DiagnosisClinical DiagnosisLeber hereditary optic neuropathy (LHON) is characterized by bilateral, painless subacute visual failure that develops during young adult life. Males are four to five times more likely than females to be affected [Yu-Wai-Man et al 2009].Acute phase Affected individuals are usually entirely asymptomatic until they develop visual blurring affecting the central visual field in one eye; similar symptoms appear in the other eye an average of two to three months later. In about 25% of cases, visual loss is bilateral at onset. The ocular fundus may have a characteristic appearance that includes disk swelling, edema of the peripapillary nerve fiber layer, retinal telangiectasia, and increased vascular tortuosity. These changes can be subtle, and approximately 20% of affected individuals show no fundal abnormalities. Visual acuity is severely reduced to counting fingers or worse in the majority of cases, and visual field testing by kinetic or static perimetry shows an enlarging dense central or centrocecal scotoma. Atrophic phase. After the acute phase, the optic discs become atrophic within six weeks of disease onset. Significant improvements in visual acuity are rare, and in most individuals, vision remains severely impaired, within the legal requirement for blind registration. Other findings. The pathologic hallmark of LHON is the selective degeneration of the retinal ganglion cell layer and optic nerve. Although visual failure is the defining clinical feature in this mitochondrial genetic disorder, cardiac arrhythmias and neurologic abnormalities such as postural tremor, peripheral neuropathy, nonspecific myopathy, and movement disorders have been reported to be more common in individuals with LHON than in controls [Man et al 2002]. In addition, there is a well-established association between all three primary LHON-causing mtDNA mutations (see Table 1) and an MS-like illness among persons of European origin, especially females [Kellar-Wood et al 1994, Jansen et al 1996, Bhatti & Newman 1999, Palace 2009]. Family history. Affected individuals are often aware of other affected family members, but up to 40% have no family history [Harding et al 1995]. These families most likely represent cases where family history is difficult to trace, given that de novo mutation is rare in LHON [Biousse et al 1997, Man et al 2003]. Electrophysiologic studies (pattern electroretinogram and visual evoked potentials) confirm optic nerve dysfunction and the absence of retinal disease. Note: These ancillary investigations are not usually necessary unless the diagnosis is uncertain.Cranial neuroimaging is necessary to exclude other compressive, infiltrative, and inflammatory causes of a bilateral optic neuropathy. In individuals presenting with LHON, magnetic resonance imaging (MRI) is often normal but may reveal a high signal within the optic nerves, the latter probably representing slight edema or gliosis in the acute and atrophic phase, respectively. TestingBiochemical studies. Although the three primary LHON-causing mtDNA mutations all affect different respiratory chain complex I subunit genes, the mutations are not always associated with a respiratory chain abnormality that can be measured in vitro [Brown 1999]. The absence of a respiratory chain complex defect therefore does not rule out the possibility of LHON. In a small number of in vivo studies using phosphorus magnetic resonance spectroscopy, the most consistent defect of mitochondrial function was identified in individuals with the m.1778G>A mutation; it was not found among those with the m.3460G>A mutation (Table 1). A striking feature of all the biochemical studies is that none found a significant difference between affected and unaffected individuals with a disease-causing mtDNA LHON-causing mutation. Balancing the current weight of evidence, LHON is associated with a respiratory chain defect that is more subtle than that seen in other mitochondrial genetic disorders. Note: (1) These discrepancies highlight the lack of understanding of the relationship between the mtDNA defect, the biochemical defect, and the clinical phenotype. (2) Biochemical studies have been superseded by molecular genetic testing and these are only indicated when establishing pathogenicity for novel putative LHON-causing mtDNA variants.Table 1. Respiratory Chain Dysfunction in LHONView in own windowMitochondrial DNA MutationIn VitroIn VivoComplex I Activity ¹ Respiratory Rate ¹ MRS ¹ m.3460G>A 60%-80%30%-35%0%m.11778G>A 0%-50%30%-50%75%m.14484T>C 0%-65%10%-20%50%See references in Man et al [2002].1. % of decrease relative to controlsMolecular Genetic TestingGenes. Mutations in the mitochondrial genes that encode subunits of NADH dehydrogenase, MT-ND1, MT-ND2, MT-ND4, MT-ND4L, MT-ND5, and MT-ND6, are known to be associated with LHON (Table 5). Mutations in three additional mitochondrial genes, MT-CYB, MT-CO3, and MT-ATP6 are also thought to cause LHON but require further confirmation as they have only been found in single affected individuals or a single family. Clinical testing Targeted mutation analysis Primary pathogenic LHON-causing mtDNA mutations. The primary pathogenic mtDNA mutations described below have been seen only in families with LHON. In one large study [Mackey et al 1996], 90% of individuals with LHON were found to have one of three point mutations of mtDNA: m.11778G>A (MT-ND4) [Wallace et al 1988], m.14484T>C (MT-ND6) [Johns et al 1992a], or m.3460G>A (MT-ND1) [Howell et al 1992]. The prevalence of each mutation varies worldwide, but the m.11778G>A mutation is by far the most common, accounting for approximately 70% of cases among Northern European populations [Mackey et al 1996]. Among French Canadians, the m.14484T>C mutation is the most common cause of LHON as a result of a founder effect [Macmillan et al 1998], but this mutation is relatively uncommon in the United Kingdom and in Scandinavia [Mackey et al 1996, Chinnery et al 2000].
Approximately 10% of individuals with LHON do not harbor one of the three common mtDNA point mutations; further investigation of these families is complex because mtDNA is highly polymorphic [Chinnery et al 1999b, Taylor et al 2003]. A number of putative mtDNA LHON-causing mutations have been described in a single family or singleton cases; however, a novel mtDNA base change cannot be considered pathogenic until it has been observed independently on two or more occasions and only in association with LHON, showing clear segregation with affected disease status.Secondary LHON-associated mtDNA variants (i.e., variants prevalent in the general population that have also been identified at higher frequencies in LHON) (e.g., m.4216T>C, m.13708G>A, m.15257G>A) [Howell et al 1995]; the interpretation and significance of these mtDNA changes is complex, and such testing is therefore not performed routinely. Sequence analysis and mutation scanning detect additional mtDNA nucleotide variants in the remaining 10% of individuals with LHON who do not harbor one of the three most common mtDNA mutations (m.3460G>A, m.11778G>A, and m.14484T>C). Table 2. Summary of Molecular Genetic Testing Used in LHONView in own windowGene SymbolsProportion of LHON Attributed to Mutations in This GeneTest MethodMutations DetectedTest AvailabilityMT-ND4~90%Targeted mutation analysism.11778G>A ClinicalMT-ND6m.14484T>C MT-ND1m.3460G>A Select mitochondrial genes ^{1~10%Sequence analysis / mutation scanning of entire mitochondrial genome 2Other mtDNA sequence variants 31. See Table 5.2. Sequence analysis and mutation scanning of the entire gene can have similar detection frequencies; however, detection rates for mutation scanning may vary considerably between laboratories based on specific protocol used.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, partial-, whole-, or multigene deletions/duplications are not detected.Interpretation of test results. Heteroplasmy, a mixture of mutant and wild-type mtDNA in leukocytes, occurs in approximately 10%-15% of individuals with LHON [Smith et al 1993, Man et al 2003]. Heteroplasmy does not influence the sensitivity of molecular genetic testing for LHON because affected individuals generally have more than 70% mutant mtDNA in leukocytes, which is easily detected by standard techniques. It is possible that the level of heteroplasmy may have a bearing on the risk of developing LHON in the asymptomatic individual and on the risk for transmission [Chinnery et al 2001]; however, no rigorous prospective studies have been performed to clarify this possibility.Testing StrategyTo confirm/establish the diagnosis in a probandAn individual suspected of having LHON should have molecular genetic testing for the three common mtDNA point mutations (targeted mutation analysis) [Yu-Wai-Man et al 2009]. If one of the three most common (primary) mtDNA LHON-causing mutations is not identified (m.3460G>A, m.11778G>A, and m.14484T>C), the individual's history and examination findings should be carefully reassessed to confirm the diagnosis. Complete mtDNA sequencing should be carried out if clinical suspicion remains high and there is no evidence of paternal transmission. Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersMitochondrial DNA mutations are responsible for a heterogeneous group of inherited diseases (see Mitochondrial Disorders Overview) that often cause a progressive neurologic disorder in association with multi-organ involvement (e.g., diabetes mellitus, cardiomyopathy) [Chinnery & Turnbull 1999, Chinnery et al 1999a].OMIM}

Natural HistoryLeber hereditary optic neuropathy (LHON) typically presents in young adults as bilateral, painless, subacute visual failure. The peak age of onset in LHON varies between the second and third decades of life depending on the published case series, with 95% of those who lose their vision doing so before the age of 50 years. Very rarely, individuals first manifest LHON in the seventh and eighth decades of life [Buchan et al 2007]. Males are four to five times more likely to be affected than females, but neither gender nor mutational status significantly influences the timing and severity of the initial visual loss.In the presymptomatic phase, fundal abnormalities such as peripapillary telangiectatic vessels and variable degrees of retinal nerve fiber layer edema have been previously documented and these can vary with time [Nikoskelainen 1994]. Using optical coherence tomography imaging, thickening of the temporal retinal nerve fiber layer was confirmed in clinically unaffected individuals with an LHON-causing mtDNA mutation, further evidence that the papillomacular bundle is selectively vulnerable in LHON [Savini et al 2005]. On more detailed investigation, some individuals with an LHON-causing mtDNA mutation can also exhibit subtle impairment of optic nerve function including: (a) loss of color vision affecting mostly the red-green system, (b) reduced contrast sensitivity, and (c) subnormal electroretinogram and visual evoked potential [Sadun et al 2006].Following onset of the acute phase, affected individuals report worsening, blurring, or clouding of central vision. Both eyes are affected within six months. The most characteristic feature is an enlarging central or centrocecal scotoma and as the field defect increases in size, visual acuity deteriorates in approximately 80% of persons to the level of counting fingers or worse. Following the nadir, visual acuity may improve; such improvement is more likely in individuals with the m.14484T>C mutation than in those with the m.11778G>A mutation.The atrophic phase is characterized by bilateral optic atrophy and dense central scotomata. Most persons remain severely visually impaired and are within the legal requirements for blind registration [Kirkman et al 2009a].Other neurologic features associated with LHON. Minor neurologic abnormalities (e.g., postural tremor, peripheral neuropathy, nonspecific myopathy, movement disorders) are said to be common in individuals with LHON [Nikoskelainen et al 1995] but are rarely clinically significant. Some individuals with LHON, usually women, may develop a progressive multiple sclerosis (MS)-like illness. In addition to a severe bilateral optic neuropathy, these individuals manifest disseminated central nervous system demyelination, with characteristic periventricular white matter lesions and unmatched cerebrospinal fluid oligoclonal bands [Bhatti & Newman 1999, Horvath et al 2000, Palace 2009]. (See Multiple Sclerosis Overview.)In a few families, mtDNA complex I mutations cause optic atrophy in association with severe neurologic deficits including ataxia, dystonia, and encephalopathy [Jun et al 1994, De Vries et al 1996, Gropman et al 2004, Tarnopolsky et al 2004, Watanabe et al 2006].Two mtDNA complex I point mutations, m.3376G>A and m.3697G>A, have been identified in persons with clinical features of both LHON and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) [Blakely et al 2005, Spruijt et al 2007].Cardiac conduction defects and LHON. A number of studies have shown an increased incidence of cardiac accessory pathways in association with LHON [Nikoskelainen 1994].OMIM

Genotype-Phenotype CorrelationsDistinct phenotypes are associated with specific LHON-causing mutations:m.11778G>A generally causes the most severe visual failure with little chance of recovery. m.14484T>C is associated with the best long-term visual outcome. m.3460G>A has an intermediate phenotype. Reported visual recovery rates among persons with LHON are summarized in Table 3.Table 3. Visual Recovery Rates by Mutation in Individuals with LHONView in own windowMitochondrial DNA MutationVisual RecoveryReferencesm.11778G>A 4%-25%Newman et al [1991], Harding et al [1995] m.14484T>C 37%-58%Johns et al [1993], MacMillan et al [1998] m.3460G>A 22%-25%Johns et al [1992b], Harding et al [1995] A multiple sclerosis-like illness has been reported in association with all three primary mtDNA LHON-causing mutations (m.3460G>A, m.11778G>A, and m.14484T>C) (reviewed in Yu-Wai-Man et al [2009]). OMIM

Differential DiagnosisIf the ophthalmologic assessment (including an assessment of acuity, color vision, visual fields, and electrophysiology) and molecular genetic testing leave any uncertainty about the diagnosis of Leber hereditary optic neuropathy (LHON), further evaluation of the anterior visual pathways and brain with contrast MRI and lumbar puncture are appropriate to exclude other potentially treatable optic neuropathies.Acute phase. A wide range of non-genetic causes of bilateral visual failure must be excluded during the acute phase. Atrophic phase. If an individual is only seen at this stage, it can be difficult to exclude other possible causes of optic atrophy, especially if there is no clear maternal family history. In these cases, neuroimaging of the anterior visual pathways is mandatory while awaiting the results of molecular genetic testing. LHON must also be distinguished from other causes of sporadic and inherited optic neuropathies such as deafness-dystonia-optic neuropathy (DDON). This disorder is characterized by prelingual or postlingual sensorineural hearing impairment in early childhood, slowly progressive dystonia or ataxia in the teens, slowly progressive decreased visual acuity from optic atrophy beginning at approximately age 20 years, and dementia beginning at approximately age 40 years. Psychiatric symptoms such as personality change and paranoia may appear in childhood and progress. The hearing impairment seems constant in age of onset and progression, whereas the neurologic, visual, and neuropsychiatric signs vary in degree of severity and rate of progression. Females may have mild hearing impairment and focal dystonia.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).OMIM

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Leber hereditary optic neuropathy (LHON), the following evaluations are recommended:Measurement of best corrected visual acuity Assessment of visual fields with static or kinetic perimetryECG may reveal a pre-excitation syndrome in both symptomatic and asymptomatic individuals who have an LHON-causing mtDNA mutation. However, such a finding does not necessitate further intervention in the absence of cardiac symptoms. It is also recommended to screen for possible associated systemic complications including diabetes mellitus and cardiomyopathy, which can further compound the visual impairment among individuals with LHON.Treatment of ManifestationsManagement of affected individuals is supportive and includes provision of visual aids, occupational rehabilitation, and registration with the relevant local social services. SurveillanceOngoing surveillance of asymptomatic individuals harboring LHON-causing mtDNA mutations is not necessary; however, they should be advised to seek immediate medical attention should they experience any visual disturbance. The frequency of follow-up for affected individuals varies depending on the individual’s circumstances and the availability of healthcare locally.Agents/Circumstances to AvoidIndividuals harboring established LHON-causing mtDNA mutations should be strongly advised not to smoke and to moderate their alcohol intake, avoiding binge-drinking episodes. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationIdebenone. Small case series have reported that oral administration of idebenone (a short-chain synthetic benzoquinone; 2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone) and/or vitamin supplementation (B₁₂ and C) can speed up visual recovery and improve final visual outcome in people with LHON [Mashima et al 2000, Carelli et al 2001]. A subsequent report of two individuals with LHON showed no visual benefit from idebenone and multivitamin supplementation [Barnils et al 2007]. To address these conflicting anecdotal findings a phase II, double-blind, randomized placebo-controlled trial was recently completed investigating the efficacy, safety, and tolerability of oral idebenone in LHON – RHODOS (Rescue of Hereditary Optic Disease Outpatient Study). In total, 85 affected individuals harboring one of the three primary mtDNA LHON-causing mutations (m.3460G>A, m.11778G>A, and m.14484T>C) were successfully enrolled into this multicenter study [Klopstock et al, in press]. Research subjects were assigned in a two-to-one randomization ratio to receive either idebenone (at a dose of 300 mg/3x/day) or placebo. This dose of idebenone was found to be safe with no significant drug-related adverse events. Patients with discordant visual acuities (defined as a difference of >0.2 LogMAR between the two eyes) and at highest risk for further visual loss in the least affected eye were more likely to benefit from treatment with idebenone. High-dose oral idebenone should therefore be considered as a treatment option, especially for individuals with LHON with relatively recent disease onset [Klopstock et al 2011]. No experimental data addressing prophylactic use of idebenone among asymptomatic individuals with mtDNA mutations are available.EPI-743. In an open-label study of five patients with acute LHON treated within 90 days of disease conversion, the antioxidant α-tocotrienol-quinone (EPI-743), a vitamin E derivative, has shown early promise [Sadun et al 2012]. An adequately powered, double-blind, randomized placebo-controlled trial is needed to confirm the visual benefit of this agent in both acute and chronic LHON [Sadun et al 2012].Gene therapy. Although key issues of safety and efficacy need to be further addressed before their application to human clinical trials, targeted gene therapy for LHON is being actively explored [Qi et al 2003, Qi et al 2004, Qi et al 2007, Lam et al 2010].Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. OMIM

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Leber Hereditary Optic Neuropathy: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameMT-ND6MitochondriaNADH-ubiquinone oxidoreductase chain 6MT-ND4MitochondriaNADH-ubiquinone oxidoreductase chain 4MT-ND1MitochondriaNADH-ubiquinone oxidoreductase chain 1MT-ATP6MitochondriaATP synthase subunit aMT-ND5MitochondriaNADH-ubiquinone oxidoreductase chain 5MT-CYBMitochondriaCytochrome bMT-CO3MitochondriaCytochrome c oxidase subunit 3MT-ND2MitochondriaNADH-ubiquinone oxidoreductase chain 2MT-ND4LMitochondriaNADH-ubiquinone oxidoreductase chain 4LData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Leber Hereditary Optic Neuropathy (View All in OMIM) View in own window 516000COMPLEX I, SUBUNIT ND1; MTND1 516001COMPLEX I, SUBUNIT ND2; MTND2 516003COMPLEX I, SUBUNIT ND4; MTND4 516004COMPLEX I, SUBUNIT ND4L; MTND4L 516005COMPLEX I, SUBUNIT ND5; MTND5 516006COMPLEX I, SUBUNIT ND6; MTND6 516020CYTOCHROME b OF COMPLEX III; MTCYB 516050CYTOCHROME c OXIDASE III; MTCO3 516060ATP SYNTHASE 6; MTATP6 535000LEBER OPTIC ATROPHYMolecular Genetic PathogenesisSee Mitochondrial Disorders Overview.Although Leber hereditary optic neuropathy (LHON) has a well-defined and focal phenotype, the pathophysiology is complex [Howell 1997]. The primary pathology in LHON involves the retinal ganglion cell layer, but it is not known how the mtDNA mutations actually cause such a focal neurodegenerative disease. It is also not known why otherwise entirely healthy individuals suddenly develop optic nerve dysfunction in young adulthood. The incomplete penetrance and predilection for males to lose vision also imply that additional genetic and/or environmental factors must modulate the phenotypic expression of LHON (see Risk Factors for Visual Loss). Alternatively, the gender bias could also result from a combination of subtle anatomic, hormonal, and/or physiologic variations between males and females.Normal allelic variants. See Mitochondrial Disorders Overview. Pathologic allelic variants. See Mitochondrial Disorders Overview. Many different mtDNA mutations have been associated with LHON in the literature and in numerous online databases. Some of these changes are rare polymorphisms and some are common sequence variants in the normal population. Great caution should be exercised in attributing significance to a "rare" LHON-causing mtDNA mutation found in a single affected individual or family.Table 5 includes only those mtDNA mutations that have strong evidence of pathogenicity.Note: The information in Table 5 is provided by the authors of this GeneReview; it has not been reviewed by GeneReviews staff.Table 5. Pathologic Allelic Variants in Mitochondrial DNA Associated with LHONView in own window% of Mutant AllelesMitochondrial DNA Nucleotide Change Gene SymbolProtein Amino Acid ChangeReference Sequences ¹ 90%m.11778G>AMT-ND4 p.Arg340HisAC_000021​.2
NP_536852​.1 m.14484T>CMT-ND6 p.Met64ValAC_000021​.2
NP_536854​.1 m.3460G>AMT-ND1 p.Ala53ThrAC_000021​.2
NP_536843​.1 10%^{2m.3635G>A m.3733G>Ap.Glu143Lysm.4171C>Ap.Leu289Metm.10663T>CMT-ND4L p.Val65AlaAC_000021​.2
NP_536851​.1 m.14459G>AMT-ND6 p.Ala72ValAC_000021​.2
NP_536854​.1 m.14482C>Am.14482C>G p.Met64Ile m.14495A>Gp.Leu60Ser m.14568C>TSee Quick Reference for an explanation of nomenclature. (Note: The mitochondrial genetic code varies from the genomic genetic code given in the Quick Reference. For the genetic code, gene structure, and other features of the mitochondrial genome see MITOMAP: A Human Mitochondrial Genome Database at www​.mitomap.org, 2007). Variants are named according to current nomenclature guidelines (www​.hgvs.org). 1. AC_000021​.2 is the mitochondrial DNA Cambridge reference sequence [Anderson et al 1982, Andrews et al 1999].2. This represents the group of patients with a clinical diagnosis of LHON but who are not found to harbor one of the three most common mtDNA mutations. This group also includes those mtDNA variants thought to cause LHON, but who require further confirmation for pathogenicity (Table 6).Note: The information in Table 6 is provided by the authors of this GeneReview; it has not been reviewed by GeneReviews staff.Table 6. Putative Pathologic Allelic Variants in Mitochondrial DNA Associated with LHONView in own windowMitochondrial DNA Nucleotide Change Gene SymbolProtein Amino Acid ChangeReference Sequences 2 m.3376G>AMT-ND1m.3635G>AMT-ND1m.3697G>AMT-ND1m.3700G>AMT-ND1m.4025C>TMT-ND1m.4160T>CMT-ND1m.4640C>AMT-ND2m.5244G>AMT-ND2m.10237T>CMT-ND3m.11696G>AMT-ND4m.11253T>CMT-ND4m.12811T>CMT-ND5m.12848C>TMT-ND5m.13637A>GMT-ND5m.13730G>AMT-ND5m.14325T>CMT-ND6m.14568C>TMT-ND6m.14729G>AMT-ND6m.14498C>TMT-ND6m.14596A>TMT-ND6m.9101T>CMT-ATP6 p.Ile192ThrAC_000021​.2
NP_536848​.1 m.9804G>AMT-CO3 p.Ala100ThrAC_000021​.2
NP_536849​.1 m.14831G>AMT-CYB p.Ala29ThrAC_000021​.2
NP_536855​.1 See Quick Reference for an explanation of nomenclature. (Note: The mitochondrial genetic code varies from the genomic genetic code given in the Quick Reference. For the genetic code, gene structure, and other features of the mitochondrial genome see MITOMAP: A Human Mitochondrial Genome Database at www​.mitomap.org, 2007). Variants are named according to current nomenclature guidelines (www​.hgvs.org). 1. The variants in these genes are thought to be pathogenic in LHON but require further confirmation, as they have been identified only in single affected individuals or a single family. (www​.mitomap.org)2. AC_000021​.2 is the mitochondrial DNA Cambridge reference sequence [Anderson et al 1982, Andrews et al 1999].Normal gene product. See Mitochondrial Disorders Overview. Abnormal gene product. See Mitochondrial Disorders Overview. OMIM}