Gene therapy improves brain white matter in aromatic l-amino acid decarboxylase deficiency

Children with aromatic l-amino acid decarboxylase (AADC) deficiency suffer from severe motor dysfunction. Restoration of dopamine levels in the putamen by gene therapy has led to significant improvement in motor function. This study explored brain structure changes in patients.

Brain diffusion tensor imaging (DTI) was performed before and 12 months after gene therapy. Whole-brain tract-specific analysis was performed to assess white matter microstructural integrity.

In the 8 patients (aged 1.67-8.42 years) enrolled in the study, gene therapy did not affect macroscopic structure. DTI before gene therapy revealed lower total mean fractional anisotropy (FA) values in patients than in the age-matched pretreatment controls (p = 0.017; median difference = -0.0136; 95% confidence interval [CI] [-0.0319, -0.0126]). After gene therapy, total mean FA increased (p = 0.012, median difference = 0.0211, 95% CI [0.0094, 0.0456]), and the values in the patients were not different from the age-matched posttreatment controls. Increase in total mean FA after gene therapy in patients was correlated with their increase in motor score (r = 0.846; p = 0.008), but was inversely correlated with their ages at the time of gene therapy (r = -0.754; p = 0.031). Corticospinal tracts, and the thalamic radiation and callosal fibers involving motor function, improved after gene therapy.

Improvement in the microstructural integrity of white matter tracts is associated with the improvement in motor function following gene therapy. Ann Neurol 2019;85:644-652.