Seizure phenotype in CLN3 disease and its relation to other neurologic outcome measures

Abstract

CLN3 disease is a pediatric neurodegenerative condition wherein seizures are common. The most common disease-causing variant is an ~1-kb deletion in CLN3. We investigated seizure phenotype in relation to genotype and to adaptive behavior, MR spectroscopy and CSF biochemical markers in a CLN3 cohort. We performed seizure phenotyping using clinical history, EEG, and the Unified Batten Disease Rating Scale (UBDRS) seizure score. We assessed correlations of seizure severity with disease severity (UBDRS capability), adaptive behavior composite score (ABC; Vineland-3), glutamate+glutamine+GABA and N-acetylaspartate+N-acetylaspartyl glutamate (MR spectroscopy), and CSF neurofilament light chain (NEFL) levels. In 20 participants, median age was 10.7 years (IQR = 7.8). Eighteen completed baseline EEG; 12 had a 1-year follow-up. Seizures were reported in 14 (8 1-kb deletion homozygotes), with median age at onset of 10.0 (IQR = 6.8). Epileptiform discharges were noted in 15 (9 homozygotes). Bilateral tonic clonic (n = 11) and nonmotor seizures (n = 7) were most common. UBDRS seizure score correlated with age (rp = 0.50; [0.08,0.77]; P = .02), UBDRS capability (rp = -0.57; [-0.81,-0.17]; P = .009) and ABC (rp = -0.66; [-0.85,-0.31]; P = .001) scores, glutamate+glutamine+GABA (rp = -0.54; [-0.80,-0.11]; P = .02) and N-acetylaspartate+N-acetylaspartyl glutamate (rp = -0.54; [-0.80,-0.11]; P = .02), and CSF NEFL (rp = 0.65; [0.29,0.85]; P = .002) levels. After controlling for age, correlations with ABC and CSF NEFL remained significant. In our CLN3 cohort, seizures and epileptiform discharges were frequent and often started by age 10 years without significant difference between genotypes. ABC and CSF NEFL correlate with UBDRS seizure score, reflecting the role of seizures in the neurodegenerative process. Longitudinal evaluations in a larger cohort are needed to confirm these findings.

Trial registration: ClinicalTrials.gov NCT03307304.

Keywords: EEG; MRS; UBDRS; adaptive behavior; batten disease; natural history; neurofilament light chain.

Conflict of interest statement

Competing interest statement: Myriam Abdennadher, Sara Inati, Ariane Soldatos, Gina Norato, Eva H. Baker, Audrey Thurm, Luca Bartolini, Ruturaj Masvekar, William Theodore, Bibiana Bielekova, Forbes D. Porter, and An N. Dang Do declare that they have no conflict of interest in connection with this article.

© 2021 SSIEM.

Figures

Figure 1.

Correlation of UBDRS seizure assessment score to clinical, imaging and biochemical markers of CLN3 disease. Y-axis labels: A) Age (years), B) UBDRS Physical scores, C) UBDRS Capability assessment given actual vision scores, D-F) Tissue metabolite concentrations (difference from reference, mM), G) ABC standardized scores, H) CSF NEFL normalized protein expression by proximal extension assay, I) CSF NEFL concentrations (pg/mL) by ELISA. X-axis label: UBDRS seizure scores. ABC: Vineland-3 adaptive behavior composite. Corr: correlation coefficient. Cr: creatine. Glx: glutamate+glutamine+GABA. NAA: N-acetylaspartate. NEFL: neurofilament light chain. UBDRS: Unified Batten Disease Rating Scale.