Optic Atrophy 3, Autosomal Dominant

A number sign (#) is used with this entry because autosomal dominant optic atrophy-3 (OPA3), also known as optic atrophy and cataract, is caused by heterozygous mutation in the OPA3 gene (606580) on chromosome 19q13.

3-Methylglutaconic aciduria type III (MGCA3; 258501), also known as optic atrophy plus syndrome, is an allelic disorder with similar but more severe features.

For a discussion of genetic heterogeneity of optic atrophy, see OPA1 (165500).

Clinical Features

Garcin et al. (1961) reported a large French family in which 14 individuals in 7 sibships spanning 4 generations had optic atrophy, cataract, and a neurologic disorder characterized by extrapyramidal signs and ataxia. Inheritance was clearly autosomal dominant. Cataract was often recognized in the first decade.

Reynier et al. (2004) and Verny et al. (2005) provided clinical follow-up of the family originally reported by Garcin et al. (1961). The oldest living patient, who was 83, reported visual impairment from infancy with worsening around age 28 years. At age 38, she had severely decreased visual acuity, optic atrophy, and cataract. Other affected family members had onset of decreased visual acuity, optic atrophy, and cataracts by the early teenage years. The 2 oldest patients (aged 83 and 60) had mild tremor of the upper extremities; the oldest also had mild extrapyramidal rigidity of the upper extremities. Neurologic signs were absent in those younger than 50. Reynier et al. (2004) reported a second family in which 4 living patients had onset of optic atrophy by early teenage years, followed by cataract. None had other neurologic signs. Reynier et al. (2004) noted that neurologic features were mild or even absent in most patients, and suggested that the phenotype be referred to as 'autosomal dominant optic atrophy and cataract' (ADOAC).

Biochemical Features

In fibroblasts derived from 16 patients with hereditary optic neuropathy, including either Leber hereditary optic neuropathy (LHON; 535000), OPA1, or OPA3, Chevrollier et al. (2008) found a common coupling defect of oxidative phosphorylation resulting in reduced efficiency of ATP synthesis. LHON fibroblasts showed a mean decrease of 39% in complex I activity compared to controls. OPA1 and OPA3 fibroblasts showed normal complex I activities, but a mean decrease of 25% in complex IV activity and a mean 60% increase in complex V activity. Resting respiration was about twice as high in all LHON, OPA1, and OPA3 fibroblasts compared to controls, reflecting a proton leak or electron slip. However, all mutant cell lines used a greater proportion of routine respiratory capacity compared to controls, suggesting a compensatory mechanism. The energy defect was most pronounced in fibroblasts from patients with additional neurologic symptoms.

Molecular Genetics

In affected members of 2 families with autosomal dominant optic atrophy and cataract, including the family first described by Garcin et al. (1961), Reynier et al. (2004) identified 2 different heterozygous mutations in the OPA3 gene (G93S; 606580.0002 and Q105E; 606580.0003, respectively). No abnormalities were found in the respiratory chain or in the mitochondrial membrane potential, or in the organization of the mitochondrial network of fibroblasts obtained from 1 affected patient. However, the fibroblasts showed increased susceptibility to staurosporine-induced apoptosis.