Retinopathy and optic atrophy: expanding phenotypic spectrum of AARS2 gene mutations

Abstract

Purpose : Optic atrophy (OA) is the end result of optic nerve injury due to any insult including isolated and syndromic genetic diseases. The purpose of this study was to demonstrate that mutations in AARS2 can present as retinopathy and optic atrophy, in addition to its previous association with progressive leukoencephalopathy with ovarian failure.

Methods : We report a patient who presented with decreased vision at 18 months of age. Detailed ophthalmologic evaluation, ERG and MRI were performed. Extensive workup including metabolic and genetic studies were performed to evaluate etiology for leukoencephalopathy followed by whole exome sequencing to identify underlying genetic etiology.

Results : Visual acuities were 5/125 OD and 5/150 OS, and fundus examination revealed bilateral optic nerve pallor. Serial MRI revealed progressive signal abnormalities with diffusion restriction in the deep cerebral white matter, subcortical cerebellar white matter, and dorsal columns of the spinal cord, followed by lesions in the splenium of the corpus callosum and middle cerebellar peduncle. ERG revealed widespread retinal dysfunction. On neurologic examination he had absent patellar reflexes and EMG revealed a demyelinating polyneuropathy. Metabolic studies, LHON and OPA1 gene testing were negative. Two missense variants c1519G>C (p.V507L and c.2165G>A (p.R722Q)] were identified in the AARS2 gene on exome analysis and found to be in trans on parental testing. The AARS2 gene has been implicated in progressive leukoencephalopathy with ovarian failure in previous investigations.

Conclusions : Mutations in the AARS2 gene are the likely cause of the retinopathy and optic atrophy in our patient. Functional studies to evaluate the pathogenicity of these mutations are pending. This patient expands the phenotypic spectrum of AARS2 gene mutations.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.