Indications of mitochondrial dysfunction in Wolfram syndrome.

Abstract

Purpose : Wolfram type 1 (WFS1) recessive mutations are associated with Wolfram syndrome (WS), defined by early-onset diabetes mellitus and optic atrophy. A longstanding debate concerns the possible mitochondrial dysfunction in WS, apparently resolved by the identification of causative mutations in wolframin, a protein mostly localized on the endoplasmic reticulum. We here explore the possible occurrence of mitochondrial dysfunction in a case-series of WS patients and report clinical, neuroradiological and ophthalmological findings.

Methods : We investigated a cohort of 11 WFS1 adult cases (34.3 ± 13.4 years). Neurophthalmological examination included visual acuity, color vision, pupil, visual field, optical coherence tomography, and fundus picture. In a subgroup of patients we also evaluated lactic acid after standardized
exercise, brain-MRI, muscle and brain MR-spectroscopy (MRS).

Results : Age at onset of visual loss was 10.1 ± 4.1 years. All but one had diabetes mellitus and 7/9 had abnormal lactic acid after exercise. Brain MRI variably demonstrated cortical, brainstem and cerebellar atrophy and white matter changes. Brain ¹H-MRS showed lactic acid traces in 2/7. Muscle ³¹P-MRS was abnormal in 1/6. Visual acuity was 0.19 ± 0.18 with impaired color vision in all cases, and abnormal pupillary response in 7/11. Fundus oculi demonstrated diffuse pallor in 8/11 (more temporal in 3/8) and temporal pallor in 3/11 (Fig 1). Visual fields demonstrated generalized defect in 9/11 and central scotoma in 2/11 (Fig 2). OCT showed diffuse and severe retinal nerve fiber thinning in all cases compared to age-matched controls (p<0.001).

Conclusions : Neurophthalmological phenotype has been poorly characterized in WS. Severe optic atrophy, more evident in the temporal sector concordant with a postmortem study showing a mitochondrial pattern of axonal loss, abnormal lactic acid after exercise and some degree of altered MRS (brain and muscle) all point to a mitochondrial dysfunction in WS.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

 

Examples of fundus pictures in WS. Upper line: temporal pallor; lower line: diffuse pallor of the optic disc.

 

Examples of visual defects in WS. (A) Diffuse defect (B) Central scotoma