Rett Syndrome: Specific MECP2 Variants are Associated With Elevated Serum Neurofilament Light Chain

Rett syndrome, a neurodevelopmental disorder predominantly affecting females, is caused by variants in MECP2. Individuals experience a decline in skills, particularly involving language and hand function; nevertheless, studies of brain pathology suggest that neurodegeneration is not involved. To further investigate the presence of neurodegeneration, we measured serum neurofilament light chain (sNfL), a sensitive biomarker of neuronal damage.

Cross-sectional study performed in a cohort of Rett syndrome females with a confirmed pathogenic MECP2 variant. sNfL levels were measured using single-molecule array assay, converted to an age-adjusted z-score, and compared with MECP2 variant type and clinical characteristics.

Included were 77 patients; mean age 14 years, median sNfL level 6.8 pg/mL. sNfL z-scores were higher in the Rett cohort compared to healthy age-matched females (P < 0.001). Elevated sNfL levels were associated with pathogenic variant type; only patients carrying variants affecting the nuclear receptor corepressor interaction domain had elevated sNfL z-scores (P < 0.001) greater than healthy age-matched females, while those with C-terminal deletions or missense variants outside this domain did not. Consistently, patients unable to walk independently and without residual hand function had higher sNfL levels than patients with residual function in these respective areas (P = 0.04).

sNfL levels were elevated in our Rett syndrome cohort, irrespective of age, indicating ongoing neuronal damage. However, on closer inspection, this finding was true only for a subset of patients with more severe pathogenic variants affecting the nuclear receptor corepressor interaction domain. sNfL may prove a useful biomarker in upcoming therapeutic trials.