Leber's Hereditary Optic Neuropathy mtDNA Mutations Research Articles

Non-Pharmaceutical Interventions against COVID-19 Causing a Lower Trend in Age of LHON Onset.

Leber hereditary optic neuropathy (LHON) is a monogenic but multifactorial disease vulnerable to environmental triggers. Little is known about how LHON onset changed during the COVID-19 pandemic and how non-pharmaceutical interventions (NPHIs) against COVID-19 impact LHON onset. One hundred and forty-seven LHON patients with the m.11778G>A mutation complaining of vision loss were involved between January 2017 and July 2022. The onset time points, age of onset, and possible risk factors were evaluated. Analyses were conducted among 96 LHON patients in the Pre-COVID-19 group and 51 in the COVID-19 group. The median (IQR) age of onset decreased significantly from 16.65 (13.739, 23.02) in pre-COVID-19 to 14.17 (8.87, 20.29) during COVID-19. Compared with the Pre-COVID-19 group, the COVID-19 group exhibited bimodal distribution with an additional peak at six; the first quarter of 2020 also witnessed a relatively denser onset, with no subsequent second spike. NPHIs against COVID-19 significantly changed patients' lifestyles, including higher secondhand smoke exposure (p < 0.001), adherence to masks (p < 0.001), reduction in time spent outdoors for leisure (p = 0.001), and prolonged screen time (p = 0.007). Multivariate logistic regression revealed that secondhand smoke exposure and mask-wearing were independent risk factors of younger LHON onset. Lower age of onset of LHON appeared after the breakout of the COVID-19 pandemic, and novel risk factors were detected, including secondhand exposure and long mask-wearing. Carriers of LHON mtDNA mutations, especially teenagers or children, should be advised to avoid secondhand smoke exposure and there are possible adverse outcomes of longer mask-wearing.

Mitochondrial optic neuropathies (MON)

AbstractWhen we first proposed the term, Mitochondrial Optic Neuropathies (MON) (Sadun AA. Mitochondrial optic neuropathies. J Neurol Neurosurg Psychiatry. 2002 Apr;72(4):423–5.), it may have seemed odd. The paradigm before then was that many things could injure the optic nerves, and genetic, nutritional and many toxic causes made the list alongside tumours, infections, inflammations, etc. Our experiences in Cuba changed this mode of thinking. There, an epidemic of optic neuropathy (CEON) was found to exist among those consuming small amounts of methanol in the presence of folic acid deficiency. This demonstrated the convergence of toxic and nutritional causes that affected the same (oxidative‐phosphorylation) systems. Several publications have demonstrated that certain metabolic optic neuropathies are more likely in the setting of genetic predispositions. In short, asymptomatic carriers of well characterized genetic disorders such as Leber's Hereditary Optic Neuropathy (LHON), may lose vision when additionally stressed by exposures to certain drugs like ethambutol or to nutritional deficiencies. Several studies have revisited the original diagnosis of tobacco‐alcohol amblyopia (their term) and found about 20% harboured LHON mtDNA mutations (Cullom, et al., Arch Ophthalmol. 1993 Nov;111(11):1482–5).We hereby present a framework for seeing many forms of metabolic (hereditary, nutritional and toxic) optic neuropathies as related. One unifier is the stereotypic clinical presentation. These patients have, after a while, very symmetric visual losses. The loss of visual acuity, colour vision, and high spatial frequency contrast sensitivity, reflects a pair of symmetrical central or cecocentral scotomas. These aforementioned functional defects are to be expected by the equally characteristic anatomical loss of the small fibres of the papillo‐macular bundle (PMB) which also explains the temporal optic disc pallor. The other unifier is that the molecular injuries cause impairments of mitochondria, and specifically oxidative phosphorylation (Ox‐Phos). We and others have further demonstrated that this especially entails the accumulation of reactive oxygen species (ROS) more than a problem with bioenergetics. This also explains the particular predilection for injury of the smallest and unmyelinated fibres of the PMB.Several drugs are causes or additional risk factors in MON. Remarkably, most drugs that are best demonstrated to injure the optic nerve are also understood to impair mitochondria and Ox‐Phos. These include ethambutol and linezolid, chloramphenicol, streptomycin, and some antivirals (Wang and Sadun, J Neuroophthalmol. 2013 Jun;33(2):172–8). These drugs can also be regarded, in addition to heavy smoking and binge drinking of alcohol, as exogenous sources of ROS that are likely to bring out Type II LHON (vs Type I LHON which is apt to be genetic/genetic, and occurs at an early age more acutely).In general, MON represent the unique susceptibility of the optic nerve, and most specifically, the small fibres of the PMB, to the ROS that are generated when mitochondrial Ox‐Phos is defective. When the ROS threshold is exceeded, these fibres are the first to decompensate and this leads to a remarkably consistent phenotype.

Analysis of the entire mitochondrial genome reveals Leber’s hereditary optic neuropathy mitochondrial DNA mutations in an Arab cohort with multiple sclerosis

Several mitochondrial DNA (mtDNA) mutations of Leber's hereditary optic neuropathy (LHON) have been reported in patients with multiple sclerosis (MS) from different ethnicities. To further study the involvement of LHON mtDNA mutations in MS in the Arab population, we analyzed sequencing data of the entire mitochondrial genome from 47 unrelated Saudi individuals, 23 patients with relapse-remitting MS (RRMS) and 24 healthy controls. Ten LHON mutations/variants were detected in the patients but were absent in the controls. Of them, the common primary pathogenic mutation m.14484T>C and the rare mutation m.10237T>C were found in one patient, whereas the rare mutation m.9101T>C was found in another patient. The remaining were secondary single nucleotide variants (SNVs) found either in synergy with the primary/rare mutations or individually in other patients. Patients carrying LHON variants also exhibited distinct mtDNA variants throughout the mitochondrial genome, eight were previously reported in patients with LHON. Moreover, five other LHON-related SNVs differed significantly in their prevalence among patients and controls (P < 0.05). This study, the first to investigate LHON mtDNA mutations/variants in a Saudi cohort may suggest a role of these mutations/variants in the pathogenesis or genetic predisposition to MS, a possibility which needs to be explored further in a large-scale.

TaqMan-MGB probe quantitative PCR assays to genotype and quantify three mtDNA mutations of Leber hereditary optic neuropathy

Leber hereditary optic neuropathy (LHON) is a degenerative disease of the optic nerve associated with one of three mitochondrial DNA (mtDNA) m.3460G>A, m.11778G>A and m.14484T>C mutations. Although several procedures are available to genotype these mutations, quantitative approaches with rapid, low-cost and easy to handle advantages for three LHON mtDNA mutations are rarely reported. Here, we firstly developed a “one-step” tetra-primer amplification-refractory mutation system (T-ARMS) PCR for qualitative genotyping of three LHON mtDNA mutations. Subsequently, we established single, duplex and triplex TaqMan MGB probe-based fluorescence quantitative PCR (qPCR) assays to perform both qualitative and quantitative analyses of three LHON mtDNA mutations. Standard curves based on tenfold diluted plasmid standard exhibited high specificity and sensitivity, stable repeatability and reliable detectable ability of TaqMan probe qPCR assays without cross-reactivity upon probes combination. Moreover, by comparing with SYBR Green qPCR, we further validated the feasibility of the triplex-probe qPCR assay for the quantitative detection of mtDNA copy number in blood samples. In conclusion, our study describes a rapid, low-cost, easy to-handle, and high-throughput TaqMan-MGB probe qPCR assay to perform both qualitative and quantitative analysis of three primary LHON mtDNA mutations, offering a promising approach for genetic screening and testing of LHON mutations.

Cardiac Disorders in Patients With Leber Hereditary Optic Neuropathy.

Cardiac abnormalities have been described in patients with Leber hereditary optic neuropathy (LHON). Some are life-threatening because of the risk of ventricular fibrillation and sudden death. The purpose of our study was to better characterize the cardiac abnormalities in a large patient cohort with LHON. A retrospective study of the electrocardiogram (EKG) results performed on all patients with LHON evaluated at The Reference Center for Rare Diseases in Ophthalmology, Paris, France, from January 2015 to June 2017. Our series included 73 patients with LHON (9 women/64 men) with a mean age of 30.29 ± 14.48 years. Although only 1 patient had cardiac complaints, cardiac abnormalities were detected in 17 patients (23.2%): 9 patients had an excitation syndrome, 6 had atrioventricular block, and 2 had repolarization abnormalities. All patients harbored mtDNA point mutations 11778 or 3460. Cardiac abnormalities occur frequently enough in patients with LHON that a baseline EKG is warranted. However, further studies are needed to determine the true cardiac risk associated with specific LHON mtDNA mutations.

Leber hereditary optic neuropathy: bridging the translational gap.

Purpose of reviewLeber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) genetic disorder in the population. We address the clinical evolution of the disease, the secondary etiological factors that could contribute to visual loss, and the challenging task of developing effective treatments.Recent findingsLHON is characterized by a preclinical phase that reflects retinal ganglion cell (RGC) dysfunction before rapid visual deterioration ensues. Children can present atypically with slowly progressive visual loss or an insidious/subclinical onset that frequently results in considerable diagnostic delays. The LHON mtDNA mutation is not sufficient on its own to precipitate RGC loss and the current body of evidence supports a role for smoking and estrogen levels influencing disease conversion. Clinical trials are currently investigating the efficacy of adeno-associated viral vectors-based gene therapy approaches for patients carrying the m.11778G>A mutation. Mitochondrial replacement therapy is being developed as a reproductive option to prevent the maternal transmission of pathogenic mtDNA mutations.SummaryLHON is phenotypically more heterogeneous than previously considered and a complex interplay of genetic, environmental and hormonal factors modulates the risk of a LHON carrier losing vision. Advances in disease modelling, drug screening and genetic engineering offer promising avenues for therapeutic breakthroughs in LHON.

No evidence of association between optic neuritis and secondary LHON mtDNA mutations in patients with multiple sclerosis

Leber's Hereditary Optic Neuropathy (LHON) shares features with Multiple Sclerosis (MS). Both diseases develop optic lesions. Frequent secondary LHON mutations in MS patients may explain the optic damage. Here, we tested the hypothesis that secondary LHON mutations are associated with optic neuritis (ON) in MS patients. We recruited 56 MS subjects with ON and 47 MS subjects without ON. DNA was extracted by salting out, after sampling of peripheral blood from each participant. We completed Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) analysis with appropriate primers and restriction endonucleases for seven secondary LHON mutations. Products were visualized using 3% agarose gel electrophoresis with the aid of DNA safe stain in a UV transilluminator. Accuracy of the genotyping procedure was confirmed by sequencing. Data was analyzed using chi square and Fisher exact tests and logistic regression analysis. There was no significant difference between the numbers of MS subjects with ON and without ON that carried secondary LHON mutations (T4216C [P=0.1], A4917G [P=0.2], G13708A [P=0.6], G15257A [P=1], G15812A [P=0.8], G15927A [P=1], G15928A [P=0.4]). The evidence from the present study are not consistent with the hypothesis that secondary LHON mutations are associated with ON in MS subjects.

Pathogenic mitochondrial DNA mutations and associated clinical features in Korean patients with Leber's hereditary optic neuropathy.

To identify the spectrum of pathogenic mitochondrial DNA (mtDNA) mutations and clinical features in Korean patients with genetically confirmed Leber's hereditary optic neuropathy (LHON). The medical records of 34 unrelated, genetically confirmed LHON patients were reviewed. Total genomic DNA was isolated from the peripheral blood leukocytes of the patients with suspected LHON, and primary or secondary mtDNA mutations were identified by direct sequencing. We analyzed the visual acuity (VA), color vision, RNFL thickness, and visual field (VF) at the final visit from 20 patients who were followed-up for more than 6 months after the onset of LHON. Among 34 patients, 21 (61.8%) had the homoplasmic primary mutation, 11 (32.4%) had the homoplasmic secondary mutation, and 2 (5.9%) had the heteroplasmic primary mutation along with the homoplasmic secondary mutation. Analysis of mtDNA sequences revealed six different types of LHON-associated mutations: two primary LHON-associated primary mutations, m.11778G>A (20 patients, 58.8%) and m.14484T>C (3 patients, 8.8%), and four secondary LHON-associated mutations, which were m.3394T>C (3 patients, 8.8%), m.3497C>T (4 patients, 11.8%), m.11696G>A (4 patients, 11.8%), and m.14502T>C (2 patients, 5.9%). Secondary mutation-carrying patients demonstrated a decreased in RNFL thickness, similar to those in primary mutation-carrying LHON patients. These patients had a higher female ratio (P = 0.019), better VA (P = 0.043) and color vision (P = 0.005), as well as better VF. In addition to common primary LHON-associated mutations, our study identified secondary mtDNA mutations, which should be considered when evaluating patients with optic atrophy.

Clinical features of MS associated with Leber hereditary optic neuropathy mtDNA mutations

Objective:To determine whether the association between multiple sclerosis (MS) and Leber hereditary optic neuropathy (LHON) (known as “Harding disease”) is a chance finding, or the 2 disorders are mechanistically linked.Methods:We performed a United Kingdom–wide prospective cohort study of prevalent cases of MS with LHON mitochondrial DNA (mtDNA) mutations. The new cases were compared with published cases, enabling a comprehensive clinical description. We also performed a meta-analysis of studies screening patients with MS for LHON mtDNA mutations to find evidence of a genetic association.Results:Twelve new patients were identified from 11 pedigrees, and 44 cases were identified in the literature. The combined cohort had the following characteristics: multiple episodes of visual loss, predominance for women, and lengthy time interval before the fellow eye is affected (average 1.66 years), which is very atypical of LHON; conversely, most patients presented without eye pain and had a poor visual prognosis, which is unusual for optic neuritis associated with MS. The number of UK cases of LHON-MS fell well within the range predicted by the chance occurrence of MS and the mtDNA mutations known to cause LHON. There was no association between LHON mtDNA mutations and MS in a meta-analysis of the published data.Conclusions:Although the co-occurrence of MS and LHON mtDNA mutations is likely to be due to chance, the resulting disorder has a distinct phenotype, implicating a mechanistic interaction. Patients with LHON-MS have a more aggressive course, and prognostication and treatment should be guarded.

Variation in MAPT is not a contributing factor to the incomplete penetrance in LHON

Leber's hereditary optic neuropathy (LHON) is a common cause of inherited blindness, primarily due to one of three mitochondrial DNA (mtDNA) mutations. LHON, which has an unexplained variable penetrance and pathology, is characterised by disruption of the mitochondrial respiratory chain ultimately resulting in degeneration of the retinal ganglion cells.Phosphorylation of the tau protein is known to cause neurodegeneration and variation in MAPT has been associated with a range of neurodegenerative disorders. Given the relationship between MAPT variation and altered mitochondrial respiratory chain function, we hypothesised that MAPT variation could contribute to the risk of blindness in LHON mtDNA mutation carriers.We studied MAPT variation in a large, well characterised LHON cohort, but were unable to find an association between MAPT genetic variation and visual failure in LHON mtDNA mutation carriers. Our findings suggest that genetic variation in MAPT is unlikely to make a major contribution to the risk of blindness among LHON mutation carriers.

Atypical presentation of Leigh syndrome associated with a Leber hereditary optic neuropathy primary mitochondrial DNA mutation

Leber hereditary optic neuropathy (LHON) is caused by point mutations in mitochondrial DNA (mtDNA), and is characterized by bilateral, painless sub-acute visual loss that develops during the second decade of life. Here we report the case of a five year old girl who presented with clinical and neuroradiological findings reminiscent of Leigh syndrome but carried a mtDNA mutation m.11778G>A (p.R340H) in the MTND4 gene usually observed in patients with LHON. This case is unusual for age of onset, gender, associated neurological findings and evolution, further expanding the clinical spectrum associated with primary LHON mtDNA mutations.

Gene–environment interactions in Leber hereditary optic neuropathy

Leber hereditary optic neuropathy (LHON) is a genetic disorder primarily due to mutations of mitochondrial DNA (mtDNA). Environmental factors are thought to precipitate the visual failure and explain the marked incomplete penetrance of LHON, but previous small studies have failed to confirm this to be the case. LHON has no treatment, so identifying environmental triggers is the key to disease prevention, whilst potentially revealing new mechanisms amenable to therapeutic manipulation. To address this issue, we conducted a large, multicentre epidemiological study of 196 affected and 206 unaffected carriers from 125 LHON pedigrees known to harbour one of the three primary pathogenic mtDNA mutations: m.3460G>A, m.11778G>A and m.14484T>C. A comprehensive history of exposure to smoking, alcohol and other putative environmental insults was collected using a structured questionnaire. We identified a strong and consistent association between visual loss and smoking, independent of gender and alcohol intake, leading to a clinical penetrance of 93% in men who smoked. There was a trend towards increased visual failure with alcohol, but only with a heavy intake. Based on these findings, asymptomatic carriers of a LHON mtDNA mutation should be strongly advised not to smoke and to moderate their alcohol intake.

Leber Hereditary Optic Neuropathy Associated with Malabsorption Syndrome After Bariatric Surgery

We report a patient who developed bilateral visual loss from Leber hereditary optic neuropathy (LHON) in conjunction with chronic malabsorption consequent to bariatric surgery. A 31-year-old man reported visual loss in his left eye and, 2 weeks later, in his right eye. His vision gradually worsened down to finger counting at a distance of 1 m, and he was admitted to the hospital for study. He had undergone vertical banded gastroplasty for morbid obesity 3 years earlier. He smoked 10 cigarettes/day and drank a few alcoholic drinks on weekends. Past ocular history was negative. Family history was remarkable for a maternal cousin with a history of unexplained poor vision since childhood. On our examination, visual acuity was 20/40 in the right eye and 20/200 in the left eye. There was a dense central scotoma in the visual field of the left eye and a pale optic disc in that eye. There was an afferent pupil defect on the left. No other ocular findings were detected, and results of the neurologic examination were unremarkable. Results of extensive hematologic, serologic, and cerebrospinal fluid studies were all normal or negative except for decreased serum levels of vitamin E at 3.4 μg/mL (normal range 5-20 μg/mL), borderline serum levels of vitamin B12 and folate (253 pg/mL and 3.6 ng/mL, respectively), and increased mean corpuscular volume at 101 fL. Results of CT and MRI of the brain and orbits were normal. Pattern-reversal visual evoked potentials revealed marked bilateral delay with P100 latencies of 130.8 ms from the right eye and 156.3 ms from the left eye. The patient received treatment with 1,000 mg/day methylprednisolone intravenously for 5 days, as well as oral vitamin B complex and vitamin E. There was no improvement in vision during his hospitalization. Genetic testing, performed at Public Foundation of Genomic Medicine (Santiago de Compostela, Spain), showed a homoplasmic mitochondrial DNA (mtDNA) mutation at position 11778A, confirming the clinical diagnosis of LHON. On a 10-month follow-up, clinical examinations showed no substantial changes. We have described a young man with a LHON mtDNA mutation and a history of moderate alcohol and tobacco abuse who developed subacute bilateral optic neuropathy in the setting of chronic malabsorption (multiple vitamin deficiency) induced by bariatric surgery. Epigenetic factors are reported to contribute to the clinical expression of LHON mtDNA mutations, including tobacco smoking, alcohol consumption, uncontrolled diabetes, ethambutol use, and antiretroviral therapy (1). There are similarities between the optic neuropathies of LHON, vitamin B1 deficiency, and vitamin B12 deficiency, suggesting that abnormalities of adenosine triphosphate levels might be the common underlying pathogenetic mechanism (2). In our patient, tobacco smoking and alcohol consumption may have contributed. Visual loss began after bariatric surgery, perhaps in the context of malabsorption. Asymptomatic 11778 mtDNA LHON carriers frequently show manifestations of optic nerve impairments in relation to environmental factors (3), just as mutations in the 12S rRNA gene of the mitochondrial genome increase susceptibility to the ototoxicity of aminoglycoside antibiotics (4). Three cases of LHON in subjects who also had low serum vitamin B12 levels at the time of symptom onset have recently been reported (5). Taken together, these observations suggest that optic neuropathy in patients carrying a primary LHON mtDNA mutation may be precipitated by vitamin deficiency. Patients who have undergone bariatric surgery show multiple biochemical abnormalities consistent with malabsorption, including low serum levels of vitamin B12, vitamin D, vitamin E, calcium, copper, or zinc. Some patients develop encephalopathy, optic neuropathy, posterolateral myelopathy, acute polyradiculoneuropathy, and polyneuropathy. Perhaps a positive family history of visual loss should prompt mtDNA investigations before bariatric surgery is considered. Diego Santos-García, MD, PhD Javier Abella, MD Section of Neurology Hospital A. Marcide Ferrol, Spain Begoña De Domingo, MD Service of Ophthalmology Hospital A. Marcide Ferrol, Spain Raúl de la Fuente-Fernández, MD Section of Neurology Hospital A. Marcide Ferrol, Spain [email protected]

Extremely Low Penetrance of Leber's Hereditary Optic Neuropathy in 8 Han Chinese Families Carrying the ND4 G11778A Mutation

To investigate the role of mitochondrial haplotypes in the development of Leber's hereditary optic neuropathy (LHON) associated with the ND4 G11778A mutation in Chinese families. Eight Han Chinese families with maternally transmitted LHON were studied using clinical, genetic, and molecular evaluations. One hundred sixty-seven subjects from 8 Chinese families with a wide age range and severity of visual impairment. All subjects underwent the clinical and genetic evaluation, as well as molecular analysis of mitochondrial DNA (mtDNA). The ophthalmologic examinations included visual acuity, visual field examination, visual evoked potentials, and fundus photography. Mitochondrial DNA analysis included the polymerase chain reaction amplification of the entire mtDNA and subsequent sequence determination. Eight families exhibited extremely low penetrance of visual impairment, with the average of 13%. In particular, 14 (12 males and 2 females) of 119 matrilineal relatives in these families exhibited the variable severity and age at onset in visual dysfunction. The average age of onset of vision loss was 17 years. Molecular analysis of mtDNA identified the homoplasimic ND4 G11778A mutation and distinct sets of variants belonging to the Asian haplogroups M8a2, D4g2, B4a1c, B5b, N9a1, D4b2b, C, and M7b1. However, there was an absence of secondary LHON-associated mtDNA mutations in these 8 Chinese families. The extremely low penetrance of vision loss in these 8 Chinese pedigrees strongly indicates that the G11778A mutation was itself insufficient to produce a clinical phenotype. The absence of secondary LHON mtDNA mutations suggest that these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the G11778A mutation in those Chinese families with very low penentrace of vision loss. However, nuclear backgrounds and environmental factors seem to be modifying factors for the phenotypic manifestation of the G11778A mutation in these Chinese families.

Detection of mtDNA*LHON G11778A mutation by real-time polymerase chain reaction using TaqMan-MGB probe technology

To develop a simple, rapid and reliable real-time PCR assay based on TaqMan technology using a new MGB probe for detecting mtDNA(*)LHON G11778A mutation and heteroplasmy directly. Twenty patients with suspicion of Leber hereditary optic neuropathy (LHON) and their maternal relatives had undergone molecular genetic evaluation. Seventeen normal individuals were used as the controls. A real-time PCR involved two MGB probes (wild-type and mutation-type) in a single tube on the iCycler IQ real-time detection system was used to detect the mtDNA(*)LHON G11778A mutation. The results were then compared with the DNA sequence analysis of the PCR products. A linear standard curve was obtained by pUCm LHON-G and pUCm LHON-A clone. In the controls (wild type), the reaction of VIC-labeled MGB probe was positive and the channel of FAM reaction was negative, the DNA sequence was 100% matched to previously published data. In 20 LHON patients and their maternal relatives, 12 cases showed mutations in DNA sequence analysis, all of them were LHON mtDNA mutation. While 5 other cases showed the combination of LHON mtDNA mutation and wide type gene phenotype, the rate of Ct value in wild type versus gene mutation was over 25%. DNA sequence analysis showed 8 of LHON mtDNA belonged to wild types and 3 cases were heteroplasmy, and the rate of Ct value in gene mutation versus wild type was lower than 25%. This real-time PCR assay is a simple, rapid and reliable method for the detection of genotyping mtDNA mutations as well as for quantifying heteroplasmy.

Leber’s hereditary optic neuropathy and vitamin B12 deficiency

Leber's hereditary optic neuropathy (LHON) is a maternally inherited optic neuropathy caused by mutations in mitochondrial DNA (mtDNA). It is also believed that several epigenetic factors have an influence on the development of LHON. A case series was observed. Three patients who developed bilateral optic neuropathy are presented. All patients had a primary LHON mutation in their mtDNA, but also a subnormal vitamin B12 serum level at the time of presentation. The clinical picture of optic neuropathy associated with vitamin B12 deficiency shows similarity to that of LHON. Both involve the nerve fibres of the papillomacular bundle. The present case reports suggest that optic neuropathy in patients carrying a primary LHON mtDNA mutation may be precipitated by vitamin B12 deficiency. Therefore, known carriers should take care to have an adequate dietary intake of vitamin B12 and malabsorption syndromes like those occurring in familial pernicious anaemia or after gastric surgery should be excluded.

The role of the ND5 gene in LHON: Characterization of a new, heteroplasmic LHON mutation

Leber's hereditary optic neuropathy (LHON) causes central vision loss from bilateral optic neuropathy. Although 13 mitochondrial DNA (mtDNA) mutations are strongly associated with LHON, only three account for roughly 90% of cases and thus are found in multiple independent LHON families. The remaining LHON mutations are rare. Here, we describe the clinical and genetic characterization of a new LHON mtDNA mutation. The 12848T mutation alters a highly conserved amino acid in the ND5 complex I gene, is not found in controls, and is heteroplasmic. Despite ND5 being the largest of the mtDNA complex I genes, ND5 mutations are quite rare in LHON.

Leber's hereditary optic neuropathy mutations in ethambutol-induced optic neuropathy.

Primary mitochondrial DNA (mtDNA) mutation at the nt 11778 site in Leber's hereditary optic neuropathy (LHON) has been reported to be present in patients with ethambutol-induced optic neuropathy. To study further this association between LHON and ethambutol-induced optic neuropathy, we tested ethambutol-induced optic neuropathy patients for the presence of the mtDNA mutations at nucleotides (nt)-11778, nt-14484, nt-3460, nt-15257, nt-9438, nt-9804, nt-13730, and nt-14459 in 24, 15, 8, 6, 5, 5, 5, and 5 patients respectively. However, none of the ethambutol-induced optic neuropathy patients was found to exhibit any pathogenic LHON mtDNA mutation. In conclusion, we found no evidence of any association between ethambutol-induced optic neuropathy and the LHON mutations.

Asian-specific mtDNA backgrounds associated with the primary G11778A mutation of Leber's hereditary optic neuropathy.

We studied 19 patients of Southeast Asian (SEA) ethnic ancestry with Leber's hereditary optic neuropathy (LHON) to investigate the mtDNA haplotypes associated with the primary mutation(s). Eighteen patients carried a mitochondrial DNA (mtDNA) G11778A mutation (Arg340His in the respiratory complex I ND4 subunit), while one had a T14484C mutation (Met64Val in the ND6 subunit). One patient had a class II LHON mtDNA mutation, G3316A. Sequencing data of the ND genes showed many single-nucleotide polymorphisms (62 SNPs in 17 individuals; 10 LHON patients and 7 normal controls) not previously reported in Europeans or Japanese. The SEA G11778A LHON mutation was associated mostly with two mtDNA haplogroups, M (47%) and a novel lineage, characterized by the gain of a 10394 DdeI site but absence of the 10397 AluI site, designated BM (37%). A significant association was observed between one SNP, A10398G, resulting in a Thr114Ala substitution in the ND3 subunit, and the primary LHON mutation. This SNP also characterizes haplogroup J, with which the European LHON 11778 and 14484 mutations show preferential association. The combination of A10398G and other SNPs, specific for the haplogroups J, M, or BM, might act synergistically to increase the penetrance of the LHON mutations, thus allowing their detection.

Leber's hereditary optic neuropathy mitochondrial DNA mutations in normal-tension glaucoma.

in Leber's hereditary optic neuropathy, increased optic nerve cupping has been reported by several authors. Recently, a mitochondrial DNA (mtDNA) mutation at nucleotide 11778 typically associated with Leber's hereditary optic neuropathy (LHON) was identified in a patient treated for glaucoma but lacking typical signs of LHON. The question arises: should all normal-tension glaucoma patients be further evaluated for LHON? we screened 54 unselected patients with normal-tension glaucoma (age range 20-96 years, 16 men and 38 women) for the primary mtDNA LHON mutations at nucleotides 3460, 11778 and 14484. none of the patients harboured the mtDNA mutations at nucleotides 3460, 11778 or 14484 (95% confidence intervals for each mutation ranged from 0% to 5.3%). primary LHON mtDNA mutations are rare or absent in unselected normal-tension glaucoma patients. Therefore, unselected normal-tension glaucoma patients should not be screened for these mutations. It is probable that only normal-tension glaucoma patients with atypical features (rapid progression, early deep central scotoma, pallor of neuroretinal rim, elevated disc, peripapillary teleangiectasia) or a positive family history of visual loss compatible with a matrilinear transmission should be further evaluated.