OPA1 Mutations Associated with Dominant Optic Atrophy Influence Optic Nerve Head Size

doi:10.1016/j.ophtha.2009.12.042

Ophthalmology

Volume 117, Issue 8, August 2010, Pages 1547-1553

Presented in part at: Association for Research in Vision and Ophthalmology Meeting, May 2007, Fort Lauderdale, Florida.

https://doi.org/10.1016/j.ophtha.2009.12.042 Get rights and content

Purpose

To analyze the influence of OPA1 gene mutations on the optic nerve head (ONH) morphology in patients with dominant optic atrophy (DOA).

Design

Cross-sectional study.

Participants

Twenty-eight patients with DOA from 11 pedigrees, which were positive for the presence of OPA1 gene mutations, and 56 age-matched control subjects, were enrolled.

Methods

The ONH of DOA patients was studied by optical coherence tomography and compared with an age-matched control group of 56 individuals.

Main Outcome Measures

ONH area, and vertical and horizontal diameters.

Results

The ONH analysis of DOA patients showed a significantly smaller optic disc area (P<0.0001), vertical (P = 0.018), and horizontal (P<0.0001) disc diameters, compared with controls. Stratification of the results for the single OPA1 mutation revealed normal ONH area with 2 mutations, whereas the only missense mutation linked to a “DOA plus” phenotype had the smallest ONH measurements.

Conclusions

The DOA patients carrying OPA1 gene mutations present, as a group, a significantly smaller ONH compared with the range of size observed in a control population; this feature may be mutation specific. This observation suggests that OPA1 is involved in shaping the anatomic conformation of the ONH in patients with DOA. The relevance of OPA1 in regulating apoptosis and modeling the eye development has been recently shown by others. Thus, mutations in the OPA1 gene may determine the previously unrecognized feature of a smaller optic disc size and this in turn may have relevance for DOA pathogenesis. Furthermore, OPA1 gene polymorphic variants may contribute to the normal variability of ONH size in the general population.

Financial Disclosure(s)

The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Section snippets

Subjects

All DOA patients with a molecularly confirmed diagnosis of OPA1 mutations who were referred to the Department of Neurological Sciences at the University of Bologna between 2002 and 2006 were invited to participate in this study. Between September and December 2006, 28 DOA patients from 11 unrelated pedigrees of European ancestry were recruited and examined by optical coherence tomography (OCT) imaging in both eyes. Exclusion criteria were the presence in 1 or both eyes of any retinal pathology

Results

For this study, we collected 28 DOA patients from 11 DOA pedigrees that segregate a pathogenic mutation in the OPA1 gene (Table 1, Table 2). The control group consisted of 56 age-matched subjects. Demographic data (mean age and gender) of patients and controls are provided in Table 1. No patients were excluded because of these criteria. The mean age was not statistically different between these 2 groups.

Table 2 shows the OPA1 mutations in the 11 pedigrees studied and the results of the OCT

Discussion

The main finding of the current study is that the OPA1 mutant DOA patients, as a group, have an overall significantly smaller ONH as shown by the different parameters measured by OCT, compared with an age-matched control population. This observation suggests that OPA1 influences ocular, and in particular, ONH development. The smaller ONH conformation in the OPA1 mutant patients may, in turn, contribute to the pathogenic mechanism of DOA possibly explaining the early onset of the disease, which

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Mitochondrial optic neuropathies
2023, Handbook of Clinical Neurology
Mitochondrial optic neuropathies have a leading role in the field of mitochondrial medicine ever since 1988, when the first mutation in mitochondrial DNA was associated with Leber's hereditary optic neuropathy (LHON). Autosomal dominant optic atrophy (DOA) was subsequently associated in 2000 with mutations in the nuclear DNA affecting the OPA1 gene. LHON and DOA are both characterized by selective neurodegeneration of retinal ganglion cells (RGCs) triggered by mitochondrial dysfunction. This is centered on respiratory complex I impairment in LHON and defective mitochondrial dynamics in OPA1-related DOA, leading to distinct clinical phenotypes. LHON is a subacute, rapid, severe loss of central vision involving both eyes within weeks or months, with age of onset between 15 and 35 years old. DOA is a more slowly progressive optic neuropathy, usually apparent in early childhood. LHON is characterized by marked incomplete penetrance and a clear male predilection. The introduction of next-generation sequencing has greatly expanded the genetic causes for other rare forms of mitochondrial optic neuropathies, including recessive and X-linked, further emphasizing the exquisite sensitivity of RGCs to compromised mitochondrial function. All forms of mitochondrial optic neuropathies, including LHON and DOA, can manifest either as pure optic atrophy or as a more severe multisystemic syndrome. Mitochondrial optic neuropathies are currently at the forefront of a number of therapeutic programs, including gene therapy, with idebenone being the only approved drug for a mitochondrial disorder.
Brain functional MRI responses to blue light stimulation in Leber's hereditary optic neuropathy
2021, Biochemical Pharmacology
Melanopsin retinal ganglion cells (mRGCs) are intrinsically photosensitive photoreceptors contributing both to image and non-image-forming (NIF) functions of the eye. They convey light signal to the brain to modulate circadian entrainment, sleep, alertness, cognition, brightness perception and coarse vision. Given that rods and cones also contribute to all these impacts of light, isolating mRGC visual and NIF roles in humans is challenging so that mRGC functions remains to be fully characterized. Here, we evaluated light-driven visual and cognitive brain responses in Leber’s Hereditary Optic Neuropathy (LHON), an inherited optic neuropathy that is characterized by a selective relative sparing of the melanopsin-expressing retinal ganglion cells (mRGCs). Twelve patients and twelve matched healthy controls (HC) were enrolled in a functional brain magnetic resonance imaging (fMRI) protocol including visual and visual-cognitive paradigms under blue (480 nm) and red (620 nm) light exposures. Primary visual cortex activation was detected in LHON patients; in particular higher occipital activation was found in response to sustained blue vs. red stimulation in LHON vs. HC. Similarly, brain responses to the executive task were larger under blue vs. red light in LHON over lateral prefrontal cortex. These findings are in line with the relative mRGC sparing demonstrated in LHON and support the mRGC contribution to both non-visual and visual brain functions, with potential implication for visual rehabilitation in hereditary optic neuropathy patients.
Dominant optic atrophy: Culprit mitochondria in the optic nerve
2021, Progress in Retinal and Eye Research
Dominant optic atrophy (DOA) is an inherited mitochondrial disease leading to specific degeneration of retinal ganglion cells (RGCs), thus compromising transmission of visual information from the retina to the brain. Usually, DOA starts during childhood and evolves to poor vision or legal blindness, affecting the central vision, whilst sparing the peripheral visual field. In 20% of cases, DOA presents as syndromic disorder, with secondary symptoms affecting neuronal and muscular functions. Twenty years ago, we demonstrated that heterozygous mutations in OPA1 are the most frequent molecular cause of DOA. Since then, variants in additional genes, whose functions in many instances converge with those of OPA1, have been identified by next generation sequencing. OPA1 encodes a dynamin-related GTPase imported into mitochondria and located to the inner membrane and intermembrane space. The many OPA1 isoforms, resulting from alternative splicing of three exons, form complex homopolymers that structure mitochondrial cristae, and contribute to fusion of the outer membrane, thus shaping the whole mitochondrial network. Moreover, OPA1 is required for oxidative phosphorylation, maintenance of mitochondrial genome, calcium homeostasis and regulation of apoptosis, thus making OPA1 the Swiss army-knife of mitochondria. Understanding DOA pathophysiology requires the understanding of RGC peculiarities with respect to OPA1 functions. Besides the tremendous energy requirements of RGCs to relay visual information from the eye to the brain, these neurons present unique features related to their differential environments in the retina, and to the anatomical transition occurring at the lamina cribrosa, which parallel major adaptations of mitochondrial physiology and shape, in the pre- and post-laminar segments of the optic nerve. Three DOA mouse models, with different Opa1 mutations, have been generated to study intrinsic mechanisms responsible for RGC degeneration, and these have further revealed secondary symptoms related to mitochondrial dysfunctions, mirroring the more severe syndromic phenotypes seen in a subgroup of patients. Metabolomics analyses of cells, mouse organs and patient plasma mutated for OPA1 revealed new unexpected pathophysiological mechanisms related to mitochondrial dysfunction, and biomarkers correlated quantitatively to the severity of the disease. Here, we review and synthesize these data, and propose different approaches for embracing possible therapies to fulfil the unmet clinical needs of this disease, and provide hope to affected DOA patients.
The polymorphisms of ATOH 7, ET-1 and ACE in non-arteritic anterior ischemic optic neuropathy
2018, Experimental Eye Research
Non-arteritic anterior ischemic optic neuropathy (NAION) is a common cause of acute optic neuropathy in the elderly. The role of the genetic polymorphisms of Atonal Homolog 7 (ATOH7), Endothelin-1 (ET-1) and Angiotensin Converting Enzyme (ACE) in NAION and the combined effects of the gene-gene and gene-medical comorbidities on NAION were not clear. We conducted a perspective, case-control study. 71 NAION patients and 142 age and sex-matched healthy controls were enrolled. Single nucleotide polymorphisms of ATOH7 (rs1900004), ET-1 (rs5370) and ACE (rs1799752) were identified by polymerase chain reaction (PCR) method and all PCR products were screened with Sanger sequencing. The prevalence of genetic factors in NAION patients were compared to normal people, and assessed in conditional logistic regression models. The modified effects of gene-gene or gene-medical comorbidities on NAION development were assessed with a multiplicative model. A significant high risk was found in the T allele of ATOH7 in NAION, with an odds ratio (OR) of 1.55 (P = 0.04). Conditional logistic regression analysis, including diabetes and hypertension, revealed that ATOH7 TT genotype carriers conferred a significantly increased risk of NAION (TT/CC + CT, OR = 3.32, 95% confidence interval (CI) = 1.16–9.53, P = 0.03). Interaction analysis showed that ET-1 (P = 0.01), ACE (P = 0.046) and hypertension (P = 0.02) have modified effects on NAION development. Our results showed that the polymorphism of optic disc associated gene-ATOH7 conferred a significant risk of NAION. Combination of ATOH7 and ET-1, ATOH7 and ACE, as well as ATOH7 and hypertension, increased the susceptibility of NAION. Our data may be useful for NAION predicting.
Mitochondrial disorders of the retinal ganglion cells and the optic nerve
2018, Mitochondrion
Citation Excerpt :
Reduction of the RNFL thickness supports the notion that the papillo-macular bundle is pre-dominantly affected in ADOA (Park and Hwang, 2015). OCT may also show a reduced size of the optic disc (Perganta et al., 2013), which may be explained by the role OPA1 plays in regulating developmental apoptosis and shaping of the optic head morphology (Barboni et al., 2010). OCT findings can be explained by degeneration of RGCs but the underlying pathomechanism is poorly understood (Sarzi et al., 2016).
To summarise and discuss recent findings and future perspectives concerning mitochondrial disorders (MIDs) affecting the retinal ganglion cells and the optic nerve (mitochondrial optic neuropathy. MON).
Literature review.
MON in MIDs is more frequent than usually anticipated. MON may occur in specific as well as non-specific MIDs. In specific and non-specific MIDs, MON may be a prominent or non-prominent phenotypic feature and due to mutations in genes located either in the mitochondrial DNA (mtDNA) or the nuclear DNA (nDNA). Clinically, MON manifests with painless, bilateral or unilateral, slowly or rapidly progressive visual impairment and visual field defects. In some cases, visual impairment may spontaneously recover. The most frequent MIDs with MON include LHON due to mutations in mtDNA-located genes and autosomal dominant optic atrophy (ADOA) or autosomal recessive optic atrophy (AROA) due to mutations in nuclear genes. Instrumental investigations for diagnosing MON include fundoscopy, measurement of visual acuity, visual fields, and color vision, visually-evoked potentials, optical coherence tomography, fluorescein angiography, electroretinography, and MRI of the orbita and cerebrum. In non-prominent MON, work-up of the muscle biopsy with transmission electron microscopy may indicate mitochondrial destruction. Treatment is mostly supportive but idebenone has been approved for LHON and experimental approaches are promising.
MON needs to be appreciated, requires extensive diagnostic work-up, and supportive treatment should be applied although loss of vision, as the most severe outcome, can often not be prevented.
Genotype-phenotype and OCT correlations in Autosomal Dominant Optic Atrophy related to OPA1 gene mutations: Report of 13 Italian families
2017, Journal of the Neurological Sciences
Citation Excerpt :
Autosomal Dominant Optic Atrophy (ADOA; OMIM 605290), firstly described by Kjer [1], represents one of the most common hereditary optic neuropathies, with an estimated prevalence of 1:12,000 to 1:50,000 [2]. ADOA usually presents insidiously in childhood with bilateral visual loss, ultimately leading to optic atrophy [3,4], with selective retinal ganglion cells (RGCs) loss as its defining pathological characteristic [5,6]. However, its clinical expressivity greatly varies even within families [4].
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.

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: Manuscript no. 2009-1102.

: Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

: Supported by a Telethon Italy grant (#GGP06233 to VC) and Italian Ministry of health grant (RF-FGB-2006-368547).

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Original articleOPA1 Mutations Associated with Dominant Optic Atrophy Influence Optic Nerve Head Size

Purpose

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Financial Disclosure(s)

Section snippets

Subjects

Results

Discussion

Prog Ret Eye Res

Biochim Biophys Acta

J Biol Chem

Cell

Cell

Surv Ophthalmol

Am J Ophthalmol

Am J Ophthalmol

Curr Opin Genet Dev

Infantile optic atrophy with dominant mode of inheritance: a clinical and genetic study of 19 Danish families

Acta Ophthalmol Suppl

Hereditary optic neuropathies

Clinical features, molecular genetics, and pathophysiology of dominant optic atrophy

J Med Genet

OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28

Nat Genet

Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy

Nat Genet

eOPA1: an online database for OPA1 mutations

Hum Mutat

OPA1 mutations associated with dominant optic atrophy impair oxidative phosphorylation and mitochondrial fusion

Brain

OPA1 mutations induce mitochondrial DNA instability and optic atrophy ‘plus’ phenotypes

Brain

Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance

Brain

Autosomal dominant optic atrophy: penetrance and expressivity in patients with OPA1 mutations

Am J Ophthalmol

Original article
OPA1 Mutations Associated with Dominant Optic Atrophy Influence Optic Nerve Head Size