Rationale:
Neuronal ceroid-lipofuscinoses (NCLs) are a family of inherited childhood-onset neurodegenerative disorders. The most frequent form, caused by CLN3 mutations, affects up to 7 per 100,000 live births1. Clinical features start by ages 4–7, including vision loss, motor and cognitive decline, and seizures. EEG abnormalities have been described clinically but there is a lack of quantitative EEG (qEEG) studies. Here, we describe qEEG findings and behavioral outcomes in a cohort of patients with CLN3 with and without epilepsy compared to healthy volunteers (HVs).
Methods:
We studied 32 CLN3 patients (mean age 12, 41% female, 51% with epilepsy) and 39 HVs (mean age 9, 46% female) with routine EEGs enrolled in NIH IRB-approved protocols. We selected 5 minutes of eyes-open resting-state EEG. Four second epochs were preprocessed using 1–45 Hz and 60 Hz notch filters, ICA-artifact rejection, and average-re-referencing. We computed power spectral densities (PSDs) and used the Fitting Oscillations & One-Over F (FOOOF) method to identify oscillatory (periodic) and aperiodic (1/f) PSD components.2 We extracted individual peak frequencies and aperiodic exponents to compare across groups using Mann-Whitney tests. qEEG metrics were also correlated with Vineland ABC adaptive behavior scores.Results:
Compared to HVs, CLN3 patients demonstrated significantly reduced individual peak frequency (p< 0.0001) and lack of peak frequency correlation with age (HV r2=0.163, p< 0.05 vs CLN3 r2=0.059, p >0.05) as well as a steeper slope of the 1/f aperiodic component (p< 0.0001). Finally, CLN3 patients with epilepsy scored significantly worse on ABC scores than those without (median 62 vs 78, p=0.0121).
Conclusions:
Our findings show altered EEG power spectra in CLN3 patients compared to HVs, most notably a reduction in individual peak frequency and steeper slope of the EEG aperiodic component. These findings may reflect impaired neural maturation and disrupted cortical rhythms characteristic of neurodevelopmental disorders, as well as altered balance between excitation and inhibition.2 The lower adaptive scores in epileptic CLN3 subjects suggest worse functioning in patients with seizures. These findings highlight the utility of PSD analysis in characterizing the neurophysiological impact of CLN3 and may suggest potential utility as biomarkers for this developmental and epileptic encephalopathies in general.
References:
1 Zhang, Y., Du, B., Zou, M., Peng, B., & Rao, Y. (2025). Neuronal ceroid lipofuscinosis—concepts, classification, and avenues for therapy. CNS Neuroscience &Amp; Therapeutics, 31(2). https://doi.org/10.1111/cns.70261
2 Donoghue, T., Haller, M., Peterson, E. J., Varma, P., Sebastian, P., Gao, R., Noto, T., Lara, A. H., Wallis, J. D., Knight, R. T., Shestyuk, A., & Voytek, B. (2020). Parameterizing neural power spectra into periodic and aperiodic components. Nature Neuroscience, 23(12), 1655–1665. https://doi.org/10.1038/s41593-020-00744-x
Funding:
This work was funded by the NINDS and NICHD Intramural Research Program (IRP).