A number sign (#) is used with this entry because of evidence that optic atrophy-12 (OPA12) is caused by heterozygous mutation in the AFG3L2 gene (604581) on chromosome 18p11.

Heterozygous mutation in the AFG3L2 gene can also cause spinocerebellar ataxia-28 (SCA28; 610246), and biallelic mutation in the AFG3L2 gene causes autosomal recessive spastic ataxia-5 (SPAX5; 614487). These disorders share some overlapping features, suggesting a phenotypic spectrum associated with AFG3L2 mutations.

Optic atrophy-12 (OPA12) is an autosomal dominant neurologic disorder characterized by slowly progressive visual impairment with onset usually in the first decade, although later onset has been reported. Affected individuals have impaired color vision, photophobia, pale optic discs, optic nerve atrophy, and decreased thickness of the retinal nerve fiber layer. Some patients may exhibit additional neurologic features, including impaired intellectual development, dystonia, movement disorders, or ataxia (summary by Caporali et al., 2020).

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

Charif et al. (2015) reported a father and son with optic atrophy associated with impaired intellectual development. At age 12, the 48-year-old father developed visual difficulties, including decreased visual acuity, photophobia, and color vision impairment. He had moderate optic disc pallor, and OCT showed a moderate decrease in the thickness of the retinal nerve fiber layer. His 18-year-old son had impaired intellectual development (IQ of 47) and was admitted to an institution at age 14 years. He had impaired visual acuity and severe optic disc pallor with decreased thickness of the retina nerve fiber layer. Brain MRI showed decreased size of the optic tract and atrophy of the optic chiasma. Neither patient exhibited ataxia, spasticity, or cerebellar symptoms.

Colavito et al. (2017) reported a 19-year-old Italian man who had a history of visual difficulties since age 6. He had impaired color vision, photophobia, and optic nerve pallor, as well as impaired visual evoked potentials. He did not have additional neurologic features; there was no spasticity or ataxia and no signs of impaired intellectual development.

Baderna et al. (2020) reported a 20-year-old man who developed optic atrophy with impaired vision and poor color perception around age 4. The disorder was slowly progressive, and he had marked optic nerve pallor at age 20. At age 18, he was diagnosed with relapsing-remitting multiple sclerosis; brain imaging showed widespread demyelinating lesions. Family history was significant for mild optic atrophy in several family members. None of the family members, including the proband, had signs of spinocerebellar ataxia.

Caporali et al. (2020) reported affected individuals from 10 unrelated families with OPA12. Most had onset of visual problems in childhood, although some had onset as adults. Features included progressive visual loss, pallor of the optic discs, and atrophy of the optic nerves. Some patients had additional variable neurologic features, including sensorineural deafness, impaired intellectual development, dystonia, and spasticity. In 1 additional family (F6), heterozygous mutation carriers had OPA12, whereas 1 family member was compound heterozygous for 2 AFG3L2 mutations and had a phenotype consistent with SPAX5. The findings expanded the phenotype associated with mutations in the AFG3L2 gene.

The transmission pattern of OPA12 in the families reported by Charif et al. (2015) and Baderna et al. (2020) was consistent with autosomal dominant inheritance.

In a father and son with OPA12, Charif et al. (2015) identified a heterozygous missense mutation in the AFG3L2 gene (R468C; 604581.0012). The variant occurred at a highly conserved residue in the AAA domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed. Neither patient had ataxia or spasticity, but both had mildly to moderately impaired intellectual development, which may or may not have been related to the AFG3L2 mutation.

In a 19-year-old Italian man with OPA12, Colavito et al. (2017) identified a heterozygous R468C mutation in the AFG3L2 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the patient's unaffected mother; DNA from the father was unavailable. Functional studies of the variant and studies of patient cells were not performed. The patient had isolated optic atrophy without additional neurologic symptoms, including lack of ataxia, cerebellar signs, or impaired intellectual development.

In 5 affected individuals spanning 3 generations of a family with OPA12, Baderna et al. (2020) identified a heterozygous missense variant affecting a conserved residue close to the AAA domain in the AFG3L2 gene (G337E; 604581.0013). The mutation, which was found by exome sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the G337E mutation abolished AFG3L2 activity, resulting in a reduction of L-OPA1 and an accumulation of S-OPA1 associated with hyperactivation of OMA1. These abnormalities were associated with altered mitochondrial morphology and dynamics and increased mitochondrial fragmentation.

In affected individuals from 10 unrelated families with OPA12, Caporali et al. (2020) identified heterozygous missense mutations in the AFG3L2 gene (see, e.g., 604581.0014; 604581.0016-604581.0017). The mutations, which were found by next-generation sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. The variants were inherited in an autosomal dominant pattern in most families, but occurred de novo in at least 2 patients. Most of the mutations localized to the ATPase domain, which is in contrast to SCA28 or SPAX5 mutations, which tend to affect the proteolytic domain. Functional studies were performed on several of the mutations. Expression of the mutations into yeast lacking the AFG3L2 orthologs showed that the mutant proteins were unable to rescue the defective oxidative phosphorylation (OXPHOS) phenotype. The mutations also impaired proteolytic and dislocase activity of the AFG3L2-associated mAAA complex, consistent with a loss of function. Patient fibroblasts showed decreased levels of L-OPA1 (605290) compared to S-OPA1, suggesting increased proteolytic cleavage of long OPA1 and abnormal accumulation of short OPA1. This was associated with increased mitochondrial fragmentation, although OXPHOS complex activity was normal. The findings suggested that unbalanced processing of OPA1 due to AFG3L2 dysfunction causes defective mitochondrial dynamics, resulting in optic atrophy. The authors noted that this mechanism fits with the paradigm of the pathogenic mechanism for mitochondrial optic neuropathies, in which retinal ganglion cells are vulnerable to mitochondrial dysfunction.