Autosomal Dominant Optic Atrophy Research Articles

The mutation R107Q alters mtSSB ssDNA compaction ability and binding dynamics.

Mitochondrial single-stranded DNA-binding protein (mtSSB) is essential for mitochondrial DNA (mtDNA) replication. Recently, several mtSSB variants have been associated with autosomal dominant mitochondrial optic atrophy and retinal dystrophy. Here, we have studied at the molecular level the functional consequences of one of the most severe mtSSB variants, R107Q. We first studied the oligomeric state of this variant and observed that the mtSSBR107Q mutant forms stable tetramers in vitro. On the other hand, we showed, using complementary single-molecule approaches, that mtSSBR107Q displays a lower intramolecular ssDNA compaction ability and a higher ssDNA dissociation rate than the WT protein. Real-time competition experiments for ssDNA-binding showed a marked advantage of mtSSBWT over mtSSBR107Q. Combined, these results show that the R107Q mutation significantly impaired the ssDNA-binding and compacting ability of mtSSB, likely by weakening mtSSB ssDNA wrapping efficiency. These features are in line with our molecular modeling of ssDNA on mtSSB showing that the R107Q mutation may destabilize local interactions and results in an electronegative spot that interrupts an ssDNA-interacting-electropositive patch, thus reducing the potential mtSSB-ssDNA interaction sites.

Two Different Nuclear Mitochondrial DNA Mutations Associated with Retinal Abnormalities

Purpose: To report the posterior pole imaging characteristics of two patients with pathogenic nuclear mitochondrial mutations. Methods: Case reports Results: The first case, a 61-year-old patient, initially diagnosed with age-related macular degeneration, exhibited focal hyperpigmentation and increased autofluorescence in the parafoveal macula, along with geographic atrophy and mild optic nerve pallor. Optical coherence tomography (OCT) showed ellipsoid zone (EZ) attenuation, hyperreflective foci colocalizing to the hyperpigmentation, subretinal deposits, and hypertransmission defects. He was found to have a pathogenic mutation of MFN2, a gene defect associated with Charcot-Marie-Tooth disease. The second case, a 65-year-old patient presented with loss of central vision with pallor of the optic nerve. OCT imaging showed widespread loss of the interdigitation zone and EZ attenuation peripheral to the foveal region. There was thinning of the ganglion cell and nerve fiber layers. A pathogenic OPA1 mutation, the leading cause of autosomal dominant optic atrophy, was found. Both MFN2 and OPA1 produce proteins integral in mitochondrial fusion. Conclusions: The findings of these cases suggest ocular examinations may be helpful in evaluating patients with nuclear mitochondrial mutations using the near microscopic resolution of OCT. Retinal imaging may highlight structural abnormalities related to mitochondrial problems and allows direct imaging of the EZ, a layer dominated by mitochondria and a place where direct imaging of mitochondria is possible, in vivo.

Genetic underpinnings explored: OPA1 deletion and complex phenotypes on chromosome 3q29

BackgroundCopy number variations (CNVs) have emerged as significant contributors to the elusive genetic causality of inherited eye diseases. In this study, we describe a case with optic atrophy and a brain aneurysm, in which a de novo CNV 3q29 deletion was identified.Case presentationA 40-year-old female patient was referred to our department after undergoing aneurysm transcatheter arterial embolization for a brain aneurysm. She had no history of systemic diseases, except for unsatisfactory best-corrected visual acuity (BCVA) since elementary school. Electrophysiological tests confirmed the findings in retinal images, indicating optic nerve atrophy. Chromosomal microarray analysis revealed a de novo deletion spanning 960 kb on chromosome 3q29, encompassing OPA1 and six neighboring genes. Unlike previously reported deletions in this region associated with optic atrophy, neuropsychiatric disorders, and obesity, this patient displayed a unique combination of optic atrophy and a brain aneurysm. However, there is no causal relationship between the brain aneurysm and the CNV.ConclusionIn conclusion, the optic atrophy is conclusively attributed to the OPA1 deletion, and the aneurysm could be a coincidental association. The report emphasizes the likelihood of underestimating OPA1 deletions due to sequencing technology limitations. Recognizing these constraints, healthcare professionals must acknowledge these limitations and consistently search for OPA1 variants/deletions in Autosomal Dominant Optic Atrophy (ADOA) patients with negative sequencing results. This strategic approach ensures a more comprehensive exploration of copy-number variations, ultimately enhancing diagnostic precision in the field of genetic disorders.

Short Wavelength Automated Perimetry, Standard Automated Perimetry, and Optical Coherence Tomography in Dominant Optic Atrophy.

Background: Blue-yellow axis dyschromatopsia is well-known in Autosomal Dominant Optic Atrophy (ADOA) patients, but there were no data on the correlation between retinal structure and short-wavelength automated perimetry (SWAP) values in this pathology. Methods: In this cross-sectional case-control study, we assessed the correlation between best corrected visual acuity (BCVA), standard automated perimetry (SAP), SWAP, and optical coherence tomography (OCT) parameters of 9 ADOA patients compared with healthy controls. Correlation analysis was performed between BCVA, mean deviation, pattern standard deviation (PSD), and fovea sensitivity (FS) values and the OCT thickness of each retinal layer and the peripapillary retinal nerve fiber layer (pRNFL). Results: The following significant and strong correlations were found: between BCVA and ganglion cell layer (GCL) and the global (G) pRNFL thicknesses; between SAP FS and GCL and the G-pRNFL thicknesses; between SWAP PSD and total retina, GCL, inner plexiform layer, inner nuclear layer, inner retinal layer and the temporal pRNFL thicknesses. We found a constant shorter duration of the SITA-SWAP compared with the SITA-STANDARD strategy. Conclusions: SWAP, SAP, and BCVA values provided relevant clinical information about retinal involvement in our ADOA patients. The perimetric functional parameters that seemed to correlate better with structure involvement were FS on SAP and PSD on SWAP.

Chinese expert consensus on the clinical diagnosis and treatment of autosomal dominant optic atrophy (2024)

Autosomal dominant optic atrophy (ADOA) primarily affects retinal ganglion cells and their axons, resulting in varying degrees of central vision loss from childhood. Due to the rarity of ADOA in clinical practice, Chinese ophthalmologists currently lack sufficient understanding of the disease and experience non-standardized diagnostic procedures and high clinical and genetic misdiagnosis rates. To address these issues, the Ophthalmology Group of China Alliance for Rare Diseases/Beijing Society of Rare Disease Clinical Care and Accessibility and the Neuro-ophthalmology Group of Ophthalmology Branch of Chinese Medical Association have established an expert panel to form consensus opinions based on extensive discussions. This consensus would enhance the knowledge and diagnostic capabilities of Chinese clinicians regarding ADOA and promote awareness of related treatment principles and genetic counseling.

OPA1 mutation affects autophagy and triggers senescence in autosomal dominant optic atrophy plus fibroblasts.

In several cases of mitochondrial diseases, the underlying genetic and bioenergetic causes of reduced oxidative phosphorylation (OxPhos) in mitochondrial dysfunction are well understood. However, there is still limited knowledge about the specific cellular outcomes and factors involved for each gene and mutation, which contributes to the lack of effective treatments for these disorders. This study focused on fibroblasts from a patient with Autosomal Dominant Optic Atrophy (ADOA) plus syndrome harboring a mutation in the Optic Atrophy 1 (OPA1) gene. By combining functional and transcriptomic approaches, we investigated the mitochondrial function and identified cellular phenotypes associated with the disease. Our findings revealed that fibroblasts with the OPA1 mutation exhibited a disrupted mitochondrial network and function, leading to altered mitochondrial dynamics and reduced autophagic response. Additionally, we observed a premature senescence phenotype in these cells, suggesting a previously unexplored role of the OPA1 gene in inducing senescence in ADOA plus patients. This study provides novel insights into the mechanisms underlying mitochondrial dysfunction in ADOA plus and highlights the potential importance of senescence in disease progression.

Natural history of mitochondrial optic neuropathies

Mitochondrial optic neuropathies (MON) may occur as a single organ disease (non‐syndromic MON) or in the context of a multisystem mitochondrial disorder (syndromic MON). By far the most frequent MON are Leber's hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA). LHON is in most cases caused by mitochondrial DNA (mtDNA) mutations m.11778G>A, m.3460G>A or m.14484T>C, while ADOA is most frequently due to mutations in the OPA1 gene. As therapy trials have been performed, are ongoing or are planned for LHON and ADOA, it is important to know about the natural history of these disorders which may help to design trials or may serve as an external comparator.In LHON, an international observational retrospective registry (REALITY) analysed the visual course and outcome in 44 LHON patients, and found (after an average follow‐up time of 32.5 months) the mean best‐corrected visual acuity (BCVA) to be 1.46 LogMAR in m.11778G>A, 1.52 LogMAR in m.3460G>A, and 0.97 LogMAR in m.14484T>C mutations carriers. In line with previous findings, children below age 12 years at onset had the best visual prognosis. Since 25 of the 44 patients had taken idebenone at some point, this work does not qualify as a natural history study, though.A meta‐analysis of 12 retrospective and 3 prospective studies included data from 695 LHON patients with the m.11778G>A mutation. This meta‐analysis was hampered by the poor and variable definition of recovery among studies, and by the fact that idebenone use could not always be excluded. Main findings were some degree of recovery in 14.4% of patients, and 11.3% in those above age 15 years. Final BCVA of better than 1.0 logMAR was rare.In an own study of 83 LHON patients (73.5% with m.11778G>A mutation), BCVA at last observation was better than 1.0 logMAR in 18.1%, between 1.0 and 1.68 logMAR in 33.7% and worse than 1,68 logMAR (off‐chart) in 48.2%. Spontaneous recovery by at least 0.2 logMAR occurred in 16.3% of patients.In OPA1‐ADOA, a retrospective analysis of data from 64 affected patients showed a mean age at visual failure onset of 7.0 years (range 1.0–16.0 years), and a mean BCVA at last observation of 1.02 LogMAR. Longitudinal data in 43 OPA1 patients with a mean follow‐up duration of 18.0 years showed on average a slow visual decline of 0.032 LogMAR/year, but some patients deteriorated much faster (range 0–0.171 LogMAR/year).In conclusion, currently available data on the natural history of MON are hampered by retrospective analysis, low sample sizes, unsystematic phenotyping, variable definitions of key outcomes (eg, recovery) and often incomplete information on the administration of idebenone or other drugs. Large multicenter studies on natural history are needed but are more and more difficult to perform with the advent and sometimes even approval of disease‐modifying treatments.

What OPA1 models teach us about potential therapy

Autosomal dominant optic atrophy (DOA) is the most common inherited optic neuropathy, affecting approximately 1 in 25 000 people. DOA has an insidious onset in early childhood. It presents typically with bilateral central painless vision loss, dyschromatopsia, and optic disc pallor due to gradual retinal ganglion cell (RGC) loss and optic nerve degeneration. 60%–70% of genetically confirmed DOA cases are associated with variants in OPA1. OPA1 is an ubiquitously expressed GTPase that regulates mitochondrial homeostasis through coordination of inner membrane fusion, maintenance of cristae structure, and maintenance of bioenergetic output. Over 250 known pathogenic variants in OPA1 have been reported, with missense variants within the GTPase domain associated with an increased susceptibility to developing DOA plus (DOA+), a multisystemic syndromic form of the disease with extraocular features, including sensorineural hearing loss and ataxia. Current therapeutic options to treat DOA are limited. Idebenone has been shown to protect against visual loss in Leber's hereditary optic neuropathy (LHON). In DOA off ‐label retrospective series show some promise in some patients.Animal models for OPA1 DOA, have been reported, including Drosophila, C elegans, Danio rerio and mouse models. They have cast light on some potential therapeutic modalities. Despite limitations, murine models of DOA are currently indispensable for understanding pathophysiology of disease, drug testing and development. They replicate many symptoms and signs of human disease. However, there are caveats. Chemically induced Complex I deficits are very toxic. Genetic models of mitochondrial mutation affect protein integrity and function and can cause severe pathologies. This is made more problematic if there is a need for aging the mouse to bring out the full phenotype. We shall review the mouse models and describe some features that aid or our understanding of pathophysiological mechanisms. Our research has characterized the earliest morphological changes as a progressive loss of synapses, dendrite retraction and RGC remodelling and loss of connectivity. In the DOA mouse Opa1+/− mouse (B6;C3‐Opa1Q285STOP), heterozygous Opa1+/− mice develop visual defects, on psychophysics (optokinetic response) and electrophysiology (VEP, PhNR), consistent with RGC dysfunction. There is depressed mitochondrial Complex I and IV activity. Visible structural changes and disrupted axon morphology in the optic nerve are seen. We have carried out a randomized, placebo‐controlled trial of the benzoquinone idebenone in our ADOA mouse, which revealed a limited therapeutic effect on RGC dendropathy and visual function.It is apparent that there are large differences between the rodent and primate visual system. The fovea of the retina, a critical component for central vision is one of the only primate‐specific components of the mammalian nervous system and is thus, not found in rodent. For these reasons, there is a strong case to use human cells. We shall review data on induced human pluripotent stem cell (hiPSC) with OPA1 mutation, with or without differentiation to RGCs, as models, and on CRISPRCas9 correction of patient‐derived OPA1 iPSC lines.

Human retinal organoids with an OPA1 mutation are defective in retinal ganglion cell differentiation and function

Autosomal dominant optic atrophy (ADOA), mostly caused by heterozygous OPA1 mutations and characterized by retinal ganglion cell (RGC) loss and optic nerve degeneration, is one of the most common types of inherited optic neuropathies. Previous work using a two-dimensional (2D) differentiation model of induced pluripotent stem cells (iPSCs) has investigated ADOA pathogenesis but failed to agree on the effect of OPA1 mutations on RGC differentiation. Here, we use 3D retinal organoids capable of mimicking invivo retinal development to resolve the issue. We generated isogenic iPSCs carrying the hotspot OPA1 c.2708_2711delTTAG mutation and found that the mutant variant caused defective initial and terminal differentiation and abnormal electrophysiological properties of organoid-derived RGCs. Moreover, this variant inhibits progenitor proliferation and results in mitochondrial dysfunction. These data demonstrate that retinal organoids coupled with gene editing serve as a powerful tool to definitively identify disease-related phenotypes and provide valuable resources to further investigate ADOA pathogenesis and screen for ADOA therapeutics.

Pyrroloquinoline quinone drives ATP synthesis in vitro and in vivo and provides retinal ganglion cell neuroprotection

Retinal ganglion cells are highly metabolically active requiring strictly regulated metabolism and functional mitochondria to keep ATP levels in physiological range. Imbalances in metabolism and mitochondrial mechanisms can be sufficient to induce a depletion of ATP, thus altering retinal ganglion cell viability and increasing cell susceptibility to death under stress. Altered metabolism and mitochondrial abnormalities have been demonstrated early in many optic neuropathies, including glaucoma, autosomal dominant optic atrophy, and Leber hereditary optic neuropathy. Pyrroloquinoline quinone (PQQ) is a quinone cofactor and is reported to have numerous effects on cellular and mitochondrial metabolism. However, the reported effects are highly context-dependent, indicating the need to study the mechanism of PQQ in specific systems. We investigated whether PQQ had a neuroprotective effect under different retinal ganglion cell stresses and assessed the effect of PQQ on metabolic and mitochondrial processes in cortical neuron and retinal ganglion cell specific contexts. We demonstrated that PQQ is neuroprotective in two models of retinal ganglion cell degeneration. We identified an increased ATP content in healthy retinal ganglion cell-related contexts both in in vitro and in vivo models. Although PQQ administration resulted in a moderate effect on mitochondrial biogenesis and content, a metabolic variation in non-diseased retinal ganglion cell-related tissues was identified after PQQ treatment. These results suggest the potential of PQQ as a novel neuroprotectant against retinal ganglion cell death.

Visual Function and Inner Retinal Structure in Relation to Birth Factors in Autosomal Dominant Optic Atrophy.

The extreme variation in expressivity of autosomal dominant optic atrophy (ADOA) is unexplained. It is present from early childhood, why there is reason to search for pre- and perinatal risk factors for poor vision in ADOA. The process of ganglion cell pruning in the fetus is of interest because mitochondria are involved in apoptosis. We hypothesized that suboptimal mitochondrial function makes the developing retina and optic nerve vulnerable to fetal stress in ADOA. We have examined visual function and inner retinal layer structure in relation to birth parameters in ADOA. The study included 142 participants with OPA1 ADOA, 62 unaffected first-degree relatives, and 90 unrelated control subjects. Outcome measures included best-corrected visual acuity, microperimetric sensitivity, nerve fiber layer (NFL) volume, and ganglion cell layer (GCL) volume. Descriptive parameters included birth weight, maternal age at birth, birth complications, and gestational age. Analysis was made using mixed modeling. The analysis showed a significant positive association between microperimetric sensitivity and longer gestational age in ADOA (0.5 dB/week, P = 0.017). Interaction analysis showed a significant different association between microperimetric sensitivity and gestational age between participants with ADOA and the control groups (P = 0.007) and a significant difference in association between NFL volume and birth weight (P = 0.04) and gestational age (P = 0.02) between variant types. The study suggests that gestational age and birth weight may affect the expressivity of ADOA. The results support that prospectively collected pre- and perinatal data should be included in future studies of the natural history of ADOA.

Dominant Optic Atrophy With Varied Phenotype in a Family of Eastern India: A Case Report of a Rare Mutation

Background: Autosomal dominant optic atrophy (ADOA) can present with a varied phenotype in the form of pure ADOA, ADOA with sensorineural hearing loss, or the extended spectrum of DOA plus syndrome. Multiple genes have been identified over the years and majority of the cases are attributed to OPA1 gene mutation. Here we present an index case of DOA plus syndrome with affection of multiple family members across 2 generations with a rare mutation detection. Case Presentation: A middle-aged female presented with onset of bilateral progressive visual blurring in the first decade followed by progressive sensorineural hearing loss since the second decade and onset of lower limb predominant cerebellar ataxia since the third decade. Routine parameters, imaging and electrophysiological studies were negative. Next generation clinical exome sequencing (NGCES) revealed an unique OPA1 gene mutation with worldwide evidence of only 3 such cases in database. Conclusion: DOA suspicion should be made in early onset visual defects with multiaxial involvement with a significant family history.

OPA1 Dominant Optic Atrophy: Pathogenesis and Therapeutic Targets.

OPA1 Dominant Optic Atrophy: Pathogenesis and Therapeutic Targets.

WFS1 autosomal dominant variants linked with hearing loss: update on structural analysis and cochlear implant outcome

BackgroundWolfram syndrome type 1 gene (WFS1), which encodes a transmembrane structural protein (wolframin), is essential for several biological processes, including proper inner ear function. Unlike the recessively inherited Wolfram syndrome, WFS1 heterozygous variants cause DFNA6/14/38 and wolfram-like syndrome, characterized by autosomal dominant nonsyndromic hearing loss, optic atrophy, and diabetes mellitus. Here, we identified two WFS1 heterozygous variants in three DFNA6/14/38 families using exome sequencing. We reveal the pathogenicity of the WFS1 variants based on three-dimensional (3D) modeling and structural analysis. Furthermore, we present cochlear implantation (CI) outcomes in WFS1-associated DFNA6/14/38 and suggest a genotype-phenotype correlation based on our results and a systematic review.MethodsWe performed molecular genetic test and evaluated clinical phenotypes of three WFS1-associated DFNA6/14/38 families. A putative WFS1–NCS1 interaction model was generated, and the impacts of WFS1 variants on stability were predicted by comparing intramolecular interactions. A total of 62 WFS1 variants associated with DFNA6/14/38 were included in a systematic review.ResultsOne variant is a known mutational hotspot variant in the endoplasmic reticulum (ER)-luminal domain WFS1(NM_006005.3) (c.2051 C > T:p.Ala684Val), and the other is a novel frameshift variant in transmembrane domain 6 (c.1544_1545insA:p.Phe515LeufsTer28). The two variants were pathogenic, based on the ACMG/AMP guidelines. Three-dimensional modeling and structural analysis show that non-polar, hydrophobic substitution of Ala684 (p.Ala684Val) destabilizes the alpha helix and contributes to the loss of WFS1-NCS1 interaction. Also, the p.Phe515LeufsTer28 variant truncates transmembrane domain 7–9 and the ER-luminal domain, possibly impairing membrane localization and C-terminal signal transduction. The systematic review demonstrates favorable outcomes of CI. Remarkably, p.Ala684Val in WFS1 is associated with early-onset severe-to-profound deafness, revealing a strong candidate variant for CI.ConclusionsWe expanded the genotypic spectrum of WFS1 heterozygous variants underlying DFNA6/14/38 and revealed the pathogenicity of mutant WFS1, providing a theoretical basis for WFS1-NCS1 interactions. We presented a range of phenotypic traits for WFS1 heterozygous variants and demonstrated favorable functional CI outcomes, proposing p.Ala684Val a strong potential marker for CI candidates.

OPA1 disease-causing mutants have domain-specific effects on mitochondrial ultrastructure and fusion

Inner mitochondrial membrane fusion and cristae shape depend on optic atrophy protein 1, OPA1. Mutations in OPA1 lead to autosomal dominant optic atrophy (ADOA), an important cause of inherited blindness. The Guanosin Triphosphatase (GTPase) and GTPase effector domains (GEDs) of OPA1 are essential for mitochondrial fusion; yet, their specific roles remain elusive. Intriguingly, patients carrying OPA1 GTPase mutations have a higher risk of developing more severe multisystemic symptoms in addition to optic atrophy, suggesting pathogenic contributions for the GTPase and GED domains, respectively. We studied OPA1 GTPase and GED mutations to understand their domain-specific contribution to protein function by analyzing patient-derived cells and gain-of-function paradigms. Mitochondria from OPA1 GTPase (c.870+5G>A and c.889C>T) and GED (c.2713C>T and c.2818+5G>A) mutants display distinct aberrant cristae ultrastructure. While all OPA1 mutants inhibited mitochondrial fusion, some GTPase mutants resulted in elongated mitochondria, suggesting fission inhibition. We show that the GED is dispensable for fusion and OPA1 oligomer formation but necessary for GTPase activity. Finally, splicing defect mutants displayed a posttranslational haploinsufficiency-like phenotype but retained domain-specific dysfunctions. Thus, OPA1 domain-specific mutants result in distinct impairments in mitochondrial dynamics, providing insight into OPA1 function and its contribution to ADOA pathogenesis and severity.

The effects of nuclear DNA mutations on mitochondrial function

The multiple functions of mitochondria, including adenosine triphosphate synthesis, are controlled by the coordination of both the mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA) genomes. Mitochondrial disorders manifest because of impairment of energy metabolism. This article focuses on mutations in two nuclear genes and their effect on mitochondrial function. Mutations in the polymerase gamma, or POLG, gene are associated with multisystemic disease processes, including Alpers Syndrome, a severe childhood-onset syndrome. Mutations in the OPA1 gene are associated with autosomal dominant optic atrophy and other neurologic, musculoskeletal, and ophthalmologic symptoms. When assessing for disorders affecting energy metabolism, sequencing of both the mtDNA genome and the nDNA whole exome sequencing is necessary.

The effect of serifs and stroke contrast on low vision reading

PurposePatients with low vision are generally recommended to use the same fonts as individuals with normal vision. However, we are yet to fully understand whether stroke width and serifs (small ornamentations at stroke endings) can increase readability. This study's purpose was to characterize the interaction between two factors (end-of-stroke and stroke width) in a well-defined and homogenous group of patients with low vision. MethodsFont legibility was assessed by measuring word identification performance of 19 patients with low vision (autosomal dominant optic atrophy [ADOA] with a best-corrected average visual acuity 20/110) and a two-interval, forced-choice task was implemented. Word stimuli were presented with four different fonts designed to isolate the stylistic features of serif and stroke width. ResultsFont-size threshold and sensitivity data revealed that using a single measure (i.e., font-size threshold) is insufficient for detecting significant effects but triangulation is possible when combined with signal detection theory. Specifically, low stroke contrast (smaller variation in stroke width) yielded significantly lower thresholds and higher sensitivity when a font contained serifs (331 points; d’ = 1.47) relative to no serifs (345 points; d’ = 1.15), E(μsans, low − μserif, low) = −14 points, 95 % Cr. I. = [−24, −5], P(δ > 0) = 0.99 and E(μserif, low − μsans, low) = 0.32, 95 % Cr. I. = [0.16, 0.49], P(δ > 0) = 0.99. ConclusionIn people with low visual acuity caused by ADOA, the combination of serifs and a uniform stroke width resulted in better text legibility than other combinations of uniform/variable stroke widths and presence/absence of serifs.

Cardiac sympathetic innervation is an unrecognized disease target in autosomal dominant optic atrophy

The Optic Atrophy-1 protein (Opa1) controls mitochondrial (mt) fusion and cristae morphology, ATP production, maintenance of mtDNA, and apoptosis. Mutations in Opa1 gene cause Autosomal Dominant Optic Atrophy (ADOA), a neurodegenerative disease characterized by “retinal ganglion cell” death and visual loss. Recently, ADOA has been described as a “multi-systemic disease” also featuring myopathy, peripheral neuropathy, Parkinsonism and cardiac rhythm alterations. Sympathetic neurons (SNs) are the main extrinsic regulators of heart activity in basal and stress conditions, and their homeostasis strikingly depend on the correct mitochondrial dynamics. We here determined the effect of ADOA genetics on cardiac sympathetic innervation. The majority of Opa1 gene mutations result in truncated forms of the protein, leading to reduction in its cellular content. To study the impact of Opa1 haploinsufficiency on cardiac innervation, we generated transgenic mice with SN-specific Opa1 deletion (TH-Opa1+/− mice), which, in heterozygosity, causes 50% reduction of protein expression. Heart function of TH-Opa1+/− mice was assessed by ECHO and ECG telemetry. Cardiac innervation was evaluated by confocal IF, and whole-mount IF in tissue clarified heart blocks. In vitro assays achieved insights on the effects of Opa1 haploinsufficiency on SNs. SNs were also evaluated in skin biopsies from ADOA patients, and age- and sex-matched controls. We here found that SN density is significantly reduced in the skin of ADOA patients, indicating thatSNs are additional, previously neglected, targets of ADOA. To isolate the effects of Opa1 haploinsufficiency in SNs, we analyzed hearts of adult and aged TH-Opa1+/− mice, which showed intact morphology and contractile function. Looking at cardiac innervation, confocal IF and 3-D reconstruction of the SN network revealed a significant reduction in innervation density, which appeared evident already in adult mice, and worsened during ageing. Consistently, TH-Opa1+/− mice showed decreased Heart Rate Variability and increased incidence of arrhythmic beats. In vitro assays demonstrated the causal role of Opa1 haploinsufficiency in affecting SNs, by compromising TrkA/NGF signaling, which is key to sustain neuronal viability. Our data demonstrates that Opa1 haploinsufficiency also affects peripheral autonomic innervation, thus explaining extra-retinal symptoms experienced by ADOA patients.

Correlation between standard automated Perimetry, short wavelength Perimetry, and optic coherence tomography parameters in ADOA patients

AbstractPurpose: To assess the correlation between white‐on‐white standard automated perimetry (SAP), short‐wavelength automated perimetry (SWAP), and spectral‐domain optical coherence tomography (SD‐OCT) parameters of patients with Autosomal Dominant Optic Atrophy (ADOA) genetically confirmed by the presence of the OPA1 gene mutation.Methods: In this observational, cross‐sectional study 25 eyes of 13 patients with a genetic diagnosis of ADOA were included. All participants performed 24‐2C SAP and 24‐2C SWAP in a randomized order. They also underwent a “Posterior Pole” and “peripapillary RNFL (pRNFL)” scanning protocol using SD‐OCT. The thickness of the ETDRS sectors of each retinal layer and pRNFL was obtained and measured. Mean deviation (MD), pattern standard deviation (PSD), and fovea sensitivity values were obtained from SAP and SWAP. Correlation analysis was performed to evaluate the association between the mean thickness of each retinal layer and visual field parameters.Results: A moderate correlation was found between SAP MD and RPE thickness on the ETDRS grid. A moderate correlation was found between SWAP MD and whole retina, INL, ORL thicknesses on the ETDRS grid. A strong correlation was found between SWAP PSD and whole retina, GCL, IPL, INL, IRL thicknesses on the ETDRS grid. A strong correlation was also found between SWAP PSD and the temporal sector and PMB values on pRNFL. A strong correlation was found between SAP fovea sensitivity and GCL thickness on the ETDRS grid. A strong correlation was also found between SAP fovea sensitivity and the global pRNFL value.Conclusions: Both SAP and SWAP parameters can provide relevant clinical information on retinal involvement in ADOA patients. The most important function parameters that seem to correlate better with structure involvement were PSD on SWAP and foveal sensitivity on SAP.

Correlations between visual function and inner retinal structure in OPA1 autosomal dominant optic atrophy

AbstractPurpose: To evaluate the influence of autosomal dominant optic atrophy (ADOA) on visual function and inner retinal layer thickness in patients harbouring a pathogenic variant in the OPA1 gene.Methods: We retrospectively investigated clinical data of 59 patients (118 eyes) with ADOA and genetically confirmed OPA1 variants. Visual function was evaluated by best corrected visual acuity (VA), and by mean deviation (MD) of automated static threshold perimetry. Macular ganglion cell layer (mGCL) volume and peripapillary retinal nerve fibre layer (pRNFL) thickness were measured by optical coherence tomography. The analysis was performed for all available data from both eyes in the whole sample. Furthermore, patients were stratified in 2 groups based on variant type (haploinsufficiency: 86 eyes, missense variants: 14 eyes).Results: The mean age at examination was 30.5 ± 16.1 years, VA was 0.55 ± 0.33 logMAR, MD was −4.73 ± 3.59 dB, mGCL volume was 0.60 ± 0.10 mm3, and pRNFL thickness was 63.8 ± 10.6 μm. VA correlated significantly with mGCL volume (p < 0.001) and with pRNFL thickness (p = 0.021). MD also correlated with pRNFL thickness (p = 0.017). Patient age was associated with mGCL volume (p < 0.001) and pRNFL thickness (p = 0.024), but not with VA or MD. MD was significantly lower in the missense group than in the haploinsufficiency group (−9.31 ± 4.07 dB vs. −4.03 ± 2.85 dB; p < 0.001), whereas VA did not differ between groups. Thickness of the pRNFL was also lower in the patients with missense variants, but only the nasal sector was significantly thinner (48.2 ± 12.8 μm vs. 58.2 ± 19.2 μm; p = 0.035).Conclusions: Visual function and inner retinal structure are closely associated in ADOA patients with OPA1 variants. Increasing age may be accompanied by a continuing degeneration of retinal ganglion cells, but seems to have less effect on further loss of visual function. Patients carrying missense variants show more pronounced optic atrophy and visual field defect.