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Appendix C Discussion

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I. Introduction

II. Analyses

III. Limitations

IV. Conclusions

V. References

Introduction

The purpose of this meta-analytic project was to conduct a quantitative review of research conducted between 1980 and 1999 examining treatment outcomes for the genetic disorder, PKU. The charge set forth by the NIH for the Consensus Development Conference on PKU was to focus this literature review on the following four broad aims:

What is the effect of treatment on cognitive and behavior outcomes?

What is known about age at diet discontinuation on outcome?

What is known about the reversibility of clinical symptoms upon reinstitution of treatment different ages?

What is known about the relationship of blood levels of phenylalanine and tyrosine, and cognition and behavior outcomes at different age levels?

Before discussing the range of meta-analytic results and their interpretation, two caveats are in order. First, with the exception of intelligence, there is little clear consensus in the field of cognitive psychology regarding how to define constructs such as attention, executive function, and speed of processing. For this project, it was important to evaluate treatment effectiveness for different cognitive and behavioral domains separately, as the past several decades of empirical research in the area of PKU suggest that there is a profile of weaknesses and relative strengths across a range of cognitive skills and behaviors. Study outcomes were classified into five overall categories (IQ, Executive Function, Attention, Behavior, and Other Cognitive and Motor Skills), each comprised of several sub-categories. For the most part, classification of the results from a particular study was guided by the authors’ interpretation of the cognitive or behavioral domain measured by the task used. For example, if the authors referred to their experimental task as a measure of "sustained attention," then the outcome was classified as such. When the authors referred to their measure as tapping more than one cognitive function or behavioral process, the outcome was classified under the single category and sub-category that was most consistent with the interpretation of the measure in the scientific literature. However, many, if not most, experimental cognitive and neuropsychological tests lack clear construct validity, and our classification of the outcome (based on the authors’ interpretations) would not be without debate. In particular, there is probably substantial overlap among tests of sustained and selective attention and those assessing the executive functions of inhibition, flexibility and working memory. Classifying the various cognitive and behavioral results into "independent" categories is a first step to exploring the profile of impairments in PKU and those processes linked to blood phenylalanine levels; however, one must be cautious in the interpretation of the findings across these categories.

Second, a clinically important question is the effect of developmental level on the effectiveness of treatment and the association of Phe level with cognitive and behavioral outcomes. However, given the incidence of PKU, one in 10 - 20,000 live births, it is rare to find studies that narrow their focus to a particular age or small age range. The unit of analysis in a meta-analysis is the average or "overall" data from each study, rather than the raw subject data. Therefore, when the vast majority of studies in an area collapse over a large age range, one cannot easily analyze for age effects.

Both of these concerns regarding cognitive and behavioral constructs and developmental level will be discussed at greater length in the last section of the discussion, "Directions for Future Research."

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Interpretation of the Analyses

Aim One

The analyses relevant to Aim One address the effect of treatment on cognitive and behavioral outcomes in individuals diagnosed with PKU. This broad question essentially asks to what degree the low Phe diet has been effective in averting the various negative cognitive and behavioral sequelae of this metabolic disorder. One approach to addressing this question is to examine studies of PKU individuals who were treated in early infancy with the restricted dietary regimen (the majority of whom are still on diet) on a range of cognitive and behavioral outcomes. In these studies, the PKU children and adults were compared to age-matched, unaffected control participants who were unrelated to the PKU participants. The effect sizes for all the outcomes were positive, indicating poorer performance or greater behavioral problems in the PKU group; however, these mean effect sizes ranged from .074 to 1.344. That is, there appears to be a profile of relative strengths and weaknesses in groups of early-treated, primarily on-diet, PKU participants relative to the unaffected peers.

The smallest mean effect sizes were found in the Behavior category, where effect sizes of 0.074 (behavior disorders) and 0.16 (general behavior ratings and self-concept) indicate that the mean scores of the PKU group were virtually indistinguishable from those of the control group. Therefore, although individual studies of general behavior (eg., Schor, 1983, 1984) and of psychopathology (eg., Fisch, Sines, & Chang, 1981) have suggested a greater degree of behavioral disturbance in early-treated PKU children, this meta-analysis indicates that the difference between the clinical and control groups is negligible. It is important to note that behavioral outcomes were combined across studies with samples that were heterogeneous with regard to age (ie., from young childhood to early adulthood). It is possible that given enough studies of participants within a smaller age range (eg., toddlers, adolescents, etc.), a future meta-analysis would identify an age range during which PKU individuals exhibit greater behavioral problems, as compared to normal controls.

The analysis of IQ overall, and the sub-categories of full-scale, verbal, and performance IQ, revealed small mean effect sizes ranging from 0.323 (verbal IQ) to 0.440 (performance IQ). Effect sizes of this magnitude indicate that the average difference between the PKU and control means on these measures is about one-third of the pooled standard deviation. These results are consistent with the general consensus among researchers and clinicians that the intellectual level of early-treated PKU individuals is within the normal range (eg., Williamson, Koch, Azen, & Chang, 1981).

The analyses of both Executive Function and Attention, two cognitive categories that are probably very closely related, revealed mean effect sizes of 0.468 and 0.658, respectively. Such effect size magnitude would be classified as "moderate" by Cohen (1992), and reflects about a one-half standard deviation difference between the means of the PKU and control groups. With regard to Executive Function, the effect size for measures of inhibition and flexibility was 0.342; however, there were too few outcomes to analyze the effect size for planning or working memory processes, specifically. The popularity of a "prefrontal dysfunction model" for PKU in which the inability to metabolize Phe into dopamine should compromise prefrontal function (eg., Welsh, 1996) has been bolstered by the evidence of recent studies that have found specific executive function deficits in this population (eg., Diamond et al., 1997; Griffiths et al., 1998; Welsh et al., 1990). However, to effectively test this model via meta-analysis, a greater number of studies of this kind need to be conducted. The analyses of Attention overall, and sustained and selective attention specifically, yielded mean effect sizes that were somewhat larger than those for Executive Function ( d range from 0.635 to 0.658). Interestingly, the results for both Executive Function and Attention converge with the evidence of a moderate mean effect size ( d = 0.50) for the Other Cognitive and Motor Skills category. This effect size appears to be driven by one moderate effect size for speed of processing measures ( d = 0.529) and one very large effect size for performance on visual-spatial tasks ( d = 1.34). The results with regard to visual-spatial performance substantiates a long-standing assumption that individuals with PKU have specific deficits in "visual analysis and synthesis" (eg., Mims, McIntyre, & Murray, 1981, 1883). One reasonable explanation for the similar mean effect sizes seen across the cognitive categories of executive function, attention, speed of processing, and visual-spatial skills is that performance on these tasks are mediated by overlapping cognitive processes. For example, one easily can see how a measure of selective attention would also require executive processes of working memory and inhibition, not to mention visual-spatial and speed of processing components. Again, the somewhat artificial demarcation among these cognitive and behavioral categories must be viewed cautiously.

A more conservative approach to examining the differences between early-treated PKU individuals and unaffected control participants across a range of behavioral domains, is to compare the clinically-diagnosed individuals to familial controls. Comparing PKU participants to their own siblings or parents will control, to some extent, the contribution of other genetic and environmental factors to performance on the cognitive and behavioral measures. Because the PKU individuals are more similar to the sibling or parental controls in terms of genetic endowment and environmental influences, one would expect them to be more similar to these control participants than they would be to non-familial controls. The results concerning the Behavior category were quite similar to the earlier analysis of non-familial controls, revealing a negligible effect size of about 0.140. Interestingly, the analysis of overall IQ, as well as full-scale, verbal and performance IQ, found somewhat larger effect sizes ( Md range from 0.597 -0 .787) than in the earlier analysis. This relatively large discrepancy between the intellectual level of PKU individuals as compared to that of their unaffected family members, is consistent with the notion that, although IQ is in the normal range, it does not achieve the levels predicted by familial IQ (Koch, Azen, Firedman, & Williamson, 1984). However, the small number of outcomes on which some of these analyses of IQ were based suggest that this may be an unreliable finding. Only one other cognitive category could be analyzed, and PKU individuals also exhibited a relatively large deficit in visual-spatial processing ( d = -0.966), as compared to siblings and/or parents.

Another way to explore the overall effectiveness of the dietary treatment regimen for PKU is to examine the degree to aspects of this treatment are related to cognitive and behavioral outcomes. For example, the age at which the dietary treatment began was inversely related to performance on standardized IQ tests, with correlations in the -0.30 range. Given that this analysis targeted studies published in the past twenty years, the vast majority of PKU participants were considered "early-treated." The age at diet initiation typically ranged from the neonatal period to sometime within the first year of life, and only a few studies included those treated after the first year. However, even with a relatively restricted range in the age at diet initiation, the expected inverse relationship between this variable and cognitive and behavioral performance was revealed. A second method for examining the effectiveness of treatment is to ask whether the quality of control while on diet influences these cognitive and behavior outcomes in predictable ways. The results of this meta-analysis indicate that individuals with early-treated PKU whose dietary control is judged to be of lower quality will exhibit deficits in IQ relative to early-treated individuals who have maintained a higher quality of dietary control. Similarly, the quality of dietary control is related to performance on measures of sustained and selective attention. Unfortunately, due to a insufficient number of effect sizes, this important treatment variable could not be explored with respect to executive functions and other cognitive and behavioral outcomes.

Finally, a set of analyses explored the nature of age differences (cross-sectionally) and age changes (longitudinally) for individuals who were currently on the phenylalanine-restricted diet. If the diet is effective, one might expect improvements with age on cognitive task performance as would be observed in their unaffected age-mates. Only a small amount of improvement was observed for IQ, as indicated by effect sizes in the 0.12 range. However, because standard scores are generally reported for IQ, these are already "age corrected" and obscure the potential improvement with age that could be seen in the raw scores. The fact that the PKU children appear to be "keeping up" with the peers in terms of their standardized score, suggests that very normal developmental improvement in intelligence was occurring. A much larger improvement in Executive Function ( d = 1.52) and specifically inhibition and flexibility skills ( d = 1.89) was observed with age; however, the small number of outcomes on which these analyses were based (less than 10), suggests that these results are of suspect reliability.

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Aim Two

The second aim of the project was to examine the influence that diet discontinuation has on a diversity of cognitive and behavioral outcomes. Again, this broad aim was explored from a few different perspectives. First, a direct comparison of on-diet performance to off-diet performance was conducted, both by looking within-subjects (ie., the same individuals on- and off-diet) and between-subjects (ie., different individuals in the on- and off-diet groups). Somewhat surprisingly, the differences between on-diet and off-diet performance was not large for IQ ( d = 0.301), Behavior ( d = 0.241) or Other Cognitive and Motor Skills ( d = 0.212). There was a larger effect size for measures of sustained and selective attention ( d = 0.772); however, this result was again based on a relatively small sample of outcomes (N=7). The smaller than expected differences between on-diet and off-diet performance may not be surprising, in light of the fact that the off-diet performances are measured on PKU individuals who are early- and continuously-treated, with some individuals maintaining treatment well into adolescence. Consistent with this explanation, the IQ performance of PKU individuals who are off diet at the time of testing compares favorable to the IQ performance of unaffected control participants ( d = 0.112). However, there is a relatively greater difference between PKU diet terminators and unaffected controls on overall Attention ( d = 0.90) and speed of processing tasks ( d = 0.688). This contrast between the results on tests of intelligence and performance on other cognitive tasks, confirms the notion expressed by many researchers (eg., Welsh et al., 1990) that standardized intelligence tests, and particularly "crystallized intelligence," may not be as sensitive to the core impairments characterizing PKU as are tests of "fluid" intelligence and information processing. A third set of analyses converge with this perspective on diet termination and cognitive sequelae: greater longitudinal changes in PKU individuals post-diet termination were seen on measures of Other Cognitive and Motor Skills ( d = 0.723), than were seen on measures of intelligence ( d = 0.137).

A clinically important issue regarding diet termination and outcome is the age at which individuals with PKU can "safely" terminate diet. Currently, clinics across the country and around the world have widely varying policies with regard to the age at which diet termination is acceptable. Ideally for a meta-analysis, one would be able to collapse across a large set of outcomes for each age or small age range during which diet discontinuation occurred. However, the reality of the empirical literature exploring PKU is that few studies have homogeneous samples with regard to diet termination, and instead, there exists a range of ages of diet discontinuation within a given sample. For the purposes of this meta-analysis, outcomes were grouped on the basis of "early diet termination" (ie., before age 8) and "late diet termination" (ie., 8 years or later). These analyses revealed moderate mean effect sizes for overall IQ ( d = 0.603) and the three sub-categories of IQ: full-scale ( d = 0.571), verbal ( d = 0.677), and performance ( d = 0.592). These positive effect sizes indicate that those individuals terminating diet early exhibited lower IQ scores than those individuals terminating diet later. These results are consistent with the finding of Holtzman, Kronmal, van Doorninck, Azen, and Koch (1986), in which diet discontinuation prior to age 6 resulted in the largest IQ discrepancies as compared to parental IQ.

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Aim Three

Another issue with substantial clinical and policy implications is the degree to which diet reinstitution in treated PKU individuals who have previously terminated diet restrictions, has a positive impact on behavior and cognition. This question is particularly important given the concerns surrounding maternal PKU, and the teratogenic effect that high levels of circulating Phe has on fetal development (eg., Waisbren, Hamilton, St. James, Shiloh, S. & Levy, H. L.,1995). For this reason, young adult women with PKU who have discontinued diet are frequently encouraged to return to the regimen. However, evidence supporting other positive cognitive and behavioral effects of diet reinstitution would suggest that this course of action may be in the best interest of both female and male PKU adults. The focus of this Aim was to investigate the impact of diet reinstitution on cognitive and behavioral processes; however, the nature and degree of this impact is most likely moderated by a variety of factors: the age at which diet was terminated, the quality of control while on the newly reinstituted diet, as well as the quality of control while on the dietary regimen previously. Unfortunately, there were relatively few studies in the NLM bibliography on diet reinstitution, making it difficult to address the general question, and nearly impossible to adequately explore the effect of moderator variables.

The effects of diet reinstitution are typically explored in a within-subjects design, examining cognitive performance or behavior both pre- and post- the return to dietary restrictions. In the attempt to explore effects of treatment within specific behavioral domains, there were too few outcomes to analyze, with the exception of the Behavior sub-category of psychological disorders. This analysis revealed essentially no effect of diet reinstitution ( d = 0.025); that is, diet reinstitution did not have a substantial positive impact on ratings of psychopathology (eg., depression, anxiety). Again, one needs to be wary of the small sample size of outcomes (N=8) in drawing conclusions from this result. Another concern regarding this finding is whether the particular rating scales used to determine characteristics of psychological disorders are sensitive to small, possibly transitory changes, that might occur with diet reinstitution.

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Aim Four

The objective of the dietary restrictions prescribed for all early-identified PKU individuals is to restrict the intake of Phe, an amino acid that cannot be metabolized due to decreased levels of phenylalanine hydroxylase. The particular genetic mutation characteristic of classical PKU, and resulting high circulating levels of Phe, disrupts catecholamine biosynthesis (McKean, 1972), as well as the neuronal uptake of critical neurochemical precursors in the central nervous system. Consistent with these ideas, Krause et al. (1985) documented the inverse association between Phe and dopamine. Thus, levels of circulating Phe at various points in development may be expected to impact brain development and function, resulting in a distinctive profile of behavioral and cognitive sequelae.

This reasoning is the rationale for examining the association between four measures of Phe level and the various cognitive and behavioral outcomes targeted in this project. First, the correlations between the Phe level concurrent with the testing session and the scores on the cognitive or behavioral measures were examined. Concurrent Phe level did exhibit the expected inverse association with overall IQ ( r = -0.643) and full-scale IQ ( r = -0.725). There was a moderate relationship between concurrent Phe and overall Attention ( r = -0.538), but a nonsignificant association with the Behavior sub-category of general behavior ratings ( r = -0.143). Somewhat surprisingly, there was a relatively large association between concurrent Phe and ratings of psychopathology ( r = -0.749); however, this result is based on a small number of outcomes (N=9). An unexpectedly strong negative correlation was found between concurrent Phe level and memory ( r = -0.93); however, the small number of outcomes (N=6) for this analysis warrants caution in the interpretation of the finding. The prefrontal dysfunction hypothesis (eg., Welsh, 1996) predicts that concurrent Phe level should be strongly associated with the behaviors subsumed within the Executive Function category; however, with the exception of the sub-category of planning ( r = -0.663), the mean effect sizes in this category are quite small. Again, this important analysis linking concurrent Phe level to executive function processes is hampered by a small sample size of relevant outcomes that were derived from only a few studies (eg., Griffiths et al., 1998; Welsh et al., 1990).

Second, the association between the highest diagnostic level of Phe prior to diet initiation, referred to as infant Phe level, and cognitive and behavioral sequelae also was explored. Relatively fewer studies report infant Phe level; thus, the number of outcomes within most specific behavior categories was insufficient to conduct this analysis. The association between infant Phe level and overall IQ was analyzed and only a weak relationship was revealed ( r = -0.215). The question as to whether high central levels of Phe during a rapid period of brain development has negative implications for cognition and behavior is an important one, but unfortunately too few published accounts of studies report this particular Phe level.

A third measure of Phe level is the mean (or median) level from the point of diet initiation to the time of testing; this level is referred to as the mean lifetime Phe level. This Phe level could be an average taken across 4 years or 24 years, depending on the age of the PKU individual tested. It reasonable to suspect that these mean lifetime Phe levels have different implications depending on the developmental period represented. With the heterogeneity within most study samples and the variability across studies with respect to age, conducting these analyses collapsing across age can make interpretation difficult. There were very weak, nonsignificant negative correlations between mean lifetime Phe level and overall IQ ( r = -0.057) and Executive Function ( r = -0.158); however, the correlation with the overall Other Cognitive and Motor Skills category was surprisingly strong ( r = -0.976). This latter correlation was based on only five outcomes and, again, may be an unreliable result.

The fourth measure of Phe level represents a combination of various measures that do not fit in the aforementioned three Phe level categories. The "other" Phe level category includes such measures as the most recent Phe level, and the mean Phe level taken during the year of the testing. A wide range of the behavior and cognitive outcomes could be analyzed with respect to the association with this "other" Phe level. This measure of Phe level was moderately correlated with overall IQ ( r = -0.424 to -0.573), but only weakly correlated with Attention ( r = -.123), Executive Function ( r = -.022), Behavior ( r = -0.129), and Other Cognitive and Motor Skills (r = -0.057).

The effects of experimental manipulations of phenylalanine, as well as other amino acids and neurochemical precursors were examined with regard to the range of behavioral and cognitive outcomes of interest. The effects of experimentally increasing Phe levels ("phe loading") was seen for overall Attention ( r =-0.385), sustained and selective attention ( r = -0.428), and motor skills ( r = -0.396). In all cases, an increase in Phe level was associated with a decrease in performance. Due to an insufficient number of outcomes from other behavioral categories, such as Executive Function, it is not known whether Phe manipulations affect other cognitive processes as well. Other studies have been designed to provide supplementation with tyrosine, L-dopa, and other amino acids to boost catecholamine production (especially, dopamine), presumed to be lacking in individuals with PKU. Although there are relatively few studies describing such supplementation procedures, there was a sufficient number of outcomes to analyze a few behavioral domains. Supplementation appeared to be positively related to better performance for Executive Function overall ( r = 0.726), and inhibition/flexibility skills specifically ( r = 0.777). Supplementation also was moderately correlated with increased scores on Attention tasks, overall ( r = 0.457).

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Limitations of This Meta-analysis

The typical meta-analytic project involves five steps: (1) formulation of the questions to be answered or specific aims, (2) execution of a complete literature search, (3) collection, classification and coding of studies meeting inclusion criteria, (4) application of statistical techniques for pooling and analyzing the compiled data, (5) evaluation and interpretation of the results in the form of a written report. While the broad aims for the project were provided by the NIH, the researchers were free to generate more specific analytic questions to address these aims.

The first limitation of this project may have been the requirement to include only studies in the NLM bibliography. While the search culminating in this bibliography was comprehensive, there are likely to be articles, dissertations, conference presentations, etc. that are missing from this bibliography that may have provided relevant data. In meta-analytic work, restricting one’s literature search to published studies creates what is known as the "file drawer problem" wherein unpublished studies (often with nonsignificant results) fail to be included in the analyses. Obviously, one outcome of this bias is that certain effect sizes may appear larger than they really are, as they have not been "balanced" by the nonsignificant findings. This is one of the many sources of publication bias that could not be examined in this project.

A second limitation is reflected in the fact that only about half of the coded outcomes could be analyzed in this meta-analysis. The most common reason for eliminating research outcomes was that insufficient information was provided in the published report to calculate an effect size estimate. For example, mean data often were presented in figures without an accompanying table providing the necessary standard deviation data. Given more time, the authors of these studies could be contacted for the necessary data, and these studies could be coded and included in the analyses. Moreover, of the 98 studies and over 1,500 outcomes for which effect size estimates could be calculated, many research questions could not be analyzed due to a small number of outcomes relevant to that question. Compounding this problem is that the ratio of number of outcomes to studies is higher than is desired for meta-analytic work. This "multiple outcome bias" reflects the concern that if a relative few studies are contributing the vast majority of outcomes to a particular analysis, then any problems with the internal or external validity of these studies (eg., recruitment of participants, methodology, etc) will complicate the interpretation of this analysis, as well.

Due to the timeframe for this project, which was extremely short by typical meta-analytic standards, the data set suffers from the following weaknesses (some of which are described above):

  • Lack of graphical exploration of the results
  • Examination of sources of heterogeneity
  • Sensitivity analyses
  • Examination of publication bias
  • Multiple outcome bias

In general, a meta-analytic project of this magnitude; that is, one that deals with complex questions, a variety of research designs, and a myriad of operational definitions for the behavioral constructs; would demand extensive pilot work and a longer time frame for proper execution (e.g., 2 to 3 years).

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Directions for Future Research

Although there has been a great deal of excellent empirical work exploring the cognitive and behavioral sequelae of PKU, further advances in this field are needed. One objective of conducting meta-analyses on data in a research domain, is to identify gaps in our knowledge base and fruitful directions for future research. The current meta-analytic project on treatment outcomes for the genetic disorder, PKU, has accomplished this goal. Although this meta-analysis was inherently limited in its scope due to the externally-imposed time constraints, gaps and a lack of clarity in the empirical literature still can be identified. Three general recommendations for future research in this area are derived from what was learned in the course of this meta-analysis of treatment effectiveness in PKU.

First, it is clear that critical questions surrounding the clinical care and management of PKU concern the issues of developmental level and age. In particular, definitive answers are sought to questions such as " at what age can the dietary restrictions be discontinued or relaxed?," "what are the implications of returning a PKU individual to diet at various ages?" and "what is the association between blood Phe level and cognition or behavior at different ages?" Unfortunately, it is the rare study in the PKU literature that selects and tests a sample of PKU individuals that are homogeneous with respect to age. Given the relatively low incidence of PKU in the population, it can take years to collect data within a restricted age band (eg., Diamond et al., 1997; Welsh et al., 1990); however, to address these very important developmental questions, this research must be conducted. In a sense, a quantitative review of the literature is only "as good" as the studies it combines for the meta-analyses, and if the individual studies do not narrow the focus to specific ages or age groups, the meta-analysis certainly cannot address these issues either. When individual studies report the correlation between the concurrent Phe level and executive function skills, for example, and their sample includes a wide age range, the manner in which age moderates this correlation is obscured. Therefore, the first recommendation that follows from this meta-analysis is that researchers in the area of PKU seriously consider how to better account for age and developmental level in their future studies.

The second recommendation for more effective research on PKU treatment outcome, is not specific to this research area, but applies to all research on cognitive and neuropsychological development in typical and atypical individuals. In light of the fact that there appears to be a profile of relative strengths and weaknesses in the cognitive skills and behavior of early-treated PKU individuals, researchers must move toward greater consensus regarding how to define and measure the key cognitive constructs comprising this profile. This meta-analysis suggested that the relative weaknesses in the cognitive profile of early-treated individuals, even while on diet, are somewhat specific to tasks of sustained and selective attention, visual-spatial processes, speed of processing, and executive functions. At this point it is a matter of debate whether particular experimental paradigms (eg., a continuous performance test) presumed to measure a specific cognitive process (eg., sustained and selective attention) actually measures that process. Before we can ascribe a characteristic pattern of cognitive strengths and weaknesses to a particular clinical condition, the construct validity of the tests typically used to measure cognitive and behavioral processes must be examined and established. In the current meta-analysis, findings were grouped by cognitive and behavioral process on the basis of the researchers’ presumptions about what processes mediated performance on their psychological measures. It is beyond the purview of meta-analysis to make judgments regarding whether the profile of weaknesses identified across studies indicates deficits in several different (albeit, related) cognitive processes or whether one common cognitive mechanism is responsible for the cluster of impairments. Our understanding of the nature and scope of cognitive constructs such as intelligence, executive function, and attention, as well as the most psychometrically-sound and conceptually-clear methods of measurement, remains one of the biggest challenges for the fields of cognitive psychology and neuropsychology.

Finally, this meta-analysis exposed several areas that are "under-researched" with regard to clinical and cognitive outcomes in early-treated PKU. These areas are challenging and difficult to explore for many of the general reasons discussed above, as well as for many reasons unique to each research question. In addition to the call for more research focused on specific age groups already mentioned, the following areas should be a priority for PKU researchers in the near future:

  • Research on the impact of diet reinstitution, with particular attention paid to moderating variables such as the age at return to diet, quality of dietary control after reinstitution, and the specific cognitive process (eg., IQ vs Executive Function) measured.
  • Research exploring the nature of executive functions in early-treated PKU individuals while on diet and after diet termination, with a particular focus on relatively neglected components of executive function, planning and working memory.
  • Research examining how deficits in visual-spatial, selective attention, speed of processing, and executive function domains may relate to each other, with the objective of identifying common underlying mechanisms that reflect specific areas of brain dysfunction in this condition.

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Conclusions

A quantitative review of the literature accomplished via meta-analytic techniques is an important companion to the more traditional qualitative review. In the case of this meta-analysis of treatment outcome research in PKU, many of the findings are consistent with interpretations set forth in recent qualitative reviews of this empirical literature. However, this initial analysis of the data set (and more analyses will follow) also has revealed some surprising results that suggest future areas of scientific investigation.

Some tentative conclusions that can be drawn from this meta-analysis project are as follows:

  • When compared to non-familial control participants, individuals with PKU appear to be less impaired in the area of intelligence, than they are in the domains of sustained and selective attention, planning, visual-spatial skills, and speed of processing.
  • When compared to familial control participants, individuals with PKU exhibit greater relative impairment in intelligence.
  • A clear difference between individuals with PKU and unaffected control participants in general behavior, self-concept, and characteristics of psychological disorders was not substantiated.
  • Aspects of the dietary regimen, such as early vs late diet termination, and poor vs excellent dietary control, show predictable effects on IQ and attention.
  • Phe levels measured on the day of testing exhibit the expected negative association with intelligence, attention, and some executive function skills. The experimental manipulation of Phe level has been shown to directly affect sustained and selective attention in some studies; whereas, supplementation with amino acids and neurochemical precursors exhibits its clearest effects on executive function.

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References

Alm, J., Bodegard, G., Larsson, A., Nyberg, G., & Zetterstrom, R. (1986). Children with inborn errors of phenylalanine metabolism: Prognosis and phenylalanine tolerance. ActaPaediatra Scandinavia, 75 , 619-25.

Anonymous. (1995). On the need for evidence-based medicine. Evidence Based Medicine, 1, 5-6.

* Arnold, G. L., Kramer, B.M., Kirby, R. S., Plumeau, P. B., Blakely, E. M., Sanger Cregan, L. S., & Davidson, P.W. (1998). Factors affecting cognitive, motor, behavioral and executive functioning in children with phenylketonuria. Acta Paediatra, 87, 565-70.

Azen, C., Koch, R., Friedman, E., Wenz, E., & Fishler, K. (1996). Summary of Findings from the United States collaborative study of children treated for phenylketonuria. European Journal of Pediatrics, 155 (Suppl. 1), S29-S32.

Azen, C.G., Koch, R., Friedman, E.G., Berlow, S., Coldwell, J., Krause, W., Matalon, R., McCabe, E., O'Flynn, M., Peterson, R., Rouse, B., Scott, C. R., Sigman, B., Valle, D., & Warner, R. (1991). Intellectual development in 12-year-old children treated for phenylketonuria. American Journal of the Disabled Child, 145, 35-9

*Barclay, A., & Walton, O. (1988). Phenylketonuria: Implications of initial serum phenylalanine levels on cognitive development. Psychological Reports, 63, 135-142.

* Beasley, M. G., Costello, P. M., & Smith, I. (1994). Outcome of treatment in young adults with phenylketonuria detected by routine neonatal screening between 1964 and 1971. Quarterly Journal of Medicine, 87, 155-160.

*Behbehani, A. W. (1985). Termination of strict diet therapy in phenylketonuria: A study on EEG sleep patterns and computer spectral analysis. Neuropediatrics, 16, 92-97.

*Behbehani, A. W., Krtsch, H., & Schulte, F. J. (1981). Cranial computerized tomography in phenylketonuria. Neuropediatrics, 12, 295-302.

*Berry, H. K., Brunner, R. L., Hunt, M. M., & White, P. P. (1990). Valine, isoleucine, and leucine. American Journal of Disease in Childhood, 144, 539-543.

*Blaskovics, M., Engel, R., Podosin, R. L., Azen, C. G., & Friedman, E.G. (1981). EEG pattern in phenylketonuria under early initiated dietary treatment. American Journal of Diseases in Childhood, 135, 802-808.

Blaskovics, M. E. (1986). Diagnosis in relationship to treatment of hyperphenylalaninaemia. Journal of Inherited Metabolic Disease, 9, (Suppl. 2), 178-182.

*Brunner, R. L., Jordan, M. K., & Berry, H. K. (1983). Early-treated phenylketonuria: Neuropsychologic consequences. Journal of Pediatrics, 102, 831-835.

*Brunner, R. L., Berch, D. B., & Berry, H. (1987). Phenylketonuria and complex spatial visualization: An analysis of information processing. Developmental Medicine and Child Neurology, 29, 460-468.

* Burgard, P., Armbruster, M., Schmidt, E., & Rupp, A. (1994). Psychopathology of patients treated early for phenylketonuria: Results of the German collaborative study of phenylketonuria. Acta Paediatra Supplement, 407, 108-110.

Burgard, P., Rupp, A., Konecki, D. S., Trefz, F. K., Schmidt, H., & Lichter-Konecki, U. (1996). Phenylalanine hydroxylase genotypes, predicted residual enzyme activity and phenotypic parameters of diagnosis and treatment of phenylketonuria. European Journal of Pediatrics, 155, (Suppl. 1), S11-S15.

*Burgard, P., Schmidt, E., Rupp, A., Schneider, W., & Bremer, H. J. (1996). Intellectual development of the patients of the German collaborative study of children treated for phenylketonuria. European Journal of Pediatrics, 155 (Suppl. 1), S33-S38.

*Burgard, P., Rey, F., Rupp, A., Abadie, V., & Rey, J. (1997). Neuropsychologic functions of early treated patients with phenylketonuria, on and off diet: Results of a cross-national and cross-sectional study. Pediatric Research, 41, 368-374.

* Cabalska, M. B., Nowaczewska, I., Sendecka, E., & Zorska, K. (1996). Longitudinal study on early diagnosis and treatment of phenylketonuria in Poland. European Journal of Pediatrics,155 (Suppl. 1), S53-S55.

*Cechak, P., Hejcmanova, L., & Rupp, A. (1996). Long-term follow-up of patients treated for phenylketonuria (PKU). European Journal of Pediatrics, 155 (Suppl. 1), S59-S63.

Chamove, A.S., & Molinaro, T. J. (1978). Monkey retarded learning analysis. Journal of Mental Deficiency Research, 22, 223.

*Chang, P., Cook, D. R., & Fisch, R. O. (1983). Prognostic factors of the intellectual outcome of phenylketonurics: On and off diet. Journal of Psychiatric Treatment and Evaluation, 5, 157-163.

*Clarke, J. T. R., Gates, R. D., Hogan, S. E., Barrett, M., & MacDonald, G. W. (1987). Neuropsychological studies on adolescents with phenylketonuria returned to phenylalanine-restricted diets. American Journal of Mental Retardation, 92, 255-262.

Cleary, M. A., Walter, J. H., Wraith, J. E., Jenkins, J. P. R., Alani, S. M., & Whittle, D. (1994). Magnetic resonance imaging of the brain in phenylketonuria. Lancet, 344, 87-90.

*Cohen, B. E., Weiss, R., Hadar, R., Normand, M., Shiloh, S., & Elhanati, D. (1988). Group work with adolescent PKU girls and their mothers. Journal of Inherited Metabolic Diseases, 11, 199-206.

*Costello, P. M., Beasley, M. G., Tillotson, S. L., & Smith, I. (1994). Intelligence in mild atypical phenylketonuria. (1994). European Journal of Pediatrics, 153, 260-263.

Craft, S., Gourovitch, M. L., Dowton, S. B., Swanson, J. M., & Bonforte, S. (1992). Lateralized deficits in visual attention in males with developmental dopamine depletion. Neuropsychologia, 30 , 341-351.

Crowley, C., Koch, R., Fishler, K., Wenz, E., & Ireland, J. (1990). Clinical trial of ‘off diet’ older phenylketonurics with a new phenylalanine-free product. Journal of Mental Deficiency Research, 34, 361-369.

Davidson, D. C. (1989). Maternal phenylketonuria. Postgraduate Medical Journal, 65 (Suppl. 2), S10-S20.

Davis, D. D., McIntyre, C. W., Murray, M. E., & Mims, S. K. (1986). Cognitive styles in children with dietary treated phenylketonuria. Educational and Psychological Research, 6, 9-15.

*de Sonneville, L. M. J., Schmidt, E., Michel, U., & Batzler, U. (1990). Preliminary neuropsychological test results. European Journal of Pediatrics, 149 (Suppl. 1), S39-S44.

Dennis, M., Lockyer, L., Lazenby, A. L., Donnelly, R. E., Wilkinson, M., & Schoonheyt, W. (1999). Intelligence patterns among children with high-functioning autism, phenylketonuria, and childhood head injury. Journal of Autism and Developmental Disorders, 29, 5-13.

Diamond, A., & Herzberg, C. (1996). Impaired sensitivity to visual contrast in children treated early and continuously for phenylketonuria. Brain, 119, 523-538.

*Diamond, A., Prevor, M.B., Callender, G., & Druin, D.P. (1997). Prefrontal cortex cognitive deficits in children treated early and continuously for PKU. Monographs of the Society for Research in Child Development, 62 (4, Serial No. 252).

Farquhar, D. L., Simpson, G. K., Steven, F., Munro, J. F. & Farquhar, J. W. (1987). Pre-conceptual dietary management for maternal phenylketonuria. Acta Paediatr Scandanavia, 76, 279-283.

*Fisch, R. O., Sines, L. K. & Chang, P. (1981). Personality characteristics of nonretarded phenylketonurics and their family members. Journal of Clinical Psychiatry, 42, 106-113.

Fisch, R. O., Tsai, M. Y., Clark, B. A. & Okagaki, T. (1981). Semen studies on phenylketonurics. Biochemical Medicine, 26, 427-434.

*Fisch, R. O., Chang, P., Sines, L., Weisberg, S. & Bessman, S. (1985). Relationship between phenylalanine tolerance and psychological characteristics of phenylketonuric families. Biochemical Medicine, 33, 236-245.

Fisch, R. O., Chang, P. N., Weisberg, S., Guldberg, P., Guttler, F., & Tsai, M.Y. (1995). Phenylketonuric patients decades after diet. Journal of Inherited Metabolic Disease, 18, 347-53.

*Fishler, K., Azen, C. G., Henderson, R., Friedman, E. G. & Koch, R. (1987). American Journal of Mental Deficiency, 92, 65-73.

Fisch, R. O., Matalon, R., Weisberg, S., & Michals, K. (1991). Children of fathers with phenylketonuria: An international survey. The Journal of Pediatrics, 118, 739-741.

Fox-Bacon, C., McCamman, S., Therou, L., Moore, W. & Kipp, D. E. (1997). Maternal PKU and breastfeeding: Case report of identical twin mothers. Clinical Pediatrics, September, 539-542.

Friedman, E. G., Koch, R., Axen, C., Levy, H., Hanley, W., Matalon, R., Rouse, B., Trefz, E. & de la Cruz, F. (1996). The international collaborative study on maternal phenylketonuria: organization, study design and description of the sample. European Journal of Pediatrics, 155(Suppl 1): S158-S161.

Giffin, F. D., Clarke, J. T. R. & d’Entremont, D. M. (1980). Effect of dietary phenylalanine restriction on visual attention span in mentally retarded subjects with phenylketonuria. Le Journal Canadien des Sciences Neurologiques, 7, 127-131.

Glass, G. V. (1976). Primary, secondary and meta-analysis of research. Educational Researcher, 5, 3-8.

Glass, G. V., McGaw, B., & Smith, M. L. (1981). Meta-analysis in Social Research. Thousand Oaks, CA: Sage Publications.

*Gourovitch, M. L., Craft, S., Dowton, S. B., Ambrose, P. & Sparta, S. (1994). Interhemishperic transfer in children with early-treated phenylketonuria. Journal of Clinical and Experimental Neuropsychology, 16, 393-404.

*Griffiths, P., Paterson, L. & Harvie, A. (1995). Neuropsychological effects of subsequent exposure to phenylalanine in adolescents and young adults with early-treated phenylketonuria. Journal of Intellectual Disability Research, 39, 365-372.

Griffiths, P., Smith, C., & Harvie, A. (1997). Transitory hyperphenylalaninaemia in children with continuously treated phenylketonuria. American Journal of Mental Retardation, 102, 27-36

*Griffiths, P., Tarrini, M. & Robinson, P. (1997). Executive function and psychosocial adjustment in children with early treated phenylketonuria: correlation with historical and concurrent phenylalanine levels. Journal of Intellectual Disability Research, 41, 317-323.

*Griffiths, P., Campbell, R. & Robinson, P. (1998). Executive function in treated phenylketonuria as measured by the one-back and two-back versions of the continuous performance test. Journal of Inherited Metabolic Disorders, 21, 125-135.

*Griffiths, P., Ward, N., Harvie, A. & Cockburn, F. (1998). Neuropsychological outcome of experimental manipulation of phenylalanine intake in treated phenylketonuria. Journal of Inherited Metabolic Disorders, 21, 29-38.

Guttler, F., & Lou, H. (1986). Dietary problems of phenylketonuria: Effect on CNS transmitters and their possible role in behavior and neuropsychological function. Journal of Inherited Metabolic Disease, 9, 168-172.

*Hendrikx, M. M. T., van der Schot, L. W. A., Slijper, F. M. E., Huisman, J., & Kalverboer, A. F. (1994). Phenylketonuria and some aspects of emotional development. European Journal of Pediatrics, 153, 832-835.

*Hilliges, C., Awiszus, D., & Wendel, U. (1993). Intellectual performance of children with maple syrup urine disease. European Journal of Pediatrics, 152, 144-147.

Hogan, S. E., Gates, R. D., MacDonald, G. W., & Clarke, J. T. R. (1986). Experience with adolescents with phenylketonuria returned to phenylalanine-restricted diets. Journal of the American Dietetic Association, 86, 1203-1207.

*Holtzman, N. A., Kronmal, R. A., van Doorninck, W., Azen, C., & Koch, R. (1986). Effect of age at loss of dietary control on intellectual performance and behavior of children with phenylketonuria. The New England Journal of Medicine, 314 , 593-598.

*Kazak, A. E., Reber, M., & Snitzer, L. (1988). Childhood chronic disease and family functioning: A study of phenylketonuria. Pediatrics, 81 , 224-229.

Knox, W.E. (1972). Phenylketonuria. In J.B. Stanbury, J.B. Wyngaarden, & D.S. Fredrickson (Eds.), The Metabolic Basis of Inherited Disease (pp. 266-295). New York: McGraw-Hill.

*Koch, R., Azen, C. G., Friedman, E. G., & Williamson, M. L. (1982). Preliminary report on the effects of diet discontinuation in PKU. The Journal of Pediatrics, 100, 870-875.

*Koch, R., Azen, C., Friedman, E.G. & Williamson, M. L. (1984). Paired comparisons between early treated PKU children and their matched sibling controls on intelligence and school achievement test results at eight years of age. Journal of Inherited Metabolic Disorders, 7, 86-90.

Koch, R., Friedman, E. G., Wenz, E., Jew, K., Crowley, C., & Donnell, G. (1986). Maternal phenylketonuria. Journal of Inherited Metabolic Diseases, 9 (Suppl. 2), 159-168.

*Koch, R., Azen, C. G., Hurst, N., Friedman, E. G., & Fishler, K. (1987). The effects of diet discontinuation in children with phenylketonuria. European Journal of Pediatrics, 146 (Suppl. 1), A12-A16.

Koch, R., Azen, C., Friedman, E. G., Fishler, K., Baumann-Frischling, C., & Lin, T. (1996). European Journal of Pediatrics, 155 (Suppl. 1), S90-S92.

*Koch, R., Fishler, K., Azen, C., Guldberg, P., & Guttler, F. (1997). The relationship of genotype to phenotype in phenylalanine hydroxylase deficiency. Biochemical and Molecular Medicine, 60, 92-101.

*Krause, W., Halminski, M., McDonald, L., Dembure, P., Salvo, R., Freides, D. & Eisas, L. (1985). Biochemical and neuropsychological effects of elevated plasma phenylalanine in patients with treated phenylketonuria. Journal of Clinical Investigation, 75, 40-48.

*Krause, W., Epstein, C., Averbook, A., Dembure, P., & Elsas, L. (1986). Phenylalanine alters the mean power frequency of electroencephalograms and plasma l-dopa in treated patients with phenylketonuria. Pediatric Research, 20, 1112-1116.

L’Abbe, K. A., Detsky, A.S., O’Rourke, K. (1987). Meta-analysis in clinical research. Annals of Internal Medicine, 107, 224-233.

*Legido, A., Tonyes, L., Carter, D., Schoemaker, A., DiGeorge, A. & Grover, W. (1991). Treatment variables and intellectual outcome in children with classical phenylketonuria. Clinical Pediatrics, 30, 417-424.

Leuzzi, V., Trasimeni, G., Gualdi, G. F., & Antonozzi, I. (1995). Biochemical, clinical and neuroradiological (MRI) correlations in late-detected PKU patients. Journal of Inherited Metabolic Diseases, 18, 624-634.

Leuzzi, V., Fois, D., Carducci, C., Antonozzi, I., & Trasimeni, G. (1997). Neuropsychological and neuroradiological (MRI) variations during phenylalanine load: Protective effect of valine, leucine, and isoleucine supplementation. Journal of Child Neurology, 12, 338-340.

*Leuzzi, V., Rinalduzzi, S., Chiarotti, F., Garzia, P., Trasimeni, G., & Accornero, N. (1998). Subclinical visual impairment in phenylketonuria. A neurophysiological study (VEP-P) with clinical, biochemical, and neuroradiological (MRI) correlations. (1998). Journal of Inherited Metabolic Diseases, 21, 351-364.

Levy, H. L., Lobbregt, D., Koch, R., & de la Cruz, F. (1991). Paternal phenylketonuria. The Journal of Pediatrics, 118, 741-743.

Lou, G. C., Guttler, F., Lykkelund, C., Bruhn, P., & Niederwieser, A. (1985). Decreased vigilance and neurotransmitter synthesis after discontinuation of dietary treatment for phenylketonuria in adolescents. European Journal of Pediatrics, 144, 17-20.

Lou, H. C., Lykkelund, C., Gerdes, A. M., Udesen, H., & Bruhn, P. (1987). Increased vigilance and dopamine synthesis by large doses of tyrosine or phenylalanine restriction in phenylketonuria. Acta Paediatra Scandinavia, 76, 560-565.

Matthew, W. S., Barbabas, G., Cusack, E., & Ferrari, M. (1986). Social quotients of children with phenylketonuria before and after discontinuation of dietary therapy. American Journal of Mental Deficiency, 91, 92-94.

Mazzocco, M. M., Nord, A. M., Foorninck, W. V., Greene, C. L., Kovar, C. G., & Pennington, B. F. (1994). Cognitive development among children with early–treated phenylketonuria. Developmental Neuropsychology, 10, 133-151.

McDonnell, G. V., Esmonde, T. F., Hadden, D. R., & Morrow, J. I. (1998). A neurological evaluation of adult phenylketonuria in Northern Ireland. European Neurology, 39, 38-43.

McKean, C.M. (1972). The effects of high phenylalanine concentrations on serotonin and catecholamine metabolism in the human brain. Brain Research, 47, 469-476.

Michals, K., Dominik, M., Schuett, V., Brown, E., & Matalon, R. (1985). Return to diet therapy in patients with phenylketonuria. The Journal of Pediatrics, 106, 933-935.

*Michals, K., Azen, C., Acosta, P., Koch, R., & Matalon, R. (1988). Blood phenylalanine levels and intelligence of 10-year-old children with PKU in the national collaborative study. Journal of the American Dietetic Association, 88, 1226-1229.

*Michel, U., Schmidt, E. & Batzler, U. (1990). Results of psychological testing of patients aged 3-6 years. European Journal of Pediatrics, 149(Suppl 1), S34-S38.

*Mims, S. S., McIntyre, C. W., & Murray, M. E. (1983). An analysis of visual motor problems in children with dietary treated phenylketonuria. Educational and Psychological Research, 3, 111-121.

*Moller, H. E., Weglage, J., Wiedermann, D., & ullrich, K. (1998). Blood-brain barrier phenylalanine transport and individual vulnerability in phenylketonuria. Journal of Cerebral Blood Flow and Metabolism, 18, 1184-1191.

*Naughten, E. R., Kiely, B., Saul, I., & Murphy, D. (1987). Phenylketonuria: Outcome and problems in a "diet-for-life" clinic. European Journal of Pediatrics, 146 (Suppl. 1), A23-A24.

Naughten, E., & Saul, I. P. (1990). Maternal phenylketonuria – the Irish experience. Journal of Inherited Metabolic Diseases, 13, 658-664.

*Netley, C., Hanley, W.B., & Rudner, H. L. (1984). Phenylketonuria and its variants: Observations on intellectual functioning. Canadian Medical Association Journal, 131, 751-754.

Pearsen, K. D., Gean-Marton, A. D., Levy, H. L., & Davis, K. R. (1990). Phenylketonuria: MR imaging of the brain with clinical correlation. Radiology, 177, 437-440.

*Pennington, B. F., van Doorninck, W. J., McCabe, L. L., & McCabe E. R. B. (1985). Neuropsychological deficits in early treated phenylketonuric children. American Journal of Mental Deficiency, 89 (5), 467-474.

Pietz, J. (1998). Neurological aspects of adult phenylketonuria. Current Opinion in Neurology, 11, 679-688.

*Pietz, J., Benninger, Ch., Schmidt, H., Scheffner, D. & Bickel, H. (1988). Long term development of intelligence (IQ) and EEG in 34 children with phenylketonuria treated early. European Journal of Pediatrics, 147, 361-367.

Pietz, J., Dreis, R., Rupp, A., Mayatepek, E., Rating, D., Boesch, C. & Gremer, H. J. (1999). Large neural amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. Journal of Clinical Investigation, 103, 1169-1178.

*Pietz, J., Dreis, R., Schmidt, H., Meyding-Lamade, U. K., Rupp, A & Boesch, C. (1996). Phenylketonuria: Findings at MR imaging and localized in vivo H-1 MR Spectroscopy of the brain in patients with early treatment. Radiology, 201, 413-420.

*Pietz, J., Dunckelmann, R., Rupp, A., Rating, D., Meinch, H. M., Schmidt, H. & Bremer, H. J. (1998). Neurological outcome in adult patients with early-treated phenylketonuria. European Journal of Pediatrics, 157, 824-830.

*Pietz, J., Fatkenheuer, B., Burgard, P., Armbruster, M., Esser, G. & Schmidt, H.(1997). Psychiatric disorders in adult patients with early-treated phenylketonuria. Pediatrics, 99, 345-350.

Pietz, J., Kreis, R., Boesch, C., Penzien, D., Rating, D. & Herschkowitz, N. (1995). The dynamics of brain concentrations of phenylalanine and its clinical significance in patients with phenylketonuria determined by in vivo H-1 magnetic resonance spectroscopy. Pediatric Research, 38, 657-663.

*Pietz, J., Landwehr, R., Dutscha, A., Schmidt, H., de Sonneville, L. & Trefz, F. K. (1995). Journal of Pediatrics, 127, 936-943.

Pietz, J., Meyding-Lamade, U. K. & Schmidt, H. (1996). Magnetic resonance imaging of the brain in adolescents with phenylketonuria and in one case of 6-pyruvoyl tetrahydropteridine synthase deficiency. European Journal of Pediatrics, 155 (Suppl 1), S69-S73.

*Pietz, J., Schmidt, E., Matthis, P., Kobialka, B., Kutscha, A. & de Sonneville, L. (1993). EEG’s in phenylketonuria. I: Follow-up to adulthood; II: Short-term diet-related changes in EEGs and cognitive function. Developmental Medicine and Child Neurology, 35, 54-64.

Pueschel, S. M., Fogelson-Doyle, L., Kammerer, B. & Matsumiya, Y. (1983). Neurophysiological, psychological, and nutritional investigations during discontinuation of the phenylalanine-restricted diet in children with classical phenylketonuria. Journal of Mental Deficiency Research, 27, 61-67.

*Realmuto, G. M., Garfinkel, B. D., Tuchman, M., Tsai, M. Y., Chang, P., Fisch, R. O. & Shapiro, S. (1986). Psychiatric diagnosis and behavioral characteristics of phenylketonuric children. The Journal of Nervous and Mental Disease, 174, 536-540.

*Reber, M., Kazak, A. & Himmelberg, P. (1987). Phenylalanine control and family functioning in early-treated phenylketonuria. Developmental and Behavioral Pediatrics, 8, 311-317.

*Rey, F., Abadie, V., Plainguet, F. & Rey, J. (1996). Long-term follow up of patients with classical phenylketonuria after diet relaxation at 5 years of age. European Journal of Pediatrics, 155 (Suppl 1), S39-S44.

*Ris, M. D., Weber, A. M., Hunt, M. M., Berry, H. K., Williams, S. E. & Leslie, N. (1997). Adult psychosocial outcome in early-treated phenylketonuria. Journal of Inherited Metabolic Disorders, 20, 499-508.

*Ris, M. D., Williams, S.E., Hunt, M. M., Berry, H. K, & Leslie, N. (1994). Early-treated phenylketonuria: Adult neuropsychological outcome. Journal of Pediatrics, 124, 388-392.

*Rupp, A. & Burgard, P. (1995). Comparison of different indices of dietary control in phenylketonuria. Acta Paediatr, 84, 521-527.

Saudubray, J. M., Rey, F., Ogier, H., Abadie, V., Farriaux, J. P., Gisolfi, H., Guibaud, P., Rey, J. & Vidailhet, M. (1987). Intellectual and school performances in early-treated classical PKU patients. European Journal of Pediatrics, 146 (Suppl 1), A20-A22.

Schaefer, F., Burgard, P., Batzler, U., Rupp, A., Schmidt, H., Gilli, G., Bickel, H. & Bremer, H. J. (1994). Growth and skeletal maturation in children with phenylketonuria. Acta Paediatr, 83, 534-541.

*Scheibenreiter, S., Tiefenthaler, M., Hinteregger, V., Strobl, W., Muhl, A., Ewald, A. & Schadler, M. (1996). Austrian report on longitudinal outcome in phenylketonuria. European Journal of Pediatrics, 155 (Suppl 1), S45-S49.

*Scheuett, V. E., Brown, E. S. & Michals, K. (1985). Reinstitution of diet therapy in PKU patients from twenty-two US clinics. American Journal of Public Health, 75, 39-42.

Schmidt, H., Mahle, M., Michel, U. & Pietz, J. (1987). Continuation vs discontinuation of low-phenylalanine diet in PKU adolescents. European Journal of Pediatrics, 146 (Suppl 1), A17-A19.

*Schidmt, E., Rupp, A., Burgard, P., Pietz, J., Weglage, J. & de Sonneville, L. (1994). Sustained attention in adult phenylketonuria: The influence of the concurrent phenylalanine-blood-level. Journal of Clinical and Experimental Neuropsychology, 16, 681-688.

*Schmidt, E., Burgard, P. & Rupp, A. (1996). Effects of concurrent phenylalanine levels on sustained attention and calculation speed in patients treated early for phenylketonuria. European Journal of Pediatrics, 155 (Suppl 1), S82-S86.

*Schmidt, H., Burgard, P., Pietz, J. & Rupp, A. (1996). Intelligence and professional career in young adults treated early for phenylketonuria. European Journal of Pediatrics, 155 (Suppl 1), S97-S100.

*Schor, D. P. (1983). Rating children three through seven years old in PKU families. Clinical Pediatrics, 22, 807-811.

*Schor, D. P. (1986). Phenylketonuria and temperament in middle childhood. CHC, 14, 163-167.

Schuler, A., Somogyi, C., Mate, M., Pataki, L., Toros, I., Woo, S. L., Eisensmith, R.C., & Fekete, G. (1994). Cognitive development related to metabolic phenotype and mutation genotype in 25 Hungarian patients with phenylketonuria. Journal of Inherited Metabolic Disease, 17, 372.

Schuler, A., Somogyi, C., Toros, I., Pataki, L., Mete, M., Kiss, E., & Nagy, A. (1996). A longitudinal study of phenylketonuria based on the data of the Budapest Screening Center. European Journal of Pediatrics, 155 (Suppl.1), S50-S52.

*Shulman, S., Fisch, R. O., Zempel, C. E., Gadish, O. & Chang, P. (1991). Children with phenylketonuria: The interface of family and child functioning. Developmental and Behavioral Pediatrics, 12, 315-321.

*Seashore, M. R., Friedman, E., Novelly, R. A. & Bapat, V. (1985). Loss of intellectual function in children with phenylketonuria after relaxation of dietary phenylalanine restriction. Pediatrics, 75, 226-232.

*Shiloh, S., Waisbren, S. E., Cohen, B. E., St.James, P. & Levy, H. L. (1992). Cross-cultural perspectives on coping with the risks of maternal phenylketonuria. Psychology and Health , 8, 435-446.

Smith, I., Beasley, M.G. & Ades, A. E. (1990). Intellegence and quality of dietary treatment in phenylketonuria. Archives of the Disabled Child, 65, 472-478.

Smith, I., Beasley, M. G., Wolff, O. H. & Ades, A. E. (1988). Behavior disturbance in 8-year-old children with early treated phenylketonuria. The Journal of Pediatrics, March, 403-408.

*Smith, M. L., Hanley, W. B.M. Clarke, J. T. R., Kim, P., Schoonheyt, W., Austin, V., & Lehotay, D. C. (1998). Randomised controlled trial of tyrosine supplementation on neuropsychological performance in phenylketonuria. Archives Dis Child, 78, 116-121.

*St. James, P. J., Younger, M. D., Hamilton, B. D. & Waisbren, S. E. (1993). Unplanned pregnancies in young women with diabetes. Diabetes Care, 16, 1572-1578.

*St. James, P. S., Shapiro, E., & Waisbren, S. E. (1999). The resource mothers program for maternal phenylketonuria. American Journal of Public Health, 89 (5), 762-764.

Stanbury, Wyndgaarden, & Friedrickson, 1983.), The Metabolic Basis of Inherited Disease (2 nd edition). New York: McGraw-Hill.

*Stemerdink, B. A., van der Molen, M. W., Kalverboer, A. F., van der Meere, J. J., Hendrikx, M. M. T., Huisman, J., van der Schot, L. W. A. & Slijper, F. M. E. (1994). Information processing deficits in children with early and continuously treated phenylketonuria. Acta Paedeatr Suppl, 407, 106-107.

*Stemerdink, B. A., van der Meere, J. J., van der Molen, M. W., Kalverboer, A. F., Hendrikx, M. M. T., Huisman, J., van der Schot, L. W. A., Lijper, F. M. E., van Spronsen, F. J. & Verkerk, P. H. (1995). Information processing in patients with early and continously-treated phenylketonuria. European Journal of Pediatrics, 154, 739-746.

Thompson, A. J., Smith, I., Brenton, D., Youl, B. D., Rylance, G., Davidson, D. D., Kendall, B. & Lees, A. J. (1990). Neurological deterioration in young adults with phenylketonuria. The Lancet, 336, 602-605.

Thompson, A. J., Tillotson, S., Smith, I., Kendall, B., Moore, S. G. & Brenton, D. P. (1993). Brain MRI changes in phenylketonuria. Brain, 116, 811-821.

Tice, K. S., Wenz, E., Jew, K. & Koch, R. (1980). Reproductive counseling for adolescent females with phenylketonuria. Journal of Inherited Metabolic Disorders, 3, 105-107.

*Trefz, F. K., Batzler, U., Konig, T., Michel, U., Schmidt, E., Schmidt, H. & Bickel, H. (1990). Significance of the in vivo deuterated phenylalanine load for long-term phenylalanine tolerance and psychointellectual outcome in patients with PKU. European Journal of Pediatrics, 149 (Suppl 1), S25-S27.

*Ullrich, K., Moller, H., Weglage, J., Schuierer, G., Bick, U., Ludolph, A., Hahn-Ullrich, H., Funders, B. & Koch, H. G. (1994). White matter abnormalities in phenylketonuria: results of magnetic resonance measurements. Acta Paediatr Suppl, 407, 78-82.

*Ullrich, K., Weglage, J., Oberwittler, C., Pietsch, M., Funders, B., van Echkhardstein, H. & Colombo, J. P. (1994). Effect of L-DOPA on pattern visual evoked potentials (P-100) and neuropsychological tests in untreated adult patients with phenylketonuria. Journal of Inherited Metabolic Disorders, 17, 349-352.

*Ullrich, K., Weglage, J., Oberwittler, C., Pietsch, M., Funders, B., van Echkhardstein, H. & Colombo, J. P. (1996). Effect of L-dopa on visual evoked potentials and neuropsychological tests in adult phenylketonuria patients. European Journal of Pediatrics, 155 (Suppl 1), S74-S77.

*Van der Schot, L. W., Doesburg, W. H. & Sengers, R. C. A. (1994). The phenylalanine response curve in relation to growth and mental development in the first years of life. Acta Paediatr Suppl, 407, 68-69.

Waisbren, S.E., Schnell, R.R., & Levy, H.L. (1980). Diet termination in children with phenylketonuria: A review of psychological assessments used to determine outcome. Journal of Inherited Metabolic Disease, 3, 149-153.

*Waisbren, S. E., Mahon, B. E., Schnell, R. R. & Levy, H. L. (1987). Pediatrics, 79, 351-355.

*Waisbren, S. E. & Levy, H. L. (1991). Agoraphobia in phenylketonuria. Journal of Inherited Metabolic Disorders, 14, 755-764.

*Waisbren, S. E., Shiloh, S., St.James, P. & Levy, H. L. (1991). Psychosocial factors in maternal phenylketonuria: prevention of unplanned pregnancies. American Journal of Public Health, 81, 299-304.

*Waisbren, S. E. & Zaff, J. (1994). Personality disorder in young women with treated phenylketonuria. Journal of Inherited Metabolic Disorders, 17, 584-592.

Waisbren, S. E., Hamilton, B. D., St. James, P. J., Shiloh, S. & Levy, H. L. (1995). Psychosocial factors in maternal phenylketonuria: women’s adherence to medical recommendations. American Journal of Public Health, 85, 1636-1641.

*Weglage, J., Funders, B., Wilken, B., Schubert, D., Schmidt, E., Burgard, P. & Ullrich, K. (1992). Psychological and social findings in adolescents with phenylketonuria. European Journal of Pediatrics, 151, 522-525.

*Weglage, J., Funders, B., Wilken, B., Schubert, D. & Ullrich, K. (1993). School performance and intellectual outcome in adolescents with phenylketonuria. Acta Paediatr, 81, 582-586.

Weglage, J., Rupp, A., & Schimdt, E. (1994). Personality characteristics in patients with phenylketonuria treated early. Pediatric Research, 35 (5), 611-613.

*Weglage, J. Pietsch, M. Funders, B., Koch, H. G. & Ullrich, K. (1995). Neurlogical findings in early treated phenylketonuria. Acta Paediatr, 84, 411-415.

*Weglage, J., Pietsch, M., Funders, B., Koch, H. G. & Ullrich, K. (1996). Deficits in selective and sustained attention processes in early treated children with phenylketonuria-result of impaired frontal lobe functions. European Journal of Pediatrics, 155, 200-204.

Weglage, J., Wiedermann, D., Moller, H. & Ullrich, K. (1998). Pathogenesis of different clinical outcomes in spite of identical genotypes and comparable blood phenylalanine concentrations in phenylketonurias. Journal of Inherited Metabolic Disorders, 21, 181-182.

*Welsh, M. C., Pennington, B. F., Ozonoff, S., Rouse, B. & McCabe, E. R. B. (1990). Neuropsychology of early-treated phenylketonuria: specific executive function deficits. Child Development, 61, 1697-1713.

Welsh, M.C. (1996). A prefrontal dysfunction model of early-treated phenylketonuria. European Journal of Pediatrics, 155 [Supplement 1], S87-S89.

Welsh, M.C., & Pennington, B.F. (2000). Phenylketonuria. K.O. Yeates, M.D. Ris, H.G. Taylor (Eds.), Pediatric Neuropsychology: Research, Theory and Practice (275-299). New York: Guilford.

*Williamson, M. L., Koch, R., Azen, C. & Chang, C. (1981). Correlates of intelligence test results in treated phenylketonuric children. Pediatrics, 68, 161-167.

*Zeman, J., Pijackova, A., Behulova, J., Urge, O., Saligova, D. & Hyanek, J. (1996). Intellectual and school performance in adolescents with phenylketonuria according to their dietary compliance. European Journal of Pediatrics,, 155 (Suppl 1), S56-S58.

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Last Updated Date: 08/29/2006
Last Reviewed Date: 08/29/2006
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