Phenotypic features related to Wolfram syndrome in 17 families

Abstract

Purpose: Wolfram syndrome, also called DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, deafness) is a rare neurodenerative autosomal recessive disorder (prevalence 1/550,000), linked to WFS1gene mutation. This gene encodes a transmembrane protein, wolframine, involved in calcium homeostasis. Our study aimed to characterize genotypic and phenotypic features of patients affected by WFS1 mutations.

Methods: Retrospective multicenter observational study, including patients with genetically confirmed Wolfram syndrome.

Results: 20 patients harbouring a WFS1 gene mutation were included in the study (18 with composite heterozygous mutations, and 2 with homozygous mutations). They belonged to 17 different families. Age at diagnosis ranged 6 to 42.Twenty three different mutations were found (greater than the number of patients, given the composite heterozygosity). A single mutation was found in 4 patients, coming from 3 different families. In this population, 100% of patients had an optic neuropathy, 95% a type I diabetes mellitus, 55% a hearing loss, 55% a diabetes insipidus, 15% neurological disorders, 35% urological disorders, 15% psychiatric disorders. Optic neuropathy was diagnosed at an average age of 10.8 years, occurring often after diabetes mellitus. Vision was very variable, ranging between 20/20 and absence of light perception. The visual loss was always slowly progressive and symmetrical. Axonal fiber abnormalities in OCT were detectable even in the absence of functional visual signs. Optic disc cupping was bigger than 5/10 in 60%. Visual field abnormalities were found in all cases. Other ophthalmic findings were rare, including cataract (1 patient), diabetic retinopathy (1 patient), and maculopathy (1 patient). In this condition, visual loss can rarely be related to other causes than optic neuropathy. Among the 20 patients included, 70% have been receiving follow-up medical care for more than 5 years. One death has occured during this period.

Conclusions: A large number of mutations are responsible for a various phenotypic features in Wolfram syndrome. Optic neuropathy, which is constant after a period of evolution, is frequently symptomatic but subclinical abnormalities can be detected with the use of OCT. This preliminary study suggests that in Wolfram syndrome there may be a phenotype/genotype correlation.

Keywords: 613 neuro-ophthalmology: optic nerve • 539 genetics • 552 imaging methods (CT, FA, ICG, MRI, OCT, RTA, SLO, ultrasound)