MON-597 - Successful Treatment of Diabetes with A GLP-1 Receptor Agonist in Wolfram-Like Syndrome

Background:
Wolfram syndrome (WS) is a rare autosomal recessive disorder caused by mutations in the WFS1 gene and is classically characterized by diabetes mellitus, diabetes insipidus, optic atrophy, and neurodegeneration. Wolfram-like syndrome represents a milder or incomplete phenotype, which can make diagnosis challenging. Diabetes in these patients is typically managed with insulin due to β-cell loss. Preclinical studies suggest that GLP-1 receptor agonists, including dulaglutide, may preserve β-cell function by mitigating endoplasmic reticulum stress–induced apoptosis.


Case Presentation:
We present a 32-year-old male referred for evaluation of uncontrolled diabetes, diagnosed at the age of 25. He was started on glargine insulin with metformin and suspected to have type 1 diabetes. His medical history was notable for mild intellectual disability, and he reports hearing difficulties. Family history revealed diabetes in multiple relatives, including a brother diagnosed in his 20s.
Laboratory evaluation revealed negative autoantibodies (islet cell cytoplasmic antibody IgG, Glutamic Acid Decarboxylase antibody (GAD), and Zinc Transport 8 (ZnT8) antibody) and a mildly low postprandial C-peptide level.
Genetic testing was negative for Maturity-Onset Diabetes of the Young (MODY) but revealed two heterozygous mutations in the WFS1 gene, which is associated with Wolfram syndrome (WS).
The patient lacked the typical features associated with WS - diabetes insipidus, blindness, or deafness (audiologic and ophthalmologic evaluations were normal), supporting a diagnosis of Wolfram-like syndrome. 
His parents were asymptomatic, and genetic testing revealed that both of his parents were carriers of the WFS1 gene mutation. 
Despite treatment with glargine, metformin, and a sodium glucose transporter inhibitor (SGLT2i), his glycemic control was suboptimal.  
Given preliminary evidence supporting GLP-1 receptor agonists in WS, a trial of dulaglutide was initiated, resulting in immediate and sustained improvement in glycemic control, an increase in his postprandial C-peptide level, and good tolerability with medication.


Conclusion:
This case supports a diagnosis of Wolfram-like syndrome in a patient with WFS1 mutations and incomplete clinical features. The favorable response to dulaglutide suggests GLP-1 receptor agonists may represent a promising therapeutic option for diabetes associated with Wolfram-like syndrome, consistent with prior preliminary data.

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