Processing speed and executive abilities in children with phenylketonuria.

Phenylketonuria (PKU) is a hereditary disorder characterized by the inefficient metabolism of the amino acid phenylalanine (Phe) due to abnormalities in the phenylalanine hydroxylase enzyme. Untreated PKU results in neurological abnormalities (Moyle, Fox, Bynevelt, Arthur, & Burnett, 2007) and intellectual disability (de Groot, Hoeksma, Blau, Reijngoud, & van Spronsen, 2010; Paine, 1957). Even with early and continuous dietary treatment to limit Phe intake, PKU is associated with slightly lower than expected intelligence (for a review, Brumm & Grant, 2010) and deficits in specific aspects of cognition such as executive abilities and processing speed (for reviews, Albrecht, Garbade, & Burgard, 2009; Christ, Huijbregts, de Sonneville, & White, 2010; DeRoche & Welsh, 2008; Janzen & Nguyen, 2010). Two primary neural mechanisms are hypothesized to underlie brain dysfunction and subsequent neuropsychological impairment in individuals with PKU: dopamine deficiency and white matter abnormalities. Turning first to dopamine, this essential neurotransmitter is synthesized from the amino acid tyrosine (Tyr), of which Phe is a precursor (for an overview, de Groot et al., 2010). Because Phe is not properly metabolized, Tyr production is limited, which in turn limits dopamine synthesis. In addition, Tyr and Phe are among the large neutral amino acids (LNAAs) that competitively bind to the large neutral amino acid type 1 (LAT1)-transporter for passage across the blood-brain barrier. Compared with other LNAAs, Phe binds more strongly with the LAT1-transporter. As a result, high blood Phe impedes the transport of available Tyr across the blood-brain barrier, which further limits dopamine synthesis (de Groot et al., 2010). Dopamine deficiency has long been viewed as the primary neural mechanism underlying brain dysfunction and impaired cognition in individuals with PKU. In recent years, however, increasing evidence has emerged suggesting that white matter abnormalities also play a role. Neuroimaging studies have identified white matter abnormalities even in individuals with early-and continuously-treated PKU (Anderson et al., 2004, 2007; Anderson & Leuzzi, 2010; White et al., 2010), with the prevalence and severity of these abnormalities increasing at higher Phe levels (Anderson et al., 2004; Anderson & Leuzzi, 2010). Of particular relevance to the current investigation, it is probable that the white matter abnormalities associated with PKU result in slowed information processing due to disruptions in the speed with which neural signals are transmitted. Indeed, slowed information processing is a common finding in studies of individuals with PKU (Anderson et al., 2007; Channon, Mockler, & Lee, 2005; Feldmann, Denecke, Grenzebach, & Weglage, 2005; Moyle, Fox, Arthur, Bynevelt, & Burnett, 2007; Moyle et al., 2007b; for a meta-analysis, Albrecht et al., 2009), and PKU-related white matter abnormalities are associated with slowed performance across a range of cognitive tasks (Anderson et al., 2004; Anderson et al., 2007). It is also possible that white matter abnormalities and slowed information processing contribute to the impairments in executive abilities observed in individuals with PKU due to inefficiencies in the interconnections between prefrontal cortex and posterior brain regions (Anderson & Leuzzi, 2010). As pointed out by Salthouse, slowed processing may result in “impairments of higher order processes such as abstraction, elaboration, or integration, because not all of the relevant information will be available in a usable form when it is needed” (Salthouse, 1996, p. 406). In the current study, processing speed and variability in processing speed were examined, as well as the relationship of each with executive abilities, in children with early- and continuously-treated PKU. In typically-developing children, information processing speed increases with age (Conners, Epstein, Angold, & Klaric, 2003; Nettelbeck & Burns, 2010), and faster processing has been associated with developmental improvements in executive abilities including working memory (Salthouse & Babcock, 1991; Salthouse, 1992; Zanto, Toy, & Gazzaley, 2010), inhibitory control (Bugg, DeLosh, Davalos, & Davis, 2007), and strategic processing (Imbo & Vandierendonck, 2007). To our knowledge, however, research has not been conducted with a focus of either variability in processing speed or the relationship between processing speed and executive abilities in children with PKU. To address these issues, RT and variability in RT were evaluated using three speeded tasks (simple reaction time, go/no-go, stimulus-response compatibility) in children with PKU and typically-developing control children. RTs from three tasks were used to ensure that processing speed findings were not due to the particularities of a single task. Executive performance on tasks assessing working memory, strategic processing, and inhibitory control was also examined in relation to RT and variability in RT. By assessing children across a broad age range (i.e., 7 to 18 years of age), it was possible to explore possible differential effects of age on RT, variability in RT, and relationships with executive abilities across our PKU and control groups. We also investigated the relationships between Phe levels, processing speed variables, and executive variables. Some researchers have identified significant negative relationships between Phe and cognition (e.g., Weglage et al., 1996; Diamond et al., 1997), whereas others have not (Mazzocco et al., 1994; Anderson et al., 2004). Reflecting this inconsistency, previous findings from our laboratory (e.g., White et al., 2002; Christ et al., 2006) have been mixed in this regard, possibly due to the restricted range of Phe in our samples of early- and continuously-treated children with PKU. Given that the current study was also conducted with early- and continuously-treated children, we expected similar mixed results. That is not to say that we consider control of Phe to be unimportant. Rather, we expected that there might simply be too little variability in Phe to detect statistically significant correlations in a consistent manner.