The Pattern of Retinal Ganglion Cell Loss in Wolfram Syndrome is Distinct From Mitochondrial Optic Neuropathies

Am J Ophthalmol. 2022 Sep:241:206-216. doi: 10.1016/j.ajo.2022.03.019. Epub 2022 Apr 20.


Purpose: To describe the clinical phenotype of a cohort of patients with Wolfram syndrome (WS), focusing on the pattern of optic atrophy correlated with brain magnetic resonance imaging (MRI) measurements, as compared with patients with OPA1-related dominant optic atrophy (DOA).

Design: Retrospective, comparative cohort study.

Methods: We reviewed 25 patients with WS and 33 age-matched patients affected by OPA1-related DOA. Ophthalmologic, neurologic, endocrinologic, and MRI data from patients with WS were retrospectively retrieved. Ophthalmologic data were compared with data from patients with OPA1-related DOA and further analyzed for age dependency dividing patients in age quartiles. In a subgroup of patients with WS, we correlated the structural damage assessed by optical coherence tomography (OCT) with brain MRI morphologic measurements. Visual acuity (VA), visual field mean defect (MD), retinal nerve fiber layer (RNFL), and ganglion cell layer (GCL) thickness were assessed by OCT and MRI morphologic measurements of anterior and posterior visual pathways.

Results: Optic atrophy was present in 100% of patients with WS. VA, MD, and RNFL thickness loss were worse in patients with WS with a faster decline since early age as compared with patients with DOA, who displayed a more stable visual function over the years. Conversely, GCL sectors were overall thinner in patients with DOA since early age compared to patients with WS, in which GCL thickness started to decline later in life. The neuroradiologic subanalysis on 11 patients with WS exhibited bilateral thinning of the anterior optic pathway, especially the prechiasmatic optic nerves and optic tracts. Optic tract thinning was significantly correlated with GCL thickness but not with RNFL parameters.

Conclusions: Our results showed a generally more severe and diffuse degeneration of both anterior and posterior visual pathways in patients with WS, with fast deterioration of visual function and structural OCT parameters since early age. The pattern observed with OCT suggests that retinal ganglion cell axonal degeneration (ie, RNFL) precedes cellular body atrophy (ie, GCL) by about a decade. This differs substantially from DOA, in which a more stable visual function is evident with predominant early loss of GCL, indirectly supporting the lack of a primary mitochondrial dysfunction in patients with WS.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cohort Studies
  • Humans
  • Mitochondria / pathology
  • Optic Atrophy, Autosomal Dominant* / diagnosis
  • Optic Atrophy, Autosomal Dominant* / genetics
  • Optic Atrophy, Autosomal Dominant* / pathology
  • Optic Nerve Diseases* / pathology
  • Retinal Ganglion Cells / pathology
  • Retrospective Studies
  • Tomography, Optical Coherence / methods
  • Vision Disorders
  • Wolfram Syndrome* / diagnosis