Funded by the NIH • Developed at the University of Washington, Seattle
Funded by the NIH • Developed at the University of Washington, Seattle
[Hereditary Optic Neuroretinopathy, LHON, Leber's Disease, Leber's Optic Atrophy, Leber's Optic Neuropathy]
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Authors:
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Patrick Yu-Wai-Man, MBBS, MRCOphth
Patrick F Chinnery, MBBS, PhD, MRCP |
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Initial Posting:
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Last Update:
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Disease characteristics. Leber hereditary optic neuropathy (LHON) is characterized by bilateral, painless, subacute visual failure that develops during young adult life. Males are approximately four times more likely to be affected than females. 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 eight weeks later. In an estimated 25% of cases, visual loss is bilateral at onset. Visual acuity is severely reduced to counting fingers or worse in most cases, and visual field testing (Goldmann perimetry or a similar technique) shows an enlarging 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). Minor neurologic abnormalities (e.g., postural tremor, peripheral neuropathy, nonspecific myopathy, movement disorders) are said to be more common in individuals with LHON but are rarely clinically significant. Some individuals with LHON, usually women, may also have a multiple sclerosis (MS)-like illness.
Diagnosis/testing. The diagnosis is based on ophthalmologic findings. Testing includes fundus examination, fluorescein angiography to identify characteristic vascular changes in the acute phase, Goldmann perimetry or a similar technique to identify the characteristic centrocecal scotoma, electrophysiologic studies (visual evoked potentials to confirm optic nerve dysfunction and pattern electroretinogram to confirm the absence of retinal disease), and cranial imaging to exclude other compressive, infiltrative, and inflammatory causes of a bilateral optic neuropathy. Approximately 95% of individuals with LHON have one of three point mutations of mitochondrial DNA (mtDNA): m.3460G>A, m.11778G>A, or m.14484T>C. Clinical molecular genetic testing for these mutations is available.
Management. Treatment of manifestations: Management of affected individuals is supportive, with provision of visual aids and registration with the relevant social services. ECG may reveal a pre-excitation syndrome in both affected and unaffected LHON carriers; it does not require further intervention in the absence of cardiac symptoms. Agents/circumstances to avoid: Individuals who have known LHON-causing mtDNA mutations are advised to avoid smoking and to moderate alcohol intake.
Genetic counseling. Leber hereditary optic neuropathy is caused by mutations in mtDNA and is transmitted by maternal inheritance. Genetic counseling for LHON is complicated by the gender- and age-dependent penetrance of the primary mtDNA 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 is unlikely to correspond to that of other fetal or adult tissues and the presence of the mtDNA mutation does not predict the occurrence, age of onset, severity, or rate of disease progression.
Leber hereditary optic neuropathy (LHON) is characterized by bilateral, painless subacute visual failure that develops during young adult life. Males are approximately four times more likely to be affected than females.
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 eight weeks later. In an estimated 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 an increased vascular tortuosity. The changes may be subtle; approximately 20% of affected individuals show no fundal abnormalities.
Visual acuity is severely reduced, to counting fingers or worse in most cases, and visual field testing (Goldmann perimetry or a similar technique) shows an enlarging central or centrocecal scotoma.
Atrophic phase. After the acute phase, the optic discs become atrophic. Significant improvements in visual acuity are rare; in most individuals, vision remains severely impaired and 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 feature in this mitochondrial 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 LHON as compared to controls [Man et al 2002]. In addition, the association between all three primary LHON-causing mtDNA mutations (see Table 1) and an MS-like illness among Caucasians, especially females, is well known [Kellar-Wood et al 1994 , Jansen et al 1996 , Bhatti & Newman 1999].
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 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.
Cranial imaging is necessary to exclude other compressive, infiltrative, and inflammatory causes of a bilateral optic neuropathy. In individuals presenting with LHON, MRI is often normal but may reveal a high signal within the optic nerves, the latter probably representing slight edema or gliosis in the atrophic phase.
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 thus 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 these biochemical studies is that none found a significant difference between affected and unaffected individuals with a disease-causing mutation. Balancing the current weight of evidence, LHON is associated with a respiratory chain defect that is more subtle than respiratory chain defects in other mitochondrial disorders and biochemical studies have been superseded by molecular genetic testing.
Note: These discrepancies highlight the lack of understanding of the relationship between the mtDNA defect, the biochemical defect, and the clinical phenotype.
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Genes. Mutations in the mitochondrial genes that encode subunits of NADH dehydrogenase, MT-ND1, MT-ND2, MT-ND4, 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
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], 95% 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, Neufeld et al 1992], 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 Caucasian 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 uncommon in the United Kingdom and in Scandinavia [Mackey et al 1996 , Chinnery et al 2000].
Approximately 5% of individuals with LHON do not harbor one of the three common mtDNA point mutations; further investigation of these families is difficult because mtDNA is highly polymorphic [Chinnery et al 1999b , Taylor et al 2003]. A number of different mtDNA mutations have been described in a single family; however, a novel base change cannot be considered pathogenic until it has been observed on two or more occasions and only in association with LHON.
Secondary LHON-causing mtDNA mutations. In addition to the primary mtDNA mutations described above, numerous additional mtDNA nucleotide changes (here referred to as "secondary" mutations) have been associated with LHON (e.g., m.4216T>C, m.13708G>A, m.15257G>A) and are also prevalent in the general population [Howell et al 1995]. Although testing for some secondary LHON-causing mutations is clinically available, the interpretation and significance of these mtDNA changes is complex, and the testing is therefore not performed routinely.
Sequence analysis and mutation scanning detect additional nucleotide variants in the other 5% of individuals with LHON who do not have a mutation detected using the panel of common mutations.
Table 2 summarizes molecular genetic testing for this disorder.
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Test Method
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Mutations Detected
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Mutation Detection Frequency by Test Method
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Test Availability
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One of three primary mtDNA NADH dehydrogenase gene mutations: m.11778G>A, m.14484T>C, m.3460G>A
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~95%
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Clinical
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Sequence analysis/mutation scanning
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Other mtDNA sequence variants
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~5%
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Interpretation of test results. Heteroplasmy, a mixture of mutant and wild-type mtDNA in blood 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 75% 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 of transmission [Chinnery et al 2001]; however, no rigorous prospective studies have been performed to clarify this possibility.
To confirm 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).
If these tests are negative, the individual's history and examination findings should be 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.
Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation in the family.
Mitochondrial DNA mutations cause a heterogeneous group of sporadic and 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].
Leber hereditary optic neuropathy (LHON) typically presents in young adults as bilateral, painless, subacute visual failure. The median age of onset in LHON varies somewhat between series, but 95% of those who lose their vision do so by age 50 years. Very rarely, individuals first manifest LHON in the seventh decade of life [Buchan et al 2007]. Males are approximately four times more frequently 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 telangiectasic 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.
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 also have a multiple sclerosis (MS)-like illness. Although the correlation between LHON and MS is a point of contention, the frequency of co-occurrence is probably greater than that attributable to chance [reviewed in Bhatti & Newman 1999 , Horvath et al 2000]. (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].
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 prognosis.
m.3460G>A has an intermediate phenotype.
Reported visual recovery rates among persons with LHON are summarized in Table 3 .
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Visual Recovery
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References
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m.11778G>A
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4%-25%
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m.14484T>C
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37%-58%
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m.3460G>A
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22%-25%
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A multiple sclerosis -like illness has been seen in association with all three mutations.
The primary LHON-causing mtDNA mutations have markedly reduced penetrance. An individual can only develop LHON if the primary mtDNA mutation is present, but approximately 50% of males and 90% of females who harbor a primary LHON-causing mtDNA mutation do not develop blindness. It is thought that additional environmental and genetic factors interact with the primary mtDNA defect and determine whether an individual harboring the LHON-causing mtDNA mutation develops the disease. The two most important risk factors are gender and age (Table 4).
Lifetime risk of 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 symptoms (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).
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Risk of Developing Symptoms
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Median Onset (Males)
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Male:Female Ratio
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Reference
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Males
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Females
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m.3460G>A
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32%
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15%
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20 yrs
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4.3:1
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m.3460G>A
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49%
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28%
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22 yrs
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1.7:1
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m.11778G>AG
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43%
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11%
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24 yrs
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3.7:1
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m.11778G>A
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51%
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9%
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22 yrs
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5.1:1
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m.14484T>C
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47%
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8%
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20 yrs
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7.7:1
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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 roughly 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 a m.11778G>A mutation load of greater 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.
A recent meta-analysis of 159 European LHON pedigrees indicates that the risk of visual loss for the three primary LHON-causing mutations is influenced by the mtDNA haplogroup [Hudson et al 2007].
The risk of 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.
On the other hand, individuals with the m.11778G>A mutation had a lower risk of visual loss when the mutation arose on haplogroup H.
However, in a study of Southeast Asian LHON pedigrees, no association between mtDNA haplogroups and the risk of 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 [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 of visual failure 35-fold for the m.11778G>A and m.14484T>C LHON-causing mutations but not for m.3460G>A. The actual causative gene at Xp21.1 has not yet been identified and the possibility of other autosomal nuclear modifier genes in LHON has also not been excluded.
Environmental factors. Many studies have reported LHON developing in individuals who have high tobacco and alcohol consumption [Riordan-Eva et al 1995 , Chalmers et al 1996]. However, a more recent case-control study failed to confirm the association between heavy smoking or alcohol intake and an increased risk of visual loss [Kerrison et al 2000]. There are also 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 environmental triggers in LHON remains circumstantial at best and calls for more robust epidemiologic evidence, a difficult task for a rare genetic condition.
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.
There is no evidence of anticipation with LHON.
In the North East of England, 1:8,500 individuals were found to harbor a primary LHON-causing mutation, and 1:31,000 had experienced visual loss as a result of LHON [Man et al 2003]. Fairly similar figures have been reported in other Caucasian 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 Caucasians [Mackey et al 1996] and approximtaley 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].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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 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.
To 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 perimetry
Currently, no available treatment improves the final visual outcome in LHON.
Management of affected individuals is supportive and includes provision of visual aids and registration with the relevant social services.
ECG may reveal a pre-excitation syndrome in both affected and unaffected LHON carriers; such a finding does not necessitate further intervention in the absence of cardiac symptoms.
Individuals harboring established LHON-causing mtDNA mutations are advised to avoid smoking and to moderate alcohol intake.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Through a multicenter European collaboration, a phase II, randomized placebo-controlled trial is currently in progress to investigate the efficacy, safety, and tolerability of oral idebenone in LHON. Further details are available at lhon.cle.ac.uk .
Targeted gene therapy is also under exploration [Qi et al 2003 , Qi et al 2004 , Qi et al 2007].
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Small case series have reported that oral administration of a quinone analogue (idebenone) and/or vitamin supplementation (B12 and C) can speed up visual recovery and improve final visual outcome [Mashima et al 2000 , Carelli et al 2001]. However, a recent study has not found any benefit from idebenone and multivitamin supplementation in LHON [Barnils et al 2007] and until more robust evidence becomes available, these regimes should be considered experimental.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.
Leber hereditary optic neuropathy (LHON) is caused by mutations in mtDNA and is transmitted by maternal inheritance.
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 symptoms.
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 simplex 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 assumed 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 transmits 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 this typically adult-onset disease. See 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 has heteroplasmy, 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 a mtDNA mutation, her sibs and mother are also at risk.
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. 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). Less data are available for the m.3460G>A mutation, and counseling for the other mutations requires cautious extrapolation.
Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for LHON is available using the same 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.
Testing of at-risk individuals during childhood. Consensus holds that individuals younger than age 18 years at risk for adult-onset disorders for which no treatment exists should not have testing in the absence of symptoms. 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 resolution on genetic testing of children.)
Family planning. The optimal time for determination of genetic risk is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made 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 of developing LHON.