Genetic susceptibility to optic neuropathy in patients with alcohol use disorder

Abstract

Background: The pathophysiology of toxico-nutritional optic neuropathies remains debated, with no clear understanding of the respective roles played by the direct alcohol toxicity, smoking and the often associated vitamin deficiencies, which are risk factors for optic neuropathy. Our aim was to investigate genetic susceptibility in patients with bilateral infraclinical optic neuropathy associated with chronic alcohol use disorder.

Methods: This retrospective cohort study included 102 visually asymptomatic patients with documented alcohol use disorder from a French reference center. Optic neuropathy was identified with optical coherence tomography (OCT), after which genetic susceptibility in the group of affected patients was investigated. Genetic testing was performed using panel sequencing of 87 nuclear genes and complete mitochondrial DNA sequencing.

Results: Optic neuropathy was detected in 36% (37/102) of the included patients. Genetic testing of affected patients disclosed two patients (2/30, 6.7%) with optic neuropathy associated with pathogenic variants affecting the SPG7 gene and five patients (5/30, 16.7%) who harbored variants of uncertain significance close to probable pathogenicity in the genes WFS1, LOXL1, MMP19, NR2F1 and PMPCA. No pathogenic mitochondrial DNA variants were found in this group.

Conclusions: OCT can detect presence of asymptomatic optic neuropathy in patients with chronic alcohol use disorder. Furthermore, genetic susceptibility to optic neuropathy in this setting is found in almost a quarter of affected patients. Further studies may clarify the role of preventative measures in patients who might be predisposed to avoidable visual loss and blindness.

Keywords: Alcohol use disorder; Ganglion cell complex; Hereditary optic neuropathy; Mitochondria; Mitochondrial DNA; Optic nerve; Optical coherence tomography; Retinal nerve fiber layer; Toxic-nutritional optic neuropathy.

Fig. 1

Workflow chart and main findings

Fig. 2

Retinal imaging in a normal patient, showing a normal appearance of the right optic nerve head on a colour photograph (upper left corner). Optical coherence tomography (OCT) images show a cross sectional analysis or the peripapillary retinal nerve fiber layer (RNFL) thickness, compared to a normative database

Fig. 3

Retinal and optic nerve imaging of the right eye in patient 24, carrying the heterozygous variant NM_002429:c.173 + 1G>A (splicing variant) in the MMP19 gene. The standard retinal photograph is within normal limits (upper left corner), but OCT shows an optic neuropathy and RNFL loss affecting the papillo-macular bundle (decreased RNFL values, in the red colored areas)