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Leber Hereditary Optic Neuropathy

Synonyms: Hereditary Optic Neuroretinopathy, LHON, Leber's Disease, Leber's Optic Atrophy, Leber's Optic Neuropathy

, BMedSci, MBBS, PhD, FRCOphth and , BMedSci, MBBS, PhD, FRCPath, FRCP, FMedSci.

Author Information
, BMedSci, MBBS, PhD, FRCOphth
Department of Ophthalmology & Mitochondrial Research Group
Institute of Genetic Medicine, Centre for Life
Newcastle University
Newcastle upon Tyne, United Kingdom
, BMedSci, MBBS, PhD, FRCPath, FRCP, FMedSci
Department of Neurology & Mitochondrial Research Group
Institute of Genetic Medicine, Centre for Life
Newcastle University
Newcastle upon Tyne, United Kingdom

Initial Posting: ; Last Update: September 19, 2013.

Summary

Disease characteristics. Leber 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. 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. Visual acuity is severely reduced to counting fingers or worse in the majority of cases, and visual field testing shows an enlarging dense central or centrocecal scotoma. After the acute phase, the optic discs become atrophic. Significant improvements in visual acuity are rare and most persons qualify for registration as legally blind (visual acuity ≤20/200). 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. Some individuals with LHON, usually women, may also develop a multiple sclerosis (MS)-like illness.

Diagnosis/testing. The diagnosis is based on ophthalmologic findings. Testing includes dilated fundus examination to identify characteristic optic disc and vascular changes in the acute phase; kinetic (Goldmann) or static perimetry to delineate the characteristic central or centrocecal scotoma; electrophysiologic studies in selected cases (visual evoked potentials to confirm optic nerve dysfunction and pattern electroretinogram to confirm the absence of retinal disease); and neuroimaging to exclude compressive, infiltrative, and inflammatory causes of a bilateral optic neuropathy. Approximately 90% of individuals with LHON have one of three point mutations of mitochondrial DNA (mtDNA): m.3460G>A, m.11778G>A, or m.14484T>C.

Management. Treatment of manifestations: Management of affected individuals is largely supportive, with the provision of visual aids, help with occupational rehabilitation, and registration with the relevant social services. ECG may reveal a pre-excitation syndrome in individuals harboring mtDNA LHON-causing mutations, but no further intervention is required in the absence of cardiac symptoms. A multidisciplinary approach to those affected individuals with extra-ocular neurologic features (ataxia, peripheral neuropathy and dystonia) should be considered to minimize the functional consequences of these complications.

Agents/circumstances to avoid: Individuals harboring mtDNA LHON-causing mutations should be strongly advised to moderate their alcohol intake and not to smoke. Avoiding exposure to other putative environmental triggers for visual loss, in particular industrial toxins and drugs with mitochondrial-toxic effects, also seems reasonable.

Therapies under investigation: A recent randomized controlled trial suggests that oral administration of idebenone could benefit individuals with LHON who are at an early stage of the disease process and still at high risk for further visual loss. Similarly, EPI-743 has been used in a small open-labelled study of five individuals with acute LHON with some early encouraging visual results.

Genetic counseling. Leber hereditary optic neuropathy is caused by mutations in mtDNA and it is transmitted by maternal inheritance. Genetic counseling for LHON is complicated by the gender- and age-dependent penetrance of the primary mtDNA LHON-causing mutations. The mother of a proband usually has the mtDNA mutation and may or may not have symptoms. In most cases a history of visual loss affecting maternal relatives at a young age is present, but up to 40% of cases are simplex (i.e., occur in a single individual in a family). A male (affected or unaffected) with a primary LHON-causing mtDNA mutation cannot transmit the mutation to any of his offspring. A female (affected or unaffected) with a primary LHON-causing mtDNA mutation transmits the mutation to all of her offspring. Prenatal diagnosis for mitochondrial mutations is possible if the disease-causing mutation in a family is known; however, accurate interpretation of a positive prenatal test result is difficult because the mtDNA mutational load in amniocytes and chorionic villi may not correspond to that of other fetal or adult tissues, and the presence of the mtDNA mutation does not predict the occurrence of disease, age of onset, severity, or rate of disease progression. Prenatal testing may be available through laboratories offering testing for the gene of interest or custom testing.

Diagnosis

Clinical Diagnosis

Leber 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 or atrophic phase, respectively [Lamirel et al 2010, van Westen et al 2011].

Testing

Biochemical 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 an LHON-causing mtDNA 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 are only indicated when establishing pathogenicity for novel putative LHON-causing mtDNA variants.

Table 1. Respiratory Chain Dysfunction in LHON

Mitochondrial DNA MutationIn VitroIn Vivo
Complex I Activity 1 Respiratory Rate 1 MRS 1
m.3460G>A 60%-80%30%-35%0%
m.11778G>A0%-50%30%-50%75%
m.14484T>C 0%-65%10%-20%50%

See references in Man et al [2002].

1. % of decrease relative to controls

Molecular Genetic Testing

Genes. 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 cause 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

    • 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, Achilli et al 2012]. 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 LHON

Gene 1Proportion of LHON Attributed to Mutations in This GeneTest MethodMutations Detected 2
MT-ND4~90%Targeted mutation analysism.11778G>A
MT-ND6m.14484T>C
MT-ND1m.3460G>A
Select mitochondrial genes 3~10%Sequence analysis / mutation scanning of entire mitochondrial genome 4Other mtDNA sequence variants 5

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. See Table 5 (pdf).

4. 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.

5. 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. For issues to consider in interpretation of sequence analysis results, click here.

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 Strategy

To confirm/establish the diagnosis in a proband

  • An 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.

Clinical Description

Natural History

Leber 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 age 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 including peripapillary telangiectatic vessels and variable degrees of retinal nerve fiber layer edema have been previously documented; 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; 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].

Genotype-Phenotype Correlations

Distinct 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 LHON

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]).

Visual Prognosis

The overall visual prognosis for individuals with LHON is poor; the majority of people will remain legally blind with a significant detrimental impact on their overall quality of life [Kirkman et al 2009a]. However, some positive prognostic factors have been identified, such as an earlier age of onset (< 20 years), a subacute presentation with slow visual deterioration, and a relatively large optic disc [Barboni et al 2006, Ramos et al 2009].

Risk Factors for Visual Loss

LHON-causing mtDNA mutations have markedly reduced penetrance. An individual can only develop LHON if a pathogenic mtDNA LHON-causing mutation is present, but approximately 50% of males and 90% of females who harbor a primary LHON-causing mtDNA mutation do not develop blindness. Additional environmental and genetic factors interact with the primary mtDNA defect and determine whether an individual ultimately develops optic nerve dysfunction and visual failure. The two most important risk factors for visual loss are gender and age (Table 4) [Yu-Wai-Man et al 2009].

Lifetime risk for visual failure in individuals with a homoplasmic primary LHON-causing mtDNA mutation. As a rule of thumb, males have an approximate 50% lifetime risk and females an approximate 10% lifetime risk of developing visual failure (Table 4). The specific risks vary from mutation to mutation, and also between studies for each mutation (depending in part on how the studies were carried out).

Table 4. Lifetime Risk for Visual Failure in Individuals with a Homoplasmic Primary LHON-Causing Mitochondrial DNA Mutation by Study

Mitochondrial DNA MutationRisk of Developing SymptomsMedian Age at Onset (Males)Male/Female RatioReference
MalesFemales
m.3460G>A32%15%20 yrs4.3:1Nikoskelainen [1994]
m.3460G>A49%28%22 yrs1.7:1Man et al [2003]
m.11778G>A43%11%24 yrs3.7:1Harding et al [1995]
m.11778G>A51%9%22 yrs5.1:1Man et al [2003]
m.14484T>C47%8%20 yrs7.7:1Macmillan et al [1998]

Age-related penetrance of LHON. The penetrance of LHON is age specific and in some studies, the median age of onset was a few years later in females. The 95th centile for age at onset is 50 years for all three primary mutations. Thus, a clinically unaffected 50-year-old male has less than a 1/20 chance of losing his vision.

Heteroplasmy. Many mitochondria (and thus many mtDNA molecules) are present in each cell. Some individuals with an LHON-causing mtDNA mutation have a mixture of mutant and wild-type species of mtDNA, a finding referred to as heteroplasmy. Heteroplasmy is present in 10%-15% of individuals with an LHON-causing mtDNA mutation. In one study, individuals with an m.11778G>A mutation load of less than 75% in their leukocytes were unaffected [Smith et al 1993]. In a retrospective analysis of 17 families heteroplasmic for the m.11778G>A mutation, males with a mutational load greater than 60% in their leukocytes had an increased frequency of optic neuropathy relative to those with lower mutation loads [Chinnery et al 2001]. However, quantifying the level of heteroplasmy for the purpose of presymptomatic testing is limited as the majority of individuals with an LHON-causing mtDNA mutation are homoplasmic.

Mitochondrial DNA haplogroups. Reflecting the evolution of human mtDNA as different populations spread across the globe, a number of stable mtDNA polymorphic variants cluster together in specific combinations known as haplogroups. Phylogenetic analysis has established that individuals of European ancestry belong to one of nine haplogroups: H, I, J, K, T, U, V, W, or X [Torroni & Wallace 1994, Herrnstadt et al 2002].

A meta-analysis of 159 European LHON pedigrees indicates that the risk for visual loss for the three primary LHON-causing mutations is influenced by the mtDNA haplogroup [Hudson et al 2007].

  • The risk for visual failure was greater when the m.11778G>A and m.14484T>C mutations arose on haplogroup J; individuals with the m.3460G>A mutation were more likely to experience visual loss if they belonged to haplogroup K.
  • In contrast, individuals with the m.11778G>A mutation had a lower risk for visual loss when the mutation arose on haplogroup H.

Haplogroup associations have been reported in families with LHON from mainland China, supporting a contributory role for mtDNA haplogroups in modulating the risk for disease expression [Ji et al 2008]. However, in a study of families with LHON from Southeast Asia, no association between mtDNA haplogroups and risk for visual loss was identified; thus, the influence of the mtDNA background on LHON penetrance requires further clarification [Tharaphan et al 2006].

Nuclear modifier genes. The predominance of affected males in LHON cannot be explained by mitochondrial inheritance. Segregation analysis of a large number of pedigrees suggests the existence of a recessive X-linked susceptibility gene acting in synergy with the mtDNA mutation to precipitate visual loss – a two-locus disease LHON model [Bu & Rotter 1991, Nakamura et al 1993]. Linkage analysis points toward a possible disease locus at Xp21.1, and a high-risk haplotype within this region [DXS8090(166)]+[DXS1068(268)] increases the risk for visual failure 35-fold for the m.11778G>A and m.14484T>C LHON-causing mutations but not for m.3460G>A [Hudson et al 2005]. Two subsequent linkage studies have provided additional evidence for an X-linked disease modifier, albeit at different chromosomal loci [Shankar et al 2008, Ji et al 2010]. The actual gene(s) on the X chromosome in which mutations are causative remain to be identified, and it is likely that other autosomal nuclear modifier genes also influence the risk for visual loss in LHON.

Environmental factors. Relatively small case series have reported a high incidence of tobacco and alcohol consumption among individuals with mtDNA LHON-causing mutations who develop visual failure [Riordan-Eva et al 1995, Chalmers et al 1996]. A larger case-control study failed to confirm the association between heavy smoking or alcohol intake and an increased risk for visual loss [Kerrison et al 2000]. However, more recent epidemiologic evidence, based on a large multicenter study of 125 Northern European LHON pedigrees, supports an increased risk for visual loss among heavy smokers, and to a lesser extent, heavy drinkers [Kirkman et al 2009b]. There are anecdotal reports of nutritional deprivation, exposure to industrial toxins, antiretroviral drugs, psychological stress, or acute illness precipitating the onset of blindness in LHON [Mackey et al 2003, Sadun et al 2003, Sadun et al 2004, Sanchez et al 2006, Carelli et al 2007]. The role of these putative environmental triggers in LHON remains circumstantial at best and calls for more robust epidemiologic evidence, a difficult task for a rare genetic condition.

Intraocular pressue. There is evidence that raised intraocular pressure could be a risk factor triggering visual loss in individuals at-risk for developing LHON. Until further evidence becomes available, it seems reasonable to set a lower threshold for initiating treatment for raised intraocular pressure in individuals with an LHON-causing mutation given the possible deleterious consequences of raised intraocular pressure on mitochondrial function and retinal ganglion cell survival [Thouin et al 2013].

Hormonal factors. The marked male bias in LHON could reflect a protective influence of female sex hormones, and this hypothesis was recently investigated using LHON cybrid cell lines. Treatment with estrogens was found to reduce reactive oxygen species levels in these LHON cybrids, with increased activity of the antioxidant enzyme superoxide dismutase. These beneficial estrogenic effects translated into more efficient mitochondrial oxidative phosphorylation [Giordano et al 2011]. Further research is needed to determine whether females with an LHON-causing mutation are at increased risk for visual loss in the perimenopausal period and following the onset of menopause.

Low-penetrance branches of LHON pedigrees. The penetrance of the primary LHON-causing mtDNA mutations seems to be decreasing in some pedigrees. In a large well-characterized Australian family with the m.11778G>A mutation [Howell & Mackey 1998], the penetrance decreased to 1% of males in certain branches of the family. This phenomenon was also noted in a seven-generation Brazilian family [Sadun et al 2003], and in families in which the LHON-causing mutation occurred in a non-haplogroup J mtDNA background [Howell et al 2003]. A similar change has not been noticed in British families with LHON [Man et al 2003]. This difference may result from unknown genetic and/or environmental factors.

Pathophysiology. The ocular pathology in LHON is limited to the retinal ganglion cell layer with sparing of the retinal pigment epithelium and photoreceptor layer. There is marked cell body and axonal degeneration, with associated demyelination and atrophy from the optic nerves to the lateral geniculate bodies. Experimental data indicate impaired glutamate transport and increased mitochondrial reactive oxygen species production that trigger retinal ganglion cell death via an apoptotic mechanism [Danielson et al 2002, Beretta et al 2004, Zanna et al 2005]. However, the selective vulnerability of retinal ganglion cells in LHON remains unexplained.

Anticipation

There is no evidence of anticipation with LHON.

Prevalence

In the North East of England, 1:8,500 individuals were found to harbor a primary LHON-causing mutation; 1:31,000 had experienced visual loss as a result of LHON [Man et al 2003]. Fairly similar figures have been reported in other Northern European populations, with an LHON prevalence of 1:39,000 in the Netherlands and 1:50,000 in Finland [Spruijt et al 2006, Puomila et al 2007].

The relative frequency of the different LHON-causing mtDNA mutations varies throughout the world. Overall, the m.11778G>A mutation is the most prevalent, accounting for 70% of cases among Northern European [Mackey et al 1996] and approximately 90% of cases in Asian populations [Mashima et al 1998, Jia et al 2006]. The m.14484T>C mutation is the most common cause of LHON among French Canadians [Macmillan et al 1998] but is much less frequent in Northern European populations [Mackey et al 1996, Chinnery et al 2001].

Differential Diagnosis

If 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 neuronopathy (DDON). This disorder, found in males, 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 consistent 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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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 perimetry
  • ECG. Although a relatively rare finding, an ECG may reveal a pre-excitation syndrome in both symptomatic and asymptomatic individuals who have an LHON-causing mtDNA mutation. Even when present, such an ECG finding does not necessitate further intervention in the absence of cardiac symptoms.
  • Screening for possible associated systemic complications including diabetes mellitus and cardiomyopathy, which can further compound the visual impairment among individuals with LHON
  • Medical genetics consultation

Treatment of Manifestations

Management of affected individuals is supportive and includes provision of visual aids, occupational rehabilitation, and registration with the relevant local social services.

A minority of individuals with LHON develop neurologic features including ataxia, peripheral neuropathy, and dystonia. This group of affected individuals should be managed by a multidisciplinary team of physicians to minimize the functional consequences of these neurologic complications.

Surveillance

Ongoing 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 Avoid

Individuals 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 Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Idebenone. 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 accelerate 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 2013]. 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. Affected individuals 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.

In the follow-up study (RHODOS-OFU), the beneficial effect of six months of treatment with idebenone seemed to persist despite discontinuation of the active medication at the end of the trial [Klopstock et al 2013]. In a large retrospective study involving 103 individuals with LHON, 44 with visual loss of one year’s duration or less were treated with idebenone and followed up for at least five years. A greater proportion of those in the treated group recovered vision compared with the untreated group, and the most consistent factor associated with visual recovery was an early initiation of treatment over a prolonged period of time [Carelli et al 2011].

EPI-743. In an open-label study of five individuals 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, Ellouze et al 2008, Lam et al 2010].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Leber hereditary optic neuropathy (LHON) is caused by mutations in mtDNA and is transmitted by maternal inheritance.

Risk to Family Members

Parents of a proband

  • The father of a proband is not at risk of having the disease-causing mtDNA mutation.
  • The mother of a proband usually has the mtDNA mutation and may or may not have developed visual loss.
  • In approximately 60% of cases, a history of visual loss affecting maternal relatives at a young age is present; up to 40% of individuals with LHON have no known family history of LHON. The explanation for these singleton cases may be that a detailed family history is not available or is unreliable, or that the proband has a de novo mtDNA mutation.
  • De novo mutations are thought to be rare.

Sibs of a proband. The risk to sibs depends on the genetic status of the mother: if the mother has the mtDNA mutation, all sibs are at risk of inheriting it.

Offspring of a proband

  • A male (affected or unaffected) with a primary LHON-causing mtDNA mutation cannot transmit the mutation to any of his offspring.
  • A female (affected or unaffected) with a primary LHON-causing mtDNA mutation will transmit the mutation to all of her offspring.
  • The presence of the mtDNA mutation does not predict the occurrence, age of onset, severity, or the rate of progression of visual loss. See Clinical Description, Risk Factors for Visual Loss for information regarding the risk to individuals with a primary LHON-causing mtDNA mutation of being affected.
  • If an affected female is heteroplasmic for the mtDNA LHON-causing mutation, she may transmit a low level of mutant mtDNA to her offspring, conferring a low disease risk [Chinnery et al 2001].

Other family members. The risk to other family members depends on the genetic status of the proband's mother: if the proband's mother has an mtDNA mutation, her sibs and mother are also at risk.

Related Genetic Counseling Issues

Penetrance. Genetic counseling for LHON is complicated by the gender- and age-dependent penetrance of the primary LHON-causing mtDNA mutations. Large studies have established accurate risks for the m.11778G>A and m.14484T>C mutations (reviewed in Yu-Wai-Man et al [2009]). Confirming the genetic status of an individual at risk for one of these mutations who is seeking counseling allows for an accurate estimation of the risks, based on established age- and gender-specific penetrance data (see Risk Factors for Visual Loss). Data for the m.3460G>A mutation are more limited; counseling for the other mutations requires cautious extrapolation.

Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for LHON is possible using the techniques described in Molecular Genetic Testing. Such testing is not useful in predicting age of onset, severity, or rate of progression in asymptomatic individuals. When testing at-risk individuals for LHON, an affected family member should be tested first to confirm the identification of the disease-causing mutation. The most important factors determining risk are gender and age. The presence of the mutation in leukocytes confers a lifetime risk (see Risk Factors for Visual Loss). For example, an 18-year-old male has a lifetime risk of approximately 50% for LHON after a positive test result. The risk declines with age but, because loss of sight can occur at any age, the risk never falls to zero. In large, multigenerational LHON pedigrees, these risks were known before the advent of molecular genetic testing. In smaller families it is important to confirm the genetic status because it is possible that the mutation is heteroplasmic in the affected individual or his mother, and it may not be present in every family member.

Testing for the disease-causing mutation in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of LHON, and the possible impact of positive and negative test results are assessed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential.

Molecular genetic testing of asymptomatic individuals younger than age 18 years and at risk for adult-onset disorders for which no treatment exists should not be performed. The principal arguments against testing asymptomatic individuals during childhood are that it removes their choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications. Children who are symptomatic usually benefit from having a specific diagnosis established. See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the mtDNA LHON-causing mutation in the mother has been identified, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks' gestation) or chorionic villus sampling (usually performed at ~10-12 weeks' gestation). Such testing may be available through laboratories that offer either testing for the gene of interest or custom testing.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Accurate interpretation of a positive prenatal test result is difficult for the following reasons:

  • Because of mitotic segregation, the mtDNA mutational load in amniocytes and chorionic villi may not correspond to that of other fetal or adult tissues.
  • The presence of the mtDNA LHON-causing mutation does not predict the occurrence, age of onset, severity, or rate of progression of visual loss in this mitochondrial genetic disorder. See Risk Factors for Visual Loss for information regarding the risk to individuals with a primary LHON-causing mtDNA mutation of being affected.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • International Foundation for Optic Nerve Disease (IFOND)
    PO Box 777
    Cornwall NY 12518
    Phone: 845-534-7250
    Fax: 845-534-7250
    Email: ifond@aol.com
  • United Mitochondrial Disease Foundation (UMDF)
    8085 Saltsburg Road
    Suite 201
    Pittsburg PA 15239
    Phone: 888-317-8633 (toll-free); 412-793-8077
    Fax: 412-793-6477
    Email: info@umdf.org
  • eyeGENE® - National Ophthalmic Disease Genotyping Network Registry
    Phone: 301-435-3032
    Email: eyeGENEinfo@nei.nih.gov

Molecular Genetics

Information 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 Databases

Data 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)

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 ATROPHY

Molecular Genetic Pathogenesis

See 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.

See Table 5 (pdf) for a list of mtDNA mutations that have strong evidence of pathogenicity.

See Table 6 (pdf) for a list of putative pathogenic mutations.

Normal gene product. See Mitochondrial Disorders Overview.

Abnormal gene product. See Mitochondrial Disorders Overview.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Published Guidelines/Consensus Statements

  1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 9-11-13. [PMC free article: PMC1801355] [PubMed: 7485175]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 9-11-13.

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Suggested Reading

  1. McFarland R, Taylor RW, Turnbull DM. A neurological perspective on mitochondrial disease. Lancet Neurol. 2010;9:829–40. [PubMed: 20650404]
  2. Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies - Disease mechanisms and therapeutic strategies. Prog Retin Eye Res. 2011;30:81–114. [PMC free article: PMC3081075] [PubMed: 21112411]

Chapter Notes

Revision History

  • 19 September 2013 (me) Comprehensive update posted live
  • 19 April 2012 (cd/pc) Revision: prenatal testing no longer listed in GeneTests Laboratory Directory; addition to therapies (EPI-743)
  • 7 July 2011 (me) Comprehensive update posted live
  • 10 March 2008 (me) Comprehensive update posted to live Web site
  • 3 October 2005 (pc) Revision: mitochondrial gene MTND2 added
  • 12 April 2005 (me) Comprehensive update posted to live Web site
  • 7 March 2003 (me) Comprehensive update posted to live Web site
  • 14 January 2002 (pc) Author revisions
  • 27 August 2001 (pc) Author revisions
  • 26 October 2000 (me) Review posted to live Web site
  • May 2000 (pc) Original submission
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