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The metabolic disorder phenylketonuria (PKU) is the most common biochemical cause of mental retardation, and affects roughly one in 10,000 children. Bridging basic neuroscience research and clinical studies, this longitudinal study (a) provides evidence that cognitive deficits result from even moderate amino acid imbalances considered acceptable under the standard treatment for PKU, (b) characterizes the nature of those cognitive deficits, and (c) identifies their biological cause. The authors discuss possible steps to correct the problem, and possible implications of the findings for children with other developmental disabilities, such as attention deficit disorder.