 and found linkage to 3q28. Subsequent sequencing of OPA1 identified a novel heterozygous missense mutation (c.1313A>G) replacing aspartic acid by glycine (p.D438G) in the GTPase domain of OPA1. Interestingly, another missense mutation at the same position (c.1313A>T, D438V) has been reported before in two unrelated German families, indicating a possible mutation hot spot. Further evidence supporting the importance of D438 is its conservation from human to acoelomata. OPA1 is believed to be the human orthologue of yeast MGM1, a dynamin-related protein required for the integrity of mitochondrial DNA. Homology modeling of the OPA1 GTPase domain revealed extensive structural similarity to the Dictyostelium dynamin A GTPase domain and showed that D438 may interact with residues of the G1 and the G4 motifs, which are crucial in coordinating GTP. Based on this analysis, we propose a mechanism which explains the gradual decline of vision in ADOA patients with OPA1 mutations at position 438.