The psychology and neuropathology of phenylketonuria.

Numerous advances have been made in our understanding of metabolic disorders over the last century, but optimal outcomes have not been achieved for individuals with phenylketonuria (PKU). We stand now on the cusp of a new era of PKU research and treatment. It is time that we thoroughly reevaluate our understanding of PKU so that we may take advantage of current innovations in neuropsychological assessment (e.g., more sensitive tasks assessing specific executive abilities), scientific technologies (e.g., neuroimaging, genetic sequencing), and treatment options (e.g., large neutral amino acid supplementation, sapropterin dihydrochloride [BH4]) that hold promise for improving quality of life for individuals with PKU. To achieve this goal, we invited international experts to aid us in assembling a comprehensive overview of the psychology, neuropsychology, and neuropathology of PKU. The reviews and empirical articles presented in this supplement of Molecular Genetics and Metabolism represent the work of 50 authors, including psychologists, psychiatrists, geneticists, dietitians, neuroscientists, and biologists from countries all over the world. Sir Archibald Garrod first described inheritedmetabolic diseases in 1908 [1], and PKU set the precedent for the identification, understanding, and treatment of such diseases. PKUwas first described as ‘‘phenylpyruvic oligophrenia” by Følling in 1934, after he identified excess phenylpyruvic acid in the urine of two siblings with mental retardation [2]. Følling’s ferric chloride test revealed a characteristic blue–green color in the urine of individuals with PKU. Følling and others, including Penrose who coined the term PKU, used this test to screen patients in psychiatric institutions and to trace the family history of individualswith PKU. Thiswork led to the knowledge that PKUwasa rare, recessively inheriteddisease inwhich themajorityof individuals had intelligence quotients (IQ) less than 50 [2,3–6]. Følling [7] identified elevated blood phenylalanine (Phe) in individuals with PKU, which is the basis for PKU diagnosis today. It was not until the 1940s and 1950s, however, that a clearer picture of the biochemistry of PKU emerged. Major advancement occurred in 1944, when Bernheim and Bernheim [8] demonstrated that the metabolic pathwaybywhichPhe is converted to tyrosine (whichwenowknow is a precursor of dopamine and other neurotransmitters) is disrupted. Another major advancement resulted from the research of Jervis and colleagues [9], who showed that hepatic phenylalanine hydroxylase (PAH) enzyme activity is deficient in individuals with PKU. Threedecades later,Wooandcolleagues [10]described thefirst PAH gene sequence, a discovery which was accompanied by optimism that gene therapymight provide a cure for PKUandothermetabolic disorders. This excitement was tempered, however, by the realization that genotype–phenotype relationships are complex, and by the significant challenges related to the development of successful gene therapies.