University of Washington PKU Clinic Management Guidelines
A summary of the treatment protocol used by the University of Washington.

Objectives of Treatment of PKU
A general overview of the objectives of treatment for all age groups.

Basic Nutrition Care Plan
An overview of a basic nutrition care plan for all ages.

Recommended Assessment Schedule
A general guideline for assessing serum phenylalanine and tyrosine levels, nutritional status, and cognitive functioning.

University of Washington PKU Self-Management Timeline
Provides a long term view of the expected developmental process and suggests incremental self-management goals for the parent and child. This is also available as an Adobe Acrobat file. Download here.

Neuropsychological Testing Guide
The neuropsychological testing protocol used by the University of Washington PKU Clinic.

Suggested Reading

American Dietetic Association. Phenylketonuria. Medical Nutrition Therapy Protocol.

Stemerdink, Nanke B. A., et al. Prefrontal dysfunction in early and continuously treated phenylketonuria in Developmental Neuropsychology. 1999 Vol 16(1) 29-57.
Abstract: Tested the hypothesis that patients with early and continuously treated phenylketonuria (PKU) are selectively impaired in cognitive functions dependent on the prefrontal cortex (PFC) over a wide age range. 36 patients (aged 8-19 yrs) with PKU and 36 controls matched for age, sex, and educational level of both parents performed computerized versions of tests shown to be sensitive to PFC functions. To assess specificity, the authors selected within each test measure shown to be specifically impaired by PFC damage as well as measures not specifically impaired by damage to the PFC (control measures). A contrast sensitivity test was administered to obtain additional and independent evidence for the mechanism proposed to underlie the specific PFC deficits. Patients with PKU demonstrated impairments on 3 of the 4 PFC measures but not on any of the control measures. Furthermore, they were found to be significantly less sensitive to contrast than were the controls. Together, these results seem to confirm that specific deficits in PFC functions persist in older patients with early and continuously treated PKU. Affiliation: U Groningen, Dept of Developmental & Experimental Clinical Psychology, Groningen, Netherlands. ((c) 1999 APA/PsycINFO, all rights reserved)

Diamond, Adele; Prevor, Meredith B.; Callender, Glenda; Druin, Donald P.
Prefrontal cortex cognitive deficits in children treated early and continuously for PKU in Monographs of the Society for Research in Child Development. 1997 Vol 62(4) 1-205.
Abstract: Investigated the prediction that children treated for phenylketonuria (PKU) would have selective deficits in cognitive functions dependent on the dorsolateral prefrontal cortex. It was hypothesized that the resultant modest elevation in the ratio of phenylalanine (Phe) to tyrosine (Tyr) in the blood, uniquely effects the cognitive functions dependent on the prefrontal cortex because of the special sensitivity of prefrontally projecting dopamine neurons to small increases in Tyr. In a 4-yr longitudinal study, the authors found that PKU children whose plasma Phe levels were 3-5 times normal performed worse than other PKU children with lower Phe levels, matched controls, their own siblings, and children from the general population on tasks that required working memory and inhibitory control abilities dependent on the dorsolateral prefrontal cortex. The impairment was as evident in the oldest range of children (3.5-7 yrs) as it was in the youngest (6-12 mo). The higher a child's Phe level, the worse the child's performance. Girls were more adversely affected than boys. The deficit appears to be selective, affecting principally one neural system, since even PKU children with Phe levels 3-5 times normal performed well on 13 control tasks. Affiliation: Eunice Kennedy Shriver Ctr, Ctr for Developmental Cognitive Neuroscience, Waltham, MA, USA. ((c) 1999 APA/PsycINFO, all rights reserved)

Griffiths, Peter; Smith, Caroline; Harvie, Ann. Transitory hyperphenylalaninaemia in children with continuously treated phenylketonuria in American Journal on Mental Retardation. 1997 Jul Vol 102(1) 27-36.
Abstract: Investigated the cognitive and behavioral effects of temporarily challenging the CNS with elevated levels of phenylalanine in treated phenylketonuria (PKU). A high phenylalanine supplement was given over 3 mo to 16 10-16 yr old early and continuously treated children with classical PKU. The Wechsler Intelligence Scale for Children (WISC) and the Rivermead Behavioral Memory Test were used to measure cognitive function and the Rutter Scales were used to assess disordered behavior. Parents and children guessed at the condition (low or high phenylalanine) imposed. The Group x Phase interaction for phenylalanine level was statistically significant, but this pattern was not mirrored in the psychological test data, and guessing was random. Results suggest that intellectual ability, memory, and conduct are not affected by medium-term hyperphenylalaninaemia in PKU after 10 or more years of treatment. Affiliation: U Stirling, Dept of Psychology, Stirling, Scotland UK. ((c) 1999 APA/PsycINFO, all rights reserved)

Griffiths, P.; Tarrini, M.; Robinson, P. Executive function and psychosocial adjustment in children with early treated phenylketonuria: Correlation with historical and concurrent phenylalanine levels in Journal of Intellectual Disability Research. 1997 Aug Vol 41(4) 317-323.
Abstract: It has been proposed that the upper limit guideline of 600 mumol 1-super(-1 ) of phenylalanine (PHE) in dietary treatment of phenylketonuria (PKU) may result in specific impairment of executive functions such as attention, planning, and set maintenance. This theory was investigated by correlating historical and concurrent PHE with executive, nonexecutive and personality tests in 15 early and continuously treated children, aged 10-13 yrs, with classical PKU, whose average PHE levels of 355 mumol 1-super(-1 ) (SD = +-144) for the pre-school period and 480 mumol 1-super(-1 ) (SD +- 193) for the primary school period corresponded to the upper limits presently recommended in the UK of 360 and 480 mumol 1-super(-1 ) respectively for these age ranges. No clear associations were found between historical or concurrent PHE levels and any of the neuropsychological or personality measures, thereby weakening the case for the emergence of executive deficits, at least when average PHE levels remain close to the upper limits now considered safe. Affiliation: U Stirling, Dept of Psychology, Stirling, Scotland UK. ((c) 1999 APA/PsycINFO, all rights reserved)

Zagreda, Leze; Goodman, Jason; Druin, Donald P.; McDonald, David; Diamond, Adele. Cognitive deficits in a genetic mouse model of the most common biochemical cause of human mental retardation in Journal of Neuroscience. 1999 Jul Vol 19(14) 6175-6182.
Abstract: Presents evidence that the genetic mouse model of phenylketonuria (PKU), Pah-super(enu2), produces cognitive impairments. For an odor discrimination and reversal (ODR) task, Ss were 19 wild-type (WT) BTBR (mean age 3.5 mo), 9 heterozygous (HZ) BTBR (mean age 6.3 mo), and 12 PKU (mean age 4.1 mo) male and female mice. For a latent learning (LL) task, Ss were 30 WT (mean age 5.12 mo), 31 HZ (mean age 7.42 mo), and 18 PKU (mean age 7.98 mo) male and female mice. PKU mice were impaired on both ODR and LL compared with HZ and WT mice of the same BTBR strain. Cinnamon-scented sand was presented on the right or left, and nutmeg-scented sand was presented on the other side; left-right location varied over trials. Digging in sand of the correct scent was rewarded by finding phenylalanine-free chocolate. Digging in the incorrect choice was stopped before the chocolate was uncovered. Once criterion was reached, the other scent was rewarded. PKU mice were impaired on reversals 2, 3, and 4, and on LL. On day 1, half the mice were allowed to explore a maze and discover the location of water. On day 2, all mice were water-deprived and were placed in the maze. Whereas pre-exposed WT and HZ mice remembered the location of the water, pre-exposed PKU mice showed no such pre-exposure benefit from day 1. Affiliation: Eunice Kennedy Shriver Ctr, Ctr for Developmental Cognitive Neuroscience, Waltham, MA, USA. ((c) 1999 APA/PsycINFO, all rights reserved)

Sullivan, Jill E.; Chang, PiNian. Review: Emotional and behavioral functioning in phenylketonuria in Journal of Pediatric Psychology. 1999 Jun Vol 24(3) 281-299.
Abstract: Reviews 17 studies from 1976-1997 on the psychological sequelae of early-treated phenylketonuria (PKU) in 5-35 yr olds. The emphasis of the studies is the impact of dietary control on emotional and behavioral functioning. Two questions are addressed: (1) What is the typical psychological profile associated with PKU? (2) Is emotional and behavioral disturbance more prevalent in PKU Ss compared to controls? Findings converge upon a profile including attentional difficulties, depression, anxiety, and low self-esteem. Methodological constraints limit conclusions regarding the nature and severity of observed difficulties. Results are discussed using a biopsychosocial framework, addressing the factors and processes that may influence emotional and behavioral functioning in this neurodevelopmental disorder. Affiliation: Northwestern Memorial Hosp, Inst of Psychiatry, Outpatient Treatment Ctr, Chicago, IL, USA. ((c) 1999 APA/PsycINFO, all rights reserved)

Fitzgerald, Brian; Morgan, J.; Keene, N.; Rollinson, R.; Hodgson, A.; Dalrymple-Smith, J. An investigation into diet treatment for adults with previously untreated phenylketonuria and severe intellectual disability in Journal of Intellectual Disability Research. 2000 Feb Vol 44(1) 53-59.
Abstract: Literature suggests that adults with previously untreated phenylketonuria (PKU) benefit from a low phenylalanine diet. This article examines providing a phenylalanine-restricted diet to 5 Ss with severe intellectual disability arising from untreated PKU. Physical, social and behavioral measures were used to monitor the effects of the diet. 4 out of the 5 Ss derived considerable benefit. The authors conclude that the restricted diet is worth trying in most individuals with previously untreated PKU, and that possible benefits are in the areas of concentration, alertness, mood, irritability and adaptive behavior. Affiliation: Chase Farm Hosp, Learning Difficulties Ctr, Middlesex, England ((c) 1999 APA/PsycINFO, all rights reserved)

Dennis, Maureen; Lockyer, Linda; Lazenby, Anne L.; Donnelly, Ruth E.; Wilkinson, Margaret; Schoonheyt, Wanda. Intelligence patterns among children with high-functioning autism, phenylketonuria, and childhood head injury in Journal of Autism & Developmental Disorders. 1999 Feb Vol 29(1) 5-17
Abstract: Reports comparisons of the Comprehension: Block Design IQ subtest pattern between 1 group of children with autistic-spectrum disorder and 3 groups of children with developmental and acquired frontal lobe disorders. Each group consisted of 8 Ss (mean age 9.33 yrs). Ss completed the Wechsler Intelligence Scale for Children (WISC)-R or WISC-III. Results show high functioning Ss with autistic-spectrum disorder show the typical pattern of lower Comprehension relative to their own scores on Block Design. This profile is shared, almost exactly, by age- and IQ-matched Ss with poorer control PKU. Distinct profiles are shown by Ss with better control PKU, who show no difference between Block Design and Comprehension, and by Ss with head injury involving frontal lobe contusion, who show slightly better Comprehension. The data bear on several questions: the relation between Comprehension deficits and language functions measured by Vocabulary; the limits of the advantages conveyed by higher IQ to autistic individuals; whether impaired Comprehension in autism indexes persisting symptoms and/or impairments on theory of mind tasks; the possibility that dopamine deficiency is common to autism and poorer control PKU; and the need for future research aimed at understanding the relations among neurodevelopmental disorders. Affiliation: Hosp for Sick Children, Dept of Psychology Research, Toronto, ON, Canada. ((c) 1999 APA/PsycINFO, all rights reserved)

Antisdel, Jeanne E.; Chrisler, Joan C. Comparison of eating attitudes and behaviors among adolescent and young women with type 1 diabetes mellitus and phenylketonuria in Journal of Developmental & Behavioral Pediatrics. 2000 Apr Vol 21(2) 81-86.
Abstract: Assessed the eating attitudes and behaviors associated with 2 chronic diseases that have strong dietary treatment components: type 1 diabetes mellitus and phenylketonuria (PKU). Ss consisted of female campers and staff members (aged 11-36 yrs) who were attending 1 of 2 summer camps that specialize in the care of females with type 1 diabetes mellitus (N = 54) and PKU (N = 30). Eating attitudes and behaviors, psychological adjustment, and disease-specific knowledge were assessed using standardized and nonstandardized self-report questionnaires. There was no overall difference in the presence of disordered eating symptomatology between those with diabetes and those with PKU. However, differences in patterns of eating attitudes and behaviors were observed. The data suggest that living with chronic diseases which are treated with dietary management may adversely affect eating attitudes and behaviors and may increase susceptibility to the development of eating disturbances. Affiliation: Joslin Diabetes Ctr, Section of Behavioral & Mental Health Research, Boston, MA, US. ((c) 1999 APA/PsycINFO, all rights reserved)

Moats, Rex A.; Scadeng, Miriam; Nelson, Marvin D., Jr. MR imaging and spectroscopy in PKU in Mental Retardation & Developmental Disabilities Research Reviews. 1999 Vol 5(2) 132-135.
Abstract: Phenylketonuria (PKU) is an autosomal recessive disorder that results in the accumulation of phenylalanine in the blood and soft tissues. Elevated levels of phenylalanine have neurotoxic effects on the developing brain, resulting in mental retardation. Early diagnosis and treatment limits the neurological damage. Magnetic resonance imaging (MRI) changes are seen in the white matter on T-sup-2 weighted imaging in many Ss. The severity of the changes do not correlate with clinical measures of neurological health. The changes correlate best with recent phenylalanine control. The levels of brain phenylalanine concentration using magnetic resonance spectroscopy have been shown not to correlate tightly with the blood phenylalanine concentration. The individual variation in the brain to blood phenylalanine is large. This individual variability may be responsible for different clinical outcomes in PKU Ss who have similar long-term blood concentrations of phenylalanine. Affiliation: Children's Hosp Los Angeles, Dept of Radiology, Los Angeles, CA, US. ((c) 1999 APA/PsycINFO, all rights reserved)

Baumeister, Alan A.; Baumeister, Alfred A. Dietary treatment of destructive behavior associated with hyperphenylalaninemia in Clinical Neuropharmacology. 1998 Feb Vol 21(1) 18-27.
Abstract: Behavior disorders frequently are associated with mental retardation. The most common interventions involve psychotropics and/or behavior modification. Etiologically based treatments are infrequent. However, several genetic diseases are associated with elevated rates of destructive responding. The hyperphenylalaninemias provide a model for alternative interventions with biological plausibility. A literature review provides the biochemical rationale for treatment with a low-phenylalanine diet. Several phenylalanine dietary control studies designed to manage aberrant responding are summarized. Together they provide evidence that dietary phenylalanine restriction is the treatment of choice among patients ranging from classic phenylketonuria to milder hyperphenylalaninemia. Corroborating evidence derived from phenylalanine loading, magnetic resonance imaging (MRI), and dietary amino acid supplementation studies is presented. Affiliation: Louisiana State U, Dept of Psychology, Baton Rouge, LA, USA. ((c) 1999 APA/PsycINFO, all rights reserved)