Genetics of Primary Inherited Disorders of the Optic Nerve: Clinical Applications

Abstract

Inherited disorders of the optic nerve significantly impact vision in children and adults. The optic nerve disorders most commonly encountered clinically are glaucoma and primary optic neuropathy including Leber's hereditary optic neuropathy (LHON) and autosomal dominant or Kjer's optic atrophy. Current knowledge of the genetics of optic neuropathy and glaucoma makes it possible to test for mutations in disease-causing genes allowing for presymptomatic testing and risk assessment, and recent advances have revealed important disease mechanisms that may suggest potential therapeutic targets. In this perspective, we describe the current approaches and limitations to genetic testing for these disorders and provide an update on the development of gene-based therapies.

Figure 1.

Characteristics of mutations causing early-onset glaucoma compared with genetic variants associated with adult-onset glaucoma. The frequency of the variant is listed on the x-axis and the magnitude of the biological effect (i.e., odds ratio or relative risk) is represented by the values on the y-axis.

Figure 2.

Distribution of mutations in early-onset glaucoma genes in a cohort of glaucoma patients with onset before age 40. Mutations in early-onset glaucoma genes are presented as a fraction of 220 patients evaluated through the genetic testing service at the Massachusetts Eye and Ear Infirmary. Eighty percent of patients with early-onset glaucoma do not have a mutation in a known gene.

Figure 3.

Distribution of mutation in mitochondrial DNA or OPA1 in a cohort of primary optic atrophy patients. Mutations in mitochondrial DNA or OPA1 are presented as a fraction of 64 patients evaluated through the genetic testing service at the Massachusetts Eye and Ear Infirmary. Fifty-six percent of patients with primary optic atrophy do not have a mutation in mitochondrial DNA, OPA1, or OPA3.