Autosomal dominant optic atrophy plus syndrome

Autosomal dominant optic atrophy plus syndrome (also known as Kjer disease plus, DOA+ syndrome, or OPA1-related optic atrophy plus syndrome) is a rare inherited neurological and ophthalmological disorder that extends beyond the classic isolated optic atrophy (Kjer disease) to involve multiple organ systems. It is most commonly caused by mutations in the OPA1 gene, which encodes a mitochondrial dynamin-like GTPase essential for mitochondrial fusion and maintenance. Because mitochondrial function is disrupted, tissues with high energy demands — particularly the optic nerves, auditory system, skeletal muscles, and central nervous system — are preferentially affected. The hallmark feature is progressive bilateral optic atrophy leading to insidious visual loss, typically beginning in childhood, with reduced visual acuity, color vision deficits (especially blue-yellow dyschromatopsia), and central or cecocentral scotomas. In the 'plus' form, patients additionally develop sensorineural hearing loss, progressive external ophthalmoplegia, ptosis, ataxia, myopathy, and peripheral neuropathy. Some individuals may also develop spastic paraplegia or a multiple sclerosis-like illness. The severity and combination of extra-ocular features are highly variable, even within the same family, reflecting incomplete penetrance and variable expressivity characteristic of this condition. There is currently no curative treatment for autosomal dominant optic atrophy plus syndrome. Management is supportive and multidisciplinary, involving regular ophthalmological monitoring, low-vision aids, hearing aids or cochlear implants for sensorineural deafness, physical therapy for ataxia and myopathy, and neurological surveillance. Genetic counseling is recommended for affected families. Research into gene therapy, mitochondrial-targeted antioxidants (such as idebenone), and other neuroprotective strategies is ongoing, but no disease-modifying therapy has yet been established as standard of care.

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