Dopaminergic restoration of prefrontal cortico-putaminal network in gene therapy for aromatic l-amino acid decarboxylase deficiency

Aromatic l-amino acid decarboxylase (AADC) is an essential dopamine-synthesizing enzyme. In children with AADC deficiency, the gene delivery of AADC into the putamen, which functionally interacts with cortical regions, was found to improve motor function and ameliorate dystonia. However, how the restoration of dopamine in the putamen in association with cortico-putaminal networks leads to therapeutic effects remains unclear. Here, we examined neuroimaging data of eight patients with AADC deficiency (five males and three females, age range 4–19 years) who received the AADC gene therapy of the bilateral putamen in an open-label phase 1/2 study. Using high-resolution positron emission tomography with a specific AADC tracer, 6-[(18)F]fluoro-l-m-tyrosine (FMT), we showed that FMT uptake increased in the broad area of the putamen over the years. Then, with the structural connectivity-based parcellation of the putaminal area, we found that motor improvement is associated with dopaminergic restoration of the putaminal area that belongs to the prefrontal cortico-putaminal network. The prefrontal area dominantly belongs to the frontoparietal control network, which contributes to cognitive-motor control function, including motor initiation and planning. The results suggest that putaminal dopamine promotes the development of an immature motor control system, particularly in the human prefrontal cortex that is primarily affected by AADC deficiency.