Knowing that the elevated phenylalanine reduces synaptic density and number of dendritic spines [18], [39], [46] and that SHANK proteins are localized in dendritic spines and mediate its maturation during brain development, findings from our cohort of untreated PKU patients with near-normal cognitive development are linking SHANK gene family and brain plasticity in PKU for the first time. Here, SHANK2 is linked to phenylketonuria.