Neurocognitive and neuroimaging outcome of early treated young adult PKU patients: A longitudinal study Francesca Nardecchia a,b , Filippo Manti a , Flavia Chiarotti c , Claudia Carducci d , Carla Carducci d , Vincenzo Leuzzi a, ⁎ a Department of Pediatrics and Child and Adolescent Neuropsychiatry, SAPIENZA University of Rome, Via dei Sabelli 108, 00185 Rome, Italy b Department of Physiology and Pharmacology, SAPIENZA University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy c Istituto Superiore di Sanità, Department of Cell Biology and Neuroscience, Viale Regina Elena 299, 00161 Rome, Italy d Department of Experimental Medicine, SAPIENZA University of Rome, Viale del Policlinico 155, 00161 Rome, Italy abstract article info Article history: Received 2 March 2015 Received in revised form 22 April 2015 Accepted 25 April 2015 Available online xxxx Keywords: Executive function White matter alteration Vulnerability Phenylalanine The aim of the study was to explore the outcome of neurocognitive deficits and neuroimaging correlates in young adult early treated phenylketonuric (PKU) patients. We conducted a longitudinal study of 14 PKU patients that were assessed for IQ and neuropsychological functioning including executive functions (EF) over 14 years of follow-up (age range at 1st and 2nd assessments were 7.8–13.5 and 22.2–27.7 years, respectively). The IQ of all 14 PKU patients was within the normal range. With respect to the 1st assessment, mean IQ at follow-up did not decrease significantly. Compared to control subjects (n = 14), mean IQ of patients was significantly lower (p = .0005). Throughout adolescence and early adulthood there was an improvement of neuropsychological functioning of PKU patients in spite of the relaxation of diet, however some deficits were still detectable when compared to controls. All patients that underwent a second MRI scan showed white matter alterations ranging from mild to severe which was correlated neither with IQ nor with EF scoring. Cognitive, neuropsychological and neuroimaging outcome was influenced from life-long and/or second decade of life metabolic control. Never- theless patients' developmental trajectories were in some cases independent from metabolic control. Our results support the hypothesis of an individual vulnerability to phenylalanine. However, as long as individual factors that account for the vulnerability to Phe are not recognized, strict dietary control is recommended for all the patients also in the second decade of life. © 2015 Elsevier Inc. All rights reserved. 1. Introduction Despite the favourable clinical outcome of early treated phenylke- tonuric (PKU; OMIM #261600) patients when compared with late- or untreated patients, a lower than expected intelligence quotient (IQ) and minor neuropsychological and psychiatric problems [1–5] remain challenging aspects of the disease and the possible targets for future improvement of the treatment. Moreover, in the last 20 years several studies have showed that for almost all early treated PKU (ETPKU) subjects, brain Magnetic Resonance Imaging (MRI) shows white matter (WM) alterations in the second decade of life [6]. The relationship (if any) between this neuroimaging alterations and neuropsychological disorders remains controversial. Diet remains the mainstay of the treatment for PKU patients. Current literature and available guidelines recommend life-long treatment [7,8]. Nevertheless the restrictive diet for PKU causes a psychosocial burden for the patients and their families. During childhood adherence to the diet lies on parents, but as children get older staying in the target phenylalanine (Phe) levels might become difficult. From adolescence on compliance with the diet is often poor indeed [9–11], disclosing the need of PKU patients for alternative therapies [12]. In the present knowledge there is a lack of longitudinally designed studies assessing the outcome of neuropsychological and neuroimaging abnormalities in PKU patients. About 14 years ago we have performed a case–control study focusing on neuropsychological functioning in young early and continuously treated PKU patients with normal IQ and brain MRI [13]. In comparison with controls, we have found an im- pairment in a number of tests exploring neuropsychological functioning with special focus on executive functions (EF). With the present longi- tudinal study we intended to explore the neurocognitive outcome and Molecular Genetics and Metabolism xxx (2015) xxx–xxx Abbreviations: PKU, phenylketonuria; Phe, phenylalanine; EF, executive function; WAIS-R, Wechsler Adult Intelligence Scale-Revised; EPMT, Elithorn's Perceptual Maze Test; WCST, Wisconsin Card Sorting Test; IDC, Index of Dietary Control; MRI, Magnetic Resonance Imaging; WM, white matter. ⁎ Corresponding author at: Via dei Sabelli 108, 00185 Rome, Italy. E-mail addresses: francesca.nardecchia@uniroma1.it (F. Nardecchia), mantifilippo@libero.it (F. Manti), flavia.chiarotti@iss.it (F. Chiarotti), claudia.carducci@uniroma1.it (C. Carducci), carla.carducci@uniroma1.it (C. Carducci), vincenzo.leuzzi@uniroma1.it (V. Leuzzi). YMGME-05900; No. of pages: 7; 4C: http://dx.doi.org/10.1016/j.ymgme.2015.04.003 1096-7192/© 2015 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme Please cite this article as: F. Nardecchia, et al., Neurocognitive and neuroimaging outcome of early treated young adult PKU patients: A longitudinal study, Mol. Genet. Metab. (2015), http://dx.doi.org/10.1016/j.ymgme.2015.04.003