MedGen

Optic atrophy-9 (OPA9) is characterized by onset of decreased visual acuity and optic disc pallor in the first decade of life, with severely reduced visual acuity and color vision deficits observed in the third decade. Although initially described as an autosomal recessive disease (Metodiev et al., 2014; Kelman et al., 2018; Gibson et al., 2020), autosomal dominant cases of OPA9 have also been reported (Charif et al., 2021). Mutation in the ACO2 gene also causes a neurodegenerative disorder, infantile cerebellar-retinal degeneration (ICRD; 614559), of which optic atrophy is a feature. Dominant and Recessive OPA9 From a cohort of approximately 1,000 patients with optic atrophy, Charif et al. (2021) identified 50 probands with dominant mutations in the ACO2 gene, and 11 patients with biallelic variants. There was no significant difference in distribution of mutation type, with two-thirds of all variants being missense mutations in both groups, and nonsense, frameshift, and splice site mutations comprising the remaining third. Age at onset of symptoms occurred during the first 2 decades, without significant difference between dominant and recessive cases. Visual acuity was significantly more affected in recessive cases than in dominant ones, with more than 60% of eyes from the recessive group having a visual acuity lower than 20/200, whereas more than 80% of eyes from the dominant group had a visual acuity above 20/200. Analysis of the optic disc as well as retinal nerve fiber layer thickness measurements indicated a preferential involvement of the temporal quadrant in both patient groups. Assessment of color vision revealed highly variable alterations, including protan, deutan, and tritan types of dyschromatopsia. Some patients had additional retinal changes, including macular microcysts as well as macular dystrophy in 1 case. Extraocular symptoms were observed in 6 (12%) of the dominant cases and in 3 (27%) of the recessive cases, including hearing impairment in 2 dominant cases, and late-onset cerebellar ataxia in 1 dominant case and in 1 recessive case. [from OMIM]

Infantile cerebellar-retinal degeneration (ICRD) is a severe autosomal recessive neurodegenerative disorder characterized by onset between ages 2 and 6 months of truncal hypotonia, athetosis, seizures, and ophthalmologic abnormalities, particularly optic atrophy and retinal degeneration. Affected individuals show profound psychomotor retardation, with only some achieving rolling, sitting, or recognition of family. Brain MRI shows progressive cerebral and cerebellar degeneration (summary by Spiegel et al., 2012). A subset of patients may have a milder phenotype with variable features, including ataxia, developmental delay, and behavioral abnormalities (Blackburn et al., 2020). Mutation in the ACO2 gene also causes isolated optic atrophy (OPA9; 616289). [from OMIM]