Kjer's Optic Neuropathy - Pathophysiology

Pathophysiology

Vision loss in Dominant optic atrophy is due to optic nerve fiber loss from mitochondria dysfunction. Dominant optic atrophy is associated with mutation of the OPA1 gene found on chromosome 3, region q28-qter. Also, 5 other chromosomal genes are described causing optic atrophy: OPA2 (x-linked), OPA3 (dominant), OPA4 (dominant), OPA5 (dominant) and OPA6 (recessive) (see OMIM 165500).

The OPA1 gene codes for a dynamin-related GTPase protein targeted to the mitochondrial inner membrane. OPA1 has distinct roles in the fusion of mitochondrial inner membranes during mitochondrial fusion events and regulation of cell death . Mitochondria are subcellular structures that generate and transform energy from metabolism into discrete usable units (ATP) for the cell’s functions (See oxidative phosphorylation, electron transport chain). Retinal ganglion cells (neurons), which make up the optic nerve, have a high energy demand and are particularly sensitive to mitochondrial dysfunction. This is especially the case for smaller and less myelinated neurons such as those found in the papillomacular bundle of the retina, which transmit information corresponding to the central visual field. Biochemical and mitochondrial morphological studies on cells from patients affected but autosomal dominant optic atrophy have shown a severe defect in the shape (with a very remarkable fragmentation of the mitochondrial tubules in small spheres) and distribution of mitochondria, occurring independently from a bioenergetic defect (respiratory chain function, ATP synthesis, and reactive oxygen species production) or apoptosis, indicating that the mitochondrial fusion defect is the primary pathogenetic mechanism., although variable bioenergetic defects can also occur as a secondary phenomenum, especially in severe cases with complicated phenotypes and accumulation of mitochondrial DNA deletions.

Over 60 different mutations of the OPA1 gene causing Kjer's have been reported, most of which occurring in the catalytic domain of the protein.

Mutations at the OPA1 gene are also associated with normal tension glaucoma (OMIM 606657) and deafness (OMIM 125250).