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.