Clinical Characteristics
Ocular Features
This form of bilateral optic atrophy may have its onset in early childhood with optic disc pallor, loss of acuity, loss of color vision, and centrocecal scotomas. However, it is often not manifest until the second decade of life. Moderate to severe temporal or diffuse pallor can be seen. The optic disc has been described as normal in 29% of documented carriers and 20% have no visual field defect. Pallor of the complete disc is found in only 10%. Consequently, the phenotype is variable, with some individuals having minimal symptoms while others have severe vision loss. The disease is progressive in some but not all families. The median visual acutity is 20/70 but ranges from normal to hand motions.
Histologic studies show atrophy of ganglion cells in the retina and loss of myelin sheaths in the optic nerve. VEPs are absent or subnormal. Optical coherence tomography reveals a significant reduction in retinal nerve fiber layer and ganglion cell layer thickness, most marked in the temporal quadrants.
Systemic Features
OPA1 is generally not associated with systemic disease. However, some have sensorineural deafness, ataxia, ptosis, and ophthalmoplegia. Families with both early and late onset have been reported. Some (~20%) individuals have a myopathy as well.
Genetics
Inheritance
This is an autosomal dominant disorder resulting from mutations in a nuclear gene, OPA1 (3q28-q29). The gene product is attached to the mitochondrial cristae of the inner membrane and metabolic studies have implicated the oxidative phosphorylation pathway which seems to be defective with reduced efficiency of ATP synthesis. Penetrance approaches 90% but this is, of course, age dependent to some extent.
An allelic disorder (125250) is associated with sensorineural deafness, ataxia, and ophthalmoplegia but its uniqueness remains to be established since the same mutations in OPA1 have been found in both conditions.
Other autosomal dominant optic atrophy disorders include OPA5 (610708) and OPA4 (605293).
Pedigree
Autosomal dominant
Autosomal dominant disorders require only one mutation for the disease to be expressed. Since an affected parent has two chromosomes, only one of which has the mutant gene, parents can expect that half (50%) of their children will receive that one and inherit the disease. It is common for individuals that inherit the mutation, however, to not have evidence of the disease (nonpenetrance).
Autosomal dominant inheritance leads to a vertical pattern of transmission