Wolfram Syndrome (WFS) is a rare, genetic, neurodegenerative disorder with associated features of diabetes mellitus (DM), diabetes insipidus, deafness, and optic atrophy. In order to design intervention studies, concrete markers of disease progression are required. DM in WFS is believed to be due to endoplasmic reticulum stress-induced failure of insulin secretion. Therefore, progressive loss of insulin production may be a viable marker of disease progression. The purpose of this study was to examine progression of DM, measured by beta-cell function, in WFS patients over time. N=44 (25F/19M) participants with genetically confirmed WFS attended the Washington University Wolfram Research Clinic from 2010-2019. A mixed meal tolerance test was administered to assess beta cell function (i.e., C-peptide). A hierarchical random coefficients model was used to relate C-peptide as a function of DM duration. Most patients (91%) had DM at time of study enrollment (N=39) or developed DM during the study (N=1). There was a significant association between C-peptide and DM duration, such that C-peptide decreased over time (F= 39.44, p=<0.0001). Given the high prevalence and easily dated onset of DM in WFS, deterioration in C-peptide could potentially be used as a biomarker to assess disease progression in intervention trials for WFS, particularly in those with duration of DM < 10 years as they may be less likely to experience a C-peptide floor effect.


M. Ray: None. T. Hershey: None. L. Chen: None. N.H. White: None. B.A. Marshall: None.


Washington University (HD070855, U54HD087011); Clinical and Translational Science Award (UL1RR024992); National Institute on Drug Abuse (5T32DA007261-27); Diabetes Research Center (DK020579); Snow Foundation, George Decker and Julio V. Santiago Pediatric Diabetes Research Fund; Mallinckrodt Institute of Radiology; McDonnell Center for Systems Neuroscience

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