[Acupuncture for glaucoma-induced optic atrophy: a randomized controlled trial].

OBJECTIVE: To observe the clinical effect of acupuncture for glaucoma-induced optic atrophy. METHODS: A total of 70 patients (89 affected eyes) with glaucoma-induced optic atrophy were randomized into an observation group and a control group, 35 cases in each group. The control group was given basic western medicine treatment. In the observation group, on the basis of the treatment in the control group, acupuncture was applied at main acupoints i.e. Baihui (GV 20), Shangjingming (Extra), Chengqi (ST 1), Fengchi (GB 20), Zusanli (ST 36), combined with supplementary acupoints based on syndrome differentiation, once every three days, twice a week. The treatment for 3 months was required in both groups. Before treatment, after treatment and in follow-up of 6 months after treatment, the best corrected visual acuity (BCVA), intraocular pressure (IOP), indexes of visual field (visual field index [VFI], mean deviation [MD], pattern standard deviation [PSD]) and mean thickness of retinal nerve fiber layer (RNFL) were observed in the two groups. RESULTS: Compared before treatment, BCVA was decreased after treatment and in follow-up in the control group (P<0.05); in the follow-up, BCVA in the observation group was higher than that in the control group (P<0.05). On each time point before and after treatment, there was no significant difference within or between the two groups (P>0.05). After treatment and in the follow-up, the mean thickness of RNFL was larger than the control group (P<0.05). CONCLUSION: On the basis of the basic western medicine treatment, acupuncture can delay the decline of vision and the thinning of retinal nerve fiber layer in patients with glaucoma-induced optic atrophy.

Bilateral compressive optic neuropathy and outer retinopathy due to optic canal hyperostosis in a child with isolated vitamin a deficiency.

PURPOSE: Vitamin A plays a crucial role in rod phototransduction, with deficient levels manifesting as night blindness. Animal models have demonstrated bone dysplasia in the setting of hypovitaminosis A. We present a rare case of bony overgrowth leading to bilateral compressive optic neuropathy, combined with outer retinopathy, in a paediatric patient secondary to isolated vitamin A deficiency. METHODS: A single case report was conducted from Toronto, Canada. RESULTS: A 12-year-old boy with known autism spectrum disorder presented with a 9-month history of progressive painless vision loss. Vision was 20/300 and hand motion in the right and left eye, respectively. Fundus photography demonstrated bilateral optic atrophy and yellow lesions notably in the right eye far periphery. Optical coherence tomography (OCT) imaging demonstrated thinning of the retinal nerve fibre layer, alterations in the ellipsoid zone, as well as retinal pigment epithelium deposits. Computed tomography imaging demonstrated sphenoid bone thickening with narrow optic canals and moderate optic atrophy bilaterally. Full-field electroretinogram (ERG) demonstrated mildly reduced dark adapted (DA) 0.01 b-wave amplitudes and electronegative configuration of DA 3.0 and DA 10.0 ERG; the light adapted ERGs were normal. The patient was treated with pulse vitamin A therapy. Subsequently, the DA ERG normalized, outer retinal changes reversed and vision stabilised; no surgical intervention was conducted. CONCLUSION: This case represents a rare presentation of compressive optic neuropathy with concomitant outer retinopathy secondary to isolated vitamin A deficiency. Despite improvement in outer retinal integrity on OCT imaging and ERG testing results following vitamin A supplementation, no functional improvement was obtained due to severe optic atrophy.

Retinopathy and optic atrophy in a case of COQ2-related primary coenzyme Q10 deficiency.

PURPOSE: To describe a case of primary coenzyme Q10 deficiency in a child manifesting as early-onset renal failure, retinal dystrophy, and optic atrophy leading to progressive vision loss. METHODS: Clinical presentation and workup including visual fields, electroretinogram, and optical coherence tomography are presented. Genetic testing was performed. RESULTS: An eight-year-old female with nephropathy requiring renal transplantation subsequently developed progressive cone-rod dystrophy and optic atrophy. The patient had negative results on a targeted next-generation sequencing retinal dystrophy panel but whole-exome sequencing revealed two variants in COQ2 (likely biallelic), consistent with a diagnosis of primary coenzyme Q10 deficiency. CONCLUSIONS: Primary coenzyme Q10 deficiency is a rare disorder with variable systemic and ocular findings; there is also genetic heterogeneity. Genetic testing aids in the diagnosis of this condition, and variants in the COQ2 and PDSS1 genes appear to have the strongest association with ocular manifestations. Oral supplementation of coenzyme Q10 may slow progression of disease. This case highlights the utility of whole-exome sequencing in the diagnosis of a rare syndromic form of ocular disease and reports a novel phenotypic association for this condition.

Acupuncture for glaucoma-induced optic atrophy: a randomized controlled trial / 中国针灸

OBJECTIVE@#To observe the clinical effect of acupuncture for glaucoma-induced optic atrophy.@*METHODS@#A total of 70 patients (89 affected eyes) with glaucoma-induced optic atrophy were randomized into an observation group and a control group, 35 cases in each group. The control group was given basic western medicine treatment. In the observation group, on the basis of the treatment in the control group, acupuncture was applied at main acupoints i.e. Baihui (GV 20), Shangjingming (Extra), Chengqi (ST 1), Fengchi (GB 20), Zusanli (ST 36), combined with supplementary acupoints based on syndrome differentiation, once every three days, twice a week. The treatment for 3 months was required in both groups. Before treatment, after treatment and in follow-up of 6 months after treatment, the best corrected visual acuity (BCVA), intraocular pressure (IOP), indexes of visual field (visual field index [VFI], mean deviation [MD], pattern standard deviation [PSD]) and mean thickness of retinal nerve fiber layer (RNFL) were observed in the two groups.@*RESULTS@#Compared before treatment, BCVA was decreased after treatment and in follow-up in the control group (P<0.05); in the follow-up, BCVA in the observation group was higher than that in the control group (P<0.05). On each time point before and after treatment, there was no significant difference within or between the two groups (P>0.05). After treatment and in the follow-up, the mean thickness of RNFL was larger than the control group (P<0.05).@*CONCLUSION@#On the basis of the basic western medicine treatment, acupuncture can delay the decline of vision and the thinning of retinal nerve fiber layer in patients with glaucoma-induced optic atrophy.

[Effect of acupuncture on retinal and choroidal thickness in patients with optic atrophy].

OBJECTIVE: To observe the effect of acupuncture on visual acuity, intraocular pressure, visual field, retinal and choroidal thickness on optic disc and macular area in patients with optic atrophy. METHODS: A total of 33 patients with optic atrophy were treated with acupuncture. Acupuncture was given at Chengqi (ST 1), Shangjingming (Extra), Qiuhou (EX-HN 7) and Fengchi (GB 20) etc., 30 min each time, once a day, for 14 days. The visual acuity, intraocular pressure, visual field indexes (mean deviation [MD], pattern standard deviation [PSD] and visual field index [VFI]), optic disc retinal nerve fiber layer thickness, macular retinal thickness and choroidal thickness of optic disc and sub-foveal were compared before and after treatment. RESULTS: Compared before treatment, the visual acuity was increased (P<0.05), the MD value was decreased (P<0.05), the thickness of nerve fiber layer on the upper temporal side of optic disc was thinner (P<0.05), and the choroidal thickness of average, nasal side and lower temporal side of optic disc was increased (P<0.05). There was significant correlation between visual field MD and retinal nerve fiber layer thickness in different quadrants before and after treatment (P<0.01). CONCLUSION: Acupuncture could improve visual acuity, increase choroidal thickness in part of optic disc area in patients with optic atrophy.

Effect of acupuncture on retinal and choroidal thickness in patients with optic atrophy / 中国针灸

OBJECTIVE@#To observe the effect of acupuncture on visual acuity, intraocular pressure, visual field, retinal and choroidal thickness on optic disc and macular area in patients with optic atrophy.@*METHODS@#A total of 33 patients with optic atrophy were treated with acupuncture. Acupuncture was given at Chengqi (ST 1), Shangjingming (Extra), Qiuhou (EX-HN 7) and Fengchi (GB 20) etc., 30 min each time, once a day, for 14 days. The visual acuity, intraocular pressure, visual field indexes (mean deviation [MD], pattern standard deviation [PSD] and visual field index [VFI]), optic disc retinal nerve fiber layer thickness, macular retinal thickness and choroidal thickness of optic disc and sub-foveal were compared before and after treatment.@*RESULTS@#Compared before treatment, the visual acuity was increased (P<0.05), the MD value was decreased (P<0.05), the thickness of nerve fiber layer on the upper temporal side of optic disc was thinner (P<0.05), and the choroidal thickness of average, nasal side and lower temporal side of optic disc was increased (P<0.05). There was significant correlation between visual field MD and retinal nerve fiber layer thickness in different quadrants before and after treatment (P<0.01).@*CONCLUSION@#Acupuncture could improve visual acuity, increase choroidal thickness in part of optic disc area in patients with optic atrophy.

Juvenile progressive optic atrophy as the presenting feature of biotinidase deficiency, a treatable metabolic disorder.

A 10-year-old girl initially diagnosed with functional visual loss was later diagnosed with progressive optic atrophy. Directed questioning at 13 years of age revealed difficulty hearing that had not been noted by the parents. Whole exome sequencing and subsequent metabolic testing confirmed biotinidase deficiency. Although biotinidase deficiency classically manifests in early childhood with multiple manifestations, such as seizures and failure to thrive, a delayed-onset form can present primarily as juvenile progressive optic atrophy. Early diagnosis is critical because biotin supplementation prevents disease and deterioration.

[Therapeutic effect of Wei's triple nine needling combined with medication on optic atrophy].

OBJECTIVE: To explore the effect of Wei 's triple nine needling on visual acuity and visual field in patients with optic atrophy. METHODS: A total of 90 patients with optic atrophy were randomized into an observation group and a control group, 45 cases in each one. Treatment of Wei 's triple nine needling combined with conventional medication were adopted in the observation group, conventional medication was given in the control group. Treatment for 4 weeks was required in both groups. Before treatment and 2, 4 weeks into treatment, the visual acuity and visual field were observed, and the clinical efficacy was evaluated in both groups. RESULTS: The total effective rate was 57.8% (26/45) in the observation group, which was superior to 28.9% (13/45) in the control group (P<0.05). After 2-week and 4-week treatment, the visual acuity was improved (P<0.01), the mean defect (MD) of visual field was decreased (P<0.01), the mean sensitivity (MS) of visual field was increased in the observation group (P<0.05, P<0.01). After 2-week and 4-week treatment, the visual acuity and the MD of visual field were improved (P<0.01, P<0.05), while the difference of MS of visual field compared before treatment had no statistical significance in the control group (P>0.05). The improvement of visual acuity, MD and MS of visual field after 2-week and 4-week into treatment in the observation group were superior to those in the control group (P<0.05, P<0.01). CONCLUSION: Wei 's triple nine needling can effectively improve the visual acuity and the defect of visual field in patients with optic atrophy.

Potentially blinding adverse drug reaction to peribulbar lignocaine anesthesia: A rare case report.

Peribulbar lignocaine anesthesia is commonly used in ophthalmic surgeries. It rarely causes any severe allergic reaction. A 63-year-old male presented with complicated pseudophakia. He underwent successful vitrectomy under local anesthesia. He later presented with acute-onset proptosis, orbital swelling, and extraocular movement restriction. He was afebrile with normal blood workup and radiological investigations and gave a similar past history. The patient was treated successfully with intravenous medications but two months later developed optic atrophy. An adverse reaction to lignocaine appears to be the most probable cause. Early detection and prompt management of this condition may avert a potentially grave visual outcome. Literature review shows that this case is one of its kinds to report this potentially blinding complication of peribulbar lignocaine anesthesia.

Hereditary polyneuropathy with optic atrophy due to PDXK variant leading to impaired Vitamin B6 metabolism.

PDXK encodes for a pyridoxal kinase, which converts inactive B6 vitamers to the active cofactor pyridoxal 5'-phosphate (PLP). Recently, biallelic pathogenic variants in PDXK were shown to cause axonal Charcot-Marie-Tooth disease with optic atrophy that responds to PLP supplementation. We present two affected siblings carrying a novel biallelic missense PDXK variant with a similar phenotype with earlier onset. After detection of a novel PDXK variant using Whole Exome Sequencing, we confirmed pathogenicity through in silico protein structure analysis, determination of pyridoxal kinase activity using liquid chromatography-tandem mass spectrometry, and measurement of plasma PLP concentrations using high performance liquid chromatography. Our in silico analysis shows a potential effect on PDXK dimer stability, as well as a putative effect on posttranslational ubiquitination that is predicted to lead to increased protein degradation. We demonstrate that the variant leads to almost complete loss of PDXK enzymatic activity and low PLP levels. Our patients' early diagnosis and prompt PLP replacement restored the PLP plasma levels, enabling long-term monitoring of clinical outcomes. We recommend that patients presenting with similar phenotype should be screened for PDXK mutations, as this is a rare opportunity for treatment.

Acupuncture treatment for optic atrophy: A protocol for systematic review.

BACKGROUND: Optic atrophy (OPA) is a very tricky disorder. Presently, no effective management is available for this condition. Previous studies have reported that acupuncture may be effective for the treatment of OPA. However, its effectiveness is still inconclusive. Thus, this study will aim to assess the effectiveness and safety of acupuncture for OPA. METHODS: A comprehensive literature search for relevant studies will be performed from the databases of PUMBED, EMBASE, CINAHI, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, Cochrane Library, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, and other literature sources from inception up to the present. No language limitations will be applied to all literature searches. We will consider all randomized controlled trials (RCTs) and case-controlled trials (CCTs) for assessing the effectiveness and safety of acupuncture for OPA. The primary outcomes include the rates of vision improvement and visual field improvement. The secondary outcomes consist of the increased visual field average sensitivity, pattern visual evoked potential (PVEP) amplitude, and shortened PVEP latency, as well as any expected and unexpected adverse reactions. Risk of bias assessment will be performed by Cochrane risk of bias for RCTs and Newcastle-Ottawa Scale for CCTs. RESULTS: In this study, we will outline details of the aims and methods on the effectiveness and safety of acupuncture for the treatment of OPA. CONCLUSION: The results of this study will summarize the most current evidence of acupuncture for the treatment of patients with OPA. DISSEMINATION AND ETHICS: The results of this study are expected to be published on peer-reviewed journals. This is a literature-based study; therefore, no ethical approval is necessary. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019135785.

Toxic Optic Neuropathy Caused by Chlorfenapyr Poisoning

PURPOSE: To report a case of toxic optic neuropathy caused by chlorfenapyr ingestion accompanied by central nervous system involvement. CASE SUMMARY: A 44-year-old female visited our clinic complaining of reduced visual acuity in both eyes for 7 days. She had ingested a mouthful of chlorfenapyr for a suicide attempt 2 weeks prior to the visit. Gastric lavage was performed immediately after ingestion at the other hospital. Her best-corrected visual acuity was finger count 30 cm in the right eye and hand motion in the left eye. Both pupils were dilated by 5.0 mm and the response to light was sluggish in both eyes. A relative afferent pupillary defect was detected in her left eye. Funduscopy revealed optic disc swelling in both eyes. Magnetic resonance imaging of the brain showed a symmetric hyper-intense signal in the white matter tract including the internal capsule, corpus callosum, middle cerebellar peduncle, and brainstem. The patient was diagnosed with toxic optic neuropathy induced by chlorfenapyr ingestion, and underwent high-dose intravenous corticosteroid pulse therapy. Three days later, the best-corrected visual acuity was no light perception in both eyes. Three months later, optic atrophy was observed in both eyes. Optical coherence tomography revealed a reduction in the thicknesses of the retinal nerve fiber layer and ganglion cell and inner plexiform layer in the macular area. CONCLUSIONS: Ingestion of even a small amount of chlorfenapyr can cause severe optic nerve damage through the latent period, despite prompt lavage and high-dose steroid treatment.

[Diffusion tensor imaging of the visual pathway in glaucomatous optic nerve atrophy]. / Diffusionsbildgebung der Sehbahn bei glaukomatöser Optikusatrophie.

In Germany more than one million inhabitants suffer from glaucoma, more than 100,000 are threatened with blindness because glaucoma is often diagnosed too late or not at all. Diagnosis and monitoring is usually carried out "only" by examination of the retina and not the whole visual pathway. However, the eye is just "the tip of the iceberg" of the actual visual pathway, which extends through the brain to the visual cortex. The interdisciplinary holistic assessment of the whole visual pathway in glaucoma is of crucial importance because glaucoma is a complex neurodegenerative disease. Subtypes, such as normal tension glaucoma (NTG), seem to originate from primary damage to the intracranial visual pathway with secondary retrograde retinal degeneration. Recent studies including glaucoma patients and healthy controls could show that diffusion tensor imaging with calculation of diffusion coefficients, i.e. fractional anisotropy (FA), mean and radial diffusivity (MD and RD) as markers of axonal integrity, provide the potential to assess the intracranial visual pathway with a high correlation to established ophthalmological examinations. In particular, calculation of FA maps of the visual pathway and accompanying voxel-based approaches, can be integrated into clinical routine. Thus, detection of glaucoma-related intracranial alterations, even in early stages of the disease, as well as differentiation of different glaucoma subtypes, is made possible. Furthermore, the diagnosis of normal tension glaucoma seems to be possible much earlier with these new imaging techniques compared to established ophthalmological work-up. Moreover, holistic imaging provides new insights into the pathophysiology of this form of glaucoma. This review article gives an overview of these novel magnetic resonance imaging techniques for assessment of the visual pathway in glaucomatous optic nerve atrophy and reveals the potential of an interdisciplinary approach.

Nonglaucomatous Cupping: Fundus Photography and Spectral Domain Optical Coherence Tomography Imaging Features.

Nonglaucomatous cupping is commonly encountered in neuro-ophthalmic practice. However, the progression of clinical and imaging findings over time has not been well described. We present serial fundus photographs and spectral domain optical coherence tomography from a pediatric patient with neuromyelitis optic spectrum disorder, which demonstrated progression of both cupping and optic atrophy in the setting of normal intraocular pressure.

Neuropatía óptica en un caso de paquimeningitis hipertrófica idiopática recurrente sin respuesta a esteroides e inmunosupresores / Optic neuropathy in a case of recurrent idiopathic hypertrophic pachymeningitis unresponsive to steroids and immunosuppressants

CASO CLÍNICO: Mujer de 38 años con pérdida visual en ojo izquierdo y papiledema bilateral. La resonancia magnética nuclear (RMN) mostraba engrosamiento de la duramadre y la presión intracraneal estaba elevada. Se descartó enfermedad infecciosa, tumoral y autoinmune. DISCUSIÓN: La respuesta inicial a corticoides fue satisfactoria con desaparición del edema de disco óptico, mejoría de la agudeza visual y mejoría radiológica. Después de un año sin tratamiento presentó un nuevo brote, desarrollando una neuropatía óptica izquierda con pérdida irreversible de visión a pesar del retratamiento con corticoides y azatioprina

CASE REPORT: A 38-year-old female patient with bilateral papilledema who presented with loss of vision in her left eye. The Magnetic Resonance Imagining (MRI) showed thickening of the dura mater, and the intracranial pressure was elevated. A cancer, infectious, and autoimmune origin was ruled out. DISCUSSION: The initial response to high doses of corticoids was satisfactory, with disappearance of the optic disc enema, with visual acuity and an improvement in the MRI. However, after one year without treatment she had a new outbreak of the disease. Despite renewed treatment with corticoids and azathioprine, the patient developed a left optic neuropathy and irreversible visual loss

[Meta analysis of acupuncture in the treatment of optic atrophy].

OBJECTIVE: To evaluate the efficacy and safety of acupuncture for optic atrophy. METHODS: All the randomized controlled trials (RCTs) on optic atrophy treatment with acupuncture were included after retrieving the PubMed, Embase, Cochrane Library, CBM, CNKI, VIP, Wanfang database from their establishment to November 2012. The bibliographies of the included studies were retrieved as well. The quality of RCTs meeting the inclusion criteria was evaluated and the data were extracted. Meta-analyses were performed with Stata 11.2 software. RESULTS: Thirteen RCTs involving 1180 eyes were included. Meta-analyses showed that the effect of acupuncture or combined with medicine was superior to medicine alone in terms of total effectiveness [OR=3.281, 95% CI ( 2.517, 4.278)], visual acuity [3.287, 95% CI (2.193, 4.925)], and visual field [3.215, 95% CI (1.580, 6.543)]. The visual sensitivity and P-VEP test showed the similar results. CONCLUSION: Acupuncture is superior to medicine in terms of improved visual acuity, visual field and P-VEP. However, large samples, and high-quality studies are needed for stronger evidence.

Dietary omega-3 fatty acids, other fat intake, genetic susceptibility, and progression to incident geographic atrophy.

OBJECTIVE: To investigate associations between dietary omega-3 fatty acids and other fat intake, genes related to age-related macular degeneration (AMD), and progression to geographic atrophy (GA). DESIGN: Observational analysis of a prospective cohort. PARTICIPANTS: A total of 2531 individuals from the Age-Related Eye Disease Study, among which 525 eyes progressed to GA and 4165 eyes did not. METHODS: Eyes without advanced AMD at baseline were evaluated for progression to GA. Behavioral data, including smoking and body mass index measurements, were collected at baseline using questionnaires. Dietary data were collected from food frequency questionnaires (FFQs) at baseline. Omega-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]), omega-6 fatty acids, monounsaturated, saturated, polyunsaturated, and total fat were adjusted for sex and calories and divided into quintiles (Q). Eight single nucleotide polymorphisms in 7 genes (CFH, ARMS2/HTRA1, CFB, C2, C3, CFI, and LIPC) were genotyped. Cox proportional hazards models were used to test for associations between incident GA and intake of dietary lipids and interaction effects between dietary fat intake and genetic variation on risk of GA. MAIN OUTCOME MEASURES: Associations between dietary fat intake reported from FFQs, genetic variants, and incident GA. RESULTS: Increased intake of DHA was significantly associated with reduced risk of progression to GA in models with behavioral factors (model A) plus genetic variants (model B) (P trend = 0.01 and 0.03, respectively). Total omega-3 long chain polyunsaturated (DHA + EPA) fatty acid intake was significantly associated with reduced risk of progression in model B (P trend = 0.02). Monounsaturated fat was associated with increased risk in model A (P trend = 0.05). DHA intake was significantly associated with reduced risk of incident GA among those with the ARMS2/HTRA1 homozygous risk genotype (hazard ratio [HR] Q5 vs Q1, 0.4; P = 0.002; P for interaction between gene and fat intake = 0.05). DHA was not associated with reduced risk of GA among those with the homozygous ARMS2/HTRA1 nonrisk genotype (HR, 1.0; P = 0.90). CONCLUSIONS: Increased self-reported dietary intake of omega-3 fatty acids is associated with reduced risk of GA and may modify genetic susceptibility for progression to GA. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Meta analysis of acupuncture in the treatment of optic atrophy / 中南大学学报(医学版)

OBJECTIVE@#To evaluate the efficacy and safety of acupuncture for optic atrophy.@*METHODS@#All the randomized controlled trials (RCTs) on optic atrophy treatment with acupuncture were included after retrieving the PubMed, Embase, Cochrane Library, CBM, CNKI, VIP, Wanfang database from their establishment to November 2012. The bibliographies of the included studies were retrieved as well. The quality of RCTs meeting the inclusion criteria was evaluated and the data were extracted. Meta-analyses were performed with Stata 11.2 software.@*RESULTS@#Thirteen RCTs involving 1180 eyes were included. Meta-analyses showed that the effect of acupuncture or combined with medicine was superior to medicine alone in terms of total effectiveness [OR=3.281, 95% CI ( 2.517, 4.278)], visual acuity [3.287, 95% CI (2.193, 4.925)], and visual field [3.215, 95% CI (1.580, 6.543)]. The visual sensitivity and P-VEP test showed the similar results.@*CONCLUSION@#Acupuncture is superior to medicine in terms of improved visual acuity, visual field and P-VEP. However, large samples, and high-quality studies are needed for stronger evidence.

Mutant NADH dehydrogenase subunit 4 gene delivery to mitochondria by targeting sequence-modified adeno-associated virus induces visual loss and optic atrophy in mice.

PURPOSE: Although mutated G11778A NADH ubiquinone oxidoreductase subunit 4 (ND4) mitochondrial DNA (mtDNA) is firmly linked to the blindness of Leber hereditary optic neuropathy (LHON), a bona fide animal model system with mutated mtDNA complex I subunits that would enable probing the pathogenesis of optic neuropathy and testing potential avenues for therapy has yet to be developed. METHODS: The mutant human ND4 gene with a guanine to adenine transition at position 11778 with an attached FLAG epitope under control of the mitochondrial heavy strand promoter (HSP) was inserted into a modified self-complementary (sc) adeno-associated virus (AAV) backbone. The HSP-ND4FLAG was directed toward the mitochondria by adding the 23 amino acid cytochrome oxidase subunit 8 (COX8) presequence fused in frame to the N-terminus of green fluorescent protein (GFP) into the AAV2 capsid open reading frame. The packaged scAAV-HSP mutant ND4 was injected into the vitreous cavity of normal mice (OD). Contralateral eyes received scAAV-GFP (OS). Translocation and integration of mutant human ND4 in mouse mitochondria were assessed with PCR, reverse transcription-polymerase chain reaction (RT-PCR), sequencing, immunoblotting, and immunohistochemistry. Visual function was monitored with serial pattern electroretinography (PERG) and in vivo structure with spectral domain optical coherence tomography (OCT). Animals were euthanized at 1 year and processed for light and transmission electron microscopy. RESULTS: The PCR products of the mitochondrial and nuclear DNA extracted from infected retinas and optic nerves gave the expected 500 base pair bands. RT-PCR confirmed transcription of the mutant human ND4 DNA in mice. DNA sequencing confirmed that the PCR and RT-PCR products were mutant human ND4 (OD only). Immunoblotting revealed the expression of mutant ND4FLAG (OD only). Pattern electroretinograms showed a significant decrement in retinal ganglion cell function OD relative to OS at 1 month and 6 months after AAV injections. Spectral domain optical coherence tomography showed optic disc edema starting at 1 month post injection followed by optic nerve head atrophy with marked thinning of the inner retina at 1 year. Histopathology of optic nerve cross sections revealed reductions in the optic nerve diameters of OD versus OS where transmission electron microscopy revealed significant loss of optic nerve axons in mutant ND4 injected eyes where some remaining axons were still in various stages of irreversible degeneration with electron dense aggregation. Electron lucent mitochondria accumulated in swollen axons where fusion of mitochondria was also evident. CONCLUSIONS: Due to the UGA codon at amino acid 16, mutant G11778A ND4 was translated only in the mitochondria where its expression led to significant loss of visual function, loss of retinal ganglion cells, and optic nerve degeneration recapitulating the hallmarks of human LHON.