LHON was the first disease to be associated with mitochondrial DNA (mtDNA) point mutations and is, therefore, maternally inherited. Whereas both the father and the mother contribute to the nuclear portion of the zygote, the mother's ovum is virtually the sole provider of the zygote's cytoplasmic contents which contains several hundred intracytoplasmic mitochondria. “Maternal inheritance” refers to the transmission of the mitochondrial genome from a mother to all her children, with no paternal mtDNA contribution. The mitochondria generate the cellular energy necessary for normal cellular function and maintenance thus those cells in tissues particularly reliant on mitochondrial energy production, such as the central nervous system, including the optic nerve, retinal pigment epithelium, and extraocular muscles will contain more mitochondria. If a new mutation occurs in the mtDNA and the proportion of mutant mtDNA exceeds a certain tissue-specific threshold, however, the wildtype mtDNA is no longer able to compensate to sustain normal cellular function, and the disease phenotype is expressed.
In LHON mitochondrial mutations affect complex I subunit genes in the respiratory chain leading to selective degeneration of retinal ganglion cells (RGCs) and optic atrophy within a year of disease onset. Three common mtDNA mutations (m.11778G.A/MTND4, m.3460G.A/MT-ND1, m.14484T.C/MT-ND6) are account for about 90% of clinical cases in multiple and ethnically divergent pedigrees. These mutations are absent or very rare among normal controls.
Except in rare cases of de novo occurrence of a primary LHON mutation, a mtDNA mutation will be present in all maternally related family members of patients with LHON, even though many will never become symptomatic. Hence, whereas the presence of a mtDNA mutation is necessary for phenotypic expression, it may not be sufficient. Since the amount of mutant mtDNA in the optic nerves of individuals at risk may differ, the degree of tissue heteroplasmy might help explain the variable phenotypes seen in patients whose mitochondrial genotypes measured in blood alone appear similar.
Other genetic factors may influence phenotypic expression of LHON such as nuclear genes that regulate the expression of mitochondrial genes.
Because male predominance of visual loss in LHON, an X-linked vision loss susceptibility gene has been hypothesized. Recent studies have identified a high-risk haplotype at Xp21 associated with a 35-fold increase in vision loss among patients with the 11778 and 14484 mutations.
Immunologic factors have also been suggested, mainly to explain the association of LHON with multiple sclerosis. However, studies have shown the HLA-DR locus is not a major genetic determinant for the development of visual loss.
Internal and external environmental factors may also play a role. Systemic illnesses, nutritional deficiencies, trauma, medications, or toxins that stress or directly or indirectly inhibit mitochondrial metabolism have been proposed to affect phenotypic expression of the disease.
Leber hereditary optic neuropathy (LHON) is estimated to be the most frequent mitochondrial disease with a prevalence ranging from 1 in 27,000 in North East England to 1 in 45,000 in a meta-analysis of reports in the European population. It has a strong male preponderance (80% to 90%), and the usual age at onset is between 15 to 35 years.
The subset of macular RGCs providing axons for the papillomacular bundle and serving central vision is affected first and preferentially resulting in a visual loss that typically begins painlessly and centrally in one eye. Some patients complain of a sensation of mist or fog obscuring their vision, whereas others note mild central fading of colors. The second eye is usually affected weeks to months later and in greater than 97% of patients within one year.
Most patients deteriorate to acuities worse than 20/200. Colour vision is affected severely, often early in the course, but rarely before the significant visual loss. Pupillary light responses may be relatively preserved when compared with the responses in patients with optic neuropathies from other causes.
Visual field defects are typically central or cecocentral. The scotomas may be relative during the early stages of visual loss but rapidly become large and absolute, measuring at least 25 to 30 degrees in diameter. A breakthrough of the scotoma is not uncommon. Unaffected eyes may show subtle cecocentral scotomas only to red test objects or as a mild depression on central automate perimetry.
There are specific funduscopic abnormalities that can be seen in patients with LHON especially during the acute phase when they present with visual loss. These include hyperemia of the optic nerve head, dilation and tortuosity of optic nerve head vessels, retinal and disc hemorrhages, macular edema, exudates, retinal striations, and obscuration of the disc margins in some cases.
A triad of signs pathognomonic for LHON is circumpapillary telangiectatic microangiopathy, swelling of the nerve fiber layer around the disc (pseudoedema), and absence of leakage from the disc or papillary region on fluorescein angiography (distinguishing the LHON from truly edematous discs).
The “classic” LHON ophthalmoscopic appearance may be helpful in suggesting the diagnosis if recognized in patients or their maternal relatives, however, its absence even during the period of acute visual loss does not exclude the diagnosis of LHON. As the disease progresses, the telangiectatic vessels disappear, and the pseudoedema of the disc resolves. Perhaps because of the initial hyperemia, the optic discs of patients with LHON may not appear pale for some time. This feature, coupled with the relatively preserved pupillary responses and the lack of pain, has led to the misdiagnosis of nonorganic visual loss in some LHON patients. Eventually, however, optic atrophy with nerve fiber layer dropout most pronounced in the papillomacular bundle will become apparent on the examination.
Recent optical coherence tomography (OCT) and histopathology studies have substantiated the occurrence of a precise pattern in retinal nerve fiber layer (RNFL) loss, disease progression, and natural history. In particular, loss of macular RGCs precedes the clinical disease onset. Clinical stages of LHON can be defined according to the time of onset and clinical investigations. In asymptomatic phase (mutation carriers) the fundus examination may be normal or there may be recognizable changes and OCT measurements including vascular abnormalities (microangiopathy and telangiectatic vessels), hyperemia of the optic disc, and RNFL swelling (pseudoedema) that is detected by OCT as increased thickness of the RNFL in the inferior and temporal quadrants.
Subacute phase is defined as 6 months from onset of clinical symptoms. As central scotoma develops and central visual acuity starts to deteriorate rapidly, and it is at this time that most patients will usually seek medical attention.
Visual acuity usually stabilizes within 4 to 6 months of the onset of symptoms. The dynamic phase is between 6 months to 1 year from the onset of symptoms. Clinical metrics such as visual fields and OCT measurements may still evolve usually plateauing at one year after onset. At this point, the dynamic phase ends with a transition into the chronic stage of the disease.
There can be variations from the classic clinical course with some patients demonstrating slowly progressive variant, and progression of visual loss is slow and gradual rather than sudden. In the childhood disease variant, the onset of visual loss happens in patients who are younger than 12 years of age and in the rare late-onset variant visual loss occurs after 65 years of age.
In most patients with LHON visual dysfunction is the only significant manifestation of the disease.
However, some pedigrees have members with associated cardiac conduction abnormalities.
“Leber’s plus” is defined as the presence of minor neurologic abnormalities in patients with LHON.
Furthermore, disease clinically indistinguishable from multiple sclerosis may occur in families with LHON, and an underlying LHON mutation may worsen the outcome of optic neuritis in a patient with multiple sclerosis.
Clinicians should perform the following clinical investigations in all patients suspected of having LHON: visual acuity, color vision, fundus examination, visual field perimetry, and OCT imaging. For childhood disease, they should measure the optic disc vertical diameter on OCT Larger diameter may be associated with a better visual prognosis. For late-onset LHON cases it is important to consider toxic exposure (e.g., smoking, drinking, and environmental factors).
With any extraocular features are present an MRI of the brain should be performed.
ECG should also be ordered for all patients with LHON as it may reveal cardiac conduction abnormalities.
All patients who harbor an LHON mutation should be strongly advised to discontinue smoking, avoid excessive alcohol intake, avoid exposure to solvents and other fumes and take daily vitamin supplements.
In 2017, an international consensus statement on the clinical and therapeutic management of LHON was published. It is noteworthy that it concluded that prognostic factors should not affect the management.
Idebenone (Raxone, Santhera Pharmaceuticals, Liestal, Switzerland) is a short-chain synthetic analog of ubiquinone that supports mitochondrial ATP synthesis and has antioxidant properties.
It was recommended that Idebenone should be started as soon as possible at 900 mg/day in patients with disease less than 1 year ago which it is still in the subacute/dynamic phase. Treatment should be continued for at least 1 year to assess the start of therapeutic response or until a plateau regarding improvement is reached. A clinically relevant response (recovery of vision) to treatment should be defined according to Improvement of 2 lines of BCVA on ETDRS charts (or from off-chart to on-chart) and automated visual field test (mean deviation). Once a favorable clinically relevant outcome has been confirmed, and after reaching a plateau, the treatment should be continued for another year.
The ideal recommended frequency of follow-up is approximately every 3 months for subacute and dynamic cases, then approximately every 6 months during the second year from the disease onset, and once a year after that.
Differential diagnosis includes other optic neuropathies especially demyelinating optic neuritis and neuromyelitis optica spectrum disease, toxic, metabolic, and compressive optic neuropathies. In addition, maculopathies and nonorganic vision loss should be considered.
In most patients with LHON, visual loss remains profound and permanent.
However, some spontaneous recovery may occur gradually over 6 months to 1 year after an initial visual loss or may suddenly occur up to 10 years after onset. It may take the form of a gradual clearing of central vision or be restricted to a few central degrees, resulting in a small island of vision within a large central scotoma which can be demonstrated on visual field testing.
The good visual outcome is strongly correlated with the young age at onset with most patients in whom the onset is before 20 years having a final visual acuity better than 20/80. Furthermore, the particular mitochondrial DNA mutation also influences prognosis, with the 11778 mutations carrying the worst prognosis for vision (only 4% reported spontaneous recovery) and the 14484 mutation the best (37% to 65% reported spontaneous recovery). Moreover, the ultimate visual acuities in patients with the 14484 mutation are significantly better than those with the 11778 and 3460 mutations.
Importantly, recurrences of visual failure are rare among patients both with and without visual recovery.
LHON is best managed by an interprofessional team that includes nurses and pharmacist.
Screening of Family Members
All maternally related relatives should be clinically screened. However, it is not necessary to perform genetic screening for LHON mutation. Currently, treatment is not recommended for relatives of an LHON patient. However, relevant lifestyle counseling is recommended.
There is no algorithm or predictive risk factors that could be used to assess the risk of becoming symptomatic.
Unfortunately, in most patients the vision loss is permanent.
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