Progressive Orexin Deficiency and Age-Dependent Glial and Axonal Biomarkers in juvenile neuronal ceroid lipofuscinosis type 3 (CLN3) Disease.

BACKGROUND

Juvenile neuronal ceroid lipofuscinosis (CLN3 disease) is a rare, childhood-onset neurodegenerative disorder. Biomarkers in cerebrospinal fluid (CSF) and plasma are not well established. This study aimed to characterize biomarker profiles in genetically confirmed CLN3, with emphasis on orexin-A and markers of neurodegeneration.

METHODS

In this exploratory cohort study, 11 individuals with CLN3 disease (age 6.8-33.6 years) 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 using standardized immunoassays.

RESULTS

Longer disease duration was associated with reduced CSF orexin-A in most participants, consistent with an acquired narcolepsy-like phenotype (excessive daytime sleepiness, hallucinations, disrupted sleep). NfL was markedly elevated in CSF and plasma across individuals, indicating ongoing axonal degeneration and supporting its role as a progression biomarker. T-tau was elevated in younger children but normalized in adolescents. GFAP, T-tau, and amyloid-beta 42 were abnormal in a subset, while phosphorylated tau, monoamine metabolites, and markers of inflammation and blood-brain barrier dysfunction were largely within reference ranges. Correlation analyses showed decreasing CSF orexin-A and T-tau and increasing NfL and GFAP, with longer disease duration.

CONCLUSIONS

Reduced CSF orexin-A and elevated NfL are key biomarker features in CLN3. Findings support a secondary narcolepsy-like phenotype and highlight these markers as candidates for disease monitoring. Larger longitudinal studies are needed to validate these observations and clarify clinical correlations.