Mild/moderate phenotypes in AADC deficiency: Focus on the aromatic amino acid decarboxylase protein

Abstract

AbstractAADC deficiency is a severe neurometabolic inherited rare disorder due to the absence or decrease of dopamine and serotonin levels, causing deep motor and neurodevelopmental impairments. The disease is often fatal in the first decade of life, and pharmacological treatments (dopamine agonists, pyridoxine, and monoamine oxidase inhibitors as the first‐line choices) can only alleviate the symptoms. Gene therapy surgery is now available for severe patients in the European Union and the United Kingdom, and follow‐up data witness encouraging improvements. In the past few years, mostly due to the increased awareness and knowledge of AADC deficiency, together with newborn screening programs and advancements in methods for genetic diagnosis, the number of mild/moderate phenotypes of AADC deficiency patients has increased to 12% of the total. A review of the genotypes (homozygous/compound heterozygous) of AADC deficiency mild/moderate patients is presented here. The pathogenicity classification of each genetic variant is discussed. Then, we focused on the type of AADC protein possessed by patients and on the predictable structural score of the homodimeric/heterodimeric species of each protein variant. Since the terminology used for genetic and protein variants is the same, we highlighted how it could be misleading. We analyzed the loss‐of‐function as a fold‐change decrease of activity of the recombinant purified AADC enzyme(s) theoretically synthesized by mild/moderate patients. A minimal residual kcat of 8% and/or kcat/Km of 1% seems necessary to avoid a severe disease manifestation. Overall, this cluster of mild/moderate patients needs consideration for a more appropriate and aimed therapeutic approach.