Phenylketonuria in adulthood: A collaborative study
ABSTRACT During 1967-1983, the Maternal and Child Health Division of the Public Health Services funded a collaborative study of 211 newborn infants identified on newborn screening as having phenylketonuria (PKU). Subsequently, financial support was provided by the National Institute of Child Health and Human Development (NICHD). The infants were treated with a phenylalanine (Phe)-restricted diet to age 6 years and then randomized either to continue the diet or to discontinue dietary treatment altogether. One hundred and twenty-five of the 211 children were then followed until 10 years of age. In 1998, NICHD scheduled a Consensus Development Conference on Phenylketonuria and initiated a study to follow up the participants from the original Collaborative Study to evaluate their present medical, nutritional, psychological, and socioeconomic status. Fourteen of the original clinics (1967-1983) participated in the Follow-up Study effort. Each clinic director was provided with a list of PKU subjects who had completed the original study (1967-1983), and was asked to evaluate as many as possible using a uniform protocol and data collection forms. In a subset of cases, magnetic resonance imaging and spectroscopy (MRI/MRS) were performed to study brain Phe concentrations. The medical evaluations revealed that the subjects who maintained a phenylalanine-restricted diet reported fewer problems than the diet discontinuers, who had an increased rate of eczema, asthma, mental disorders, headache, hyperactivity and hypoactivity. Psychological data showed that lower intellectual and achievement test scores were associated with dietary discontinuation and with higher childhood and adult blood Phe concentrations. Abnormal MRI results were associated with higher brain Phe concentrations. Early dietary discontinuation for subjects with PKU is associated with poorer outcomes not only in intellectual ability, but also in achievement test scores and increased rates of medical and behavioural problems.
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- "Untreated PKU is characterized by neurological and behavioral problems, such as severe mental retardation, epilepsy, developmental delays, and anxiety disorders  . Outcome is clearly related to blood Phe concentrations  . Since the introduction of the neonatal screening for PKU in 1974 in The Netherlands, early diagnosis and treatment are feasible and have reduced most of the neurological problems . "
ABSTRACT: Despite early and continuous treatment many patients with phenylketonuria (PKU) still experience neurocognitive problems. Most problems have been observed in the domain of executive functioning (EF). For regular monitoring of EF, the use of the Behavior Rating Inventory of Executive Function (BRIEF) has been proposed. The aim of this study was to investigate whether the BRIEF is indeed a useful screening instrument in monitoring of adults with PKU. Adult PKU patients (n=55; mean age 28.3±6.2years) filled out the BRIEF-A (higher scores=poorer EF) and performed computerized tasks measuring executive functions (inhibition, cognitive flexibility, and working memory). The outcome of the BRIEF-A questionnaire was compared with the neurocognitive outcome as measured by three tasks from the Amsterdam Neuropsychological Tasks (ANT). Forty-two percent of the PKU patients scored in the borderline/clinical range of the BRIEF-A. Six of the 55 patients (11%) scored >1 SD above the normative mean, mostly on the Metacognition Index. With respect to ANT measurements, patients mainly showed deficits in inhibitory control (34-36%) and cognitive flexibility (31-40%) as compared to the general Dutch population. No significant correlations between the two methods were found, which was confirmed with the Bland-Altman approach where no agreement between the two methods was observed. Only with respect to inhibitory control, patients scored significantly worse on both BRIEF-A and ANT classifications. No other associations between classification according to the BRIEF-A and classifications according to the ANT tasks were found. Patients reporting EF problems in daily life are not necessarily those that present with core EF deficits. The results of this study suggest that regular self-administration of the BRIEF-A is not a sufficient way to monitor EF in adult PKU patients. Copyright © 2014 Elsevier Inc. All rights reserved.Molecular Genetics and Metabolism 12/2014; 114(3). DOI:10.1016/j.ymgme.2014.12.302 · 2.83 Impact Factor
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- "studies, higher blood Phe levels have been correlated with ADHD symptoms  and executive functioning impairment . While less data are available for continuously treated adults with PKU, those who discontinue treatment have lower intellectual ability and achievement test scores than those who continue to maintain metabolic control . These findings, in aggregate, suggest the possibility that ADHD symptoms and impaired executive functioning may be caused by potentially reversible brain dysfunction that results from disruption in monoamine synthesis by high blood Phe levels rather than irreversible 'toxic' brain damage from high blood Phe levels during early life. "
ABSTRACT: Symptoms of attention deficit hyperactivity disorder (ADHD), particularly inattention, and impairments in executive functioning have been reported in early and continuously treated children, adolescents, and adults with phenylketonuria (PKU). In addition, higher blood phenylalanine (Phe) levels have been correlated with the presence of ADHD symptoms and executive functioning impairment. The placebo-controlled PKU-ASCEND study evaluated the effects of sapropterin therapy on PKU-associated symptoms of ADHD and executive and global functioning in individuals who had a therapeutic blood Phe response to sapropterin therapy. The presence of ADHD inattentive symptoms and executive functioning deficits was confirmed in this large cohort of 206 children and adults with PKU, of whom 118 responded to sapropterin therapy. In the 38 individuals with sapropterin-responsive PKU and ADHD symptoms at baseline, sapropterin therapy resulted in a significant improvement in ADHD inattentive symptoms in the first 4 weeks of treatment, and improvements were maintained throughout the 26 weeks of treatment. Sapropterin was well-tolerated with a favorable safety profile. The improvements in ADHD inattentive symptoms and aspects of executive functioning in response to sapropterin therapy noted in a large cohort of individuals with PKU indicates that these symptoms are potentially reversible when blood Phe levels are reduced.Molecular Genetics and Metabolism 11/2014; 114(3). DOI:10.1016/j.ymgme.2014.11.011 · 2.83 Impact Factor
- "The current established treatment for PKU consists of life-long dietary Phe restriction, which is challenging in practice as it is demanding in schedule, unpleasant in taste, carries risk for nutritional deficiencies, and is a substantial psychosocial burden, associated with reduction in quality of life (Harding, 2000; National Institutes of Health Consensus Development Panel, 2001). Furthermore, it was reported that decline in intellectual function (Koch et al., 1984), behavioral performance (Koch et al., 2002), and severe emotional dysfunction, including attention deficit disorder (Antshel and Waisbren, 2003), depression, and anxiety (Waisbren and Levy, 1991), are often observed in noncompliant patients with PKU. Because of these shortcomings, the focus of PKU research has shifted since the beginning of the twenty-first century to the improvement of current therapy and development of alternative options (Sarkissian et al., 2009). "
Dataset: Rebuffat et al Hum Gene Ther 2010