Progressive Orexin-A Deficiency and Elevated NfL Mark CLN3 Disease Progression

Juvenile neuronal ceroid lipofuscinosis (CLN3 disease) is a rare, severe childhood-onset neurodegenerative disorder characterized by progressive vision loss, motor dysfunction, and cognitive decline. Despite its devastating impact, reliable biomarkers in cerebrospinal fluid (CSF) and plasma for disease progression and severity are not well-established. This lack hinders effective disease monitoring and the development of targeted therapies. Understanding the specific neurochemical changes, such as those involving orexin-A and markers of neurodegeneration, is crucial for identifying objective measures of disease activity and therapeutic response.

This exploratory cohort study investigated biomarker profiles in 11 individuals with genetically confirmed CLN3 disease (age 6.8-33.6 years). Participants underwent one or two lumbar punctures with paired blood sampling. CSF and plasma levels of orexin-A, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), total tau (T-tau), phosphorylated tau, amyloid-beta 42, monoamine metabolites, and markers of inflammation and blood-brain barrier integrity were measured. All analyses utilized standardized immunoassays to ensure consistency and reliability across samples.

Longer disease duration was consistently associated with reduced CSF orexin-A in most participants, aligning with the observed acquired narcolepsy-like phenotype, which includes excessive daytime sleepiness, hallucinations, and disrupted sleep. Notably, NfL levels were markedly elevated in both CSF and plasma across all individuals, strongly indicating ongoing axonal degeneration and supporting its utility as a robust progression biomarker in CLN3 disease. T-tau was elevated in younger children but then normalized in adolescents, suggesting age-dependent dynamics. GFAP, T-tau, and amyloid-beta 42 were found to be abnormal in a subset of patients, while phosphorylated tau, monoamine metabolites, and markers of inflammation and blood-brain barrier dysfunction largely remained within reference ranges. Correlation analyses further solidified these findings, showing a clear trend of decreasing CSF orexin-A and T-tau, alongside increasing NfL and GFAP, with longer disease duration.

CSF orexin-A deficiency and markedly elevated NfL are identified as key biomarker features in CLN3 disease, reflecting both a narcolepsy-like phenotype and ongoing axonal damage.