Emotional Outcome of Adolescents and Young Adults With Early and Continuously Treated Phenylketonuria

Transcription

1 Journal of Pediatric Psychology, Vol. 26, No. 8, 2001, pp Emotional Outcome of Adolescents and Young Adults With Early and Continuously Treated Phenylketonuria Jill E. Sullivan, PhD University of Minnesota Objective: To assess the emotional functioning of adolescents and young adults with early and consistently treated phenylketonuria (PKU). Methods: Twenty PKU-affected participants, ages 14 25, were compared with age-matched chronically ill (n 17) and peer (n 16) controls on a structured clinical interview, the Minnesota Multiphasic Personality Inventory, and the Tennessee Self-Concept Scale-2. Affected participants and nonparticipants were assessed using a multidomain assessment of functioning interview. Results: There were no significant differences between groups for observable psychiatric disorders or emotional and functional symptoms. No significant differences were found in self-concept. Although there were no differences between groups for IQ or treatment variables, PKU-affected participants were more likely than nonparticipants to have sought help for psychological concerns. Conclusions: Results suggest that early-treated PKU-affected adolescents and young adults do not show a higher risk for psychological disturbance than appropriate controls. Key words: phenylketonuria; PKU; metabolic disorder; chronic illness; cystic fibrosis; juvenile onset diabetes; asthma; adolescents; young adults; emotional functioning; behavioral functioning. Phenylketonuria (PKU), an autosomal recessive disorder with an incidence rate of 1:10 20,000, is caused by the absence or inactivity of phenylalanine hydroxylase, the enzyme that converts the amino acid phenylalanine to tyrosine. Management of PKU requires an individually tailored diet of foods low in phenylalanine and supplementation of the essential nutrients the body cannot produce. Routine screening of newborns and the widespread initiation of dietary treatment within the first 3 months of life have essentially eliminated the se- All correspondence should be sent to Jill E. Sullivan, Northwestern Memorial Hospital, Outpatient Treatment Center, 222 East Superior, 4th Floor, Chicago, Illinois jzsulliv@nmh.org. vere, irreversible cognitive deficits and psychiatric disturbance associated with untreated PKU. In accordance with standard medical practices, PKU-affected individuals who began receiving treatment before 1980 typically discontinued the diet between ages 6 and 8. Many studies of early-treated, off-diet PKU-affected individuals, including participants ages 6 to 35, converge upon characteristics of attention deficit-hyperactivity disorder (Chang & Fisch, 1976; Fisch, Sines, & Chang, 1981; Realmuto et al., 1986; Schor, 1986; Smith, Beasley, Wolff, & Ades, 1988; Waisbren & Zaff, 1994). Psychiatric disorders within the depression and anxiety spectrums (Fisch et al., 1995; Realmuto et al., 1986; Wais Society of Pediatric Psychology

2 478 Sullivan bren & Levy, 1991) and internalizing symptoms (Pietz et al., 1997) have been documented and corroborated by studies using the Minnesota Multiphasic Personality Inventory (MMPI) (Fisch et al., 1981; Waisbren & Zaff, 1994). Low self-confidence, social maturity deficits, and poor interpersonal relationships have been widely reported (Chang & Fisch, 1976; Fisch et al., 1981; Matthews, Barabas, Cusak, & Ferrari, 1986; Smith et al., 1988; Waisbren & Zaff, 1994), indicating an overall association between the absence of phenylalanine (phe) restriction and emotional dysfunction (Smith et al., 1988). Intellectual outcome depends on adequate phe control during the first 8 to 10 years of life. Because the effects of toxic elevations of phe after this time are unknown, many treatment clinics now advise patients to maintain the restricted diet throughout their lives. Preliminary research indicates that patients treated early and strictly do not show a higher incidence of psychological maladjustment than healthy controls before age 13 (Griffiths, Tarrini, & Robinson, 1997; Weglage, Rupp, & Schmidt, 1994). However, research with older adolescents corroborates indications of negative self-image, social withdrawal, low frustration tolerance (Weglage et al., 1992), distractibility, problems with peers, and a significantly higher rate of moderately severe psychiatric symptoms compared to age-matched controls (Burgard, Armbruster, Schmidt, & Rupp, 1994). If these formulations are correct and if, despite treatment, serum phe continues to affect cerebral functioning, then individuals with PKU would be expected to exhibit more emotional and behavioral disturbance than normal controls. In fact, only 5 of the 17 studies conducted to date included a normative comparison group. Therefore, research still needs to address whether the emotional adjustment of individuals with treated PKU differs significantly from that of peer controls. It also is important to consider the psychosocial effects of chronic illness on emotional development. Data regarding the relationship between chronic illness and psychological adjustment have been equivocal (see review by Wallander, Varni, Babani, Banis, & Wilcox, 1988). Recent research has focused on chronic illness as a psychosocial stressor rather than a pathognomonic diathesis for emotional and behavioral difficulties. Chronic illnesses vary greatly in biochemical and physical consequences but may produce similar psychosocial sequelae, particularly diminished self-concept (Seigel, Golden, Gough, Lashley, & Sacker, 1990). By comparing PKU-affected participants to those with other chronic illnesses, one can examine the issue of whether emotional outcome is illness-specific. A single study to date has attempted this type of analysis, finding a significant difference between PKUaffected and diabetic patients on a measure of agoraphobia (Waisbren & Levy, 1991). This investigation was designed to examine the quality and pattern of emotional adjustment in early and consistently treated adolescents and young adults with PKU in comparison to agematched peers and chronically ill controls. This comparison group was included to further empirical exploration of illness-specific emotional and functional sequelae. A third goal of this research involved attention to methodological issues that have limited the conclusions drawn from previous studies. According to the recommendations outlined in Sullivan and Chang (1999), this protocol included a proband group that was homogeneous for the diagnosis of classical PKU, onset and length of dietary treatment, and adequacy of phenylalanine control; controlled for IQ; and used age-appropriate, standardized measures that assess the clinical features suggested by previous research and allow comparisons across studies. In comparison to the other groups, probands were expected to show more observable psychiatric disorders and emotional or functional symptoms (i.e., significantly more psychiatric symptoms and clinical diagnoses, as well as clinically significant elevations on a measure of personality and current symptomatology). Both probands and chronically ill controls were expected to differ significantly from healthy peers with regard to self-concept. Method Participants The institutional review board of the University of Minnesota fully approved the protocol of this investigation. Master lists from the PKU Clinic at Fairview University Medical Center were reviewed to identify patients years old with early-treated, classical PKU. Because psychiatric disorder is known to be more common in children and adolescents with intellectual disability (Einfeld & Tonge, 1996), potential participants were selected on the basis of

3 Emotional Outcomes in Early-Treated PKU 479 Table I. Demographic Data PKU nonparticipants PKU participants Chronically ill Peers Characteristic (n 12) (n 20) (n 17) (n 16) Males Females Age Education 12 years High school Some college College Most recent mean phe level mg/dl mg/dl (range: ) (range: ) Age at onset of treatment days days (range: 10 23) (range: 3 90) Duration of treatment years years (range: 6 23) (range: 5 21) % Maintaining treatment 58.3% (n 7) 80% (n 16) having previously measured IQs within the normal range (i.e., 80). These inclusion criteria yielded 38 potential participants with current address information. Two comparison groups were recruited, including a group of age-matched controls with other chronic illnesses. Each of the chronic illnesses represented in this study, including PKU, is genetically determined and not eminently terminal, demands daily compliance with dietary/medical therapies and frequent visits to specialty clinics, and may involve problems managing treatment. This chronically ill control group (n 17) was composed of patients with cystic fibrosis (n 6) and juvenile onset diabetes (n 4) from the Pediatric Pulmonary and the Pediatric Endocrinology Clinics at Fairview University Medical Center and asthmatic patients (n 7) from the Pulmonology Clinic at Children s Health Care in St. Paul, MN. Probands and chronically ill controls recruited same-sex, age-matched peer controls (n 16) without histories of chronic illness. Because PKU is genetically determined, comparisons to family members provide a unique context for the examination of long-term outcomes. Sibling controls [n 6] were recruited through the 21 participants with one or more unaffected full siblings between the ages of 14 and 25 years. Results for this group have not been included as they are considered to be highly tentative due to sample size. All families initially were contacted by letters sent to their last known address. Letters for peer controls were enclosed. Patients who did not wish to be recruited were asked to contact investigators either by telephone or pre-stamped postcards. The remaining patients were contacted by telephone to further explain the purpose of the study and schedule visits. Recruitment was complicated by the fact that many families were currently living some distance from the study site (e.g., out of state or in Canada). Of the initial pool of 38 eligible probands, 52.6% participated. Nine probands did not attend their scheduled appointments, even when multiple visits were scheduled, and nine probands refused to participate. Of the 78 eligible chronically ill patients, 21.8% participated. Eleven patients failed to attend their scheduled visits and 50 potential participants refused to participate. Demographic characteristics are presented in Table I. PKU probands and controls were nearly evenly distributed across gender, age, and educational levels. Groups also were similar with respect to marital, employment, and socioeconomic status (SES). Participants were predominantly Caucasian, single, and either full-time students or employed full-time. Participants reported personal income if financially independent; otherwise, parental income was used. Median annual parental income was $40,000 $50,000 for all groups. Median annual personal income was $20,000 $30,000 for all groups. Groups did not significantly differ demographically.

4 480 Sullivan Materials The presence or absence of current and lifetime clinical diagnoses, as well as the frequency and severity of cumulative psychiatric symptoms that correspond to DSM-IV diagnostic criteria, were assessed using portions of an age-appropriate, standardized diagnostic interview. Subthreshold diagnoses (i.e., all established criteria were met, but clinically significant impairment was not present in an important area of functioning) also were considered. Participants years old were administered the Diagnostic Interview for Children and Adolescents Revised Adolescent Version for DSM-IV (DICA-R-A; Reich, Leacock, & Shanfeld, 1995). Participants years old were administered the Structured Clinical Interview for Axis I DSM-IV Disorders Nonpatient Version (SCID-NP; First, Spitzer, Gibbon, & Williams, 1994), as well as portions of the DICA-R-A to assess past symptoms and diagnoses of disorders usually first diagnosed in childhood. Participants were administered all of the items from the standard scales of the age-appropriate version of the MMPI-A (Butcher et al., 1992) or MMPI- 2 (Butcher, Dahlstrom, Graham, Tellegen, & Kaemmer, 1989), as a measure of personality and current emotional and functional symptoms. Raw scores were converted to T-scores (M 50, SD 10); T- scores 65 are considered clinically significant. Each profile was scored by National Computer Systems (NCS) in Minneapolis. The Tennessee Self-Concept Scale 2 (TSCS:2) is an 82-item self-rating scale designed to assess how one feels about himself or herself, which can be administered to individuals ages who can read at a third-grade level (Fitts & Warren, 1996). Sample items include I am satisfied to be just what I am and I get along well with other people. Raw scores were converted to T-scores (M 50, SD 10); T-scores 40 indicate significant disturbances in self-concept. Each questionnaire was scored with carbonized sheets. Proband participants and nonparticipants who could be reached by telephone were administered a semistructured interview developed for this project. Probands were asked a total of 23 questions, providing a brief assessment of self-reported psychiatric treatment; lifetime episodes of perceived clinically significant impairment of social, occupational, and academic functioning; and psychosocial and environmental problems. Content was based on those areas delineated as DSM-IV Axis IV categories (e.g., problems with primary support group, educational problems, legal difficulties, and economic problems). Sample items included, Have you ever been treated by a psychologist, psychiatrist, or other professional counselor? and Has there ever been a period of time when you were unable to work or go to school? Participants were asked to report their age at and details surrounding these events. Items were rated dichotomously. Using a 3-point scale (i.e., more often, less often, or about as often), probands also were asked to rate frequency relative to peers of illness, of visits to the doctor, and of important activities missed due to illness, and to rate their perception of their overall health relative to peers using a 5-point scale (i.e., extremely poor to much better than). Procedure All individuals were assessed on an outpatient basis between January 1997 and May 1998 during one 4-hour session. Minors were accompanied by their parents; written informed consent and/or assent was obtained at that time. All tests were administered according to standard instructions. Although this study primarily was designed to address emotional outcome in early-treated PKU, each participant also completed a computerized neuropsychological battery. Cognitive testing took place during either the first or second hour of the assessment; these data will not be reported here (Luciana, Sullivan, & Nelson, in press). Chart review of medical records of PKU probands was utilized to obtain IQ scores from each participant s most recent neuropsychological assessment and the most recently collected serum phe levels. As these data are collected routinely by the treating clinic, this investigation did not include direct assessment of current IQ. The average IQ obtained (M , SD 11.33) was not significantly different from that of the normal population (M 100, SD 15). Seventy percent (n 14) of the PKU probands had serum phe measured within a year of this investigation; the correlation between the most recent levels and averages for the preceding five years was r.75. Phenylalanine and treatment data are presented in Table I. To assess for possible self-selection bias among probands, each PKU-affected patient who met inclusion criteria was re-contacted by phone once data collection was completed. Verbal consent or assent was obtained, following a review of standard

5 Emotional Outcomes in Early-Treated PKU 481 Table II. Mean Number of Psychiatric Symptoms and Diagnoses by Group Chronically PKU ill Peers Variable M (SD) M (SD) M (SD) F p Subthreshold symptoms 1.6 (1.5) 1.4 (1.9) 1.25 (1.29) Threshold symptoms 5.7 (6.98) 5.24 (7.4) 7.25 (9.58) Subthreshold diagnoses.30 (.57).12 (.33).25 (.45) Full diagnoses.20 (.52).12 (.49).44 (1.03) Combined diagnoses.50 (.89).24 (.75).69 (1.25) Table III. number of full psychiatric symptoms, subthreshold symptoms, full psychiatric diagnoses, subthreshold diagnoses, or the total number of combined diagnoses (i.e., full and subthreshold). The means and standard deviations obtained by each group on the MMPI-2/A are presented in Table III. All scores were within normal range. Statistically, groups were indistinguishable and no specific trends were observed. The percentage of participants obtaining clinically significant scores on at least one scale was similar for the PKU (35%), chronically ill (41.2%), and peer (25%) groups, ( 2 [2, n 53].977, p.614). These results do not support the hypothesis that probands would show more observable psychiatric disorders and emotional or functional symptoms than chronically ill and peer controls. Though groups did not differ in cumulative and discrete psychiatric symptomatology, significantly more of the chronically ill groups had sought help for psychological concerns. Compared to none of the peer controls, 40% of the PKU-affected participants and 50% of the chronically ill participants, ( 2 [2, n 53] , p.01), reported that they had received services from a psychologist, psychiaconsent issues. Demographic information and general adjustment data were provided, and chart reviews of IQ and treatment data were completed for 66.7% (n 12) of those who declined to complete the full protocol. Data were analyzed using SPSS for Windows, version Chi-square analyses on nominal data and analyses of variance (ANOVAs) on continuous interval data were conducted to ascertain significant between-group differences. When group differences were found, post hoc comparisons using Tukey s LSD were conducted. To reduce the risk of Type I errors resulting from multiple comparisons, observed significance levels of p.01 were considered to be significant; observed significance levels of p.05 are discussed as trends. Results Means and Standard Deviations on the MMPI-2/A PKU Chronically ill Peers Scale M (SD) M (SD) M (SD) F p Hs (8.49) (11.74) (10.86) D (11.67) (10.54) (7.29) Hy (6.82) (13.52) (10.29) Pd (8.30) (10.25) (9.30) Mf (11.21) (9.94) (11.60) Pa (9.10) (17.00) (12.21) Pt (11.15) (13.03) (11.82) Sc (10.58) (18.17) (13.11) Ma (7.81) (10.75) (12.32) Si (11.87) (12.10) (11.15) Total number elevations (1.23) 1.12 (2.21) 0.75 (1.73) Cumulative and Discrete Psychiatric Symptomatology As shown in Table II, ANOVAs found no statistically significant differences between groups for the mean

6 482 Sullivan Table IV. Means and Standard Deviations on the TSC:2 PKU Chronically ill Peers Scale M (SD) M (SD) M (SD) F p Total (11.59) (11.67) (12.23) Conflict (10.80) a (9.17) (8.79) Physical (7.19) (12.83) (10.63) Moral (8.83) (11.53) (11.28) Personal (10.06) (11.99) (9.44) Family (9.12) (12.28) (11.91) Social (8.18) (11.63) (11.65) Academic (10.96) (8.66) (9.80) Identity (9.07) (11.17) (12.57) Satisfaction (9.01) (11.40) (10.44) Behavior (8.11) (11.14) (12.53) Critical items 1.00 (1.84) 1.24 (2.73) 1.13 (1.86) Total number of elevations (2.24) 1.47 (2.43) 1.50 (2.34) a Using.01, the average score of the chronically ill group was nearly significantly different than that of the PKU group at p.05. trist, or other professional counselor. These services included individual and family treatment, as well as psychiatric evaluations that were not a component of routine illness-related evaluations or participation in research projects. Self-Concept PKU-affected participants achieved a mean T-score of for total self-concept, which was not significantly different from that for comparison groups. Mean scores are shown in Table IV. The conflict score for the chronically ill group was nearly significantly lower than the PKU group (p.05), indicating a defensive tendency for chronically ill participants to define themselves in terms of negation rather than assertion. No significant differences were found between groups on individual self-concept scales, supplementary scales, the number of critical items endorsed, or the number of scale scores falling in the clinically significant range. Only 20% of the PKU group, 11.8% of the chronically ill group, and 18.75% of peers obtained total scores indicating clinically significant deficits in self-concept, ( 2 [2, n 53].493, p.782). These results do not support the hypothesis that PKU-affected and other chronically ill participants would differ significantly from healthy peers with regard to self-concept. Participant Representativeness Possible self-selection bias among probands was assessed with data from 80% (n 16) of the PKUaffected participants and 66.7% (n 12) of the nonparticipants. The average IQ of nonparticipants ( ) did not significantly differ from that of participants, and there were no differences between groups for average phe level, age at onset of dietary treatment, duration of dietary treatment, or current treatment compliance. Trend analyses revealed that, while all of the initial participants who were available for follow-up were actively participating with the treating clinic, 25% of nonparticipants were not, ( 2 [1, n 28] 4.48, p.05). Participants and nonparticipants did not differ with regard to self-reported incidents of impaired self-care, problems related to peer groups, educational difficulties, occupational problems, financial difficulties, or interactions with the legal system. Despite being indistinguishable demographically and with regard to important treatment variables, half of the participants reported having received individual or family treatment, ( 2 [1, n 28] 8.40, p.01), compared to none of the nonparticipants. However, affected groups did not report significantly different rates of social, academic, or occupational impairment. When asked to rate their overall health relative to peers, 96.4% of all affected participants rated their health as the same as or somewhat better than most of their peers. There were no differences in perceptions of health between participants and nonparticipants with regard to frequency of illnesses, visits to the doctor, or activities missed due to illness. The results obtained are not consistent with selection bias toward healthier or higher functioning probands.

7 Emotional Outcomes in Early-Treated PKU 483 Discussion This study was designed to include use of standardized measures, control groups that were matched for age and gender, and a sample of probands that was homogeneous for IQ, age, and length of dietary treatment, thus addressing methodological problems that have limited the validity of results from previous investigations. The results obtained indicate that early-treated PKU-affected adolescents and young adults, ages 14 to 25, were not at increased risk for diagnosable psychiatric disorders, clinically significant impairment on the MMPI-2/A, or deficits in self-concept. Neither did other chronically ill adolescents and young adults show greater deficits in self-concept compared to healthy controls. The only difference obtained between the PKU-affected and chronically ill groups indicated a defensive tendency for chronically ill participants to define themselves in terms of negation rather than assertion on the TSC:2, whereas PKU-affected participants typically presented a balanced self-description. Thus, the overall pattern and quality of observed emotional adjustment do not appear to be illness-specific. These data do not disregard the conceptualization of chronic illness as a stressor; however, chronic conditions do not preclude healthy emotional adjustment. In fact, high percentages of both the PKU-affected and chronically ill groups were attending school or employed full-time, maintained a positive view of their appearance and health status, defined themselves as broadly competent, and viewed themselves in generally positive ways. Despite these competencies, 40% of the PKUaffected participants and 50% of the chronically ill group reported that they had sought help for psychological concerns, though these data indicate that they apparently were not treated for symptomatology meeting full criteria for psychiatric diagnosis. Given that none of the PKU-affected nonparticipants reported receiving these services, the proband sample may have been composed of those patients who had a stronger interest in psychological issues or those who had been assisted by the treating clinic to a greater degree. The consistency between the results from structured interviews and the MMPI-2/A, which measured overall emotional and psychological functioning, and the semistructured interview that assessed psychosocial and health-related problems, suggests that the interview was a valid measurement tool for obtaining information that was not otherwise available from nonparticipants. Although some is known about the nonparticipants from the PKU group, little is known about the chronically ill patients who declined to participate. These patients generally were unwilling to participate with a lengthy assessment battery when they received no direct benefits or perceived benefits for their own treatment, had no personal connection with research personnel, and regularly participate in treatment-related assessments. These factors indicate the need for collaborative studies across treatment clinics with standardized, longitudinal protocols. Overall, these data are consistent with current research converging upon a profile of normal emotional adjustment in chronically ill groups. Negative results with regard to the incidence of significant psychological impairment in PKU probands seem to suggest that early and continuous dietary treatment has a protective effect. However, given that PKU is a chronic, developmental disorder, and the adequacy of phe control decreases throughout the life span, disturbances in emotional and behavioral functioning may develop as these adolescents and young adults continue to mature and negotiate developmental demands. Collaborative strategies geared toward prevention and treatment across the life span should include ongoing contact with clinicians for neuropsychological testing, assessment of psychosocial functioning, anticipation of significant events (e.g., worsening of clinical status, transitions in education, and unexpected pregnancy), and to serve as a conduit to forms of intervention (e.g., individual counseling or family therapy). Follow-up studies of adult adjustment will be a priority for elucidating the impact of long-term phenylalanine control and illness-related stress on emotional, behavioral, and personality development. Acknowledgments Jill E. Sullivan is now at Northwestern Memorial Hospital. These data served as the basis for this author s doctoral dissertation. This research was supported by a grant from the PKU Foundation at the University of Minnesota. Received February 16, 2000; revisions received August 23, 2000, and November 20, 2000; accepted December 21, 2000

8 484 Sullivan References 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 Paediatrica, 407(suppl.), Butcher, J. N., Dahlstrom, W. G., Graham, J. R., Tellegen, A., & Kaemmer, B. (1989). Minnesota Multiphasic Personality Inventory-2 (MMPI-2): Manual for administration and scoring. Minneapolis: University of Minnesota Press. Butcher, J. N., Williams, C. L., Graham, J. R., Archer, R., Tellegen, A., Ben-Porath, Y. S., & Kaemmer, B. (1992). Minnesota Multiphasic Personality Inventory-Adolescent (MMPI-A): Manual for administration, scoring, and interpretation. Minneapolis: University of Minnesota Press. Chang, P., & Fisch, R. O. (1976). Observation of behavioral and personality characteristics of phenylketonurics according to their dietary duration: Early treatment and normal intelligence. Psychological Reports, 39, Einfeld, S., & Tonge, B. J. (1996). Population prevalence of psychopathology in children and adolescents with intellectual disability: II: Epidemiological findings. Journal of Intellectual Disability Research, 40(2), First, M. B., Spitzer, R. L., Gibbon, M., & Williams, J. B. W. (1994). Structured clinical interview for Axis I DSM-IV disorders. New York: New York State Psychiatric Institute, Biometrics Research Department. 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, Fisch, R. O., Sines, L. K., & Chang, P. (1981). Personality characteristics of nonretarded phenylketonurics and their family members. Journal of Clinical Psychiatry, 42(3), Fitts, W. H., & Warren, W. L. (1996). Tennessee Self-Concept Scale (TSCS:2). Los Angeles: Western Psychological Services. 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(4), Luciana, M., Sullivan, J., & Nelson, C. A. (in press). Individual differences in phenylalanine levels moderate performance on tests of executive function in adolescents and young adults treated early and continuously for PKU. Child Development. Matthews, W. S., Barabas, G., Cusack, E., & Ferrari, M. (1986). Social quotients of children with phenylketonuria before and after discontinuation of dietary treatment. American Journal of Mental Deficiency, 91(1), Pietz, J., Fatkenheuer, B., Burgard, P., Armbruster, M., Esser, G., & Schmidt, H. (1997). Psychiatric disorders in adult patients with early-treated phenylketonuria. Pediatrics, 99(3), Realmuto, G. M., Garfinkel, B. D., Tuchman, M., Tsai, M., Chang, P., Fisch, R. O., & Shapiro, S. (1986). Psychiatric diagnosis and behavioral characteristics of phenylketonuric children. Journal of Nervous and Mental Disease, 174(9), Reich, W., Leacock, N., & Shanfeld, K. (1995). Diagnostic Interview for Children and Adolescents Revised-Adolescent Version (DICA-R-A). St. Louis: University of Washington. Schor, D. P. (1986). Phenylketonuria and temperament in middle childhood. Children s Health Care, 14(3), Seigel, W. M., Golden, N. H., Gough, J. W., Lashley, M. S., & Sacker, I. M. (1990). Depression, self-esteem, and life events in adolescents with chronic diseases. Journal of Adolescent Health Care, 11, Smith, I., Beasley, M. G., Wolff, O. H., & Ades, A. E. (1988). Behavior disturbance in 8-year-old children with early treated phenylketonuria. Journal of Pediatrics, 112(3), Stevenson, J. E., Hawcroft, J., Lobascher, M., Smith, I., Wolff, O. H., & Graham, P. J. (1979). Behavioural deviance in children with early treated phenylketonuria. Archives of Disease in Childhood, 54, Sullivan, J. E., & Chang, P. (1999). Review: Emotional and behavioral functioning in phenylketonuria. Journal of Pediatric Psychology, 24(3), Waisbren, S. E., & Levy, H. L. (1991). Agoraphobia in phenylketonuria. Journal of Inherited Metabolic Disease, 14, Waisbren, S. E., & Zaff, J. (1994). Personality disorder in young women with treated phenylketonuria. Journal of Inherited Metabolic Disease, 17, Wallander, J. L., Varni, J. W., Babani, L., Banis, H. T., & Wilcox, K. T. (1988). Children with chronic physical disorders: Maternal reports of their psychological adjustment. Journal of Pediatric Psychology, 13(2), 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, Weglage, J., Rupp, A., & Schmidt, E. (1994). Personality characteristics in patients with phenylketonuria treated early. Pediatric Research, 35(5),