OBJECTIVES: AADCd is a rare genetic disorder of monoamine neurotransmitter synthesis that typically manifests by one-year of age. Patients with AADCd have minimal functional motor movement and rarely meet developmental milestones. PDMS-2 assesses motor function in young children, and Bayley-III could identify developmental delays, including non-motor (cognitive, social/emotional) delays. Clinical trials of the gene therapy eladocagene exuparvovec (EE) assessed changes in motor function of AADCd patients using PDMS-2. This study characterized the meaningful score difference (MSD) of PDMS-2 and correlations with Bayley-III and motor milestones (MM).

METHODS: Data from three AADCd single-arm trials of EE were analyzed. Total PDMS-2 MSD for improvement was estimated by anchoring against change in MM (head control, sitting unassisted, standing with support, walking with assistance). Mean-difference and receiver operating characteristic (ROC) curve approaches were used. Correlations between change from baseline (CFB) in Total PDMS-2 vs. Bayley-III (cognition and language domains), and Total PDMS-2 vs. MM, were calculated.

RESULTS: From 30 patients (median follow-up: 60-months), MSD of Total PDMS-2 was 45-points using mean-difference, and 30-40-points using the ROC approach and maximizing specificity (minimizing false signals of improvement). Correlations between CFB Total PDMS-2 and Bayley-III improved over time and were significant from Month 6 onwards (Month 6: r=0.599, p=0.0032; Month 18: r=0.796, p=0.0002; Month 60: r=0.861, p=0.0007). Correlations between improvements in MM and Total PDMS-2 were significant both for patients aged≥4 (r=0.934, p<0.0001) and <4 years (r=0.892, p<0.0001).

CONCLUSIONS: AADCd patients treated with EE experienced meaningful improvements in gross motor function, reflected by significant improvements in Total PDMS-2 score. The MSD estimated may help interpret improvements in PDMS-2, addressing historical uncertainty around levels of improvement associated with meaningful change. Correlation of CFB PDMS-2 and Bayley-III cognition and language domains suggest that in AADCd, motor-function improvements measured with PDMS-2 may be associated with improvements in other, including non-motor, domains.