Phenylketonuria in Children and Mothers: Genes, Environments, Behavior

ABSTRACT— Phenylketonuria (PKU) is an inborn metabolic error in which metabolism of phenylalanine into tyrosine is disrupted. If the diet of an infant with PKU is not restricted, blood phenylalanine levels are elevated, leading to irremediable brain damage and severe mental retardation. Children with PKU who are placed early and continuously on a low-phenylalanine diet develop normal levels of intelligence, and brain damage is largely prevented. However, if the diet of a mother with PKU is unrestricted during her pregnancy, high phenylalanine levels in her blood can cross the placental barrier and damage the developing fetus in multiple ways. These results demonstrate how genes and environmental factors combine to create prenatal environments that can have profound effects on the growth and development of offspring during infancy and childhood.     

Developmental Timing of Exposure to Elevated Levels of Phenylalanine Is Associated with ADHD Symptom Expression

This study addresses attention deficit hyperactivity disorder (ADHD), with a focus on how the timing of a known biological insult affects ADHD symptom expression. The sample consists of children exposed to elevated levels of phenylalanine, either postnatally as in Phenylketonuria (PKU; n = 46) or prenatally as in Maternal PKU (MPKU; n = 15). Non-hyperphenylalaninemic siblings of children with PKU (n = 18) serve as controls. Results indicate that elevated levels of phenylalanine are associated with ADHD symptoms. The manifestations of the symptom expression are dependent on exposure timing: prenatal exposure is associated with a higher likelihood of expressing hyperactive/impulsive symptoms and postnatal exposure is associated with a higher likelihood of expressing inattentive symptoms. This toxicity is dose-dependent and higher levels of phenylalanine appear more detrimental.     

Cross-cultural perspectives on coping with the risks of maternal phenylketonuria

Abstract

Maternal phenylketonuria (PKU) refers to the deleterious effects on a fetus due to high maternal phenylalanine levels. Prevention of these effects requires that women with PKU reduce their blood phenylalanine levels prior to and throughout pregnancy which means that they plan their regnancies and adhere to a phenylalanine restricted diet. According to a psycho-social model of maternal PKU, a first necessary step in preventing the effects of maternal PKU is prevention of unplanned pregnancies i.e.: using effective family planning practices. In the present study, findings are presented on seventy-five phenylketonuric women (60 from the United States and 15 from Israel) who participate in a prospective longitudinal study, to reveal the reasons why the proportion of pregnancies treated prior to conception has consistently been higher in Israel than in the United States. The two groups were interviewed and administered a battery of tests and questionnaires measuring a wide range of variables associated with family planning. Subjects in the United States were found to have more knowledge about fertility, contraception and maternal PKU. Israeli subjects held more negative attitudes towards and were less engaged in premarital sexual relationships, more frequently used oral contraceptives, had stronger motivation to have their own children, and perceived their disease to have a more negative effect on their lives. These findings suggest that the issues in maternal PKU are cultural as well as medical and psychosocial.     

Using the Impact of Event Scale to Evaluate Psychological Response to Being a Phenylketonuria Gene Carrier

The birth of a child with phenylketonuria (PKU) is almost always a shock to the parents, who are faced with the realities of caring for a child with special needs and the need to cope with the realization that they are obligate carriers of the responsible gene. The Impact of Event Scale (IES) was used to assess the psychological impact of being a PKU gene carrier on 83 parents of children with PKU. IES scores decreased significantly from the time of initial diagnosis of PKU to the current time. The magnitude of the psychological impact did not correlate with the age of the parent, the number of years since the diagnosis of PKU, or the health or development of the child. As more tests become available for detecting the presence of disease-related genes, instruments such as the IES may prove useful in the evaluation of psychological responses to genetic information.     

Parenting a Child with Phenylketonuria (PKU): an Interpretative Phenomenological Analysis (IPA) of the Experience of Parents

Phenylketonuria (PKU) is a rare inherited metabolic disorder which can cause neurological damage if left untreated. PKU is identified through newborn screening in developed countries, and treatment begins immediately to prevent these severe consequences. When a child is diagnosed, parents must assume immediate responsibility for the management of PKU and prevention of neurological damage. Quantitative studies have identified significant psychosocial stressors for parents, but little is known about how the parents experience this process. This study aimed to explore the experiences of parents of children with PKU under the age of two. It is the first study to examine these experiences in this way. Seven parents were interviewed about their experiences, and interpretative phenomenological analysis was used to analyse the data. Three main themes were identified: control, striving for normality and acceptance of PKU as a continuum. Links between the themes and processes underpinning the results were explored with relation to existing literature and theories from a clinical psychology perspective. The role of acceptance of PKU was central to the parent’s experiences. Clinical implications and suggestions for further research are discussed.     

“I Feel Lucky” – Gratitude Among Young Adults with Phenylketonuria (PKU)

If persons with phenylketonuria (PKU) do not start a protein restricted diet in early infancy, they will suffer severe brain damage. Previous qualitative research on adults and adolescents with PKU has identified stigmatization, uncertain risk perceptions, considerable time spent on preparing food, and incongruence between the PKU diet and certain lifestyle demands. The aim of this study was to explore young and early treated Norwegian adults’ experiences, by conducting in-depth interviews in 2011 with 11 adults with PKU, aged 20–30. Being the first qualitative study on people with PKU in Norway, the process was inspired by grounded theory. All participants reflected on their own health and existence by expressing positive counterfactual thoughts. They considered themselves lucky to have had parents who had managed the diet, they were grateful for the time and place they were born, and for information and treatment availability, although the results also show some ambiguous attitudes towards the hospital which provided the treatment. The expression of gratitude in association with having PKU suggests a major positive coping strategy. It contributes to a more holistic understanding of the experiences and attitudes of young, Norwegian adults with PKU, as it provides a counterweight to the negative experiences.     

An olfactory discrimination procedure for mice

This paper describes an olfactory discrimination procedure for mice that is inexpensively implemented and leads to rapid discrimination learning. Mice were first trained to dig in small containers of sand to retrieve bits of buried chocolate. For discrimination training, two containers were presented simultaneously for eight trials per session. One container held sand mixed with cinnamon, and the other held sand mixed with nutmeg. Both containers were baited with chocolate buried in the sand. One odor was designated S+, and mice were allowed to dig and retrieve the chocolate from this container. The other odor was S-, and both containers were removed immediately if subjects began to dig in an S- container. After meeting a two-session acquisition criterion, subjects were given a series of discrimination reversals. In Experiment 1, 12 Swiss-Webster mice (6 male and 6 female) acquired the olfactory discrimination in three to five sessions and completed 3 to 10 successive discrimination reversals within a 50-session testing limit. In Experiment 2, subjects were 14 Pah(enu2) mice, the mouse mutant for phenylketonuria; 7 were homozygotes in which the disorder was expressed (PKU), and 7 were heterozygotes with normal metabolism (non-PKU). Thirteen mice completed pretraining in four to seven sessions, acquisition required 3 to 12 sessions, and all mice completed at least three reversals. Learning rates were similar in PKU and non-PKU mice. We discuss issues related to implementation and several potentially useful procedural variations.     

Relationships between cognitive and behavioral measures of executive function in children with brain disease.

This study addressed the clinical and construct validity of the Behavior Rating Inventory of Executive Function. (BRIEF: Gioia, Isquith, Guy, & Kenworthy, 2000), a questionnaire designed to tap behavioral aspects of executive functions in children. BRIEF profiles in early treated phenylketonuria (PKU; n=44), early treated hydrocephalus (n=45), frontal focal lesions (n=20) and controls (n=80) were examined. Clinical validity was supported through significant between-group comparisons, especially between the frontal focal lesion group and other groups. To examine construct validity, raw scores on cognitive executive function measures including the Contingency Naming Test (CNT), Rey Complex Figure (RCF), Tower of London (TOL), and Controlled Oral Word Association Test (COWAT), were correlated with BRIEF scale scores. Few significant correlations were found, indicating cognitive and behavioral measures appear to tap different constructs within the executive function domain. A dissociation was found between behavioral and cognitive impairments in the frontal as opposed to PKU and hydrocephalus groups. This is discussed in relation to underlying pathology, the cognitive measures used, and possible limitations in the BRIEF's usefulness for measuring behavioral executive dysfunction in groups only mildly affected by neurological compromise.     

Relationships Between Cognitive and Behavioral Measures of Executive Function in Children With Brain Disease

This study addressed the clinical and construct validity of the Behavior Rating Inventory of Executive Function. (BRIEF: Gioia, Isquith, Guy, & Kenworthy, 2000), a questionnaire designed to tap behavioral aspects of executive functions in children. BRIEF profiles in early treated phenylketonuria (PKU; n = 44), early treated hydrocephalus (n = 45), frontal focal lesions (n = 20) and controls (n = 80) were examined. Clinical validity was supported through significant between-group comparisons, especially between the frontal focal lesion group and other groups. To examine construct validity, raw scores on cognitive executive function measures including the Contingency Naming Test (CNT), Rey Complex Figure (RCF), Tower of London (TOL), and Controlled Oral Word Association Test (COWAT), were correlated with BRIEF scale scores. Few significant correlations were found, indicating cognitive and behavioral measures appear to tap different constructs within the executive function domain. A dissociation was found between behavioral and cognitive impairments in the frontal as opposed to PKU and hydrocephalus groups. This is discussed in relation to underlying pathology, the cognitive measures used, and possible limitations in the BRIEF's usefulness for measuring behavioral executive dysfunction in groups only mildly affected by neurological compromise.     

Contributions of Neuroscience to Our Understanding of Cognitive Development

ABSTRACT— One major contribution of neuroscience to understanding cognitive development has been in demonstrating that biology is not destiny—that is, demonstrating the remarkable role of experience in shaping the mind, brain, and body. Only rarely has neuroscience provided wholly new insights into cognitive development, but often it has provided evidence of mechanisms by which observations of developmental psychologists could be explained. Behavioral findings have often remained controversial until an underlying biological mechanism for them was offered. Neuroscience has demonstrated promise for detecting cognitive problems before they are behaviorally observable—and, hence, promise for early intervention. In this article, we discuss examples drawn from imitation and mirror neurons, phenylketonuria (PKU) and prefrontal dopamine, maternal touch and stress reactivity, and nongenetic (behavioral) intergenerational transmission of biological characteristics.     

Current status of newborn screening: decision-making about the conditions to include in screening programs

Newborn screening is considered a highly successful public health program that has resulted in the reduction of mortality, mental retardation, and other serious disabilities in thousands of children since the introduction of screening for phenylketonuria (PKU) in the 1960s. Programs are based in state public health departments such that each state independently reaches decisions as to which conditions should be mandated for inclusion in programs, leading to considerable variability among the states as to what is being screened. New technologies and knowledge of the genetics of many conditions have greatly expanded the number of conditions with potential for inclusion in newborn screening.     

Model phenylketonuria (PKU) in the albino rat: behaviroal, biochemical, and neuroanatomical effects.

Model phenylketonuria was induced in albino rats by injecting (at 1-20 days of age) and feeding (at 21-80 days) L-phenylalanine and D-L-para-chloro-phenylalanine. Behavioral testing on an eight-item battery occurred twice: first, whil the animals were either receiving the excess phenylalanines or not (original); and second, following a 90-day drug-free recovery period (retention). Results indicated drug-dependent deficits in learning and activity on both original and retention tests. Serum phenylalanine, serum tryptophan, and liver phenylalanine hydroxylase activity levels were positively correlated with the behavioral deficit. Clumped dense material in some myelin sheaths and associated degeneration of axons were found in experimental subjects.     

Ecology And The Science Of Psychology

This study explored the feasibility of discriminating among subtypes of mental retardation on the basis of observable behavior. The major focus was on discrimination between Ss whose low I.Q. could be attributed to normal chromosomal or single locus genetic defects. Concurrently the study sought t o distinguish among diagnostic subgroups of the second category. Three groups of institutionalized subjects were used: Undifferentiated (presumed polygenic segregants), PKU, and Down's Syndrome.     

Quantitative amino acid determination in the serum and cerebrospinal fluid in endogenous depressions

The levels of 20 amino acids were measured in the plasma and cerbrospinal fluid of 41 patients with endogenic depressions. The plasma levels of 12 amino acids were found to be significantly lower in the patients than in the control group, but cerebrospinal fluid levels were significantly lower only in the case of taurine, glutamine, phenylalanine and aginine. Comparison of the same amino acid levels in treated and non-treated patients showed that serine and alpha-aminobutyric acid serum concentrations were higher in the nontreated patients. The tyrosine and phenylalanine levels in the cerebrospinal fluid of the patients who had received medicamentous treatment were higher than in the other group.     

Infrastructure and Scaffolding: Interpretation and Change of Research Involving Human Genetic Information

This essay addresses the relationship of interpretation to change, at two levels. One level concerns the revolutionary claims of molecular biology and biotechnology about using genetic information, read literally or with a minimum of interpretation, to reshape human life. The other level concerns the relationship in social studies of science and technology (STS) between interpreting projects in the life sciences and influencing their direction. On that level, the essay is experimental, employing a series of vignettes that introduce themes and questions—scaffolding—intended to stimulate readers to make their own connections between interpretation and change, in science, STS, and society. The vignettes in Part 1, which range from treatment of individuals with PKU or MAOA genes to personalized medicine and biobanks, indicate in different ways that the use of genetic information always requires social infrastructure. Once attention is given to the actual or implied social infrastructure, the prospect of reshaping life using human genetic information raises more questions than it answers. This thread carries over into Part 2, which speaks to an area of STS that needs more development, namely, conceptualizing the structure of the social context of scientific and technological developments and the nature of human agency in the ongoing restructuring of that context. The vignettes create a picture in which the influence on science of an STS interpretation will, like any effort to produce change, depend on how it links with other engagements and with the heterogeneous components that make up ongoing, intersecting processes of science in society.     

Attentional flexibility and perseveration: developmental aspects in young children.

Whereas a growing interest in the development of attentional flexibility (AF) and in perseverative behavior, being one marker of this component, exists in neuropsychological studies and in the domain of developmental psychopathology (e.g., PKU, infantile schizophrenia, autism and Parkinson's disease) (Pennington & Ozonoff, 1996; Stahl & Pry, 2002), only a few studies have concerned themselves with this subject in normal children. It is thus of interest to add more empirical data to the existing literature in this domain. Therefore, the aim of our study was to explore the development of AF and of perseverative errors in young preschool children with normal development, aged 1.5 to 6 years. Using set-shifting tasks of increasing difficulty level, three age groups were compared with respect to their AF skills.Results show a developmental factor underlying AF, with different levels of this form becoming more and more complex with age, ranging from a rudimentary visual form to a complex representational form of flexibility. Overall, few perseverative errors occurred and they decreased with age. Results are discussed from a developmental and neuropsychological perspective.     

Discrimination by rhesus monkeys of diets containing supplemental amino acids.

Following an opportunity to demonstrate a preference for water with or without the addition of the amino acid isoleucine, methionine, phenylalanine, or tryptophan at a concentration proportional to that in whole egg protein, 9 monkeys were subjected on 4 occasions to a 7-day experimental week when they received an isocaloric diet containing only one-fourth the amount of protein of their normal diet. An identical low-protein diet supplemented with one of the above amino acids, again at a concentration proportional to that in egg, was presented for an equivalent period during the experimental week and the amounts consumed of each diet were compared. Ss failed to exhibit a preference or an aversion for water supplemented with any of the amino acids; however, all low-protein diets supplemented with an amino acid were consumed in greater quantities than a low-protein diet lacking a supplement. On Days 6 and 7 of the experimental weeks when protein depletion was most severe, Ss significantly (p less than .05) preferred the diet supplemented with isoleucine to a diet lacking the supplement.     

Endogenous psychoses in relation to absent phenylalanine hydroxylase activity in thrombocytes

Out of 100 psychotic patients who underwent neurobiochemical examination, in 24 cases activity of phenylalanine hydroxylase in the thrombocytes was found to be absent. 38% of these cases were susceptible to stimulation in vitro by means of folic acid derivative, without actually reaching a normal level of activity. The patients are presented first as a homgeneous group, then in the two major diagnostic divisions, and divided according to the biochemical data. An account is given of early experiences in the treatment of the more intractable cases.     

Brain dopamine and kinematics of graphomotor functions

Three experiments were performed in an attempt to achieve a better understanding of the effect of dopamine on handwriting. In the first experiment, kinematic aspects of handwriting movements were compared between healthy participants and patients with Parkinson's disease (PD) on their usual dopaminergic treatment and following withdrawal of dopaminergic medication. In the second experiment, the writing performance of healthy participants with a hyperechogenicity of the substantia nigra as detected by transcranial sonography (TCS) was compared with the performance of healthy participants with low echogenicity of the substantia nigra. The third experiment examined the effect of central dopamine reduction on kinematic aspects of handwriting movements in healthy adults using acute phenylalanine and tyrosine depletion (APTD). A digitising tablet was used for the assessment of handwriting movements. Participants were asked to perform a simple writing task. Movement time, distance, velocity, acceleration and measures of fluency of handwriting movements were measured. The kinematic analysis of handwriting movements revealed that alterations of central dopaminergic neurotransmission adversely affect movement execution during handwriting. In comparison to the automatic processing of handwriting movements displayed by control participants, participants with an altered dopaminergic neurotransmission shifted from an automatic to a controlled processing of movement execution. Central dopamine appears to be of particular importance with regard to the automatic execution of well-learned movements.     

Pilot programs in newborn screening

The term "pilot study" has been used over the years to describe the evaluation of the many elements involved in deciding whether a proposed condition should be added to a newborn screening (NBS) panel, and until recently, was unilaterally used to describe the evaluation of the assay to be used before the condition was officially adopted by a state for its newborn screening panel. Since Guthrie's introduction of screening for PKU, each time a new condition was added to the panel, the screening assay itself was validated through a population-based trial, in which the test was performed with de-identified samples to avoid association between the test result and the infant. This is considered by the laboratory as the "pilot phase" of adding a new condition. To advance the science of NBS, especially to accommodate new technologies that may provide new types of information (genetic versus physiological) for each new condition, pilot programs are essential. Involvement of the clinical community serves to improve these evaluations and provides the needed clinical validation of decisions made as a result of it. This paper describes the historical context of pilot programs in population-based NBS that utilize laboratory-based markers as indicators of concern; specifically, three applications that demonstrate different approaches to the use of pilots in adding conditions to a NBS panel are described.