Hereditary optic neuropathies are defined by loss of vision due to abnormalities of the optic nerve. The most prevalent forms due to pathogenic/likely pathogenic (P/LP) variants in the OPA1 gene include Leber’s hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy. Other genes associated with optic atrophy include OPA3, TMEM126A, and common mitochondrial DNA P/LP variants (Kloth et al., 2019; Lenaers et al., 2012). There are many other rare genetic syndromes (ex. Joubert syndrome, Bosch-Boonstra-Schaaf syndrome, and Brown-Vialetto-van Laere Syndrome) that cause optic atrophy along with other symptoms such as ataxia, hearing loss, or neurodegeneration.
Optic atrophy type 1 (OPA1) has an estimated prevalence in the general population of 1 in 50,000 people, with the prevalence being as high as 1 in 10,000 in Denmark. Individuals who have OPA1 have bilateral and symmetric optic nerve pallor associated with progressive decrease in visual acuity, which typically begins between 4 to 6 years of age. Affected individuals also experience visual field defects or narrowing of the visual field and color vision defects (acquired blue-yellow loss/tritanopia). Visual impairment ranges from mild/near normal vision to severe/legal blindness, but is usually described as moderate (6/10 to 2/10). The level of visual impairment can vary greatly among individuals with OPA1 and even among family members. The vision loss usually progresses slowly, and there is no spontaneous recovery of vision. A clinical diagnosis of OPA1 can be made in individuals with the following characteristics (taken from Delettre-Cribaillet et al., 2007; Votruba et al., 2003; Alward, 2003):
- bilateral vision loss that is usually symmetric
- optic nerve pallor, usually bilateral and symmetric; temporal in about 50% of individuals and global in about 50%
- visual field defect that is typically centrocecal, central, or paracentral
- color vision defect
- childhood onset
- family history
OPA1 is caused by P/LP variants in the OPA1 gene, and is inherited in an autosomal dominant fashion. Sequence variants, including the common Danish founder variant (c.2826delT), are most often reported and can be identified by OPA1 gene sequencing. However, deletions and duplications of the OPA1 gene have been reported. Patients suspected of having optic atrophy type 1 are recommended to have molecular genetic testing of OPA1 to confirm and/or establish a clinical diagnosis (Delettre-Cribaillet et al., 2015). Currently, there are many genetic testing options available and although the diagnostic yield of testing in this space has increased over time. A recent review of commercially available tests reported that phenotype-based targeted testing should be considered over broad panels, which is in part due to the well-described false discovery rate (Procopio et al., 2023). Approximately 10% of individuals with a confirmed genetic diagnosis of OPA1 can have extraocular features, including sensorineural hearing loss, ataxia, and myopathy. Type I diabetes has also been reported as an overlapping symptom. Treatment and management of OPA1 is based on clinical symptoms present.
Wolfram syndrome (WFS) is a progressive neurodegenerative condition (Barrett et al., 2009). Typical features, described by Barrett et al., (2009) include sensorineural hearing loss, cerebellar ataxia, peripheral neuropathy, dementia, psychiatric illness, and endocrine dysfunction such as type I diabetes. Camtosun et al. (2015) and Grenier et al. (2016) identified P/LP variants in WFS1 in individuals with optic atrophy without evidence of the clinical features consistent with Wolfram syndrome and recommend genetic testing for WFS1 in patients even in the absence of the full spectrum of clinical features consistent with Wolfram syndrome. A small targeted panel that includes OPA1 and other genes of interest associated with optic atrophy/neuropathy may be useful for some patients, as medical management can be impacted by knowledge of risks associated with specific syndromes.