Clinical features of OPA1-related optic neuropathy: a retrospective case series

Abstract

Purpose: Dominant optic atrophy (DOA) is the most common hereditary optic neuropathy. The most common form of DOA, DOA type 1 (Kjer’s disease) accounts for 40-60% of cases and is associated with mutation of the OPA1 gene. Previously, clinical studies focusing on OPA1 mutations have been limited to a few mutations and clinical parameters. In the present study, we evaluated and analyzed detailed clinical information for patients referred to a major tertiary care center for OPA1 testing for suspected DOA.

Methods: In this retrospective case series, we review the clinical records of 62 patients referred for PCR-based sequencing of OPA1. Missense and small deletions/insertions found by sequencing were compared with those reported in the literature, and objective analyses were used to determine the likelihood of pathogenicity for specific DNA changes. A subset of patients was selected for Multiplex Ligation-dependent Probe Amplification (MLPA) analysis. The clinical features examined include, but are not limited to, visual acuity, Ishihara testing, automated visual field testing, and dilated fundoscopy.

Results: Clinical data was available for 54 patients (31 male; 23 female). The majority (28/41; 68.3%) were referred by an optometrist/ophthalmologist for a problem related to optic nerve appearance. Of the 62 patients that underwent diagnostic OPA1 sequencing, 18 (29.0%) were found to have potentially disease-causing coding mutations: 3 splice site mutations, 3 missense mutations, and 12 nonsense/truncating mutations. The common TTAG deletion comprised 7 of the 12 nonsense mutations in 4 unrelated families, confirming previous reports of this mutation hot spot. Three sequence mutations are novel. MLPA analysis identified 5 patients with large-scale deletions/duplications unrecognized by sequencing. Deletion spans ranged from 3 exons to the entire gene. Automated visual field testing was the most sensitive measure of disease status as assessed in a subset of individuals followed over 1-5 years.

Conclusions: Our results show that OPA1 mutations are a common cause of optic neuropathy in the tertiary referral setting and large-scale genomic aberrations account for a small subset of OPA1-related neuropathies. Automated visual field testing may be the best measure of disease progression in these patients.

Keywords: 613 neuro-ophthalmology: optic nerve • 463 clinical (human) or epidemiologic studies: prevalence/incidence • 539 genetics