Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rapid progressing pediatric neurodegenerative disorder caused by deficiency of the lysosomal enzyme tripeptidyl peptidase 1. The only approved therapy is intracerebroventricular enzyme replacement therapy (ICV-ERT) with cerliponase alfa, which slows down the decline in motor and language function. Neurofilament light chain (NfL) and glial fibrillary acid protein (GFAP) are biomarkers elevated in various neurodegenerative disorders. However, large scale and long-term data in CLN2 are lacking.
We analyzed NfL levels in 302 CSF samples and GFAP levels in 195 CSF samples of 54 CLN2 patients with late-infantile CLN2 phenotypes covering treatment periods up to 505 weeks. NfL- and GFAP-levels were correlated with treatment duration as well as the Hamburg CLN2 motor/language clinical rating scale (ML-score).
In untreated patients before ICV-ERT, increased NfL levels showed a moderate correlation with lower Hamburg ML-scores start prior to ICV-ERT which did not persist after treatment start. GFAP showed no correlation with the disease stage at any time point. Throughout ICV-ERT, NfL levels followed a biphasic course with highest levels prior to treatment and a rapid annual reduction of 52 % over the first two treatment years subsequently, levels stabilized. GFAP showed a biphasic course as well: Over the first six years of ICV-ERT, statistical analysis of GFAP showed stable levels, but afterwards they began to rise with an annual increase of 45%.
These data show, that NfL may serve as a biomarker for monitoring initial treatment response in CLN2 disease but has limitations in tracking disease progression during long-term treatment. GFAP appears not to be a meaningful biomarker in early disease stages. However, it might show relevance in later therapy stages. Overall, both biomarkers do not sufficiently embody clinical disease stages and therapy response over the entire treatment period and therefore cannot replace clinical scorings.