Gene Therapy for Amino Acid Decarboxylase Deficiency: Clinical and Imaging Outcomes in a French Cohort.

BACKGROUND

Intracerebral gene therapy is effective for amino acid decarboxylase (AADC) deficiency, but relationships between anatomical putaminal coverage, metabolic dynamics, and clinical recovery remain poorly understood.

OBJECTIVES

Assess safety, long-term efficacy, and clinical-radiological correlations in a genetically diverse European cohort of AADC deficiency.

METHODS

Six patients received bilateral intraputaminal rAAV2-hAADC infusion. Motor (GMFM-88), functional (CP-CHILD, Vineland-II), oculogyric crises (OGC), and dyskinesia outcomes were evaluated alongside magnetic resonance imaging (MRI) volumetric coverage and longitudinal 18F-fluorodopa (18F-DOPA) positron emission tomography (PET) parameters.

RESULTS

All patients achieved genotype-independent motor improvements and OGC reduction, with no serious adverse events. Clinical recovery did not correlate with the putaminal coverage volume, indicating a biological threshold effect. Transient dyskinesias coincided with an early 18F-DOPA uptake peak (1-3 months post-operative), followed by clinical resolution and sustained activity, reflecting homeostatic synaptic plasticity.

CONCLUSION

Eladocagene exuparvovec offers durable clinical benefits across diverse genotypes. Therapeutic efficacy and the subsequent neuroplasticity sequence seem to depend on reaching a critical threshold of dopamine production rather than on exhaustive anatomical coverage of the putamen. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.