Changes in visual acuity using low vision devices in patients with Leber hereditary optic neuropathy: A retrospective study

Purpose: This study was conducted to estimate the visual acuity improvement in patients with Leber hereditary optic neuropathy (LHON) with the help of low vision devices (LVDs) and to analyze the types of distant and near LVDs prescribed to the patients with LHON. Methods: A retrospective case review of 74 subjects with LHON who were referred to a low vision care clinic at a tertiary eye center from 2016 to 2019 were recruited. The reason for referral was assessed from the patients’ electronic medical records (EMR). Demographic data of the patients, visual acuity status, type of LVD prescribed, and visual acuity improvement with LVD were documented. Results: Out of 74 patients, 91.9% (n = 68) were male, and the median age of patients was 21 (16) years. A 4× monocular telescope was prescribed for 2.7% of patients (n = 2) and SEETV binocular telescope for 1.4% (n = 1) was advised for distance. The most commonly prescribed near LVD was the 6× cutaway stand magnifier for 22 patients (29.7%). Four patients (5.4%) were prescribed with Notex, the most commonly prescribed non?optical LVD. Niki CCTV (12.2%, n=9) was the most commonly prescribed assistive device. The subjects were divided into three groups based on age: group I consisted of those <18 years of age, group II 18–40 years, and group III >40 years for the interpretation of visual improvement. There was a statistically significant improvement (group I: P < 0.001, group II: P < 0.0001, group III: P < 0.003) in near vision with help of LVDs in all three groups. Conclusion: The use of LVDs and rehabilitation can help patients with LHON to lead a better life and will be more beneficial

Research progress of risk factors of Leber’s hereditary optic neuropathy / 中华眼底病杂志

Leber’s hereditary optic neuropathy (LHON) is a paradigm maternal hereditary eye disease, mainly involving the retinal and macular fibers of the optic disc in the anterior ethmoid plate of the sclera. LHON has the characteristics of sex bias among males and incomplete penetrance. Primary mitochondrial DNA mutations m.11778G>A, m. 14484T>C, m.3460G>A are the molecular basis of LHON. However, other risk factors, such as secondary mitochondrial DNA mutations, mitochondrial haplotypes, nuclear modification genes, estrogen, vitamin B12 and environmental factors, work together to affect its phenotypic expression. The clinical diagnosis of LHON mainly limited to the detection of the primary mutation site of mitochondrial DNA. Therefore, comprehensive analysis of multiple risk factors of LHON will facilitate to construct multi-dimensional model of prevention, diagnosis and treatment system, which provide accurate and individualized medical services for patients. These may alleviate the incidence in LHON families. It also provides new ideas and different angles for the in-depth study of the pathogenesis of LHON.

Analysis of retinal sublayer thickness in Leber hereditary optic neuropathy and G11778A mutation carriers / 中华眼底病杂志

Objective:To analyze the thickness of peripapillary retinal nerve fiber layer (pRNFL) and photoreceptor (PR) sublayer in Leber hereditary optic neuropathy (LHON) and G11778A mutation carriers. Methods:A cross sectional study. From September 2020 to October 2021, 68 LHON patients (136 eyes) (patient group) and 40 G11778A mutation carriers (80 eyes) of LHON patients' families (carrier group) were included in the study. All patients were found to have G11778A mutation by Genetic testing. Forty healthy volunteers with 80 eyes matched to the age and gender of the patient group were recruited as a normal control group. All eyes were examined by optical coherence tomography (OCT). The pRNFL thickness was automatically measured by the built-in software of the OCT device. The total retinal thickness (MT) and the thickness of the outer bundle layer (OPL), outer nuclear layer (ONL), external limiting membrane to retinal pigment epithelium (ELM-RPE) in macular OCT images were measured by Image J software. Linear mixed model was used to analyze and compare the thickness of pRNFL, macular fovea and four layers above the nasal and temporal paracentral retina in patients, carriers and normal controls. The correlation between pRNFL and macular retinal sublayer thickness and the course of disease was also analyzed. Results:The thickness of the upper and lower pRNFL, temporal pRNFL and average pRNFL of the patients were smaller than those of the carriers and the normal control group ( P<0.01), and the nasal pRNFL thickness of the patients was smaller than that of the carriers ( P<0.01). Fovea: compared with the normal control group, the thickness of MT and ONT in the patient group was decreased, ONL thickness decreased in carrier group, with the significant different ( P<0.05). Parafovea: compared with normal control group, the thickness of MT and temporal ONL decreased and temporal OPL increased in the patients group, with the significant different ( P<0.05). In the carrier group, the thickness of MT and temporal, nasal ONL decreased, and the thickness of nasal OPL increased, with the significant different ( P<0.05). Compared with the carrier group, the MT thickness of the patient group was decreased, and the nasal ONL and nasal ELM-RPE thickness were increased, with the significant different ( P<0.05). Correlation analysis results showed that the thinning of pRNFL in the superior, nasal, temporal and average ( r=-0.22, -0.21, -0.25, -0.22), and the thickening of ELM-RPE in foveo-temporal ( r=0.19) were correlated with the course of disease ( P<0.05). Conclusions:The pRNFL of LHON patients with G11778A mutation becomes thinner and is related to the course of the disease. There were significant differences in the thickness of MT and PR sublayers between patients and carriers compared to the normal control group.

Gene therapy for Leber hereditary optic neuropathy / 中华眼底病杂志

Leber hereditary optic neuropathy (LHON) is a matrilineal hereditary optic neuropathy in which mitochondrial DNA mutations lead to retinal ganglion cell degeneration. At present, the treatment for LHON is limited. Early symptomatic treatment and medical treatment may improve the vision of patients. In recent years, rapid progress has been made in gene therapy. Many clinical studies have confirmed its safety and efficacy. Monocular gene therapy is helpful to improve the visual function of LHON patients, and it can also improve the visual acuity of uninjected eyes. Patients do not have serious eye or systemic adverse events during the treatment period, showing good safety and tolerance. Studies with larger sample size and longer follow-up time are needed to further verify the efficacy and safety of gene therapy in the future. Gene therapy is expected to become a safe and effective treatment, bringing hope to LHON patients.

Electroretinogram changes in patients and carriers with Leber hereditary optic neuropathy / 中华眼底病杂志

Objective:To observe the characteristics of pattern electroretinogram (PERG) and the photopic negative response (PhNR) of flash electroretinogram (FERG) in patients and carriers with Leber hereditary optic neuropathy (LHON).Methods:A cross sectional, observational study. Thirty-two patients (64 eyes) diagnosed with LHON (LHON group) and 15 normal members with the same mutation in patient's family (carrier group) were included in this study from February 2021 to November 2021 in the Department of Ophthalmology of Renmin Hospital of Wuhan University. All patients in LHON group were males (100.0%, 32/32) and the average age was 23.34±7.41 years. In the carrier group of 15 cases (30 eyes), there were 2 males (13.3%, 2/15) and 13 females (86.7%, 12/15). The average age was 43.44±7.65 years. Twenty-four healthy subjects (48 eyes) in the same period were selected as the control group. Among them, there were 8 males (33.3%, 8/24) and 16 females (66.7%, 16/24). The average age was 23.42±2.54 years. All subjects were examined with the GT-2008V-VI visual electrophysiology instrument of Chongqing Gotec Medical Equipment Limited Company for PERG and FERG. P50 and N95 amplitudes of PERG and PhNR, a wave and b wave amplitudes of FERG were recorded. The peripapillary retinal nerve fiber layer (pRNFL) thicknesses of the nasal, superior, temporal, inferior and average quadrants were measured by spectral domain optical coherence tomography (SD-OCT). The amplitudes of a wave, b wave, PhNR, P50 wave, N95 wave and pRNFL thickness between the three groups were compared by one-way ANOVA. Pearson correlation analysis was used to analyze the correlation between different parameters.Results:Compared with the control group, the amplitudes of PhNR in LHON group and carrier group decreased significantly ( F=11.973, P<0.001). The results of correlation analysis showed that the amplitude of PhNR in LHON group was significantly correlated with the thickness of nasal and temporal pRNFL ( r=0.249, 0.272; P=0.048, 0.030). There was no significant difference in P50 wave amplitude between patients, carriers and controls ( F=1.342, P=0.265). There was no significant difference in N95 wave amplitude between patients and controls ( P=0.960). Conclusion:The PhNR amplitudes of FERG in LHON patients and carriers decrease significantly compared to controls.

Efficacy evaluation of intravitreal injection of rAAV2- ND4 gene for Leber hereditary optic neuropathy / 中华实验眼科杂志

Objective:To evaluate the safety and clinical effect of gene therapy for Leber hereditary optic neuropathy (LHON).Methods:A multi-center prospective non-randomized controlled trial was conducted.Eighty eyes of 40 LHON patients with mitochondrial DNA 11778 mutation were enrolled in Taihe Hospital from December 2017 to February 2018.Intravitreal injection of recombinant adeno associated virus 2-NADH dehydrogenase 4 (rAAV2- ND4) was carried out in the unilateral eye with worse visual acuity or the right eye (if the visual acuity of both eyes was equal) of each subject as the treated group and the fellow eyes as the untreated group.The best corrected visual acuity (BCVA) was detected using a standard logarithmic chart and intraocular pressure (IOP) was measured with a non-contact tonometer before treatment and 1, 3, 6, 12 months after treatment.The manifestations of the ocular anterior segment and fundus were examined by slit lamp microscopy and color photography.The changes of visual acuity and IOP before and after gene therapy were compared, and complications were evaluated between the treated group and the untreated group.The effective rate defined as visual acuity improved ≥0.3 LogMAR at the end of follow-up was assessed.This study adhered to the Declaration of Helsinki and the study protocol was approved by an Ethics Committee of Taihe Hospital (No.201807). Written informed consent was obtained from each subject prior to any medical examination and treatment. Results:The visual acuity improved 6 eyes in the treated group and 4 eyes in the untreated group, and 13 patients showed bilateral improvement.The visual acuity improvement ≥0.3 LogMAR in 23 patients with the effective rate 57.5%.The BCVA was (1.51±0.62) LogMAR and (1.62±0.58) LogMAR at the end of following-up in the untreated group and treated group, respectively, which were significantly higher than (1.75±0.46) LogMAR and (1.83±0.47) LogMAR before treatment (both at P<0.01), and no significant difference was found in BCVA between the two groups ( Fgroup=0.084, P=0.772). There was no significant difference in IOP between the two groups before and after treatment ( Fgroup=0.557, P=0.575; Ftime=2.314, P=0.106). No serious complications were found in all subjects during following-up. Conclusions:rAAV2- ND4 gene therapy is safe and effective for LHON, and binocular vision can be improved by monocular intravitreal injection of rAAV2- ND4 gene.

Correlation between retinal nerve fiber layer thickness and visual prognosis in patients of Leber Hereditary optic neuropathy with 11778 mutation / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To study the correlation between retinal nerve fiber layer(RNFL)thickness changes and long-term visual function in Leber hereditary optic neuropathy(LHON)patients with 11778 mutations, and evaluate the role of early RNFL thickness in predicting long-term visual function.<p>METHODS: A retrospective analysis with 44 eyes from 23 LHON patients who were diagnosed with 11778 G>A/ND4 mutations by mt-DNA sequencing were included. The patients were divided into two groups based on whether BCVA is above LogMAR 0.5(equivalent to 0.3 decimal,WHO Low Vision standard)or not at 30mo follow up. Then, when the RNFL data of the two groups of patients at each predetermined time point(course of disease)were obtained, the candidate cutoffs of RNFL thickness were obtained by comparing the mean RNFL thicknesses of the two groups. Based on the obtained candidate cutoff values, the eyes with different RNFL values were divided into two groups for statistical analysis to determine whether the cutoff values can be used to predict prognosis of BCVA and visual field. Finally, the earliest cutoff value of RNFL thickness that can predict both BCVA and visual field is the target value. <p>RESULTS: According to the distribution of mean RNFL values in the eyes of patients with different BCVA groups, the candidate cut-off values of RNFL were determined as: 130μm after 2mo, 100μm after 4mo, 80μm after 8mo, and 65μm after 12mo from onset. Further analysis revealed that the RNFL value exceeds 80μm of 8mo after onset can be a better cutoff value to distinguishes the long-term vision, and which can predict both MD and MS of visual field with good distinction(all <i>P</i><0.05). It was found that the long-term BCVA of 100% of the eyes with RNFL values less than 80μm after 8 months from onset was lower than LogMAR 0.5(equivalent to 0.3 decimal); while for eyes with RNFL thickness higher than 80μm after 8mo from onset, 31% of patients had vision greater than LogMAR 0.1(equivalent to 0.8 decimal), and only 34% of patients had long-term prognosis of low vision. In addition, the BCVA, MD and MS of visual field of the eyes with RNFL value exceeded 80μm were significantly better than those with eyes with RNFL less than 80μm.<p>CONCLUSION: In this study, whether the RNFL value exceeded 80μm after 8mo from onset can be used as the best predictive cut-off value for judging long-term BCVA and visual field.

A Case of Leber Hereditary Optic Neuropathy Showing Optic Disc Hyperfluorescence

PURPOSE: We report an unusual case of Leber hereditary optic neuropathy presenting with optic disc hyperfluorescence. CASE SUMMARY: A 17-year-old male with sequential painless visual loss 3 weeks apart affecting first the left and then the right eye presented to our neuro-ophthalmology clinic. His best-corrected visual acuity was counting fingers in the right eye and 0.32 in the left eye. Fundus examination showed mild optic disc edema and hyperemia in both eyes, which were worse in the right eye. Fluorescein angiography revealed dye leakage from the right optic disc in the late phase. The results of magnetic resonance imaging of the brain and spinal cord were normal, and lumbar puncture study was unremarkable. Mitochondrial DNA sequencing revealed a pathognomonic 11778 mutation for Leber hereditary optic neuropathy. His vision deteriorated to 0.03 in both eyes 6 months later, but slowly started to improve 11 months after onset. At 2 years, his corrected visual acuity was 0.2 in both eyes. CONCLUSIONS: To our knowledge, this is the first report of optic disc hyperfluorescence in Leber hereditary optic neuropathy. This finding suggests that this mitochondrial optic neuropathy can masquerade as optic neuritis.

Recent advances in treatment of Leber's hereditary optic neuropathy / 眼科新进展

Leber's hereditary optic neuropathy (LHON) is an inherited mitochondrial disorder characterized by bilateral progressive vision loss.Current management includes therapies directed at enhancing mitochondrial function and preventing oxidative damage.This article reviews the progress of treatments from mitochondria cocktail,idebenone,gene therapy,EPI-743,brimonidine,traditional Chinese medicine and physical therapy,providing a new insight in the treatments of LHON.

Mutation analysis of a Chinese pedigree of Leber hereditary optic neuropathy with only male patients / 中华实验眼科杂志

Background Leber hereditary optic neuropathy (LHON) is a maternally inherited disorder characterized by a bilateral acute or subacute painless central visual loss in young adults,predominately in males.So far no one theory can completely explain all clinical manifestations of LHON.Objective This study was to investigate whether there is a linkage between X-chromosomal and mitochondrial mutation in the inheritance of a Chinese LHON pedigree with only male patients.Methods This study was approved by Ethic Committee of Affiliated First Hospital of Zhengzhou University and followed by Declaration of Helsinki.A Chinese LHON pedigree was included in Anyang city from January 2008 to August 2016.Periphery blood of 5-10 ml was collected from 4 sufferers,13 maternal members and 10 non-maternal members for DNA extraction and PCR sequencing.The gene scanning and genotyping analysis were performed by ABI-PRISM 3100 genetic analyzer and Genotyper 3.7 software,and linkage analysis was carried out with Linkage software for the calculation of logarithm of odds (LOD).Mitochondrial DNA (mtDNA) sequence,fluorescence-based Genescan for X-chromosomal sequence were analyzed in the propositus and haplotype was evaluated.Results A total of 5 generations and 71 families were included in the pedigree,with 6 male sufferers,30 maternal members and 41 non-maternal members.The visual acuity was ≤0.10,and the central visual field defection,the optic nerve flushing was found in the acute phase,different levels of the optic nerve fibers atrophy were found in the chronic phase;visual evoked potential (VEP) amplitude was low and peak latency were found in the male patients,and no any ocular abnormality was seen in the maternal members,meeting a maternally inherited characteristics,with the penetranee of 20％.The three primnary mutations were not been found in this family bv PCR sequencing,mtDNA sequencing appeared 31 variation of loci in the proband,including a known G3635A mutation,as well as an unknown ND5 A12340G missense mutation and ND4 T11809C synonymous mutation as well as 28 polymorphism of locus,and the proband was mitochondrial haplotype F1.The maternal families were mutation carriers of G3635A and AI2340G loci,while the same mutation was not found in the normal family members and 107 controls.The maximum two point parametric LOD score was 1.46(θ=0.0) for marker DXS1060,1oeated at Xp22.3,and the two-point and multipoint non-parametric linkage analysis were significant (all at P＞0.05).Conclusions The ND5 A12340G and ND1 G3635A mutations coexist in this LHON family,and the ND5 A12340G mutation is a newly reported mutation.There is no evidence for an X-linked modifiers loci in this Chinese LHON family.

Use of Idebenone for the Treatment of Leber's Hereditary Optic Neuropathy

Abstract Leber's hereditary optic neuropathy (LHON) is one of the most frequent mitochondrial disorders. It is caused by mutations in genes of the mitochondrial DNA coding for subunits of the respiratory chain and leads to severe bilateral vision loss, from which spontaneous recovery is infrequent. Retinal ganglion cells show a selective vulnerability to mitochondrial dysfunction in LHON. Idebenone is the first medication approved for LHON. It is a short-chain benzoquinone, which is an analogue of coenzyme Q10, but with distinct properties and mechanisms of action. Idebenone is a potent antioxidant and inhibitor of lipid peroxidation. Importantly, it facilitates electron flux directly to complex III, bypassing the dysfunctional complex I of the mitochondrial respiratory chain, thereby increasing adenosine triphosphate (ATP) production. In the Rescue of Hereditary Optic Disease Outpatient Study (RHODOS) randomized placebo-controlled clinical trial, 85 patients with LHON were enrolled, in the first 5 years after symptom onset, and randomized to either idebenone 900 mg/d for 6 months or placebo. Idebenone was well tolerated, and although the prespecified primary end point (best recovery in visual acuity [VA]) did not reach statistical significance, all secondary end points (change in best VA, change of VA of best eye at baseline, and change of VA in all eyes) showed a trend toward visual recovery in favor of idebenone. An increasing body of evidence shows that idebenone is effective and safe for the treatment of patients with LHON, including a large retrospective open-label study, several case reports and case series, an expanded access program, and ongoing post-authorization clinical studies. Here, we review the literature on idebenone for the treatment of patients with LHON.

A Case of Atypical Leber Hereditary Optic Neuropathy Associated with MT-TL1 Gene Mutation Misdiagnosed with Glaucoma

PURPOSE: Leber hereditary optic neuropathy (LHON) is one of the most common hereditary optic neuropathies caused by mutations of mitochondrial DNA. Three common mitochondrial mutations causing LHON are m.3460, m.11778, and m.14484. We report a rare mutation of the mitochondrial tRNA (Leu [UUR]) gene (MT-TL1) (m.3268 A > G) in a patient with bilateral optic atrophy. CASE SUMMARY: A 59-year-old female diagnosed with glaucoma 3 years earlier at a community eye clinic presented to our neuro-ophthalmology clinic. On examination, her best corrected visual acuity was 0.4 in the right eye and 0.7 in the left eye, and optic atrophy was noticed in both eyes. Optical coherence tomography revealed retinal nerve fiber layer (RNFL) thinning in both eyes; average RNFL thickness was 52 µm in the right eye and 44 µm in the left eye, but the papillomacular bundle was relatively preserved in both eyes. Goldmann perimetry demonstrated peripheral visual field defects, mostly involving superotemporal visual field in both eyes. Mitochondrial DNA mutation test showed an unusual mutation in MT-TL1 gene seemingly related to this optic neuropathy. CONCLUSIONS: We found a rare mutation (m.3268 A > G) of the mitochondrial DNA in a patient having bilateral optic atrophy, which led to the diagnosis of LHON. There have been previous reports about mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and infantile myopathy caused by MT-TL1 mutation, but this is the first case of LHON associated with the same mutation. In this case of LHON associated with MT-TL1 mutation, atypical clinical features were observed with a relatively mild phenotype and peripheral visual field defects.

Clinical phenotype and maternal mutation analysis of Leber hereditary optic neuropathy / 中华实验眼科杂志

Background Leber hereditary optic neuropathy (LHON) is a maternally inherited disease caused by mitochondrial DNA (mtDNA) mutation with the common mutation sites of m.3460 G＞A,m.11778 G＞A and m.14484 T＞C,and other mutation sites are rare.Understanding the mutation type of mtDNA in LHON patients has an important clinical significance.Objective This study was to analyze the clinical features of LHON and detect the mitochondrial mutation.Methods Twelve unrelated Chinese patients who was diagnosed as LHON were included in Peking University People's Hospital from 2010 to 2014.The visual acuity,perimetry,ocular segment,visual evoked potential,fundus were binocularly examined.The peripheral blood of 4 ml was collected from each patient and mtDNA was amplified and sequenced by using PCR.Three common genetic mutation sites for LHON and other mutation sites were determined and analyzed.This study protocol was approved by Ethic Committee of Peking University People's Hospital and complied with Helsinki Declaration.Written informed consent was obtained from each patient prior to any medical examination.Results Of the 12 patients,11 were male and 1 was female.The visual acuity of both eyes reduced simultaneously in 7 patients,and the visual acuity of left eye and the right eye first reduced in 3 patients and 1 patient,respectively.There was no significant correlation in the visual impairment between the left and right eyes (P＞0.05).In the near vision of the patients,J7 was invisible in 18 eyes,and J7 were obtained in 3 eyes,J6 were obtained in 2 eyes and J2 was obtained in 1 eye.In the distant vision of the patients,hand movement was obtained in 1 eye,light perception was obtained in 1 eye,0.01-0.1 were obtained in 18 eyes and 0.12-0.3 were obtained in 2 eyes.The visual field defect of nasal lateral was found in 7 eyes,visual field defect of temporal lateral was found in 3 eyes and the visual field defect of central was found in 8 eyes.mtDNA sequencing revealed that m.3460 G＞A mutation was seen in 3 patients,m.11778 G＞A mutation was seen in 5 patients and m.14484 T＞C mutation was seen in 2 patients.In addition,other 2 mutations were found in 2 patients,which were m.3497 C＞T and m.10663 T＞C mutations at the MT-ND1 and MT-ND4L genes,respectively.Conclusions LHON is more common in male.Visual impairment shows the varying degrees between both eyes of patients and appears to be severe in near vision.Central visual field defect is common in LHON patients.This study detects m.3497 C＞T and m.10663 T＞C mutation in Chinese LHON patients.

Clinical feature of 9 patients harboring mtDNA G11778 A mutation with Leber hereditary optic neuropathy / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To evaluate the clinical feature of 9 patients harboring mitochondrial DNA ( mtDNA ) G11778A mutation with Leber hereditary optic neuropathy ( LHON) . ●METHODS: Nine LHON patients were enrolled and followed- up between 2012 to 2015 in Shenzhen Eye Hospital, clinical data were collected and analyzed. ●RESULTS: Six cases had maternal inheritance history ( 67%) . Three were sporadic cases. The patients aged from 9 to 43 years old, with average age of (22. 00±9. 42) years. Simultaneous onset with both eyes was in 5 cases (56%). Successively onset was in other 4 cases (44%). The ratio between male and female was 2:1. In the last follow-up, the visual acuity was finger counted in 2 eyes (11%), 0. 01-0. 1 in 12 eyes (67%), 0. 12-0. 4 in 2 eyes (11%),≥0. 4 in 2 eyes (11%). All patients had pale disc and clear boundary. ln the Humphrey visual field examination, 10 eyes had typically cecocentral or paracentral scotoma, 8 eyes had diffuse visual field defect. ●CONCLUSION: ln the 9 LHON patients with mtDNA G11778A mutation, simultaneous onset cases were more than successively onset cases within 1y cases. In most cases, LHON patients kept stable visual acuity. Rare cases had a raise in visual acuity within 1y. Majority patients had typically cecocentral or paracentral visual field scotoma. In the last stage of LHON, visual field present diffused defect. The secondary affected eye was similar performed defect as the former one.

Research progress of Leber hereditary optic neuropathy / 中华实验眼科杂志

Leber hereditary optic neuropathy (LHON) is one of the most common maternally transmitted hereditary retinal diseases,which is mainly caused by one of the three point mutations in mitochondrial DNA(mt DNA) (G11778A,G3460A and G14484C).LHON is characterized by painless,acute or sub-acute bilateral visual loss in young men with central scotoma.Incomplete dominance and gender bias are two puzzles of this disease.Although currently there is no effective therapy to prevent or cure the LHON,the ongoing clinical trials of gene therapy have showed initial success in some LHON patients with G11778A mutation.Here we summarized recent research progress of LHON,focusing on the clinical features,molecular and pathogenic mechanisms,animal models,and gene therapy of it.

Effect of environmental factors on Leber hereditary optic neuropathy / 中华实验眼科杂志

Leber hereditary optic neuropathy (LHON) is a maternally inherited disorder associated with mitochondrial DNA (mtDNA) mutations.In the LHON families in different ethnic backgrounds,the mutations of ND1 G3460A,ND4 G11778A and/or ND6 T14484C in the genes encoding subunits of respiratory chain complex Ⅰ account for more than 50％.But,as we know,the phenotypes of mitochondrial diseases are varied,so the same mutational points may generate different clinical phenotypes,and conversely,different mtDNA mutation variants may generate the similar phenotypes.Some states of LHON including the prone to male,incomplete penetrance,and phenotypic variability of vision loss suggest that other modifier factors probably play a synergic role in the development of LHON.Environmental factor,such as chronic cyanide poisoning,smoking,drinking,trauma,nutrition deficiency and mtDNA methylation,affects mitochondrial function.Therefore,there is an inheritance of gene and environment interactions affecting LHON.

The relationship of visual prognosis and G11778A point mutation in Leber hereditary optic neuropathy / 中华实验眼科杂志

Background Leber hereditary optic neuropathy (LHON) is a disease characterized by maternal inheritance.A number of mitochondrial DNA (mtDNA) mutation has been thought to be associated with this disease.Objective This study was to investigate the clinical and molecular genetic properties of LHON in two Chinese families.Methods Forty subjects from two Chinese families with LHON were enrolled in Affiliated First Hospital of Zhengzhou University,including 28 maternal members (10 of these members are LHON and 12 controls from two families.All the participants had a complete ophthalmic examination including visual acuity,direct ophthalmoscopy,color sensation and visual evoked potentials.MtDNA was extract from the whole blood sample of all participants.PCR-DNA sequencing was performed to detect the point mutation of the G11778A,T14484C,and G3462A for each subject.Written informed consent was obtained from each subject prior to this study.Results Only G11778A point mutation was identified in all 28 maternal members from the two families.No point mutation of G11778A was identified in non-maternal members,and no point mutation of the T14484C and G3462A were found in the two families.Conclusions The inherited pattern of these two families shows typical clinical and genetic features of LHON.LHON patients with G1 1778A mutation have a poor prognosis of visual acuity.

Analysis of retinal nerve fiber layer thickness and macular thickness in unaffected female carrier of Leber hereditary optic neuropathy / 中华实验眼科杂志

Background Researches documented that retinal nerve fiber layer thickness (RNFLT) in unaffected carriers of Leber hereditary optic neuropathy (LHON) becomes thickened in different quadrants to different degrees.But the change of their macular thickness is still unclear.Objective This study was to clarify RNFLT and macular thickness by optical coherence tomography (OCT) in unaffected female carriers of LHON families.Methods Five female LHON patients (5 eyes) from 5 LHON families,eighteen unaffected female carriers (18eyes) from 18 LHON families and twenty-five age-matched healthy female controls (25 eyes) were included in this study.The patients and genetic carriers were diagnosed in PLA General Hospital from 2011 September to 2012 October.Regular ocular examination were performed followed by OCT measurement of retinas.The Optic Disc Cube 200×200 and Macular Cube 200×200 protocols were used during the OCT measurement.Average (360°) RNFLT,RNFLT at four quadrantic sections,cube average macular thickness and macular thickness of nine Early Treatment Diabetic Retinopathy Study (ETDRS) sub-areas were compared among the LHON genetic carriers,LHON patients and normal controls.Results Compared to the normal control group,significant reduced values were seen in temporal,superior,nasal and inferior side of sub-area macular thickness in the LHON female carriers (P=0.022,0.046,0.024,0.008).In addition,but no significant differences were found in cube average thickness,central subarea macular thickness,temporal,superior,nasal and inferior side of lateral sub-area macular thickness,average RNFLT,and temporal,superior,nasal and inferior quadrant RNFLT between the LHON female carriers and normal controls (P=0.102,0.051,0.238,0.663,0.1 10,0.104,0.419,0.371,0.158,0.063,0.563).Compared to the unaffected female carrier group,female patients showed significant reductions in cube average macular thickness,temporal,superior,nasal and inferior side of sub-area macular thickness,temporal,superior,nasal and inferior side of lateral sub-area mac ular thickness,average R NFLT and temporal,superior,and inferior quadrant RNFLT (P =0.000,0.000,0.000,0.007,0.002,0.002,0.000,0.000,0.040,0.000,0.016,0.000,0.000) except for the central subarea macular thickness and nasal quadrant RNFLT (P=0.388,0.580).Conclusions Unaffected LHON female carriers show a normal peripapillary RNFLT,but the macular thickness at medial sub-area is thinner.This first report offers an information of macular structure change in unaffected LHON female carriers,which suggest that macular damage appears prior to RNFLT change.

Study on real-time probe technique detecting mtDNA 11778 point mutation in Leber hereditary optic neuropathy patients / 中华实验眼科杂志

Background Although Leber hereditary optic neuropathy (LHON) and optic neuritis have different causes and managements,their clinical manifestations are difficult to be distinguished.Real-time fluorescence quantitative polymerase chain reaction(RTFQ-PCR) is a high flux,simple,rapid and specific detecting technology,so establishing a specific diagnosis method of LHON with RTFQ-PCR has a practical significance.Objective Purpose of the present study was to establish a real-time Taqman probe for mitochondrial DNA (mtDNA)11778G＞A mutation in LHON patients.Methods Primers and Taqman probe for mtDNA 11778G＞A mutation were designed based on mtDNA complete geneme.Eighty-four patients with LHON were selected from the LHON DNA bank of Molecular Biology Laboratory,Henan Eye Institute,and 40 normal physical examinees aged 18-20 years were from Henan People's Hospital.2 ml of periphery blood was collected from each individual.Based on the double-blindness principle,mtDNA 11778G＞A mutation was tested by both Taqman probe and sequencing to check the reliability of real-time Taqman probe.Results The mtDNA 11778G＞A mutation was found in 23 out of 84 patients,and 61 showed a negative result by the technique of real-time Taqman probe.The Ct values of 23 patients with mtDNA 11778G＞A mutation were 22.993 ±0.708,but those of 5 normal controls were 0.These findings showed a consistent rate of 100％ with the sequencing results.In addition,both the false positive rate and the false negative rate were zero.Conclusions Real-time Taqman probe technique is an accurate,convenient,sensitive,specific and intuitionistic method for the diagnosis of mtDNA 11778G＞A mutation in LHON patients.It is feasible and suitable to screen the LHON patients with mtDNA 11778G＞A mutation in a large scale.