Efficacy of GLP-1 Agonist Therapy in Autosomal Dominant WFS1-Related Disorder: A Case Report.

BACKGROUND: Wolfram syndrome is a rare neurodegenerative disorder, characterized by the presence of diabetes insipidus, diabetes mellitus, optic atrophy, and sensorineural deafness. The majority of cases are due to autosomal recessive biallelic variants in the WFS1 gene; however, pathogenic autosomal dominant (AD) mutations have also been described. Glucagon-like peptide (GLP-1) agonists have been studied in both animal models and humans with classic Wolfram syndrome. CASE: We present a 15-year-old female with a personal and family history of congenital strabismus, bilateral cataracts, low-frequency sensorineural hearing loss, and diabetes mellitus. Trio whole exome sequencing revealed a previously unknown maternally inherited heterozygous variant in exon 8 of the WFS1 gene c.2605_2616del12 p.Ser869_His872del, leading to the diagnosis of AD WFS1-related disorder. Treatment with a GLP-1 agonist resulted in marked improvement in glycemic control and discontinuation of insulin therapy. This patient's response to a GLP-1 agonist provides suggestive indirect evidence for a role of WFS1 on β-cell endoplasmic reticulum stress and suggests that treatment with a GLP-1 agonist should be considered in patients with dominant forms of WS.