Perspective on the future of genetic counseling assistants - Should it be a steppingstone or a stand-alone career?

Classic phenylketonuria (PKU) is caused by defective activity of phenylalanine hydroxylase (PAH), the enzyme that coverts phenylalanine (Phe) to tyrosine. Toxic accumulation of phenylalanine and its metabolites, left untreated, affects brain development and function depending on the timing of exposure to elevated levels. The specific mechanisms of Phe-induced brain damage are not completely understood, but they correlate to phenylalanine levels and on the stage of brain growth. During fetal life, high levels of phenylalanine such as those seen in maternal PKU can result in microcephaly, neuronal loss and corpus callosum hypoplasia. Elevated phenylalanine levels during the first few years of life can cause acquired microcephaly, severe cognitive impairment and epilepsy, likely due to the impairment of synaptogenesis. During late childhood, elevated phenylalanine can cause alterations in neurological functioning, leading to ADHD, speech delay and mild IQ reduction. In adolescents and adults, executive function and mood are affected, with some of the abnormalities reversed by better control of phenylalanine levels. Altered brain myelination can be present at this stage. In this article, we review the current knowledge about the consequences of high phenylalanine levels in PKU patients and animal models through different stages of brain development and its effect on cognitive, behavioural and neuropsychological function.