Neurofilament light chain but not glial fibrillary acidic protein serum levels are elevated in Wolfram syndrome.

Wolfram syndrome is a rare genetic disorder caused by pathogenic variants in the WFS1 gene. Progressive neurodegeneration, a key feature of the disease, is an important target of current and future clinical trials. Serum neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are promising blood-based biomarkers of neuroaxonal damage and reactive astrogliosis, respectively, that may be useful alternative or adjunctive outcome measures to current measures of disease progression. To determine if serum NfL and/or GFAP levels are elevated in Wolfram syndrome compared to controls and whether they can serve as monitoring biomarkers. Serum NfL and GFAP levels were log10 transformed and compared between individuals with Wolfram syndrome (n = 45) and multiple control groups, including their parents (n = 55), unaffected siblings (n = 12), and unrelated individuals with (n = 47) and without (n = 29) newly diagnosed Type 1 diabetes. Within the Wolfram group, serum levels were related to clinical measures and regional brain volumes and assessed longitudinally. NfL levels were higher in the Wolfram group relative to all control groups (p < 0.001, η p 2 = 0.51) after adjusting for age and sex, whereas GFAP levels were not different between any of the groups. Within the Wolfram group, neither NfL nor GFAP levels changed over time, and NfL levels did not correlate reliably with any measures of clinical disease severity or neurodegeneration (p > 0.05 after excluding outliers). Serum NfL elevation in Wolfram syndrome may reflect the ongoing, relatively slow neurodegeneration occurring in this disorder. However, without any correspondence between serum levels and currently used clinical and neuroimaging metrics, it has limited utility as a monitoring biomarker of disease progression in this patient population. Future studies may be warranted to determine if NfL could be a treatment-response marker in Wolfram syndrome clinical trials.