CLN3 disease is a neurodegenerative disorder with onset in childhood. It affects multiple functions at different developmental stages. Incomplete understanding of the pathophysiology hampers identification of cell and tissue biochemical compounds reflective of the disease process. As treatment approaches are being explored, more sensitive, objective, quantifiable, and clinically relevant biomarkers are needed.
We collected prospective biosamples from 21 phenotyped individuals with CLN3. We measured neurofilament light chain (NEFL) levels, a marker of neuronal damage, in cross-sectional CSF and serum samples from individuals with CLN3 and in pediatric non-CLN3 controls using two different assays.
Cerebrospinal fluid (CSF) and serum NEFL levels are significantly higher in CLN3 (CSF: 2096 ± 1202; serum: 29.0 ± 18.0 pg/mL) versus similarly aged non-CLN3 (CSF: 345 ± 610; serum: 6.7 ± 3.2 pg/mL) samples. NEFL levels correlate with Unified Batten Disease Rating Scale and adaptive behavior composite scores, and magnetic resonance (MR) spectroscopy markers. NEFL levels from CSF and serum are strongly correlated (rp = 0.83; p < 0.0001).
CSF and serum NEFL levels increase in multiple neurologic conditions. Here, we show that CSF and serum NEFL levels also increase in CLN3 (versus non-CLN3) and correlate with other disease-relevant measures. These findings suggest NEFL as a relevant and feasible biomarker for applications in CLN3 clinical trials and management.
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The data that support the findings of this study are available from the corresponding author upon reasonable request.
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We dedicate this work to the study participants, their families, and the support organizations for the motivation and inspiration they have provided. We thank Jonathan W. Mink (University of Rochester Medical Center) for his expert inputs on UBDRS implementation. We thank colleagues and staff who enabled the conduct of this study and the preparation of the manuscript. The National Institutes of Health (NIH) Intramural Research Program of NICHD, National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Mental Health (NIMH), the NIH Clinical Center, National Institute of Neurological Disorders and Stroke (NINDS), and an NIH Clinical Center Bench-to-Bedside Award supported this work.
The authors declare no Competing interests.
We evaluated study participants and collected biospecimens as part of natural history studies approved by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Institutional Review Board (CLN3 [NCT03307304]; creatine transporter deficiency [CTD; NCT02931682]; Smith–Lemli–Opitz syndrome [SLOS; NCT00001721]; Niemann–Pick disease, type C [NCT00344331]). The main inclusion criteria for CLN3 disease study participants is having pathogenic variants in CLN3, with no restriction on disease phenotype. Parents or guardians and participants older than 7 years of age provided consent and assent, respectively. We provided de-identified participant-level data. The study adhered to the principles set out in the Declaration of Helsinki.
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Dang Do, A.N., Sinaii, N., Masvekar, R.R. et al. Neurofilament light chain levels correlate with clinical measures in CLN3 disease. Genet Med (2020). https://doi.org/10.1038/s41436-020-01035-3