Leber Hereditary Optic Neuropathy

Leber hereditary optic neuropathy (LHON) is a maternally inherited form of optic neuropathy that is associated with several mitochondrial DNA (mtDNA) mutations.367,385,613,906 Although five such mutations have been identified (nucleotide positions 11778, 3460, 14482, 15257, 4160),.411,413,415,604 over 95% of LHON cases are primarily the result of 1 of 3 mitochondrial DNA point mutations (G11778A [50–76% of families], G3460A [7–30%], T14484C [7–30%]). 529,536,627,788 It is likely that other mitochondrial dysfunction plays a role in nonhereditary cases of LHON-like optic neuropathy.5 It manifests typically in the second or third decade of life, but the age of onset may vary widely. The sex predilection varies in different geographic areas; the male-to-female ratio in the United States is 9:1, but in Japan it is about 6:4. On the basis of reported cases, 50–80% of males and 8–32% of females at risk experience significant visual loss. About 50% of the males and 10% of the females with the genetic defect develop optic neuropathy. The condition usually presents between ages 15 and 35 years (range: 1–80 years) as unilateral blurred vision that progresses rapidly, with sequential involvement of the other eye within days to a few months. Infrequently, the second eye involvement may occur simultaneously (after many years) or, rarely, not at all. The visual acuity commonly stabilizes at or below 20/200, but it varies widely, with a range of 20/40 to no light perception. Even after bilateral visual loss, patients may retain brisk pupillary responses, possibly attributable to selective sparing of melanopsin-containing retinal ganglion cells. Color vision is severely diminished. The time course of visual loss differs from that of optic neuritis in that it continues to evolve over several months. The characteristic visual field defect is a central or cecocentral scotoma that may extend superiorly in some patients. The visual loss is permanent in most cases but, occasionally, patients may show variable recovery of vision even years after the acute episode. This recovery is typically restricted to a few central degrees and appears to be more likely in patients with the 11,778 deletion.828 Patients whose acuity improves to the greatest degree are generally younger at the time of visual loss.

Prior to and during the acute stages, the retinal examination usually shows a characteristic triad of signs: circumpapillary telangiectatic microangiopathy, pseudoedema of the disc and surrounding nerve fiber layer, and the absence of leakage on fluorescein angiography (Fig. 4.12).809 The discs are typically relatively cupless and crowded looking, with late branching vessels. These funduscopic changes may also be seen in presymptomatic cases and in asymptomatic maternal relatives. However, some patients with LHON never display these classic findings.620 Affected patients eventually

show optic atrophy with nerve fiber layer dropout, most notably in the papillomacular bundle. Several patients with the 15,257 mutation have been reported to show a macular degeneration resembling Stargardt disease.359

Because LHON may be associated with cardiac abnormalities, an electrocardiogram (EKG) or a 24-h Holter monitor should be performed. Preexcitation syndromes, including Wolff–Parkinson–White and Lown–Ganong Levine are found in 8–9% of patients with LHON.544,629,630 Prolongation of the QT interval has also been noted.654 Palpitations, syncope, myocardial hypertrophy, and sudden death have been reported in pedigrees with LHON.91,263,488,630,631,815,934 Histological changes in skeletal musculature, without clinical myopathy, may also occur.133

LHON is often misdiagnosed.368,412 In adults, it may be mistaken for dominant optic atrophy, anterior ischemic optic neuropathy,87 or tobacco-alcohol amblyopia.178 Because singleton cases are surprisingly common,620 it is common for LHON in children or adolescents to be diagnosed as optic neuritis, especially when CNS involvement coexists.668 Such associated neurologic involvement, if it occurs, is usually mild. Unusual cases may be associated with severe neurologic disease, making them difficult to differentiate from multiple sclerosis or Devic disease, especially if the characteristic fundus changes are absent. Rarely, a Leighlike encephalomyelopathy can accompany LHON.274,722 The extraocular muscles in LHON and chronic progressive external ophthalmoplegia (CPEO) show marked differences. A “mosaic-like” pattern caused by selective damage of muscle fibers was found in one patient with CPEO, whereas a diffuse increase in mitochondria with preservation of myofibrils characterized the LHON case. The increase in mitochondrial number may reflect a compensatory strategy for extraocular muscles and skeletal muscle.133 A Leber-like optic neuropathy has been associated with dystonia and basal ganglia lesions in several pedigrees.347,637 Although a disease that is clinically indistinguishable from multiple sclerosis may also coexist with LHON,72a191,255,491,526,626,628,661 studies of children with multiple sclerosis have not found Leber mutations.425,643,930 In that setting, genetic testing is needed to make the distinction. No treatment for LHON has been shown to be effective to date.

Until recently, controversy existed regarding the existence of an X-chromosome-encoded modifying gene that is invoked to explain the male predominance.615,901 Recently, two optic neuropathy susceptibility loci have been reported.379,790

The cause for incomplete penetrance in LHON is poorly understood.129,790 Both environmental and genetic factors have been studied as potential modulators of the penetrance of the disease. Although the preeminent epigenetic factors are reported to be tobacco and alcohol,178 one large study found no significant association between tobacco and alcohol consumption and vision loss among individuals harboring

Fig. 4.12  Leber hereditary optic neuropathy. This 10-year-old boy developed bilateral loss of vision in both eyes to level of counting fingers. Optic discs appeared somewhat swollen (a) right disc; (b) left disc with peripapillary telangiectatic microangiopathy most apparent in

inferotemporal arcade below left disc. His mother showed similar optic disc appearance but was normally sighted. Four months later, his optic discs appeared diffusely pale; telangiectasia and swollen appearance were absent (c) right disc; (d) left disc)

LHON mutations.438 There is also some evidence that systemic illnesses may trigger the clinical disorder in a predisposed individual.220 The toxic/nutritional modulation of the clinical manifestation of LHON may, in a general sense, be bidirectional. Sadun et al753 investigated an epidemic of optic neuropathy in Cuba and found that nutritional and toxic factors were producing an acquired mitochondrial injury, with a resulting clinical syndrome that resembles LHON. Tobacco smoking and alcohol intake have been linked with the development of LHON in some, but not all, studies. The use of some prescription drugs, dietary supplements, or exposure to toxins have all been associated with the onset of disease in anecdotal reports. The male bias in LHON suggests that one or more genes on the X chromosome may be responsible for the incomplete penetrance. Although all descendents in a maternal lineage would inherit a mitochondrial mutation and be at risk for optic neuropathy, a digenic model would predict that only

those who also inherit an X-linked recessive mutation would actually develop the disease.790

The commonly observed intrafamilial phenotypic variability may also be explained on the basis of mtDNA heteroplasmy (the coexistence of normal and mutant mtDNA in variable combinations in different patients).810 Only when the percentage of affected mitochondria is high does the disorder become clinically manifested. However, epigenetic factors appear to play a role in the pathogenesis, as attested to by identical twins who are discordant for the disease.414 In LHON, the physical constraints near the lamina cribrosa may limit the size and transport of mitochondria, eventually leading to energy depletion and retinal ganglion cell degeneration.130,749,752 Although several theories have been advanced,130,226 it is not known why central visual loss occurs as an all-or-nothing event, what factors produce this ictus, why it never recurs, or how central vision, once extinguished, can spontaneously improve.