Clinical background
Historical development
Leber’s hereditary optic neuropathy (LHON) is a maternally inherited disease that presents with sudden or subacute nonsynchronous bilateral vision loss. Males in their second and third decade of life are typically affected. The classic visual field loss is a large and dense cecocentral scotoma usually associated with a decline of vision to greater than 20/200. LHON was first described by Von Graefe in 1858 and then characterized formally into a distinct clinical entity by Leber in 1871. Originally, it was believed to be X-linked and inherited with partial penetrance. Erickson in 1972 was the first to propose that LHON could have a maternal inheritance pattern from a mitochondrial mutation. Then in 1988, Wallace and colleagues confirmed the hypothesis by identifying a G to A mutation at nucleotide position 11778 in the mtDNA of nine pedigrees.
Key symptoms and signs
LHON commonly manifests with acute or subacute painless central vision loss in one eye associated with dyschromatopsia. Within days, months, or rarely years, the second eye is similarly affected and the average interval time is 1.8 months. A few months after onset, the vision loss will typically plateau at or below 20/200. Acutely on clinical examination, the optic discs may appear hyperemic with a characteristic circumpapillary telangiectatic microangiopathy ( Figure 43.1 ). The nerve fiber layer will be swollen without evidence of leakage of dye on fluorescein angiography, leading to the term pseudopapilledema. Over time, axonal loss of the papillomacular bundle (PMB) leads to temporal pallor and eventually severe and diffuse optic atrophy and large absolute cecocentral scotomas are found on visual field testing ( Figure 43.2 ).
Genetics
Approximately 95% of the LHON cases of northern European descent are caused by the three most common mtDNA mutations at nucleotide positions 3460, 11778, and 14484. These three mutations all result in an amino acid substitution in complex I of the respiratory chain. To date, more than 37 point mtDNA mutations have been identified. Of these point mutations, genes encoding for ND1 and ND6 appear to occur the most frequently. The ND1 and ND6 subunits are essential for mtDNA-encoded subunit assembly of complex I.
However the presence of LHON mtDNA mutations does not necessarily correlate with vision loss. Only 50% of men and 10% of women who carry the LHON mtDNA mutation develop the optic neuropathy. However, over 80% of affected patients are male.
Epidemiology
Studies in the north-east of England found that the minimum point prevalence of visual failure due to LHON was 3.22 per 100 000 and the minimum point prevalence for the LHON mtDNA mutation was 11.82 per 100 000. Therefore, LHON has a population prevalence similar to many autosomally inherited neurological disorders.
Differential diagnosis
There are other conditions of inherited optic neuropathies, such as Kjer’s dominant optic atrophy (OPA1) and Wolfram syndrome (WFS1 gene on chromosome 4), that share similar clinical characteristics and hence must be differentiated from LHON. Though these inherited optic neuropathies are coded by somatic genes, it does not mean that they are not mitochondrial optic neuropathies. Indeed, we now know that their gene products do indeed interact in or with mitochondria. Metabolic optic neuropathies, including a large number of toxic and nutritional optic neuropathies, must also be considered in the differential diagnosis of LHON; nutritional deficiencies include insufficient levels of folic acid and vitamin B 12 and toxic mitochondrial optic neuropathies such as ethambutol, chloramphenicol, and linezolid. Combinations of nutritional deficiencies and toxic exposure include tobacco–alcohol amblyopia and the Cuban epidemic of optic neuropathy.
Treatment
As yet, no treatment for LHON has been proven effective. Antioxidants, such as vitamins C, E, and coenzyme Q10, have been offered to patients with LHON. This is based on theoretical grounds related to the electron transfer chain of oxidative phosphorylation, but without any demonstration of clinical efficacy. A coenzyme Q10 analog (idebenone) seems slightly more promising; it offers the additional advantage of transport into mitochondria and a few anecdotal case reports have demonstrated some clinical improvement.
Prognosis
Visual recovery has been reported up to several years after vision loss and it is dependent on the age of onset and the specific mtDNA mutation. 14484 mtDNA mutations tend to have the best prognosis, whereas 11778 mtDNA mutations have the worst.
Pathology
A few cases of molecularly characterized LHON have been studied histopathologically; however these tissues were examined several decades after the clinical onset of disease. The most striking finding was the dramatic loss of retinal ganglion cells (RGC) and their axons, which constitute the nerve fiber layer and optic nerve ( Figure 43.3 ). The centrally located small-caliber fibers of the PMB were completely lost, whereas the larger axons of the periphery were spared. Mitochondria tend to accumulate in the retinal nerve fiber layer (rNFL) and particularly just anterior to the lamina cribrosa. In the retrolaminar optic nerve, damaged mitochondrial accumulations occurred in demyelinated fibers, with activated astrocytes, glial cells, and lipofuscin-laden macrophages being observed near areas of relative axonal sparing. A wide variability in myelin thickness was seen along with evidence of some remyelination.
As yet, no cases of histopathology of LHON have been obtained and examined during the acute phase of the disease. In this regard, rNFL analysis by optical coherence tomography (OCT) has been valuable and demonstrates significant thickening of the rNFL during the early and acute stages of LHON. These findings were most evident in the superior quadrant, followed by the nasal and inferior quadrants. Consistent with the PMB rNFL loss, less significant thickening was observed in the temporal quadrant. In the late stages, OCT revealed that the rNFL was significantly thinned and atrophic, with the temporal fibers being the most severely affected and the nasal fibers being relatively spared. Taken as a whole, these studies suggest that the pathophysiology of LHON in the rNFL begins in the PMB and is associated with axonal swelling of the arcuate bundles. As atrophy sets in, the smaller-caliber fibers of the PMB are affected first. Later, the larger-caliber fibers of the arcuate bundles become thinned with comparative sparing of the nasal periphery.
Etiology
As yet, parts of the pathogenesis of LHON remain unclear. However, the underlying inherited basis of this disorder is understood. Though the primary etiologic cause is a mitochondrial genome (mtDNA) mutation, the presence of the LHON mtDNA mutation is necessary but not sufficient to lead to serious visual loss. As this is not a somatic mutation, the term carrier has been applied to those with the mutation but without significant visual loss. Many patients who are asymptomatic carriers may demonstrate subclinical disease, manifested as subtle dyschromatopsia. Affected patients are then said to have converted when they suffer abrupt and serious loss of vision. Thus, the penetrance of LHON is variable. Other genetic, epigenetic, and environmental factors appear to play a role in triggering the phenotypic expression of the disease. Studies of a large Brazilian pedigree of over 300 individuals have demonstrated this variable penetrance and the role of some environmental factors. In particular, smoking tobacco and drinking alcohol seem to increase significantly the odds of conversion from carrier to affected status.
Genetic factors
The three most common LHON mtDNA mutations are at nucleotide positions 3460, 14484, and 17788. Approximately 8–25% are due to the 3460 mutation, 10–15% account for the 14484, and 50–70% have the 17788 mutation. A higher amount of Asian LHON patients have the 11778 mtDNA mutation. In most LHON patients and family members, the mtDNA mutation is homoplasmic, containing only mitochondria with the pathogenic mutation. Approximately 14% of LHON patients carry both the mutant and wild-type DNA, a condition known as heteroplasmy. Studies have estimated that the heteroplasmy threshold for the phenotypic expression of LHON was 75–80%. The prevalence of at least some heteroplasmy was 5.6%, 40%, and 36.4% for the 11778, 3460, and 14484 mtDNA mutations, respectively, in 167 unrelated LHON pedigrees.
As stated earlier, approximately 50% of men and 10% of women who carry the LHON mtDNA mutation progress to develop the optic neuropathy. This male bias would suggest that the X chromosome plays a nuclear modulating role in the phenotypic expression of the disease. A previous study of 100 European pedigrees harboring all three mtDNA mutations identified a susceptibility locus on chromosome Xp21-q21. An additive interaction was observed between this high-risk nuclear haplotype spanning markers DXS8090-DXS1068 and mtDNA haplogroups. It found that 100% of individuals with both this chromosome X haplotype and a nonhaplogroup J background were visually impaired. Another novel susceptibility locus on chromosome Xq25-27.2 has been identified in a large Brazilian pedigree that carry a homoplasmic 11778 mtDNA mutation on a haplogroup J background.
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