Intellectual functioning

Intellectual functioning was assessed in 63% of the articles in the literature. In 41% of these studies, intellectual level was measured as a control variable. In all studies on intellectual functioning, the mean Full Scale Intelligence Quotient (FSIQ) score of children with ECT-PKU group was within the normal range. The mean FSIQ of the group with ECT-PKU was compared with a control group or test norms in most studies (73% vs. 6%, respectively). In 52% of these studies, children with ECT-PKU performed significantly lower than controls or test norms. Approximately half of the studies on intellectual functioning used complete intelligence tests (e.g., WISC—Weschler Intelligence Scale for Children). The other half used abbreviated versions of these scales or g factor tests (e.g., WASI—Wechsler Abbreviated Scale of Intelligence). A majority of studies that identified lower intellect used entire rather than abbreviated tests (62% vs. 36%, respectively).

Aside from the slight downward shift in FSIQ, only five studies have compared verbal and perceptual reasoning in children with ECT-PKU to controls or normative samples. And results were mixed. To our knowledge, only two studies have compared Verbal Intelligence Quotient (VIQ) to Performance Intelligence Quotient (PIQ) within group, again with mixed results. Cappelletti et al. (Reference Cappelletti, Cotugno, Goffredo, Nicolò, Bernabei, Caviglia and Di Ciommo2013) found no significant discrepancy between VIQ and PIQ, whereas Griffiths et al. (Reference Griffiths, Demellweek, Fay, Robinson and Davidson2000) found lower PIQ than VIQ.

Visual perception, visual–spatial and visual construction abilities, and motor skills

Visual perception was assessed in seven studies (13% of the literature). Findings suggested that visual perception was intact. Mixed results were found concerning sensitivity to visual contrast (Diamond & Herzberg, Reference Diamond and Herzberg1996; Stemerdink et al., Reference Stemerdink, van der Molen, Kalverboer, van der Meere, Huisman, de Jong, Slijper, Verkerk and van Spronsen1999).

Seven studies examined visual–spatial and visual construction abilities (13% of the literature). Only two studies used simple spatial tasks (spatial subtests of British Abilities Scales and Beery-Developmental Test of Visual Motor Integration scales). Impairments were not revealed in such tasks. Deficits were mainly demonstrated on tasks with more complex demands. Six studies used visual constructive tasks, including five that used the copy component Rey–Osterrieth Complex Figure Test (ROCF). Deficits were identified in four of these studies.

Four studies examined praxis (7% of the literature). Only fine motor skills and higher-order motor control were explored. Simple motor tasks (e.g., Purdue Pegboard or Tapping) and complex motor tasks requiring coordination and planning (e.g., target tracking) were used. Impairment was consistently reported for both simple and complex motor tasks.

Language and academic achievement

Language can be subdivided into subdomains such as receptive and expressive language, as well as specific areas of functioning that include phonology, syntax, semantics, and pragmatics. There are no studies that have systematically examined all these aspects of language in children with ECT-PKU. In particular, no studies have examined phonology and pragmatic abilities. Five studies (9% of the literature) used oral language tests. Impairments were identified in only one of those studies (Soleymani et al., Reference Soleymani, Keramati, Rohani and Jalaei2015). The ECT-PKU group performed significantly lower than controls in both receptive and expressive language, as well as syntax and semantics. This group with ECT-PKU displayed a lower FSIQ and VIQ. Intellectual level was not specified in the other four studies on oral language.

Academic difficulties have been described in children with ECT-PKU (Stemerdink et al., Reference Stemerdink, Kalverboer, van der Meere, van der Molen, Huisman, de Jong, Slijper, Verkerk and van Spronsen2000). Reading and spelling were examined in five studies (9% of the literature) and mathematics in six studies (11% of the literature). All these studies used composite scores from achievement tests (e.g., Wide Range Achievement Test). Two of five studies have shown a deficit in reading and only one study has shown a deficit in spelling. To our knowledge, no study systematically examined basic reading and writing skills, as well as reading comprehension. Four out of six studies have shown a deficit in mathematics. Only one work examined both calculations and applied word problems (Chang et al., Reference Chang, Gray and O’Brien2000). Children with ECT-PKU performed significantly lower than test norms for calculations, not for applied word problems.

Memory

Explicit memory was examined in nine studies (17% of the literature). Five studies assessed visual memory with the delayed recall condition of the ROCF or the Rey Visual Design Learning Test, and eight studies used verbal memory tasks (only with word-list-learning tasks). Six out of nine memory studies (67%) reported impairment in visual (4/5 studies) as well as verbal memory (5/8 studies).

Although memory functions can be subdivided into specific processes (i.e., encoding, storage, and retrieval), no study systematically examined all these aspects. Learning was consistently measured in word-list- or design-learning tasks (eight studies). Impaired learning was found in five of these studies. In word-list-learning tasks, it is possible to implement executive strategies to enhance learning (e.g., semantic clustering). In the only two studies that have measured “cluster scores,” children with ECT-PKU consistently had a lower use of this strategy. No word-recognition scores were used in the literature. The storage component of memory in children with ECT-PKU was assessed with delay-recall scores in only three studies and was consistently preserved.

EFs and attention-deficit hyperactivity disorder

EFs were widely investigated by 78% of the studies in the literature, with impairments identified in 86% of these studies. Forty-two different executive tasks were listed. In 88% of the studies on this topic, various tasks implying “cool” EFs (see “cool/hot” executive taxonomy, Zelazo & Müller, Reference Zelazo, Müller and Gaswami2002) were used. Cool EFs are elicited by more purely cognitive aspects of EFs, which are characterized by relatively abstract and decontextualized problems. Cool EFs in these studies encompassed abilities such as planning, inhibition, shifting, and working memory (Lehto et al., Reference Lehto, Juujärvi, Kooistra and Pulkkinen2003; Levin et al., Reference Levin, Culhane, Hartmann, Evankovich, Mattson, Harward, Ringholz, Ewing-Cobbs and Fletcher1991). Hot EFs are required for problems that are characterized by high affective involvement or demand flexible appraisals of the affective significance of stimuli. Hot EFs were investigated with only one recent study, which concluded that adolescents with ECT-PKU have a degree of impairment on social-cognitive functioning and social skills (Jahja et al., Reference Jahja, van Spronsen, De Sonneville, van der Meere, Bosch, Hollak, Rubio-Gozalbo, Brouwers, Hofstede, de Vries, Janssen, van der Ploeg, Langendonk and Huijbregts2016). EFs in everyday life were explored in four studies (only with the parental version of the BRIEF—Behavior Rating Inventory of Executive Function). Three studies displayed an executive impairment in everyday life, especially in the metacognition domain. None of these studies compared the BRIEF parental rating to executive performance-based tests. When executive dysfunction was found, its specificity was not systematically studied by comparing it to intellectual level (45% of the studies on EFs controlled this variable). Executive difficulties persisted in 89% of studies on EFs when FSIQ was controlled. Only four studies (i.e., 9% of the studies) on EFs have examined executive dysfunction specificity by comparing it to nonexecutive cognitive abilities (Antshel & Waisbren, Reference Antshel and Waisbren2003a; Griffiths et al., Reference Griffiths, Robinson, Davies, Hayward, Lewis, Livingstone and Plews2005; Stemerdink et al., Reference Stemerdink, van der Molen, Kalverboer, van der Meere, Huisman, de Jong, Slijper, Verkerk and van Spronsen1999; Welsh et al., Reference Welsh, Pennington, Ozonoff, Rouse and McCabe1990). In all these studies, executive impairments were still observed when nonexecutive abilities were controlled.

Executive deficits could potentially explain an overlap of clinical phenotypes between PKU and ADHD (Barkley, Reference Barkley1997; Sonuga-Barke et al., Reference Sonuga-Barke, Sergeant, Nigg and Willcutt2008). Antshel and Waisbren (Reference Antshel and Waisbren2003a, Reference Antshel and Waisbren2003b) showed that 13% of their sample of children with ECT-PKU met criteria for diagnosis of ADHD (2.5 times higher than controls), with a higher proportion of inattentive symptoms. There was no significant difference for hyperactive/impulsive symptoms. Arnold et al. (Reference Arnold, Vladutiu, Orlowski, Blakely and DeLuca2004) showed that medication for attention problems was used by 26% of their sample of children with ECT-PKU (5 times more than controls). No study has examined EFs related to the presence or absence of ADHD in children with ECT-PKU. One study showed that children with ECT-PKU exhibited more impulsivity than children with a diagnosis of ADHD combined type (without PKU) on a Go/No-Go task (Wiersema et al., Reference Wiersema, van Der Meere and Roeyers2005) but this study did not specify whether some of the ECT-PKU participants met the diagnostic criteria for ADHD.

Processing speed

In some studies (Feldmann et al., Reference Feldmann, Denecke, Pietsch, Grenzebach and Weglage2002; Weglage et al., Reference Weglage, Pietsch, Denecke, Sprinz, Feldman, Grenzebach and Ullrich1999), executive difficulties were interpreted as a slower information processing speed. In five studies, processing speed was controlled in studying executive performances (Antshel & Waisbren, Reference Antshel and Waisbren2003a; Christ et al., Reference Christ, Steiner, Grange, Abrams and White2006; Huijbregts et al., Reference Huijbregts, De Sonneville, van Spronsen, Berends, Licht, Verkerk and Sergeant2003; Janos et al., Reference Janos, Grange, Steiner and White2012; White et al., Reference White, Nortz, Mandernach, Huntington and Steiner2001, i.e., 12% of the studies on EFs). In 60% of these studies, executive difficulties were observed when processing speed was controlled.

Information processing speed was poorly explored with specific tasks. Seven studies (13% of the literature) used simple reaction time tasks or tests involving the processing speed index of Wechsler scales. Six out of seven studies (86%) have shown a slower information processing speed (Anderson et al., Reference Anderson, Wood, Francis, Coleman, Warwick, Casanelia, Anderson and Boneh2004, Reference Anderson, Wood, Francis, Coleman, Anderson and Boneh2007; Antshel & Waisbren, Reference Antshel and Waisbren2003a; Huijbregts et al., Reference Huijbregts, De Sonneville, Licht, van Spronsen, Verkerk and Sergeant2002c, Reference Huijbregts, De Sonneville, van Spronsen, Berends, Licht, Verkerk and Sergeant2003; Janos et al., Reference Janos, Grange, Steiner and White2012).

Blood phenylalanine level

Currently, blood phenylalanine level is the most widely used measure to monitor metabolic control and adapt treatment. Average phenylalanine levels (i.e., mean or median) have been shown to predict neuropsychological outcome (Waisbren et al., Reference Waisbren, Noel, Fahrbach, Cella, Frame, Dorenbaum and Levy2007). Early initiated and continued dietary treatment is crucial for the intellectual development of patients (see Brumm & Grant, Reference Brumm and Grant2010). Two meta-analyses (Fonnesbeck et al., Reference Fonnesbeck, McPheeters, Krishnaswami, Lindegren and Reimschisel2013; Waisbren et al., Reference Waisbren, Noel, Fahrbach, Cella, Frame, Dorenbaum and Levy2007) on patients with ECT-PKU showed significant correlations between FSIQ and (1) phenylalanine levels during childhood and adolescence (e.g., critical period) and (2) mean lifetime phenylalanine level. Significant but moderate correlations were found between FSIQ and concurrent phenylalanine levels (i.e., within months prior to evaluation or collected at the same day of evaluation). Moreover, Waisbren et al. (Reference Waisbren, Noel, Fahrbach, Cella, Frame, Dorenbaum and Levy2007) suggested safe upper target of blood phenylalanine concentrations between 320 and 420 μmol/L until the age of 12 years. Fonnesbeck et al. (Reference Fonnesbeck, McPheeters, Krishnaswami, Lindegren and Reimschisel2013) indicated that a mean concentration of 400 μmol/L was associated with an increased risk of an FSIQ less than 85. It should be noted that many candidate studies were excluded from these meta-analyses due to incomplete reporting of data or results. Moreover, there is a notable lack of consistent methodologies across studies considered. From a clinical perspective, this provides a basis for being cautious in interpreting measures of these results. Recent researches suggested that phenylalanine levels continue to have a negative impact on FSIQ scores during adulthood (Koch et al., Reference Koch, Burton, Hoganson, Peterson, Rhead, Rouse, Scott, Wolff, Stern, Guttler, Nelson, de la Cruz, Coldwell, Erbe, Geraghty, Shear, Thomas and Azen2002; Waisbren et al., Reference Waisbren, Noel, Fahrbach, Cella, Frame, Dorenbaum and Levy2007), which requires dietary restriction throughout life [for American guidelines, see Camp et al. (Reference Camp, Parisi, Acosta, Berry, Bilder, Blau, Bodamer, Brosco, Brown, Burlina, Burton, Chang, Coates, Cunningham, Dobrowolski, Ferguson, Franklin, Frazier, Grange, Greene, Groft, Harding, Howell, Huntington, Hyatt-Knorr, Jevaji, Levy, Lichter-Konecki, Lindegren, Lloyd-Puryear, Matalon, MacDonald, McPheeters, Mitchell, Mofidi, Moseley, Mueller, Mulberg, Nerurkar, Ogata, Pariser, Prasad, Pridjiann, Rasmussen, Reddy, Rohr, Singh, Sirrs, Stremer, Tagle, Thompson, Urv, Utz, van Spronsen, Vockley, Waisbren, Weglicki, White, Whitley, Wilfond, Yannicelli and Young2014) and Vockley et al. (Reference Vockley, Andersson, Antshel, Braverman, Burton, Frazier, Mitchell, Smith, Thompson and Berry2014); for European guidelines, see van Spronsen et al. (Reference van Spronsen, van Wegberg, Ahring, Bélanger-Quintana, Blau, Bosch, Burlina, Campistol, Feillet, Giżewska, Huijbregts, Kearney, Leuzzi, Maillot, Muntau, Trefz, van Rijn, Walter and MacDonald2017)]. While a causal relationship between blood phenylalanine levels and brain dysfunction is well-demonstrated, a recent longitudinal study showed that disease-independent individual factors may influence the consequences of the biochemical alteration, contributing to an individual vulnerability to phenylalanine and interindividual variability in FSIQ outcome of ECT-PKU (Manti et al., Reference Manti, Nardecchia, Paci, Chiarotti, Carducci, Carducci, Dalmazzone, Cefalo, Salvatici, Banderali and Leuzzi2017).

For the other cognitive abilities, correlations between phenylalanine levels and performances in the tests are inconsistent from one task to another [see Christ et al. (Reference Christ, Huijbregts, De Sonneville and White2010a) for EFs; Janzen & Nguyen (Reference Janzen and Nguyen2010) and Luciana et al. (Reference Luciana, Sullivan and Nelson2001) for nonexecutive cognitive abilities]. However, long-term memory performances were intact when the mean blood phenylalanine concentrations (whether concurrent phenylalanine or lifetime phenylalanine levels) were under 360 μmol/L, in comparison with ECT-PKU children with phenylalanine levels above 360 μmol/L (Leuzzi et al., Reference Leuzzi, Pansini, Sechi, Chiarotti, Carducci, Levi and Antonozzi2004b; Smith et al., Reference Smith, Saltzman, Klim, Hanley, Feigenbaum and Clarke2000). Similar results have been obtained for EFs (De Sonneville et al., Reference De Sonneville, Schmidt, Michel and Batzler1990; Diamond et al., Reference Diamond, Prevor, Callender and Druin1997; Huijbregts et al., Reference Huijbregts, De Sonneville, Licht, van Spronsen, Verkerk and Sergeant2002c, Reference Huijbregts, De Sonneville, van Spronsen, Licht and Sergeant2002d; Smith et al., Reference Smith, Saltzman, Klim, Hanley, Feigenbaum and Clarke2000), in particular in younger children (i.e., under 11 years) (Huijbregts et al., Reference Huijbregts, De Sonneville, Licht, Sergeant and van Spronsen2002a). In a recent study with younger ECT-PKU children (i.e., under 12 years), only those patients with phenylalanine levels under 240 μmol/L (rather than 360 μmol/L) obtained similar executive performances than controls (Jahja et al., Reference Jahja, Huijbregts, De Sonneville, van Der Meere and van Spronsen2014). Longitudinal studies of ECT-PKU showed less executive deficits during adolescence, despite a significant increase of phenylalanine levels, raising the hypothesis of a decrease vulnerability of PKU patients against elevated phenylalanine levels with aging (Nardecchia et al., Reference Nardecchia, Manti, Chiarotti, Carducci, Carducci and Leuzzi2015; Weglage et al., 2009). Only few studies employed within-subject designs where phenylalanine levels are manipulated through dietary changes. Strong effects of phenylalanine manipulation were found on EF performances (Huijbregts et al., Reference Huijbregts, De Sonneville, Licht, van Spronsen and Sergeant2002b) and reaction time (Leuzzi et al., Reference Leuzzi, Mannarelli, Manti, Pauletti, Locuratolo, Carducci, Carducci, Vanacore and Fattapposta2014a), but not on short-term and long-term memory, or fine motor coordination (Griffiths et al., Reference Griffiths, Ward, Harvie and Cockburn1998). Sensitivity to increase of phenylalanine was higher in younger (i.e., under 13 years) as compared to older people with PKU (Leuzzi et al., Reference Leuzzi, Mannarelli, Manti, Pauletti, Locuratolo, Carducci, Carducci, Vanacore and Fattapposta2014a).

Fluctuation in phenylalanine concentrations

Recent studies suggested that variability of blood phenylalanine levels over time appeared to correlate inversely and strongly with FSIQ (Burgard et al., Reference Burgard, Schmidt, Rupp, Schneider and Bremer1996; Hood et al., Reference Hood, Grange, Christ, Steiner and White2014; Vilaseca et al., Reference Vilaseca, Lambruschini, Gómez-López, Gutiérrez, Fusté, Gassió, Artuch and Campistol2010) and with executive performances (Arnold et al., Reference Arnold, Kramer, Kirby, Plumeau, Blakely, Cregan and Davidson1998; Hood et al., Reference Hood, Grange, Christ, Steiner and White2014; Jahja et al., Reference Jahja, Huijbregts, De Sonneville, van Der Meere and van Spronsen2014). However, in some studies, the correlation between fluctuation in phenylalanine and FSIQ was at the trend level of significance (Anastasoaie et al., Reference Anastasoaie, Kurzius, Forbes and Waisbren2008) or was not significant (Viau et al., Reference Viau, Wengreen, Ernst, Cantor, Furtado and Longo2011). Different indices of variability in phenylalanine have been used in the literature: SD (standard deviation, degree of dispersion in phenylalanine around a regression line), SEE (standard error of estimate, residual variation in phenylalanine around a regression line), and Spikes (number of phenylalanine levels that were at least 600 μmol/L greater than either the preceding or succeeding phenylalanine level). Interpretation and comparison of findings were limited by inconsistencies in tasks and indices of variability used across the studies.

Phenylalanine-to-tyrosine ratios

PAH deficiency causes increase in blood phenylalanine, decrease in tyrosine, and therefore theoretically an increase in phenylalanine-tyrosine ratio. A high phenylalanine-tyrosine ratio indicates that phenylalanine levels are in a range that could interfere with the transport of available tyrosine across the blood–brain barrier, resulting in a decreased availability of tyrosine for dopamine synthesis. Therefore, phenylalanine-tyrosine ratio might be of interest considering the fact that tyrosine levels are more closely related to dopamine levels than phenylalanine levels (Diamond et al., Reference Diamond, Prevor, Callender and Druin1997). Clinical relevance of this ratio as an outcome measure is unknown. Recent studies suggested that high lifetime phenylalanine-tyrosine ratios (Diamond et al., Reference Diamond, Prevor, Callender and Druin1997; Jahja et al., Reference Jahja, Huijbregts, De Sonneville, van Der Meere and van Spronsen2014; Luciana et al., Reference Luciana, Sullivan and Nelson2001; Sharman et al., Reference Sharman, Sullivan, Young and McGill2009a, Reference Sharman, Sullivan, Young and McGill2009b, Reference Sharman, Sullivan, Young and McGill2015) and high concurrent phenylalanine-tyrosine ratios (Jahja et al., Reference Jahja, Huijbregts, De Sonneville, van Der Meere and van Spronsen2014; Luciana et al., Reference Luciana, Sullivan and Nelson2001) could explain executive impairments in children with ECT-PKU. Currently, it is difficult to determine the threshold above which a high phenylalanine-tyrosine ratio is harmful.

Nutritional status

Even if it is not clear that PKU leads to a specific nutrient deficiency (Camp et al., Reference Camp, Parisi, Acosta, Berry, Bilder, Blau, Bodamer, Brosco, Brown, Burlina, Burton, Chang, Coates, Cunningham, Dobrowolski, Ferguson, Franklin, Frazier, Grange, Greene, Groft, Harding, Howell, Huntington, Hyatt-Knorr, Jevaji, Levy, Lichter-Konecki, Lindegren, Lloyd-Puryear, Matalon, MacDonald, McPheeters, Mitchell, Mofidi, Moseley, Mueller, Mulberg, Nerurkar, Ogata, Pariser, Prasad, Pridjiann, Rasmussen, Reddy, Rohr, Singh, Sirrs, Stremer, Tagle, Thompson, Urv, Utz, van Spronsen, Vockley, Waisbren, Weglicki, White, Whitley, Wilfond, Yannicelli and Young2014), dietary treatment of PKU has been associated with deficiencies in several antioxidant vitamins and cofactors, such as selenium and coenzyme Q10 (Artuch et al., Reference Artuch, Colomé, Sierra, Brandi, Lambruschini, Campistol, Ugarte and Vilaseca2004; Colomé et al., Reference Colomé, Artuch, Vilaseca, Sierra, Brandi, Lambruschini, Cambra and Campistol2003; Lombeck et al., Reference Lombeck, Jochum and Terwolbeck1996; Przyrembel & Bremer, Reference Przyrembel and Bremer2000; van Bakel et al., Reference van Bakel, Printzen, Wermuth and Wiesmann2000). Many nutrients have roles in cognition. For example, selenium status has been linked to attention performances in children with ECT-PKU, but not with FSIQ, verbal learning, fine motor, spatial, and executive tasks (Gassió et al., Reference Gassió, Artuch, Vilaseca, Fusté, Colome and Campistol2008). Currently, there is a paucity of studies on nutritional status and its role as a determinant of neuropsychological outcome.

Tetrahydrobiopterin or sapropterin therapy

The tetrahydrobiopterin cofactor is essential for PAH activity (Erlandsen & Stevens, Reference Erlandsen and Stevens2001). Until recently, the main treatment for PKU was phenylalanine-restricted diet. Since 2008, an additional synthetic analogue to tetrahydrobiopterin has been developed (Burton et al., Reference Burton, Grange, Milanowski, Vockley, Feillet, Crombez, Abadie, Cederbaum, Dobbelaere, Smith and Dorenbaum2007; Levy et al., Reference Levy, Milanowski, Chakrapani, Cleary, Lee, Trefz, Whitley, Feillet, Feigenbaum, Bebchuk, Christ-Schmidt and Dorenbaum2007). A subgroup of patients has been shown to respond to treatment with tetrahydrobiopterin. The frequency of tetrahydrobiopterin responsiveness varies, depending on genotype, severity of PKU, and residual PAH activity (Heintz et al., Reference Heintz, Cotton and Blau2013; Karacic et al., Reference Karačić, Meili, Sarnavka, Heintz, Thöny, Ramadža, Fumić, Mardeşić, Barié and Blau2009; Zhang et al., Reference Zhang, Ye, Qiu, Han and Gu2005). Significant decrease in blood phenylalanine levels were seen in children with ECT-PKU following oral administration of tetrahydrobiopterin (Fiege & Blau, Reference Fiege and Blau2007; Leuret et al., Reference Leuret, Barth, Kuster, Eyer, De Parscau, Odent, Gilbert-Dussardier, Feillet and Labarthe2012; Longo et al., Reference Longo, Siriwardena, Feigenbaum, Dimmock, Burton, Stockler, Waisbren, Lang, Jurecki, Zhang and Prasad2015). Moreover, sapropterin may increase stability in blood phenylalanine levels (Burton et al., Reference Burton, Bausell, Katz, LaDuca and Sullivan2010) and could play a role in microstructural white matter integrity as an evidence using diffusion tensor imaging (White et al., Reference White, Antenor-Dorsey, Grange, Hershey, Rutlin, Shimony, McKinstry and Christ2013). Few studies regarding neuropsychological outcomes of children with ECT-PKU with tetrahydrobiopterin treatment have been conducted. In tetrahydrobiopterin-responsive children with PKU and ADHD symptoms, sapropterin treatment resulted in significant improvement of ADHD inattentive symptoms on the ADHD-Rating Scale (but not on ADHD hyperactivity/impulsivity scores) and on metacognition score of parental BRIEF inventory (but not on behavioral regulation score). These improvements were maintained throughout 26 weeks of treatment (Burton et al., Reference Burton, Grant, Feigenbaum, Singh, Hendren, Siriwardena, Phillips, Sanchez-Valle, Waisbren, Gillis, Prasad, Merilainen, Lang, Zhang, Yu and Stahl2015). In a mixed sample of 12 tetrahydrobiopterin-responsive children and adults with PKU, tetrahydrobiopterin treatment was associated with improvements in working memory n-back task performances after 6 months of treatment. Younger participants with PKU showed greater gains in working memory performance (Christ et al., Reference Christ, Moffitt, Peck and White2013). The first studies comparing ECT-PKU group of children and adolescents treated by tetrahydrobiopterin- versus dietary-treatment did not show significant difference on FSIQ, visual–spatial, fine motor functions, and EFs (Gassió et al., Reference Gassió, Vilaseca, Lambruschini, Boix, Fusté and Campistol2010), or social cognition (Jahja et al., Reference Jahja, van Spronsen, De Sonneville, van der Meere, Bosch, Hollak, Rubio-Gozalbo, Brouwers, Hofstede, de Vries, Janssen, van der Ploeg, Langendonk and Huijbregts2016).