Leber hereditary optic neuropathy (LHON) is due to mutations in the mitochondrial genome. The worldwide prevalence of LHON is estimated to be between 1:30,000 and 1:50,000. This prevalence varies in different populations and in most populations is unknown. It is usually bilateral although often sequential. Vision loss is acute or subacute and painless. Patients usually have a large central or cecocentral scotoma. LHON is expressed predominantly in males with approximately 80 to 90% of affected patients being male, but it can affect either gender at almost any age. The reason for male predominance is not well understood.

All mitochondrial deoxyribonucleic acid (mtDNA) pathogenic mutations associated with LHON have incomplete clinical penetrance, so symptoms are not always present in individuals who have the mutation. This variable penetrance may reflect the action of unlinked modifier genes, epigenetic changes, or environmental factors. For example, alcohol intake or smoking seem to raise the chance of vision loss, and may negatively affect the chance of spontaneous recovery in those who experience loss of vision. The phenotypic expression of LHON may also be affected by the type of mtDNA mutation and mitochondrial haplotype.

Most patients deteriorate to acuities of 20/200 or worse. Color vision is affected early and severely, and visual fields typically show central or cecocentral defects. Depending on the underlying mtDNA point mutation and haplotype, up to 60% of patients may have some degree of spontaneous improvement. A younger age at the time of initial visual loss is associated with a better visual outcome. It has been suggested that the pupillary function is relatively preserved in the affected eyes of LHON patients. Some cases have been reported of partial spontaneous recovery of visual acuity, especially in children and with m.14484T>C mutation. The eyes can be affected simultaneously or sequentially, with an average interval between eyes being affected of approximately 2 months.

Funduscopic abnormalities may be seen, particularly during the acute phase of visual loss, when there may be hyperemia of the optic nerve head, dilatation and tortuosity of vessels, hemorrhages, circumpapillary telangiectatic microangiopathy, or circumpapillary nerve fiber layer swelling (▶ Fig. 31.1). Over time, the optic nerves become pale without distinguishing clinical features. There may also be nonglaucomatous cupping of the disc and arterial attenuation.

31.2 Molecular Genetics

The precise pathogenesis of LHON has not yet been fully determined. Three primary mtDNA point mutations are found in more than 95% of patients: m.11778G>A (ND4), m.3460G>A (ND1), and m.14484T>C (ND6). More than 30 other infrequent mitochondrial mutations have also been associated with LHON. mtDNA mutations associated with LHON may be heteroplasmic or homoplasmic based on blood testing. Although there may be some correlation between clinical expression and degree of heteroplasmy, it must be remembered that mutation load can vary greatly from one tissue to another. Therefore, blood testing may not directly reflect the mutation load at the level of the optic nerve. Symptomatic individuals are typically homoplasmic for an mtDNA mutation in their blood, but there are exceptions and affected individuals with varying degrees of heteroplasmy for the family mtDNA mutation have been reported. This limitation to test interpretation is one of the many challenges in counseling at-risk family members.

31.3 Differential Diagnosis

31.3.1 Autosomal Dominant Optic Atrophy (OMIM 165500)

Autosomal dominant (AD) optic atrophy, also known as Kjer’s optic atrophy, is the most common form of hereditary optic neuropathy. It is caused by mutations in OPA1 (3q29). The incidence is approximately 1 in 10,000 to 50,000 live births. It is a childhood-onset disorder typically characterized by a bilateral slow and progressive loss in central vision, dyschromatopsia, and paracentral scotomas. The optic disc pallor is typically sectorial and temporal, sometimes referred to as “pie in the sky” atrophy, but may be more severe and complete. The expression displays both inter- and intrafamilial variability with incomplete penetrance. Symptoms typically start during the first or second decade of life. Some patients with mutations in OPA1 may also develop extraocular neurologic features, such as deafness, progressive external ophthalmoplegia, muscle cramps, hyperreflexia, and/or ataxia (“optic atrophy plus syndrome”).

In addition, there are other known loci for optic atrophy, which are included in ▶ Table 31.1.

31.3.2 3-Methylglutaconic Aciduria Type III (OMIM 258501)

This autosomal recessive (AR) condition is also known as recessive optic atrophy type 3 (OPA3) or optic atrophy plus syndrome. It is an allelic disorder of OPA3, and is caused by mutation in the OPA3

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