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The risk of Leber hereditary optic neuropathy (LHON) has largely been extrapolated from disease cohorts, which underestimate the population prevalence of pathogenic primary LHON variants as a result of incomplete disease penetrance. Understanding the true population prevalence of primary LHON variants, alongside the rate of clinical disease, provides a better understanding of disease risk and variant penetrance. We identified pathogenic primary LHON variants in whole-genome sequencing data of a well-characterized population-based control cohort and found that the prevalence is far greater than previously estimated, as it occurs in approximately 1 in 800 individuals. Accordingly, we were able to more accurately estimate population risk and disease penetrance in LHON variant carriers, validating our findings by using other large control datasets. These findings will inform accurate counseling in relation to the risk of vision loss in LHON variant carriers and disease manifestation in their family. This Matters Arising paper is in response to Lopez Sanchez et al. (2021), published in The American Journal of Human Genetics. See also the response by Mackey et al. (2022), published in this issue.
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Atrofia Óptica Hereditária de Leber , Humanos , Atrofia Óptica Hereditária de Leber/epidemiologia , Atrofia Óptica Hereditária de Leber/genética , Penetrância , Mutação , DNA Mitocondrial/genética , Fatores de RiscoRESUMO
Leber's Hereditary Optic Neuropathy (LHON) is a rare, maternally inherited eye disease, predominantly due to the degeneration of retinal ganglion cells (RGCs). It is associated with a mitochondrial DNA (mtDNA) point mutation. Our previous study identified that the m.15927G>A homoplasmic mutation damaged the highly conserved basepairing (28C-42G) in anticodon stem of tRNAThr, caused deficient t6A modification and significantly decreased efficiency in aminoacylation and steady-state levels of tRNAThr, and led to mitochondrial dysfunction. Meanwhile, mechanisms underlying mtDNA mutations regulate intracellular signaling related to the mitochondrial and cellular integrity are less explored. Here, we manifested that defective nucleotide modification induced by the m.15927G>A mutation interfered with the expression of nuclear genes involved in cytoplasmic proteins essential for oxidative phosphorylation system (OXPHOS), thereby impacting the assemble and integrity of OXPHOS complexes. As a result of these mitochondrial dysfunctions, there was an imbalance in mitochondrial dynamics, particularly distinguished by an increased occurrence of mitochondrial fission. Excessive fission compromised the autophagy process, including initiation phase, formation and maturation of autophagosome. Both Parkin-mediated mitophagy and receptor-dependent mitophagy were significantly impaired in cybrids haboring the m.15927G>A mutation. These changes facilitated intrinsic apoptosis, as indicated by increased cytochrome c release and elevated levels of apoptosis-associated proteins (e.g., BAK, BAX, cleaved caspase 9, cleaved caspase 3, and cleaved PARP) in the mutant cybrids. This study demonstrates that the m.15927G>A mutation contributes to LHON by dysregulating OXPHOS biogenesis, aberrant quality control, increased autophagy, inhibited mitophagy, and abnormal apoptosis.
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Leigh syndrome spectrum (LSS) is a primary mitochondrial disorder defined neuropathologically by a subacute necrotizing encephalomyelopathy and characterized by bilateral basal ganglia and/or brainstem lesions. LSS is associated with variants in several mitochondrial DNA genes and more than 100 nuclear genes, most often related to mitochondrial complex I (CI) dysfunction. Rarely, LSS has been reported in association with primary Leber hereditary optic neuropathy (LHON) variants of the mitochondrial DNA, coding for CI subunits (m.3460G>A in MT-ND1, m.11778G>A in MT-ND4 and m.14484T>C in MT-ND6). The underlying mechanism by which these variants manifest as LSS, a severe neurodegenerative disease, as opposed to the LHON phenotype of isolated optic neuropathy, remains an open question. Here, we analyse the exome sequencing of six probands with LSS carrying primary LHON variants, and report digenic co-occurrence of the m.11778G > A variant with damaging heterozygous variants in nuclear disease genes encoding CI subunits as a plausible explanation. Our findings suggest a digenic mechanism of disease for m.11778G>A-associated LSS, consistent with recent reports of digenic disease in individuals manifesting with LSS due to biallelic variants in the recessive LHON-associated disease gene DNAJC30 in combination with heterozygous variants in CI subunits.
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Doença de Leigh , Atrofia Óptica Hereditária de Leber , Humanos , Doença de Leigh/genética , Atrofia Óptica Hereditária de Leber/genética , Masculino , Feminino , Adulto , DNA Mitocondrial/genética , Complexo I de Transporte de Elétrons/genética , Criança , Adolescente , NADH Desidrogenase/genética , Mutação , Adulto Jovem , Sequenciamento do Exoma , Pré-EscolarRESUMO
Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by visual loss, and rarely associated with extraocular manifestations including multiple sclerosis-like lesions. The association of LHON and neuromyelitis optica spectrum disorders has rarely been reported. Here is reported a case of glial fibrillary acidic protein astrocytopathy presenting with area postrema syndrome in a patient with previously diagnosed recessive LHON due to mutations in the nuclear gene DNAJC30. This case emphasizes the necessity of extensive investigations for other treatable conditions in patients with LHON and otherwise unexplained extraocular involvement and the possibility that also visual symptoms can respond to immune therapy.
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Proteína Glial Fibrilar Ácida , Mutação , Atrofia Óptica Hereditária de Leber , Humanos , Atrofia Óptica Hereditária de Leber/genética , Atrofia Óptica Hereditária de Leber/complicações , Proteína Glial Fibrilar Ácida/genética , Astrócitos/patologia , Astrócitos/metabolismo , Masculino , Proteínas de Choque Térmico HSP40/genética , Adulto , FemininoRESUMO
PURPOSE OF REVIEW: Degeneration of the maculopapillary bundle (MPB) is a prominent feature in a spectrum of optic neuropathies. MPB-selective degeneration is seen in specific conditions, such as nutritional and toxic optic neuropathies, Leber hereditary optic neuropathy (LHON), and dominant optic atrophy (DOA). Despite their distinct etiologies and clinical presentations, which encompass variations in age of incidence and monocular or binocular onset, these disorders share a core molecular mechanism: compromised mitochondrial homeostasis. This disruption is characterized by dysfunctions in mitochondrial metabolism, biogenesis, and protein synthesis. This article provides a comprehensive understanding of the MPB's role in optic neuropathies, emphasizing the importance of mitochondrial mechanisms in the pathogenesis of these conditions. RECENT FINDINGS: Optical coherence tomography studies have characterized the retinal nerve fiber layer changes accompanying mitochondrial-affiliated optic neuropathies. Selective thinning of the temporal optic nerve head is preceded by thickening in early stages of these disorders which correlates with reductions in macular ganglion cell layer thinning and vascular atrophy. A recently proposed mechanism underpinning the selective atrophy of the MPB involves the positive feedback of reactive oxygen species generation as a common consequence of mitochondrial dysfunction. Additionally, new research has revealed that the MPB can undergo degeneration in the early stages of glaucoma, challenging the historically held belief that this area was not involved in this common optic neuropathy. A variety of anatomical risk factors influence the propensity of glaucomatous MPB degeneration, and cases present distinct patterns of ganglion cell degeneration that are distinct from those observed in mitochondria-associated diseases. This review synthesizes clinical and molecular research on primary MPB disorders, highlighting the commonalities and differences in their pathogenesis. KEY POINTS (BOX): 1. Temporal degeneration of optic nerve fibers accompanied by cecocentral scotoma is a hallmark of maculopapillary bundle (MPB) degeneration. 2. Mechanisms of MPB degeneration commonly implicate mitochondrial dysfunction. 3. Recent research challenges the traditional belief that the MPB is uninvolved in glaucoma by showing degeneration in the early stages of this common optic neuropathy, yet with features distinct from other MPB-selective neuropathies. 4. Reactive oxygen species generation is a mechanism linking mitochondrial mechanisms of MPB-selective optic neuropathies, but in-vivo and in-vitro studies are needed to validate this hypothesis.
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Doenças do Nervo Óptico , Humanos , Doenças do Nervo Óptico/patologiaRESUMO
Leber hereditary optic neuropathy (LHON) is an important example of mitochondrial blindness with the m.11778G>A mutation in the MT-ND4 gene being the most common disease-causing mtDNA variant worldwide. The REFLECT phase 3 pivotal study is a randomized, double-masked, placebo-controlled trial investigating the efficacy and safety of bilateral intravitreal injection of lenadogene nolparvovec in patients with a confirmed m.11778G>A mutation, using a recombinant adeno-associated virus vector 2, serotype 2 (rAAV2/2-ND4). The first-affected eye received gene therapy; the fellow (affected/not-yet-affected) eye was randomly injected with gene therapy or placebo. The primary end point was the difference in change from baseline of best-corrected visual acuity (BCVA) in second-affected/not-yet-affected eyes treated with lenadogene nolparvovec versus placebo at 1.5 years post-treatment, expressed in logarithm of the minimal angle of resolution (LogMAR). Forty-eight patients were treated bilaterally and 50 unilaterally. At 1.5 years, the change from baseline in BCVA was not statistically different between second-affected/not-yet-affected eyes receiving lenadogene nolparvovec and placebo (primary end point). A statistically significant improvement in BCVA was reported from baseline to 1.5 years in lenadogene nolparvovec-treated eyes: -0.23 LogMAR for the first-affected eyes of bilaterally treated patients (P < 0.01); and -0.15 LogMAR for second-affected/not-yet-affected eyes of bilaterally treated patients and the first-affected eyes of unilaterally treated patients (P < 0.05). The mean improvement in BCVA from nadir to 1.5 years was -0.38 (0.052) LogMAR and -0.33 (0.052) LogMAR in first-affected and second-affected/not-yet-affected eyes treated with lenadogene nolparvovec, respectively (bilateral treatment group). A mean improvement of -0.33 (0.051) LogMAR and -0.26 (0.051) LogMAR was observed in first-affected lenadogene nolparvovec-treated eyes and second-affected/not-yet-affected placebo-treated eyes, respectively (unilateral treatment group). The proportion of patients with one or both eyes on-chart at 1.5 years was 85.4% and 72.0% for bilaterally and unilaterally treated patients, respectively. The gene therapy was well tolerated, with no systemic issues. Intraocular inflammation, which was mostly mild and well controlled with topical corticosteroids, occurred in 70.7% of lenadogene nolparvovec-treated eyes versus 10.2% of placebo-treated eyes. Among eyes treated with lenadogene nolparvovec, there was no difference in the incidence of intraocular inflammation between bilaterally and unilaterally treated patients. Overall, the REFLECT trial demonstrated an improvement of BCVA in LHON eyes carrying the m.11778G>A mtDNA mutation treated with lenadogene nolparvovec or placebo to a degree not reported in natural history studies and supports an improved benefit/risk profile for bilateral injections of lenadogene nolparvovec relative to unilateral injections.
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Atrofia Óptica Hereditária de Leber , Humanos , DNA Mitocondrial/genética , Terapia Genética , Inflamação/etiologia , Mutação/genética , Atrofia Óptica Hereditária de Leber/genética , Atrofia Óptica Hereditária de Leber/terapiaRESUMO
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 2186 patients referred for suspected hereditary optic neuropathies. The positive diagnosis rate in individuals referred for Leber hereditary optic neuropathy testing was 18% (199/1126 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% (451/1680 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.
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Atrofia Óptica Autossômica Dominante , Atrofia Óptica Hereditária de Leber , Doenças do Nervo Óptico , Humanos , Atrofia Óptica Hereditária de Leber/genética , Estudos Retrospectivos , Atrofia Óptica Autossômica Dominante/genética , Atrofia Óptica Autossômica Dominante/patologia , Doenças do Nervo Óptico/genética , Mutação/genética , DNA Mitocondrial/genética , ATPases Associadas a Diversas Atividades Celulares/genética , Proteases Dependentes de ATP/genética , Proteínas de Transporte/genética , Proteínas Mitocondriais/genética , Proteínas de Membrana/genéticaRESUMO
Lenadogene nolparvovec (GS010) was developed to treat a point mutation in mitochondrial ND4 that causes Leber hereditary optic neuropathy. GS010 delivers human cDNA encoding wild-type ND4 packaged into an rAAV2/2 vector that transduces retinal ganglion cells, to induce allotopic expression of hybrid mitochondrial ND4. GS010 clinical trials improved best-corrected visual acuity (BCVA) up to 5 years after treatment. Interestingly, unilateral treatment improved BCVA bilaterally. Subsequent studies revealed GS010 DNA in visual tissues contralateral to the injected eye, suggesting migration. Here we tested whether unilateral intraocular pressure (IOP) elevation could influence the transfer of viral ND4 RNA in contralateral tissues after GS010 delivery to the IOP-elevated eye and probed a potential mechanism mediating translocation in mice. We found IOP elevation enhanced viral ND4 RNA transcripts in contralateral visual tissues, including retinas. Using conditional transgenic mice, we depleted astrocytic gap junction connexin 43 (Cx43), required for distant redistribution of metabolic resources between astrocytes during stress. After unilateral IOP elevation and GS010 injection, Cx43 knockdown eradicated ND4 RNA transcript detection in contralateral retinal tissues, while transcript was still detectable in optic nerves. Overall, our study indicates long-range migration of GS010 product to contralateral visual tissues is enhanced by Cx43-linked astrocyte networks.
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Astrócitos , Conexina 43 , Camundongos , Humanos , Animais , Astrócitos/metabolismo , Conexina 43/genética , Conexina 43/metabolismo , NADH Desidrogenase/genética , NADH Desidrogenase/metabolismo , Dependovirus/genética , Dependovirus/metabolismo , Vetores Genéticos , Terapia Genética , Camundongos Transgênicos , RNA , DNA Mitocondrial/genéticaRESUMO
PURPOSE: Peripapillary hyperreflective ovoid mass-like structures (PHOMS) represent an optical coherence tomography (OCT) finding that has been characterized in different forms of pseudopapilledema. The aim of this study was to investigate the prevalence of PHOMS in patients affected by acute LHON using structural OCT, and to provide a detailed description of these findings. METHODS: Patients with a clinical and molecularly confirmed diagnosis of acute LHON (visual loss having occurred less than 6 months) were enrolled from the neuro-ophthalmology clinic at San Raffaele Scientific Institute. Patients had a complete ophthalmologic evaluation, including imaging with structural OCT. RESULTS: Our analysis included 16 patients (21 eyes-8 males and 8 females) with acute LHON. Structural OCT exhibited PHOMS in 12 eyes from 9 patients with a prevalence rate of 57.1%. In a subsequent topographical assessment in the peripapillary area, the most common location of PHOMS was the temporal region (12 out of 12 eyes), while the nasal region was affected in 2 eyes (16.7%). Considering the 12 eyes with PHOMS, mean ± SD temporal peripapillary RNFL thickness was 87.5 ± 28.4 microns. The temporal peripapillary RNFL thickness was significantly lower in eyes without PHOMS (63.7 ± 32.2 microns; P = 0.40). At the 12-month follow-up visit, PHOMS disappeared in 10 out of 12 eyes. CONCLUSIONS: Acute LHON eyes have PHOMS which are mainly confined to the temporal peripapillary sector. PHOMS may represent swelled retinal fibers that have herniated or are in stasis.
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Atrofia Óptica Hereditária de Leber , Doenças do Nervo Óptico , Masculino , Feminino , Humanos , Atrofia Óptica Hereditária de Leber/diagnóstico , Retina , Tomografia de Coerência Óptica/métodosRESUMO
BACKGROUND: To investigate the peripapillary retinal nerve fibre layer (RNFL) thickness changes and analyse factors associated with visual recovery of G11778A Leber hereditary optic neuropathy (LHON) patients. METHODS: Patients diagnosed with G11778A LHON between July 2017 and December 2020 in Tongji hospital were included in this follow-up study. Patients were grouped according to disease duration. Variations in the RNFL thickness in each quadrant at different disease stages were characterised using optical coherence tomography. According to the absence or presence of significant visual acuity improvements, LHON patients of disease duration ≥ 6 months were divided into two groups. A bivariate logistic regression model was constructed to analyse the potential factors associated with spontaneous visual recovery. RESULTS: This study included 56 G11778A LHON patients (112 eyes) and 25 healthy controls (50 eyes), with a mean follow-up of 5.25 ± 1.42 months. All quadrants and mean RNFL thicknesses of LHON patients first increased and then decreased, except for the temporal RNFL. As the disease progressed, RNFL thinning slowed; however, gradual RNFL thinning occurred. Logistic regression revealed that baseline best corrected visual acuity was related to spontaneous visual recovery of LHON patients with disease duration ≥ 6 months. CONCLUSION: The pattern of RNFL involvement could be helpful in the differential diagnosis of LHON and other optic neuropathies. LHON patients with better vision are more likely to experience some degree of spontaneous visual acuity recovery after the subacute phase.
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Fibras Nervosas , Atrofia Óptica Hereditária de Leber , Células Ganglionares da Retina , Tomografia de Coerência Óptica , Acuidade Visual , Humanos , Atrofia Óptica Hereditária de Leber/fisiopatologia , Atrofia Óptica Hereditária de Leber/diagnóstico , Masculino , Feminino , Fibras Nervosas/patologia , Células Ganglionares da Retina/patologia , Tomografia de Coerência Óptica/métodos , Seguimentos , Adulto , Acuidade Visual/fisiologia , Adulto Jovem , Disco Óptico/patologia , Disco Óptico/diagnóstico por imagem , Adolescente , Pessoa de Meia-Idade , Estudos Retrospectivos , Campos Visuais/fisiologiaRESUMO
INTRODUCTION: Leber hereditary optic neuropathy (LHON) is a maternally inherited, acute or subacute, optic neuropathy. The typical symptoms include reduced visual acuity and central scotoma. Despite the presence of deep central scotoma, some patients with LHON are able to perform daily activities. This study aimed to investigate the correlation between the residual visual field and visual acuity, critical flicker frequency, and fixation ellipse in patients with chronic LHON. METHODS: Residual visual function (defined as sensitivity points where patients sensed the size V stimulus) of both eyes was evaluated in 10 patients with LHON carrying the m.11778 mitochondrial DNA mutation and with median age of onset and disease duration of 29 and 16.5 years, respectively. The central visual field was measured as static perimetry using the Humphrey visual field testing 30-2 program with the size III or V stimulus. Moreover, best-corrected visual acuity, critical flicker frequency, and the correlation between fixation ellipse and residual central visual fields were determined. The analysis was performed through a linear mixed-effects model. RESULTS: The residual visual sensitivity in the inferior nasal visual field was significantly correlated with the logMAR (p < 0.05). The fixation ellipse fell within the residual visual field region with higher sensitivity. CONCLUSIONS: Patients with chronic LHON tended to retain the sensitivity detectable with the size V stimulus at the central inferior nasal visual field regions, where the fixation ellipse fell. Visual acuity, which influences daily activity, was spatially correlated with residual visual sensitivity.
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Atrofia Óptica Hereditária de Leber , Campos Visuais , Humanos , Escotoma/diagnóstico , Atrofia Óptica Hereditária de Leber/diagnóstico , Testes de Campo Visual , Transtornos da VisãoRESUMO
Leber's hereditary optic neuropathy (LHON) is one of the hereditary optic neuropathies and is principally caused by three frequent mitochondria deoxyribonucleic acid (DNA) pathogenic variants (m.11778 G>A, m.3460 G>A, and m.14484T>C). These pathogenic variants account for 90% of LHON cases, with rare pathogenic variants accounting for the remaining cases. We report the first Japanese case of LHON with the m.13051 G>A pathogenic variant, which is a rare primary pathogenic variant of LHON. A 24-year-old woman developed subacute visual loss in both eyes over several months. The best corrected visual acuity (BCVA) was 6/120 in her right eye (OD) and 6/7.5 in her left eye (OS). A relative afferent pupillary defect was not detected. Humphrey visual field testing revealed a central scotoma OD and a temporal paracentral scotoma OS. Fundus examination showed the presence of a pale optic disc OD and optic disc swelling with peripapillary microangiopathy OS. Orbital magnetic resonance imaging showed no abnormal findings. As the mitochondrial DNA gene testing demonstrated the m.13051 G>A pathogenic variant, the patient was diagnosed with LHON. Subsequently, her BCVA worsened to 6/600 in each eye, followed by a nearly plateau-like progression thereafter. This mutation has been primarily reported in Europe but has not yet been confirmed in the Asian region. This case also indicates the importance of examining the whole mitochondrial DNA gene for pathogenic variants in cases where one of the three major pathogenic variants has not been not detected.
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BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease due to mutations in mitochondrial DNA. However, there is no effective treatment for this disease. LHON-linked ND6 14484T > C (p.M64V) mutation caused complex I deficiency, diminished ATP production, increased production of reactive oxygen species (ROS), elevated apoptosis, and impaired mitophagy. Here, we investigated if the allotopic expression of human mitochondrial ND6 transgene corrected the mitochondrial dysfunctions due to LHON-associated m.14484T > C mutation. METHODS: Nucleus-versions of ND6 was generated by changing 6 non-universal codons with universal codons and added to mitochondrial targeting sequence of COX8. Stable transfectants were generated by transferring human ND6 cDNA expressed in a pCDH-puro vector into mutant cybrids carrying the m.14484T > C mutation and control cybrids. The effect of allotopic expression of ND6 on oxidative phosphorylation (OXPHOS) was evaluated using Blue Native gel electrophoresis and extracellular flux analyzer. Assessment of ROS production in cell lines was performed by flow cytometry with MitoSOX Red reagent. Analyses for apoptosis and mitophagy were undertaken via flow cytometry, TUNEL and immunofluorescence assays. RESULTS: The transfer of human ND6 into the cybrids carrying the m.14484T > C mutation raised the levels of ND6, ND1 and ND4L but did not change the levels of other mitochondrial proteins. The overexpression of ND6 led to 20~23% increases in the assembly and activity of complex I, and ~ 53% and ~ 33% increases in the levels of mitochondrial ATP and ΔΨm in the mutant cybrids bearing m.14484T > C mutation. Furthermore, mutant cybrids with overexpression of ND6 exhibited marked reductions in the levels of mitochondrial ROS. Strikingly, ND6 overexpression markedly inhibited the apoptosis process and restored impaired mitophagy in the cells carrying m.14484T > C mutation. However, overexpression of ND6 did not affect the ND6 level and mitochondrial functions in the wild-type cybrids, indicating that this ND6 level appeared to be the maximum threshold level to maintain the normal cell function. CONCLUSION: We demonstrated that allotopic expression of nucleus-versions of ND6 restored complex I, apoptosis and mitophagy deficiencies caused by the m.14484T > C mutation. The restoration of m.14484T > C mutation-induced mitochondrial dysfunctions by overexpression of ND6 is a step toward therapeutic interventions for LHON and mitochondrial diseases.
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NADH Desidrogenase , Atrofia Óptica Hereditária de Leber , Humanos , Trifosfato de Adenosina , Apoptose/genética , DNA Mitocondrial/genética , Mutação , Atrofia Óptica Hereditária de Leber/genética , Atrofia Óptica Hereditária de Leber/metabolismo , Espécies Reativas de Oxigênio , NADH Desidrogenase/genéticaRESUMO
BACKGROUND: The aim of this study was to investigate the neuroretinal structure of young patients with Leber hereditary optic neuropathy (LHON). METHODS: For this retrospective cross-sectional analysis, the peripapillary retinal nerve fiber layer (pRNFL) thickness and the macular retinal layer volumes were measured by optical coherence tomography. Patients aged 12 years or younger at disease onset were assigned to the childhood-onset (ChO) group and those aged 13-16 years to the early teenage-onset (eTO) group. All patients received treatment with idebenone. The same measurements were repeated in age-matched control groups with healthy subjects. RESULTS: The ChO group included 11 patients (21 eyes) and the eTO group 14 patients (27 eyes). Mean age at onset was 8.6 ± 2.7 years in the ChO group and 14.8 ± 1.0 years in the eTO group. Mean best-corrected visual acuity was 0.65 ± 0.52 logMAR in the ChO group and 1.60 ± 0. 51 logMAR in the eTO group (p < 0.001). Reduced pRNFL was evident in the eTO group compared to the ChO group (46.0 ± 12.7 µm vs. 56.0 ± 14.5 µm, p = 0.015). Additionally, a significantly lower combined ganglion cell and inner plexiform layer volume was found in the eTO compared to the ChO group (0.266 ± 0.0027 mm3 vs. 0.294 ± 0.033 mm3 , p = 0.003). No difference in these parameters was evident between the age-matched control groups. CONCLUSION: Less neuroaxonal tissue degeneration was observed in ChO LHON than in eTO LHON, a finding that may explain the better functional outcome of ChO LHON.
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Atrofia Óptica Hereditária de Leber , Humanos , Adolescente , Criança , Atrofia Óptica Hereditária de Leber/tratamento farmacológico , Estudos Retrospectivos , Células Ganglionares da Retina , Estudos Transversais , Tomografia de Coerência Óptica/métodosRESUMO
BACKGROUND: Leber hereditary optic neuropathy (LHON) is a rare but bilaterally blinding disease. Three characteristic disease-causing point mutations, and other less common mutations, are most often found on the mitochondrially encoded genes of NADH-ubiquinone oxidoreductase core subunits (MT-ND). The purpose of this study is to provide an overview of LHON mutations in Southwestern Ontario and to describe the associated demographic and clinical characteristics. METHODS: A retrospective genetic and clinical chart review was performed from January 2015 to 2020. Patients were identified within a mitochondrial mutation database and included if a mutation was detected on the MT-ND1, -ND4, or -ND6 genes. A clinical chart review was done on all available patients. RESULTS: Forty-five of 63 patients identified had classic disease-causing mutations (6.7% m.3460G>A, 44.4% m.11778G>A, and 48.9% m.14484T>C). Several of the remaining 18 patients had rare mutations previously documented in association with LHON. Of the 14 patients with clinical charts accessible for review, 12 had symptomatic disease, and all but one had bilateral optic neuropathies. Nine patients had classic LHON mutations and 3 had possible novel mutations; 7 were males; 9 had final visual acuity ≤ 20/200 in at least one eye; and 6 of those had ≤20/400 in both eyes. CONCLUSIONS: This study adds to the literature on LHON in Canada, and specifically Southwestern Ontario. The demographic and clinical data regarding LHON in this geographic location, as well as possible novel disease-causing mutations, provide important information to aid clinicians in recognizing cases of LHON that may otherwise be disregarded.
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Atrofia Óptica Hereditária de Leber , Masculino , Humanos , Feminino , Atrofia Óptica Hereditária de Leber/epidemiologia , Atrofia Óptica Hereditária de Leber/genética , Ontário/epidemiologia , Estudos Retrospectivos , DNA Mitocondrial/genética , Mutação/genéticaRESUMO
Leber's hereditary optic neuropathy (LHON) is a disease that affects the optical nerve, causing visual loss. The diagnosis of LHON is mostly defined by the identification of three pathogenic variants in the mitochondrial DNA. Idebenone is widely used to treat LHON patients, but only some of them are responders to treatment. In our study, we assessed the maximal respiration rate (MRR) and other respiratory parameters in eight fibroblast lines from subjects carrying LHON pathogenic variants. We measured also the effects of idebenone treatment on cell growth and mtDNA amounts. Results showed that LHON fibroblasts had significantly reduced respiratory parameters in untreated conditions, but no significant gain in MRR after idebenone supplementation. No major toxicity toward mitochondrial function and no relevant compensatory effect in terms of mtDNA quantity were found for the treatment at the tested conditions. Our findings confirmed that fibroblasts from subjects harboring LHON pathogenic variants displayed impaired respiration, regardless of the disease penetrance and severity. Testing responsiveness to idebenone treatment in cultured cells did not fully recapitulate in vivo data. The in-depth evaluation of cellular respiration in fibroblasts is a good approach to evaluating novel mtDNA variants associated with LHON but needs further evaluation as a potential biomarker for disease prognosis and treatment responsiveness.
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Atrofia Óptica Hereditária de Leber , Humanos , Atrofia Óptica Hereditária de Leber/tratamento farmacológico , Atrofia Óptica Hereditária de Leber/genética , DNA Mitocondrial/genética , Mitocôndrias/genética , FibroblastosRESUMO
Leber hereditary optic neuropathy (LHON) is a rare disorder causing a sudden painless loss of visual acuity in one or both eyes, affecting young males in their second to third decade of life. The molecular background of the LHON is up to 90%, genetically defined by a point mutation in mitochondrial DNA. Recently, an autosomal recessive form of LHON (LHONAR1, arLHON) has been discovered, caused by biallelic variants in the DNAJC30 gene. This study provides the results of the DNAJC30 gene analysis in a large group of 46 Polish patients diagnosed with LHON, together with the clinical characterization of the disease. The c.152A>G (p.Tyr51Cys) substitution in the DNAJC30 gene was detected in all the patients as homozygote or compound heterozygote. Moreover, we identified one novel variant, c.293A>G, p.(Tyr98Cys), as well as two ultra-rare DNAJC30 variants: c.293A>C, p.(Tyr98Ser), identified to date only in one individual affected with LHONAR1, and c.130_131delTC (p.Ser44ValfsTer8), previously described only in two patients with Leigh syndrome. The patients presented here represent the largest group of subjects with DNAJC30 gene mutations described to date. Based on our data, the autosomal recessive form of LHON caused by DNAJC30 gene mutations is more frequent than the mitochondrial form in Polish patients. The results of our study suggest that Sanger sequencing of the single-exon DNAJC30 gene should be a method of choice applied to identify a molecular background of clinically confirmed LHON in Polish patients. This approach will help to reduce the costs of molecular testing.
Assuntos
Proteínas de Choque Térmico HSP40 , Atrofia Óptica Hereditária de Leber , Humanos , Masculino , DNA Mitocondrial/genética , Mitocôndrias/genética , Mutação , Atrofia Óptica Hereditária de Leber/genética , Polônia , Doenças Raras/genética , Proteínas de Choque Térmico HSP40/genéticaRESUMO
A 29-year-old female with no family history presented with bilateral progressive blurred vision. Her symptoms appeared at 12-years-old and her visual acuity had since deteriorated from 0.6 to 0.2 bilaterally with decreased critical flicker frequency and bilateral central scotomas. She did not have a relative afferent pupillary defect. Fundoscopy revealed no distinct disc hyperaemia, atrophy, or peripapillary telangiectatic vessels. The retinal nerve fibre layer appeared normal on optical coherence tomography in each eye; however, loss of the interdigitation zone and the disruption of the ellipsoid zone at the fovea were observed in both eyes. Multifocal electroretinography revealed decreased amplitudes at both macula regions. Mitochondrial deoxyribonucleic acid analysis identified an m.14502T>C mutation, one of the primary mutations causing Leber's hereditary optic neuropathy (LHON). Despite the presence of a marked LHON mutation, however, she was clinically diagnosed as having an occult macular dystrophy. There have only been five previous case reports, all of which were sporadic, which detail the clinical characteristics of the m.14502T>C mutation. The m.14502T>C phenotype is somewhat consistent with that of the other major mutations, including young onset, bilateral progressive visual impairment, and a typical LHON fundus. Nevertheless, m.14502T>C alone has an extremely low penetrance and its phenotype may be minimal or subclinical, as seen in our case. Since little is known about the clinical course of the m.14502T>C mutation it may be possible that the LHON phenotype may appear in later stages of life. Moreover, m.14502T>C may function as a modifier gene, which alters the phenotype of other coexisting major LHON mutations, including penetrance and the severity of the disease, through synergistic effects.
RESUMO
Leber's hereditary optic neuropathy (LHON) and autosomal recessive optic neuropathy (ARON) are degenerative diseases of the optic nerve caused by mutations in nuclear or mitochondrial DNA (nDNA, mtDNA). The clinical picture of these diseases is similar, but there are some differences in how the visual functions change in patients with different molecular genetic variants of hereditary optic neuropathies (HON). PURPOSE: This study evaluates the long-term changes in morphological and functional parameters in patients with different genetic variants of HON. MATERIAL AND METHODS: The study included 84 patients (165 eyes) with a genetically confirmed LHON or ARON diagnosis. The patients underwent best-corrected visual acuity (VA) test, color vision (CV) examination, computerized perimetry using the program for low vision assessment, optical coherence tomography (OCT). RESULTS: Over the course of the follow-up (60 months or longer) HON patients were revealed to have higher VA in c.152A>G and m.14484T>C mutations compared to mutations m.11778G>A and m.3460G>A. The final VA 0.5 or higher in patients with c.152A>G and m.14484T>C mutations in 54 and 71% of cases, and only in 6 and 13% of cases - with m.11778G>A and m.3460G>A mutations. Direct correlation was determined between minimal VA in the first year after disease onset and the final VA (K=0.67; p<0.001). In all patients with the investigated mutations CV recovered slightly quicker than VA. CONCLUSION: HON associated with c.152A>G and m.14484T>C mutations have better prognosis compared to LHON caused by m.11778G>A and m.3460G>A mutations. Vision recovery prognosis is worse in patients who had significant decrease of visual acuity at the disease onset. OCT findings reveal preservation of visual functions in all mutations.
Assuntos
Atrofia Óptica Hereditária de Leber , Nervo Óptico , Humanos , Atrofia Óptica Hereditária de Leber/diagnóstico , Atrofia Óptica Hereditária de Leber/genética , Mutação , DNA Mitocondrial/genética , PrognósticoRESUMO
Patients with Leber Hereditary Optic Neuropathy (LHON) in most cases have one of the three most common mutations: m.11778G>A in the ND4 gene, m.3460G>A in the ND1 gene, or m.14484T>C in the ND6 gene. According to the international Mitomap database, in addition to these three most common mutations, there are 16 other primary mutations that are even more rare. There are nucleotide substitutions that are classified as candidate or conditionally pathogenic mutations. Their involvement in the disease development is not proven due to insufficient research. Moreover, in many publications, the authors describe new primary and potential mitochondrial DNA mutations associated with LHON, which are not yet included in the genetic data bases. This makes it possible to expand the diagnostic spectrum during genetic testing in the future. The advancements in genetic diagnostic technologies allow confirmation of the clinical diagnosis of LHON. The importance of genetic verification of the disease is determined by the existing problem of differential diagnosis of hereditary optic neuropathies with optic neuropathies of a different origin.