Abstract
BACKGROUND AND OBJECTIVES: Lafora disease (LD) is a severe, ultra-rare childhood-onset progressive myoclonus epilepsy caused by biallelic pathogenic variants in either EPM2A or NHLRC1 and currently without cure. Body fluid-derived biomarkers have remained largely unexplored in LD. Neurofilament light chain (NfL) levels in serum (sNfL) and CSF (cNfL) reflect ongoing neurodegeneration and have been established as prognostic and therapeutic biomarkers in various neurologic disorders. In this study, we assessed the utility of NfL as a biomarker of LD in a multicenter cohort of patients with LD. METHODS: We conducted cross-sectional and longitudinal measurements of NfL levels in serum (n = 32) and CSF (n = 25) samples from a cohort of 31 patients with LD (26 independent families; mean age 21 years; age range 10.2-40.3; f:m = 16:15; EPM2A:NHLRC1 = 16:15) at diverse disease stages (median LD stage 2) and age-matched control participants with transient minor neurologic conditions (mean age 21.9 years; age range 11.1-41.3; f:m 22:8), treated at 3 referral centers in Ulm, Bologna, and Dallas. At each visit, we assessed LD stage (median LD stage 2; range 0-4) and LD clinical performance score (median score 10.5; range 0-18), allowing for correlation with NfL measurements. RESULTS: When compared with control participants (mean sNfL 7.72, 95% CI 6.79-8.65; mean cNfL 306.8, 95% CI 251.5-362.2), CSF and serum NfL levels were increased in patients with LD (mean sNfL 13.95, 95% CI 11.20-16.69; mean cNfL 576.9, 95% CI 465.3-688.5). cNfL values exhibited less variability than sNfL, resulting in superior discriminatory performance between those with LD and controls in receiver operating characteristic (ROC) analyses (AUC sNfL = 0.80; cNfL = 0.88). NfL levels tended to increase longitudinally when samples had been collected ≥12 months after baseline. sNfL levels correlated with both disease stage (r = 0.56) and LD Clinical Performance Scale score (r = -0.49), but not with disease duration (owing to genotype-dependent clinical heterogeneity). DISCUSSION: Our findings support the utility of NfL, particularly sNfL, as a promising biomarker of disease progression in LD. While further research is needed to fully elucidate the potential of NfL in this context, it holds immediate promise as an exploratory outcome measure in ongoing and future clinical trials.