Authors :
Presenting Author: Paul Malik, PharmD, PhD – Ionis
Joni Saby, PhD – Children's Hospital of Philadelphia
Steven Lee, MD, PhD – Baylor College of Medicine/Texas Children's Hospital
Chen Chen, MS – Ionis
Eric Marsh, MD PhD – Children's Hospital of Philadelphia
Matthew McGinley, PhD – Texas Children's Hospital and Baylor College of Medicine
Christine Coquery, PhD – Ionis
Rationale:
MECP2 duplication syndrome (MDS) is a rare, X-linked neurodevelopmental disorder caused by an increase in copy number of the MECP2 gene and overexpression of MeCP2 protein, typically in males. MDS is characterized by infantile hypotonia, global developmental delay leading to severe intellectual disability, limited or absent speech, recurrent respiratory infections, and often drug-resistant seizures. While electrophysiology-based responses to stimuli are generally attenuated in children with neurodevelopmental disorders, including MDS, their clinical relevance in people with MDS is unknown. We present preliminary data from an ongoing natural history study to evaluate electrophysiology parameters as potential biomarkers relative to clinician-reported outcomes.
Methods:
NH00006 (NCT06014541) is a multi-center, non-interventional, prospective and retrospective study in males ≥ 1 month of age with genetically confirmed MDS. The 104-week prospective part includes up to 8 clinic visits comprising biomarker sample collection, clinician- and caregiver-reported outcome measures, electrophysiologic assessments (resting-state quantitative electroencephalogram [qEEG] and visual and auditory evoked potentials [VEPs/AEPs]), and pupillometry evaluating constriction dynamics following light flash stimulus. The qEEG recordings were collected using the Geodesics Magstim with quantitation performed using BESA and MATLAB. VEPs were assessed using a contrast-reversing black/white checkerboard (2 Hz refresh rate) and AEPs using an oddball paradigm (85% standard tones; 15% deviant tones). Pupillometry was recorded over 4 seconds using the PLR4000 pupillometer. Correlations with clinical measures were evaluated with mixed models adjusting for effects of potential confounding variables (eg, seizures, age). Preliminary data as of March 10, 2025 are presented.
Results:
At the data cut, 26 males with a mean ± standard deviation age at screening of 9.3 ± 5.4 years were enrolled; 23 participants completed ≥ 1 qEEG assessment and 5 completed ≥ 1 pupillometry session. Relative power features from qEEG assessments were generally stable over 6 months. There were significant correlations (all p < 0.01) between most qEEG parameters and the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-3) cognitive raw score (COG) and MDS Clinical Global Impression of Severity (MDS CGI-S) score (both metrics of disease severity in MDS; Table; Figure). Participants with more severe functional impairment also had attenuated pupil constriction dynamics (eg, greater latency [COG Fixed Effect, −2.7], lower amplitude [CGI-S Fixed Effect, −1.5] and velocity [COG Fixed Effect, −0.04; all p < 0.05]).