The value of CSF neurotransmitter monitoring in the outcome of gene therapy in aromatic amino acid decarboxylase (AADC) defect

Objective: Aromatic amino acid decarboxylase defect (AADCd) is an ultrarare autosomal recessive condition due to pathogenetic DDC variants, presenting with early psychomotor delay, movement disorders, and autonomic dysregulation, leading to severe neurological and intellectual disability. Intracranial AAV2-mediated DDC delivery proved to improve the natural history of the disease. We explored the usefulness of the assessment in CSF of metabolic biomarkers of the disease [3-O-methyldopa (3-OMD), 5-hydroxyindolacetic acid (5-HIAA), and homovanillic acid (HVA)], for the post-treatment clinical monitoring. Methods: We collected clinical and CSF neurotransmitter data from 30 published patients and a personal case, to assess the relationship between post-treatment clinical and metabolic variations in subjects with concomitant clinical and CSF evaluation before and at least 6 months after the surgery. Results: HVA levels increase in many, but not all, patients with a broad variability. No correlation was found between clinical improvement and biogenic amine repletion in CSF. No correlation was detected between pre-treatment clinical severity score and post-treatment HVA variation. Low 5-HIAA and high 3-OMD were not affected by the therapy. Conclusion: Current evidence suggests CSF metabolites do not overcome the predictive value of clinical observation on clinical outcomes and should be reserved for patients unresponsive to the therapy.