Longitudinal progression of diabetes mellitus in Wolfram syndrome: The Washington University Wolfram Research Clinic experience

Abstract

Objective (1) Describe the progression of diabetes mellitus over time in an observational study of Wolfram syndrome, a rare, genetic, neurodegenerative disorder, which often includes diabetes mellitus and is typically diagnosed during childhood or adolescence. (2) Determine whether C‐peptide could be used as a marker of diabetes progression in interventional trials for Wolfram syndrome. Methods N = 44 (25F/19M) participants with genetically confirmed Wolfram syndrome attended the Washington University Wolfram Research Clinic annually from 2010 to 2019. Medical history, physical examinations, blood sampling, and questionnaires were used to collect data about diabetes mellitus and other components of Wolfram syndrome. Beta‐cell function was assessed by determination of C‐peptide during a mixed meal tolerance test. Random coefficients models evaluated the rate of progression of C‐peptide over time, and power analyses were used to estimate the number of subjects needed to detect a change in C‐peptide decline during an intervention trial. Results 93.2% of patients had diabetes mellitus. Mean HbA1c across all study visits was 7.9%. C‐peptide significantly decreased with increasing duration of diabetes mellitus (p < 0.0001); an optimal break point in C‐peptide decline was identified to occur between 0.1 and 2.3 years after diabetes mellitus diagnosis. Twenty patients per group (active vs. control) were estimated to be needed to detect a 60% slowing of C‐peptide decline during the first 2.3 years following diabetes diagnosis. Conclusion C‐peptide declines over time in Wolfram syndrome and could potentially be used as a marker of diabetes progression in interventional studies for Wolfram syndrome, especially within the first 2 years after diabetes diagnosis.

Neuro-Ophthalmologic Variability in Presentation of Genetically Confirmed Wolfram Syndrome: A Case Series and Review

“…Despite DM typically presenting before OA, Patient 3 did not report a history of DM. Although rare, patients with genetically confirmed WS presenting with OA without DM have been reported [3,5,14]. In a study of 59 patients, there were three patients who did not present with DM, one of them presumed to be because of young age, while the other two were adults [5].…”

Early Diagnosis of Wolfram Syndrome by Ophthalmologic Screening in a Patient with Type 1B Diabetes Mellitus: A Case Report

“…As in the present case, we propose that patients with T1BDM who have preserved endogenous insulin secretion may be eligible for ophthalmologic screening to investigate for WS. In patients with WS, the decline in endogenous insulin secretion is gradual and often maintained for a long time after diagnosis ( 9 ), whereas insulin secretion is usually depleted within a few years in patients with T1DM, especially in early childhood-onset cases ( 10 ).…”

Wolfram Syndrome 1 in Two Brothers Treated with Insulin Pump

“… 2 , 4 The genetic variants in WFS1 lead to the accumulation and response of unfolded proteins in the ER, which induces stress, and when it chronifies along with physiologic or pathologic processes, it stimulates cell apoptosis. 4 , 5 Thus, the pancreatic and neuronal cells are affected, which explains the appearance of DM and neurodegeneration. 4 , 5 As a marker of progression, DM has garnered particular interest because it is the earliest feature to be recognized and consequently controlled; it is remarkable due to the strong correlation between metabolic control of DM, the number of associated symptoms, and the progression of neurodegenerative diseases.…”

“… 4 , 5 Thus, the pancreatic and neuronal cells are affected, which explains the appearance of DM and neurodegeneration. 4 , 5 As a marker of progression, DM has garnered particular interest because it is the earliest feature to be recognized and consequently controlled; it is remarkable due to the strong correlation between metabolic control of DM, the number of associated symptoms, and the progression of neurodegenerative diseases. 5 , 6 …”