Optic atrophy

Inherited optic atrophy typically presents with painless, usually bilateral impairment of visual acuity. The clinical hallmark is optic-disc pallor, reflecting loss of retinal ganglion cells and their axons. Colour-vision abnormalities and central or centrocaecal visual-field defects are common. Hereditary optic neuropathies may follow an acute, subacute or slowly progressive course, depending on the underlying genetic condition.

Retinal ganglion cells are particularly vulnerable to mitochondrial dysfunction, and many inherited optic neuropathies are caused by pathogenic variants affecting mitochondrial function. These variants may occur in nuclear genes or in mitochondrial DNA; mitochondrial DNA variants are transmitted through the maternal line.

Hereditary optic atrophy may manifest at any age, although many forms begin in childhood, adolescence or early adulthood. Age at onset, severity and disease course vary considerably according to the underlying genetic cause. Hereditary optic atrophy may occur as an isolated condition or as part of a multisystem disorder. Associated extraocular manifestations may include sensorineural hearing impairment, ataxia, peripheral neuropathy, myopathy and progressive external ophthalmoplegia.

The overall prevalence of inherited optic atrophy is not well established. Autosomal dominant optic atrophy is considered the most common inherited optic neuropathy and therefore accounts for a substantial proportion of genetically determined cases. Population-based prevalence estimates for this form range from approximately 1 in 12,000 to 1 in 25,000 individuals.

Most genetic causes of inherited optic atrophy affect mitochondrial function and may involve either nuclear genes or mitochondrial DNA. The encoded proteins contribute to mitochondrial energy production, membrane dynamics, structural maintenance and quality control. Pathogenic variants disrupt mitochondrial homeostasis and energy metabolism, leading to the preferential degeneration of retinal ganglion cells and their axons. The resulting optic atrophy may occur as an isolated condition or as part of a multisystem disorder.

Inherited optic atrophy shows heterogeneous inheritance patterns, including autosomal dominant, autosomal recessive, mitochondrial and X-linked inheritance. The mode of inheritance depends on the underlying genetic cause. OPA1 is the most important cause of autosomal dominant optic atrophy, whereas FDXR is a representative cause of autosomal recessive optic atrophy, often with additional neurological or systemic manifestations. is the most prominent example of mitochondrial inheritance and is caused by pathogenic variants in mitochondrial DNA transmitted through the maternal line. For some genes, including WFS1, ACO2 and OPA3, both dominant and recessive disease associations have been described, although the associated phenotypes may differ in presentation and severity.

• Molecular genetic testing can identify the underlying genetic cause, support confirmation of the clinical diagnosis, enable testing of at-risk family members and provide information relevant to family planning.
• Identification of the underlying genetic condition can guide condition-specific monitoring, including assessment for associated neurological or systemic manifestations. Management and therapeutic options are evaluated individually by the treating physicians.

• Strachan EL, Mac White-Begg D, Crean J, Reynolds AL, Kennedy BN, O’Sullivan NC. The role of mitochondria in optic atrophy with autosomal inheritance. Front Neurosci. 2021;15:784987. doi:10.3389/fnins.2021.784987. PMID:; PMCID:PMC8634724.
• Maresca A, Carelli V. Molecular mechanisms behind inherited neurodegeneration of the optic nerve. Biomolecules. 2021;11(4):496. doi:10.3390/biom11040496. PMID:; PMCID:PMC8064499.