Download emotional and behavioral functioning in phenylketonuria.

Journal of Pediatric Psychology, Vol. 24, No. 3, 1999, pp. 281–299
Review: Emotional and Behavioral
Functioning in Phenylketonuria
Jill E. Sullivan,1 BA, and PiNian Chang,2 PhD
1
University of Minnesota and 2Fairview University Medical Center
Objective: To examine 17 studies of the psychological sequelae of early-treated phenylketonuria (PKU) with
emphasis on the impact of dietary control on functioning. Two questions are addressed: (1) What is the typical psychological profile associated with PKU? (2) Is emotional and behavioral disturbance more prevalent
in PKU-affected individuals compared to appropriate controls?
Method: Computerized searches of PsycINFO identified studies using behavioral, personality, and diagnostic measures.
Results: Findings converge upon a profile including attentional difficulties, depression, anxiety, and low
self-esteem. Methodological constraints limit conclusions regarding the nature and severity of observed difficulties. A single study has used comparison groups appropriate for the simultaneous examination of the
questions posed (Waisbren and Levy, 1991).
Conclusions: We discuss results using a biopsychosocial framework, addressing the factors and processes
that may influence emotional and behavioral functioning in this neurodevelopmental disorder. We outline
potential lines of new investigation that address critical methodological factors.
Key words: phenylketonuria; PKU; psychopathology; emotional functioning; behavioral functioning; biopsychosocial; neurodevelopmental disorder; chronic illness.
Phenylketonuria (PKU), the first metabolic disorder
associated with severe mental retardation, was discovered by Dr. Asbørn Følling in 1934. This autosomal recessive metabolic disorder has an overall
incidence rate of 1:10,000–20,000 with a large degree of ethnic variation. This disorder, rare among
African Americans and Asians, is more prevalent
among people of Celtic and Central European descent (Armarego, Randles, & Waring, 1984).
Phenylketonuria is caused by the absence or inactivity of phenylalanine hydroxylase (PAH), the
All correspondence should be sent to Jill E. Sullivan, Northwestern
Memorial Hospital, Institute of Psychiatry, Outpatient Treatment Center,
446 East Ontario Street Suite 800, Chicago, Illinois 60611. E-mail:
[email protected].
q 1999 Society of Pediatric Psychology
enzyme that converts the amino acid phenylalanine to tyrosine. The conversion of phenylalanine
is important for the biogenesis of several neurotransmitters, including dopamine and serotonin,
and prevents the accumulation of metabolites, such
as phenylpyruvic acid (Barden, Kessel, & Schuett,
1984). Excess phenylalanine causes other amino
acids to become rate-limiting and competes with
the transport system by which other large amino
acids cross the blood brain barrier (“Why Does
Phenylalanine Do Harm in PKU?,” 1986). The accumulation of phenylalanine and its metabolites is believed to be toxic to the central nervous system. In
1963, the Guthrie bacterial inhibition assay was introduced for newborn screening, mandatory in 43
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states and available on a voluntary basis elsewhere
(Threseler, 1988). Most cases are identified at birth
by routine screening practices and are successfully
treated.
In 1951, Woolf and Vulliamy discovered that
serum phenylalanine levels responded to dietary
restriction of phenylalanine; this discovery was followed in 1954 by the introduction of treatment
with diets low in phenylalanine by Bickel et al.
(Scriver, 1994). High-protein foods, such as meat,
fish, poultry, eggs, and dairy products, are high in
phenylalanine and are not allowed in the PKU diet.
The only products that contain no phenylalanine
are sugar, oil, and pure starch. Trace amounts of
phenylalanine are necessary to ensure proper
growth. A restricted, vegetarian-like diet is designed
with a nutritionist to provide sources of protein
with little or no phenylalanine. Medical formulas,
such as Lofenalac, are used to supplement vitamins,
minerals, and the tyrosine that the body cannot
synthesize, while keeping serum levels of phenylalanine within the “safe range” of less than 10 mg/dL
(Castiglioni & Rouse, 1992). Blood tests and reviews
of diet records are conducted on a regular basis.
Since PAH activity varies from person to person, individualized treatment plans are based on dietary
intake, weight, and serum phenylalanine levels
(Castiglioni & Rouse, 1992).
Since the widespread initiation of dietary treatment, the severe, irreversible brain damage previously associated with untreated PKU has been
essentially eliminated. Treatment beginning within
days of birth results in better intellectual functioning and little clinical benefit if begun after age three
years (Sutherland, Umbarger, & Berry, 1966). Current recommendations advise that treatment be
continued indefinitely (Castiglioni & Rouse, 1992),
although most patients relax or discontinue the diet
during adolescence. Levy and Waisbren (1994) note
that treatment criteria applied in childhood are virtually unachievable after age 12. As age increases,
growth and protein synthesis decline; thus, a higher
percentage of ingested phenylalanine is left to be
metabolized and more will accumulate in an adolescent than in a small child. Furthermore, time
constraints, social pressure, dissatisfaction with
restrictions, and growing independence during adolescence challenge adherence to these recommendations (Levy & Waisbren, 1994).
Because the pathophysiological components of
PKU are well understood, a biopsychosocial model
addresses the range of factors and processes that
Sullivan and Chang
may influence functioning in this neurodevelopmental disorder. Consideration is given not only to
the impact of genetic susceptibility, neurological
development, and disruptions in neurophysiological functioning but also to the bi-directional and
dynamic influences of temperament and personality factors, cognitive abilities, environmental
events, and the impact of specific stressors at critical
periods of development (Gottlieb, 1992). Further
consideration is given to the active role each individual takes in his or her own development, including adherence to dietary treatment, preferred
coping responses, social relationships, and nicheseeking.
Mental retardation and specific intellectual impairments have been the primary focus of research
involving PKU (see review by Waisbren, Brown, de
Sonneville, & Levy, 1994). Clinicians also have recognized the importance of investigating the neurotoxic effects of phenylalanine and the quality of
dietary control on behavioral disturbances associated with PKU. However, two important questions
remain: (1) What is the typical psychological profile
associated with PKU? (2) Is concomitant emotional
and behavioral disturbance more prevalent in individuals with PKU compared to appropriate control
groups?
We obtained literature from searches in PsycINFO of “phenylketonuria” and the following
key words: “mental disorder,” “psychopathology,”
“emotional functioning,” “behavioral functioning,” and “personality.” These searches identified
studies that utilized such measures as behavior rating scales, diagnostic assessments, and personality
inventories. We obtained additional references from
the individual articles reviewed. A total of 38 studies
were identified. We excluded case studies, literature
from foreign journals, research prior to 1975, studies of late-treated or untreated PKU, dissertation abstracts, and articles that discussed but did not assess
PKU-affected samples. As this review focuses on individual functioning following sustained changes
in dietary status, family studies and investigations
of short-term phenylalanine challenges also were
excluded. In all, 17 studies were reviewed.
Because this article spans research over the past
20 years, the nomenclature used in some investigations is no longer consistent with current thinking
on the psychological functioning of individuals
with chronic illnesses. Sensitive to the impact of labeling and historic focus on “deviance,” current
ideology has shifted toward an emphasis on the
Emotional and Behavioral Functioning in PKU
continuum between normality and abnormality.
While many of the studies obtained could be identified as investigations of concomitant psychopathology, “difference” (e.g., dimensional differences in
tendencies, characteristics, and quality of functioning) will be emphasized throughout this review.
Emotional and Behavioral Functioning
Before the widespread use of infant screening, patients with untreated PKU often exhibited severe
behavioral disturbances in addition to mental retardation; these disturbances included psychotic, autistic, and aggressive disorders (Wood, Friedman, &
Steisel, 1967). Affective lability, hyperkinesis, erratic
behavior, severe temper tantrums, and irritability
also were reported (Bjornson, 1964; Hackney, Hanley, Davidson, & Lindsao, 1968; Jervis, 1954; Koch,
Fishler, Schild, & Ragsdale, 1964; Wright & Tarjan,
1957). Although untreated PKU appeared to be associated with severe psychiatric disturbance, the diagnosis of comorbid mental disorder is complicated
by the presence of severe mental retardation, sensorimotor deficits, and impaired social and communication skills that may predispose these individuals
to aggressive, disruptive, or autistic-like behaviors.
Since the initiation of dietary treatment, psychotic and autistic symptomatology is no longer believed to characterize individuals with PKU. Before
1980, dietary treatment typically was discontinued
prior to the school years. Because it is difficult to
adhere to the restrictive diet and because early,
short-term follow-up studies did not show intellectual deterioration following diet discontinuation (Holtzman, Welcher, & Mellits, 1975; Kang,
Sollee, & Gerald, 1970; Koch, Azen, Friedman, &
Williamson, 1982), it was believed to be safe to terminate the diet after the age of 6 years. However,
since PKU is a metabolic disorder, effects following
diet discontinuation may be manifest not only in
changes in cognitive abilities but also in other kinds
of functioning. Therefore, it is important to examine findings related to emotional and behavioral
functioning in PKU-affected individuals who were
treated early, but discontinued dietary treatment.
Emotional and Behavioral Functioning in
Early-Treated, Diet-Discontinued Individuals
Behavior Rating Scales. Matthews, Barabas, Cusack,
and Ferrari (1986) reviewed the records of 16 chil-
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dren with early-treated PKU. The mean age at loss
of dietary control was 5.92 years. Scores on a measure of social competency, the Vineland Social Maturity Scale (Doll, 1965), were compared before and
after discontinuation of the diet. Mean phenylalanine levels and social quotients were measured
twice before diet discontinuation. The social quotients of half of the subjects fell in the aboveaverage range (Time 1, M 5 109.1; Time 2, M 5
110.5). Social quotients were reassessed 0–2 years
and 2–4 years after diet discontinuation. Scores
dropped an average of 10 points (Time 3, M 5 98.5;
Time 4, M 5 98.6). No significant correlations were
found between serum levels and on-diet social quotients (Time 1, r 5 0.19; Time 2, r 5 20.11); however, significant correlations emerged following diet
discontinuation (Time 3, r 5 20.45; Time 4, r 5
20.65). These findings indicate a decline in social
functioning, including deficits in self-help behaviors, socialization, and communication skills, with
a loss of phenylalanine control. It should be noted
that serum levels before diet discontinuation were
approximately 15 mg/dL and rose to approximately
25 mg/dL after discontinuation of treatment; therefore, the average dietary control of these subjects
always exceeded the recommended level of # 10
mg/dL. Results obtained from groups with poor
treatment histories cannot be assumed to generalize
to patients who have maintained better dietary
control.
Holtzman et al. (1986) examined behavioral
functioning following diet discontinuation by administering the Louisville Behavior Checklist
(Miller, 1967) to 82 8-year-old children with earlytreated PKU. Subjects were divided into three
groups according to age at which dietary control
was lost (higher mean percentile scores indicate a
higher frequency of behavioral problems): loss of
dietary control before six years of age (M 5 57.5 6
25.5), loss between six and eight years (M 5 45.1 6
29.5), and loss after eight years (M 5 34.0 6 26.0).
The correlation between age at which dietary control was lost and behavior problems scores (r 5
20.24) was significant, indicating an association between early loss of control and poorer functioning.
However, because this investigation used a singlegroup design, it is impossible to reach conclusions
regarding whether these subjects were functioning
at a lower level than matched controls.
Using parent and teacher report on the Rutter
Behavior Scales, A and B (Rutter, 1967; Rutter, Tizard, & Whitmore, 1970), Stevenson et al. (1979)
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found higher levels of behavioral disturbance at age
eight in 99 early-treated/diet-discontinued children
with PKU compared to controls matched for age
and gender. Teachers identified significantly more
of the patient sample (40%) as being behaviorally
deviant versus the control sample (20%), with significantly more neurotic deviance (22%) than controls (8%). Differences in the proportions showing
antisocial deviance were not statistically significant.
Sex differences were significant for males with PKU
compared to controls in terms of both overall behavioral deviance and neurotic deviance; females
with PKU were not rated as significantly different
from controls. Neurotic behavioral deviance as
rated by teachers was exhibited by PKU-affected
boys over the whole IQ range, though behavioral
deviance in girls was restricted to those with IQs below 70. Parents also identified a greater proportion
of the patient sample as neurotically deviant (31%)
than antisocial (18%); sex differences were insignificant.
Unfortunately, this study is widely cited as having established a clear link between PKU and concomitant behavioral disturbance. It is important to
note that the mean IQ of the PKU group fell in the
low average range (M 5 86.5) and 21% of the subjects had IQs in the mentally deficient range. Psychiatric disorder is known to be more common in
children and adolescents with intellectual disability, with prevalence rates of approximately 41% in
4–18-year-olds with IQs # 70 (Einfeld & Tonge,
1996; Rutter et al., 1970). Furthermore, Burgard,
Armbruster, Schmidt, and Rupp (1994) found that
Full Scale IQ below 90 was associated with a threefold risk of moderately severe behavioral disturbance in subjects with PKU. This suggests that IQ
alone may account for the high rates of behavioral
deviance observed in these children.
Smith, Beasley, Wolff, and Ades (1988) included
this sample in a larger study of 544 8-year-old children with early-treated PKU. Teachers were asked to
complete Rutter Behavior Questionnaires for the
proband and two same-age, same-sex peers. Both
male and female affected individuals showed significantly more neurotic behavioral deviance, as
well as hyperactivity, twitches, solitary behavior,
thumb sucking, unresponsiveness, restlessness,
fidgeting, inability to “settle,” fearfulness, and
worry. PKU-affected boys also showed significantly
less likeability than controls, while affected girls
engaged in more nail-biting and were described
as more miserable than controls. Children from
Sullivan and Chang
families in the “manual labor” class showed significantly more deviant behavior than children
from “nonmanual” groups, and deviant behavior
was associated with increased average phenylalanine concentrations in affected children.
As these authors note, teacher raters were not
blind to patient status, which may have influenced
reporting on this subjective measure (Smith et al.,
1988). Furthermore, although investigators were interested in the influence of gender, social class, and
phenylalanine control on behavior, they failed to
assess the variable that likely accounted for the high
rates of behavioral disturbance found in the initial
study. Since this sample included the subjects with
borderline and mentally deficient IQs from the Stevenson et al. (1979) study, it is unlikely that probands with similarly impaired intellectual abilities
were excluded from the larger sample. The results
of studies that report significant psychiatric disturbance in subjects with borderline or mentally deficient intellectual functioning cannot be assumed to
generalize to PKU-affected individuals with normal
IQs.
Some studies have specifically excluded affected
subjects with IQs that fall below the low average
range. Chang and Fisch (1976) investigated differences between phenylketonuric children with normal intelligence divided into groups based on
length of diet compliance. Subjects were rated by
teachers and parents on the Behavior-Personality
Problem Rating Scale (Siegel, Balow, Fisch, & Anderson, 1968), a “simplified form” of an unstandardized scale with unreported reliability and validity.
Although both groups showed high incidences of
short attention span, low frustration tolerance, social withdrawal, and low self-confidence, a significant correlation (r 5 .57) was found between
duration of dietary treatment and total problem
scores. Subjects in the long-term diet group received
significantly more unfavorable ratings on social
withdrawal and passivity than subjects in the shortterm diet group. The authors attributed these findings to the psychosocial strain of extended dietary
treatment.
Chang and Fisch (1976) defined their “shortdiet group” as subjects who had been on the diet for
less than 100 months, while the “long-diet group”
consisted of subjects who maintained the diet for
more than 100 months. Subjects in the “short-diet
group” maintained treatment for approximately
80% of their lives; subjects in the “long-diet group”
maintained treatment for approximately 74% of
Emotional and Behavioral Functioning in PKU
their lives. The proportion of time that the two
groups of subjects maintained dietary treatment is
not significantly different (x2 5 1.01, df 5 1). However, subjects in group two are significantly older
than those in group one; therefore, it is possible to
interpret these findings in terms of a much stronger
correlation between age and total problem scores
(r 5 .76). Over time, younger subjects also may exhibit similar problems. Furthermore, the decision to
maintain treatment was not experimentally controlled; it is possible that clinicians and parents
were more likely to maintain dietary restrictions for
those children who were seen as having more behavioral problems, which presents a second alternative explanation for these findings.
To examine behavioral functioning following
diet discontinuation by age 8, Schor (1986) administered the Middle Childhood Temperament questionnaire (Hegvik, McDevitt, & Carey, 1982) to the
parents of 18 8–12-year-old children with earlytreated PKU and hyperphenylalaninemia. The PKU
group differed significantly from the standardization sample on four of the nine temperament
scales, showing less predictability, less intensity of
response, less persistence, and more distractibility.
Rating scale scores did not correlate with IQ, age at
diet initiation, or age at termination of treatment.
Approach correlated negatively with maximum serum phenylalanine (r 5 2.72), while the level of external stimulation needed to evoke a response
correlated negatively with the most recent serum
phenylalanine level (r 5 2.47). These results indicate that higher serum phenylalanine levels resulted in less withdrawal from new stimuli and the
need for greater stimulation to evoke a behavioral
response. Although it is reported that subjects with
hyperphenylalaninemia did not differ from subjects
with classical PKU, it should be noted that statistical
power may be insufficient for detecting differences
that may exist between members of the proband
group.
Waisbren and Levy (1991) investigated manifestations of agoraphobia in 50 women with earlytreated PKU and normal intelligence who had not
been previously identified as agoraphobic. They
found that 20% (n 5 10) of women in their PKU
sample obtained scores within the agoraphobic
range on the Mobility Inventory (Chambless, Caputo, Jasin, Gracely, & Williams, 1985) compared to
9% (n 5 4) of normal controls and 6% (n 5 3) of a
sample with diabetes. The proportion of PKUaffected subjects with scores in the agoraphobic
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range was not found to be significantly different
from controls; however, because the power available for this nonparametric test is less than 0.50, a
difference that does exist would be detected less
than 50% of the time. The investigators were able
to uncover a significant difference between the proportions of PKU-affected versus diabetic subjects
with scores in the agoraphobic range. This suggests
that agoraphobia is not likely to be a general effect
of chronic illness, but may be an emotional complication of off-diet PKU. While women with PKU who
had discontinued the diet (n 5 23) showed a significant correlation (r 5 .43) between phenylalanine levels and agoraphobia scores, only one of the
seven women with mild hyperphenylalaninemia
and one of the eight women still adhering to dietary
restrictions had scores within the agoraphobic
range (Waisbren & Levy, 1991).
Diagnostic Assessments. The aforementioned
studies examined general social and behavioral
functioning but did not assess the presence of diagnosable clinical disorders. Realmuto et al. (1986)
administered structured psychiatric interviews, the
Diagnostic Interview for Children and Adolescents
(DICA), and the Diagnostic Interview for Children
and Adolescents-Parent version (DICA-P) (Herjanic & Campbell, 1977), to 13 9–20-year-old earlytreated PKU patients and their parents. Dietary
treatment had been discontinued between the ages
of seven to nine years. Six subjects (46%) met full
criteria for current DSM-III psychiatric diagnoses.
These diagnoses included attention deficit disorder,
oppositional defiant disorder, adjustment disorder
with depressed mood, phobias, and encopresis. Six
of the 13 subjects had satisfied the criteria for attention deficit disorder in the past, and two had depressive symptoms without meeting full diagnostic
criteria.
Although this study is noteworthy as the first to
assess diagnosable symptomatology in this population, it is difficult to draw conclusions regarding
these findings. The authors fail to provide information concerning the use of informants in diagnostic
decisions, for example, whether diagnoses reflect
the reporting of one individual, if both reporters
were asked to reach a consensus on each symptom,
or whether information from informants was combined using either/or rules (i.e., if either the parent
or the child endorsed a symptom, the symptom was
counted toward the diagnosis). Therefore, it
is impossible to determine the possible impact of
informant bias. Furthermore, adult subjects fall
286
outside the recommended age range for these measures. Finally, the authors fail to provide comparisons to controls or prevalence rates for the general
population; therefore, it is impossible to reach conclusions regarding the significance of the reported
prevalence of psychiatric disorder in this sample.
Fisch et al. (1995) used self-reported psychiatric
histories during a follow-up study of 19 earlytreated phenylketonuric patients who terminated
their dietary regimen between the ages of 4.5–13
years and had been off the diet for at least 12 years.
They found that 26% (n 5 5) reported a history of
mental illness diagnosed by a psychologist or psychiatrist, including depression, dysthymia, impulse
control disorder, and simple phobia.
The IQs of subjects reporting mental illness
ranged from 72–85, falling in the borderline to lowaverage range, and were significantly lower than the
average IQ of subjects reporting no mental illness.
Lack of IQ-matched controls makes it impossible to
conclude whether the prevalence of mental illness
reported for these individuals differs significantly
from the rate found for others with similarly impaired intellectual abilities. Furthermore, because
this sample is heterogeneous for length of dietary
treatment (range 2.75–11 years), it is impossible to
draw conclusions regarding the extent to which
these findings reflect the impact of exposure to critically high serum levels of phenylalanine in these
five subjects. Finally, use of self-reports of diagnosed
mental illness would not detect subjects who had
met criteria for psychiatric diagnoses but had not
sought treatment or subjects with significant symptomatology that did not meet full criteria for diagnosis. Administration of standardized psychiatric
interviews to all subjects, with the presentation of
both categorical assessments and dimensional measures of the frequency or severity of psychological
symptoms, would more accurately document the
prevalence of clinical disorders in this sample.
Pietz et al. (1997) administered a standardized
psychiatric interview, the Mannheimer ElternInterview (Esser, Blanz, Geisel, & Laucht, 1989), to
35 PKU patients, ages 17 to 33 years. A control
sample consisted of 181 18-year-old subjects participating in a longitudinal epidemiological study.
Forty symptoms related to functional and emotional disorders (e.g. phobias, generalized anxiety,
and depressed mood), antisocial and conduct disorders, hyperkinesis, and other specific symptoms
(e.g., enuresis, tics, and anorexic behavior) were
rated by clinicians on a 3-point scale (not present,
Sullivan and Chang
moderately present, and clearly present) and used
to reach ICD-10 diagnoses. Results indicate that
25.7% of PKU patients and 16.1% of controls met
criteria for moderate or severe psychiatric disturbance; although this difference was not statistically
significant, the probability of committing a Type II
error (i.e., failing to detect differences that do exist)
is $ 0.50. While externalizing and internalizing
symptoms were equally present in controls, PKU patients exhibited internalizing symptoms only.
Depressed mood, phobias, generalized anxiety, hypochondriac worries, and anxiety involving the
workplace were more prevalent in PKU subjects and
significantly differentiated the groups.
Personality Inventories. The Minnesota Multiphasic Personality Inventory (MMPI) (Hathaway & McKinley, 1942), a standardized measure of personality
and psychological functioning, also has been implemented in this field of research. Fisch, Sines, and
Chang (1981) compared the mean MMPI profile of
19 PKU-affected individuals with those of their parents and unaffected siblings. The Q-sort technique
was used to rate each profile on a 9-point scale, indicating the degree of pathology. Sixty-three percent
(n 5 8) of the male PKU profiles were rated as pathological, with a mean psychopathology rating (5.9)
that was significantly greater than that for female
PKU subjects (3.5), female siblings (3.8), fathers
(4.4), and mothers (3.4). Mean profiles of male PKU
subjects and male siblings (5.1) were not significantly different. Comparison groups were not significantly different from each other.
The mean profile of the adult male PKU group
was the only profile considered to indicate clinically
significant results. The average profile of this group
reflects depression, worry, tension, nervousness,
poor judgment, ruminative and ideational tendencies, as well as low self-esteem, social withdrawal,
poor interpersonal relationships, hyperactivity,
emotional lability, and odd or circumstantial thinking (Butcher & Williams, 1992). While the mean
profile of the adolescent male PKU group is within
normal limits, scale elevations are suggestive of similar difficulties, as well as bodily concerns and vague
somatic complaints. Mean profiles of adult and adolescent females with PKU, adult and adolescent siblings, and parents were all within normal range.
It is difficult to discern the clinical meaningfulness of these results. The groups used in this
study are heterogeneous for important variables, including age, treatment, and IQ, which may confound the results obtained. Furthermore, the MMPI
Emotional and Behavioral Functioning in PKU
was administered to children as young as nine
years, using norms established by Marks, Seeman,
and Haller (1974). Although these norms can be
used with boys and girls as young as 12 years, there
is no evidence supporting the accuracy of interpretations with younger children. Furthermore, these
norms may not adequately discriminate between
normal adolescents and those with clinically significant problems. Studies have shown that boys
and girls in clinical settings frequently produced
false-negative (i.e., normal limit) profiles on these
norms (for review, see Butcher & Williams, 1992).
These limitations make it difficult to accurately assess the functioning of the adolescent subjects included in this study.
Fisch, Chang, Sines, Weisberg, and Bessman
(1985) compared MMPI profiles of 15 PKU patients,
their 42 unaffected siblings, and 28 parents. The
siblings were divided into two groups, presumed
heterozygotes and presumed noncarriers of the PKU
gene, based on serum phenylalanine/tyrosine ratios
following an oral dose of phenylalanine. This study
replicates many of the problems of the Fisch et al.
(1981) study, including use of groups that are heterogeneous for age, treatment, and IQ, and use of
poorly sensitive norms (Marks et al., 1974). Profiles
were compared using Q-sort ratings of the degree of
pathology, Index of Psychopathology scores, mean
psychopathology curves, and Goldberg “Deviant”
versus “Normal” classifications. No significant differences were found among the four subject groups,
although analyses revealed a trend toward more abnormality in the profiles of PKU-affected individuals, followed by their presumed heterozygote
siblings, with the lowest rate of abnormality occurring in the presumed non-carrier sibling group.
Waisbren and Zaff (1994) compared MMPI profiles of females with PKU, ages 11–35 years, who
were late-treated or who had terminated dietary
treatment for at least five years (n 5 12) with those
who were early and continuously treated (n 5 16).
They found that women with PKU who were either
late-treated or who had terminated the diet showed
significantly greater T-scores on six of the eight clinical scales on the MMPI: Depression, Psychopathic
Deviate, Paranoia, Psychasthenia, Schizophrenia,
and Hypomania. This group also had significantly
higher scores on Social Introversion. A significantly
greater proportion (75%) of the late-treated/off-diet
group had scores greater than or equal to 70 on one
or more of the clinical scales compared to the ondiet subjects (19%).
287
Although the average profile of the late-treated/
off-diet subjects showed significantly higher elevations on six of the eight scales, only two elevations
(Paranoia and Schizophrenia) reached the level of
clinical significance. These elevations indicate
moodiness, irritability, low self-esteem, social withdrawal, poor judgment, difficulty concentrating
and attention deficits, as well as bizarre or circumstantial thinking and difficulty separating fantasy
from reality (Butcher & Williams, 1992). Furthermore, eight of the nine subjects who reported
receiving professional treatment for emotional
problems were in the late-treated/off-diet group.
It should be noted that five of the subjects in
the late-treated/off-diet group had returned to diet
“due to attention deficits and emotional lability,”
behavioral symptoms that may otherwise have
been present at the time of testing. Also, Waisbren
and Zaff (1994) used nonstandard administration
procedures by reading MMPI test items aloud to several of their subjects; this may have compromised
the confidentiality of responses, increasing the likelihood that subjects may respond in socially desirable ways or limit the number of symptom items
endorsed. These methodological limitations affect
the strength, but not direction, of the results obtained. However, it also should be noted that the
late-treated/off-diet group included three subjects
who were initially diagnosed because of developmental delays; given the small sample size, any continued difficulties demonstrated by these subjects
would skew results in the reported direction. While
these authors conclude that their findings suggest
that there are protective effects of long-term dietary
treatment, research investigating the quality of
emotional and behavioral functioning in early and
continuously treated PKU-affected individuals has
been limited.
Emotional and Behavioral Functioning
in Individuals Treated Early and
Continuously
Since 1980, recommendations regarding length of
dietary treatment for PKU have been modified considerably. Since intellectual outcome depends on
good dietary control during the first 8–10 years of
life (Holtzman et al., 1986; Michals, Azen, Acosta,
Koch, & Matalon, 1988; Smith, Beasley, & Ades,
1991) and the effects of toxic elevations of phenylalanine after this time are unknown, most PKUaffected individuals now are advised to maintain
288
the restricted diet throughout the lifecourse. However, research investigating emotional and behavioral disturbance in patients who have continuously maintained the diet has been limited.
Three of the following studies were conducted
by researchers affiliated with the German Collaborative Study of Children Treated for Phenylketonuria, an interdisciplinary, multicenter study by the
departments of pediatrics of several German universities. Through this national prospective study, patients with early-treated PKU receive routine
nutritional, medical, neuropsychological, and psychological assessment, as well as psychological
counseling. This may serve as a protective or ameliorative factor; therefore, these patients may not be
representative of the entire early and continuously
treated population.
Weglage, Rupp, and Schmidt (1994) studied 10year-old patients (n 5 58) who were treated early
and maintained a strict dietary regimen. They
found that these patients did not show a higher risk
for emotional and behavioral maladjustment when
compared to the standardization sample of the Personality Questionnaire for Children (PFK 9–14)
(Seitz & Rausche, 1992), the most widely used personality questionnaire for children in Germanspeaking countries. This study has sufficient power
(0.93) for detecting differences as small as 0.50 standard deviation. These results indicate that patients
treated early and strictly do not show a higher incidence of psychological maladjustment compared
with healthy controls at the age of 10 years. However, given that PKU is a chronic, developmental
disorder, these findings do not rule out the possibility that behavioral and emotional disturbances may
appear at a later time, particularly given that average phenylalanine concentrations while on-diet
have been shown to increase continuously with age
(Weglage et al., 1992).
Weglage et al. (1992) examined the psychosocial
and personality characteristics of 34 early and continuously treated adolescents with PKU, ages 11–18
years. Results from the Mannheimer Biographic Inventory (Jager et al., 1973) indicate that compared
to controls, PKU patients reported less autonomy,
lower evaluation of status in school, less achievement motivation, lower frustration tolerance, more
negative self-images, and more health concerns.
Patients saw their total social situations as significantly more restricted. The PFK 9–14 was administered to the 17 PKU-affected subjects in this age
Sullivan and Chang
group; their scores were compared to the those of
the 1,237 controls from the measure’s standardization sample. Of the 15 primary factors that assess
behavioral patterns, needs, motives, and self-image,
the PKU group received significantly lower scores
on “autonomy and self-sufficiency” and “masculinity of attitudes.” A comparable measure, the Freiburger Personality Inventory (FBI-R) (Fahrenberg,
Hampel, & Selg, 1983), was administered to 16 subjects, ages 15–18. Compared to 343 controls, the
PKU-affected subjects in this age group reported
that they were significantly less satisfied with life,
less socially oriented, less oriented toward success,
more bothered by physical complaints, less open,
less extraverted, and less emotional.
Although most of the patients (77%) found it
very difficult to maintain the diet and 94% wished
to discontinue treatment immediately, significant
within-group differences were found concerning dietary control. Those PKU patients with poor control
had significantly more social and emotional problems, including less autonomy, more dependency
on adults, lower frustration tolerance, less extraversion, less satisfaction with life, and more emotional
excitability (Weglage et al., 1992). These results indicate that despite the difficulty of maintaining the
restrictive diet, patients with better control have
fewer psychosocial problems compared to those
with poor treatment compliance.
Burgard et al. (1994) administered the interview
used by Pietz et al. (1997) to 60 13-year-olds with
PKU. The PKU-affected adolescents showed a
double rate of moderate symptoms compared to
age-matched controls. However, this sample included subjects with IQs in the mentally deficient
range, and subjects with IQs , 90 were three times
as likely to be diagnosed with moderate or severe
symptomatology. The distribution of the four diagnostic categories was not significantly different between groups and no individual symptom was
significantly more prevalent in the PKU group;
however, power is limited and the probability of
committing a Type II error is $ 0.50. The main
symptoms rated as moderate or severe for PKU subjects included headaches, disciplinary problems at
school, sibling rivalry, problems with peer relations,
distractibility, temper tantrums, nail-biting, and lying. There was no relationship between severity
level and gender or mean phenylalanine level in the
first years of life.
A similar study examined psychological func-
Emotional and Behavioral Functioning in PKU
tioning in continuously treated American patients.
Griffiths, Tarrini, and Robinson (1997) administered the Devereaux Scales of Mental Disorders
(Naglieri, LeBuffe, & Pfeiffer, 1994) to the parents
of 15 early and continuously treated 10–13-year-old
children with classical PKU. Items related to conduct, attention, anxiety, depression, autism, and
acute problems were rated on 5-point Likert scales.
Mean T-scores obtained did not differ significantly
from population norms and scores were not correlated with historical or concurrent phenylalanine
levels.
Conclusions from Investigations of
Behavioral Disturbance in PKU
At the beginning of this review a question was
posed: “What is the typical psychological profile associated with PKU?” Many studies converge upon a
pattern of behavioral disturbance exhibited by offdiet PKU-affected individuals that resembles
attention-deficit/hyperactivity disorder. These findings include characteristics such as short attention
span and low frustration tolerance (Chang & Fisch,
1976), distractibility (Schor, 1986), hyperactivity
(Fisch et al., 1981; Smith et al., 1988), fidgeting or
restlessness (Smith et al., 1988), difficulty concentrating and attention deficits (Waisbren & Zaff,
1994), as well as past or current DSM-III diagnoses
of attention deficit disorder (Realmuto et al., 1986).
Psychiatric disorders within the depression spectrum and phobias are also reported (Fisch et al.,
1995; Realmuto et al., 1986), as are clinically significant indications of depression and worry on the
MMPI (Fisch et al., 1981; Waisbren & Zaff, 1994).
Low self-esteem, social withdrawal, and poor interpersonal relationships have been reported in several
investigations (Chang & Fisch, 1976; Fisch et al.,
1981; Waisbren & Levy, 1991; Waisbren & Zaff,
1994).
Studies examining emotional and behavioral
functioning in those who have received continuous
dietary treatment corroborate indications of distractibility, low frustration tolerance, negative selfimage, social withdrawal, and difficulty with peer
relations in subjects older than 10 years (Burgard et
al., 1994; Weglage et al., 1992). Increased incidences
of psychiatric disorders have not been found in
these samples. Continuously treated PKU-affected
adolescents have shown a double rate of moderate
289
psychiatric symptoms compared to age-matched
controls, although this may be confounded with
IQ, and no PKU-specific symptoms or diagnoses
have emerged (Burgard et al., 1994; Griffiths et al.,
1997).
Several methodological problems in the existing
literature limit the conclusions that can be drawn
regarding the nature and severity of observed difficulties. A basic limitation of research with this population is sample sizes that provide insufficient
power for detecting differences between proband
and comparison groups. In several of the studies reviewed, the probability of committing a Type II was
greater than 0.50 (Burgard et al., 1994; Chang &
Fisch, 1976; Pietz et al., 1997; Waisbren & Levy;
1991). This is a particular problem when groups are
heterogeneous for variables that are likely to confound the results obtained, including length of dietary treatment, phenylalanine control, and IQ.
For example, taken at face value, it appears that
there may be gender differences within PKUaffected samples. Stevenson et al. (1979) and Fisch
et al. (1981) found that PKU-affected males significantly differed from controls in terms of psychological functioning, while their female counterparts
did not. Fisch et al. (1981) hypothesized that PKUrelated, gender-specific factors, such as more serious
perinatal complications, lower average IQ, higher
cultural and social expectations leading to an inability to cope with the usual stresses of adult life
and the demands of chronic illness, are responsible
for the differences observed. Such interpretations
must be generated cautiously when statistical power
is so low that investigators may be failing to detect
differences that actually do exist between female
groups and controls. Studies that have focused on
PKU-affected females also reveal clinically significant findings (Waisbren & Levy, 1991; Waisbren &
Zaff, 1994). Furthermore, the average MMPI profile
obtained by late-treated/off-diet adult female subjects (Waisbren & Zaff, 1994) is generally similar to
the profile of off-diet adult male subjects (Fisch et
al., 1981). Finally, most studies converge on an
overall pattern of internalizing characteristics (Fisch
et al., 1995; Pietz et al., 1997; Smith et al., 1988;
Stevenson et al., 1979; Waisbren & Levy, 1991) and
many have found no gender-based differences in
functioning (Burgard et al., 1994; Realmuto et al.,
1986; Smith et al., 1988; Weglage et al., 1994).
It should be noted that many of these studies
rely heavily on group comparisons on measures of
290
central tendency or linear relationships between
groups rather than measures of strength of association or effect size. For example, although the differences between groups are statistically significant,
the effect size is small for “autonomy and selfsufficiency” (Weglage et al., 1992) while the effect
size for age and total problem score is large in the
study by Chang and Fisch (1976); thus, the later result is more practically significant (Kirk, 1995).
Serious methodological limitations and the poor
design of several studies contribute to the underdeveloped nature of this body of literature. These limitations include poorly selected measures, inclusion
of subjects who fall outside the recommended age
range for the measures used, use of poorly sensitive
norms, nonstandard administration procedures,
and failure to provide sufficient information regarding diagnostic decisions. Furthermore, although
the subjects in the reviewed studies were recruited
from nonclinical populations, investigators offer no
comment on the representativeness of these participants. It is important to consider whether individuals who agree to participate in research
investigations differ in any important ways from
those who do not (e.g., in terms of IQ, socioeconomic status [SES], or treatment compliance), especially if particularly high- or low-functioning
patients are less likely to participate.
Given these limitations, which are summarized
in Table I, it is impossible to rule out alternative explanations for the findings of studies to date. Furthermore, it is not possible to draw conclusions
regarding the other question posed: “Is concomitant emotional and behavioral disturbance more
prevalent in individuals with PKU compared to appropriate control groups?” Because many investigations used uncontrolled single-group designs,
failing to provide comparisons to controls or normative data, it has been impossible to reach conclusions regarding the significance of the reported
prevalence of concomitant psychological difficulties in PKU-affected samples. It is not clear that
emotional and behavioral disturbance is more prevalent in affected individuals with normal intelligence than in the normal nonaffected population.
Also, with the exception of the investigation of
Waisbren and Levy (1991), it has been impossible
to conclude whether social and emotional problems reported by PKU patients are specific to PKU
versus factors generally associated with chronic disease.
Sullivan and Chang
Potential Lines of Investigation of
Behavioral Disturbance in PKU
Both the ultimate (mutation in the phenylalanine
hydroxylating system) and proximate (serum levels
of phenylalanine) causes, as well as the proximal
phenotype (phenylalanine hydroxylase deficiency),
of PKU are known (Scriver, 1994). However, continued research relevant to the distal phenotype of
PKU is needed. If emotional and behavioral disturbance is a concomitant complication of PKU, what
are the factors that contribute to its etiology? Explanations for the rates of behavioral disturbance
among PKU-affected individuals include (1) the
neurobiochemical effects of excessive phenylalanine levels and (2) the psychological effects of
chronic illness on behavior and personality development.
Concomitant psychological disturbance may be
attributable to a variety of biological factors, including the toxic effects of serum phenylalanine levels
that remain above normal range, prenatal effects of
tyrosine deprivation and toxic level phenylalanine
concentrations in the placentas of carrier mothers
(Bessman, 1972), or the direct effects of excess phenylalanine on other amino acids, neurotransmitter
synthesis, and the developing central nervous system (“Why Does Phenylalanine Do Harm in PKU?,”
1986). Aberrant levels of dopamine precursors and
metabolites, as well as reduced levels of norepinephrine and serotonin, have been found in the
plasma, urine, and cerebrospinal fluid of individuals
who have discontinued dietary treatment (see review by Gttler & Lou, 1986). Interestingly, results
consistent with a diminished supply of dopamine
and norepinephrine include depressive symptomatology and features characteristic of attention
deficit disorder, including hyperactivity, impulsivity, and short attention span. Indications of hyperactivity and impaired attention also are consistent
with a diminished supply of serotonin, as are findings of irritability, oppositionality, and low frustration tolerance.
Further investigations could elucidate the role
of phenylalanine control in the development of
emotional and behavioral disturbances in PKU. To
investigate whether concomitant emotional and
behavioral disturbance is more prevalent in individuals with continuously treated PKU, it will be
necessary to compare probands who are homogeneous for IQ, age, and dietary treatment to age- and
99 subjects with mean
N 5 544, early-
treated 8-yr-old
children.
Smith et al.
(1988)
(range: 85–120).
Not reported. Mean IQ
of 97.
N 5 18, early-treated
children, ages 8–12.
Schor (1986)
Yes. Mean IQ 5 101
N 5 13, early-treated
children, ages 8–18.
Parent report.
5 with hyperphenylalaninemia.
until age 8.
15 subjects maintained diet
Temperament Questionnaire.
subjects with classical PKU and
Sample consisted of 13
Compared to age-
proband subjects did not
at offset of treatment.
with IQ, age at onset, or age
Ratings were not correlated
did differ from controls.
differ from each other but
(N 5 506) from
standardization sample.
diagnosis and treatment,
matched controls
Despite differences in
to controls is not provided.
problem score. Comparison
between age and total
indicate a correlation
behavior problems. Results
Middle Childhood
continuation of treatment
may have been more likely
for children with more
proportion of time on-diet was
experimentally controlled,
Treatment groups were not
subjective nature of report.
confounded by IQ and
Unclear. Results may be
confounded by low IQ.
Unclear. Results may be
controls are not provided.
Unclear. Comparisons to
controls are not provided.
Unclear. Comparisons to
Clinical significance
between groups.
form. Parent and teacher
report.
accurately defined, as the
None.
controls.
gender-matched
N 5 1,088 age- and
gender, but not IQ.
matched for age and
N 5 197 controls
None.
None.
Controls
not significantly different
Rating Scale, shortened
Behavior-Personality Problem
Teacher report.
Rutter Behavior Scales (B).
B. Parent and teacher report.
Rutter Behavior Scales, A &
Louisville Behavior Checklist.
Scale. Psychologist ratings.
Vineland Social Maturity
Measures
Note: groups are not
Length of treatment $5 yrs.
deficient range.
(1976)
reported whether any subjects
had discontinued treatment.
IQs in the mentally
Chang & Fisch
control” (i.e., average phe
levels of #10 mg/dL). Not
range. At least 21 had
were classified with “good
IQ in the low average
Not reported. Included
Approximately 28% of subjects
dietary control is not reported.
21 had IQs in the
mentally deficient range.
Information regarding length
of treatment and quality of
No. Mean IQs fell in the
low average range; N 5
N 5 99, early-treated
8-yr-old children.
15 mg/dL.
IQs ,60.
Loss of control defined as the
age at which serum phe was .
Excluded children with
Mean IQ 5 101 6 13.4.
always exceeded 10 mg/dL.
Stevenson et
(1986)
Poor. Average serum phe
IQ 594.8.
Dietary control
Not reported. Mean
Control for IQ
al. (1979)
N 5 82, early-treated
8-yr-old children.
Holtzman et al.
was 5.92 yrs.
diet discontinuation
N 5 16, early-treated
children. Mean age at
(1986)
PKU sample
Methodological Limitations of Investigations of Emotional and Behavioral Disturbance in PKU
Matthews et al.
Reference
Table I.
from controls.
reported; mean age
Levy (1991)
N 5 19 subjects, ages
9–28 yrs.
yrs.
Fisch et al.
(mentally deficient
patients, ages 17–33
(1997)
(1981)
ranged from 61
N 5 35, early-treated
Pietz et al.
treated subjects, 6 late-treated
subjects, and 3 untreated
subjects.
IQs in the borderline
range.
Sample consisted of 10 early-
a relaxed diet, and 14 off-diet
subjects on a strict diet, 16 on
No. Sample consisted of 5
included subjects with
Mean IQ 5 98.4 Sample
96.8 6 16.4.
superior). Mean IQ 5
range) to 131 (very
No. Full-scale IQs
detected.
norms used.
recommended age range for
below age 12 fall outside the
MMPI. Self-report. Subjects
clinicians provided ratings.
Eltern-Interview. Trained
interview, the Mannheimer
A standardized psychiatric
heterogeneous for important
variables. Adolescent norms
used have poor sensitivity.
female siblings (N 5 8),
fathers (N 5 17), and
mothers (N 5 19).
Unclear. Proband group is
Included probands’
$0.50.
committing a Type II error is
the probability of
group difference; however,
No significant between-
male siblings (N 5 19),
epidemiological study.
in a longitudinal
18-yr-old subjects
consisted of 181
reporting no mental illness.
Control sample
the mean IQ for patients
not meet full criteria for
diagnoses would not be
illness was 23.3 points below
time of follow-up.
IQ 5 93.0 6 15.8.
Results may be confounded
by low IQ. Mean IQ of
symptomatology that does
psychologist. Subjects who
for 12–28 yrs (M 5 19.1 yrs) at
119 (high aver.). Mean
controls are not provided.
Unclear. Comparisons to
subjects reporting mental
by a psychiatrist or
yrs). Subjects had been off-diet
(borderline range) to
None.
not provided.
Comparisons to controls are
reported without context.
Unclear. Prevalence rates are
and subjects with
mental illness diagnosed
from 2.75–11 yrs (M 5 6.4
None.
chronic illness.
have not sought treatments
Self-reported history of
Length of treatment ranged
ranged from 72
No. Full-scale IQs
N 5 19, early-treated
subjects, ages 18–33.
Measure is unsuitable for
aver. range.
(1995)
informants is not provided.
the borderline and low
adult subjects.
reports. Info about use of
between ages of 7 and 9 yrs.
and DICA-P. Self- and parent
versus a general effect of
women.
Treatment discontinued
complication of off-diet PKU
47 acquaintances were
or untreated subjects.
results indicate that findings
are likely to be a
diabetes (N 5 49). It is
not reported whether all
limited power. However,
Type II error is high due to
and women with
Probability of committing a
Age-matched
Clinical significance
acquaintances (N 5 47)
Controls
treated subjects still on diet,
Diagnostic interviews, DICA,
report.
Mobility Inventory. Self-
Measures
23 off-diet, and 12 late-treated
phenylalaninemia, 8 early-
subjects with mild hyper-
Sample consisted of 7
Dietary control
subjects obtained IQs in
16.71. However, 2
Fisch et al.
N 5 13, early-treated
subjects, 9–20 yrs old.
Realmuto et al.
(1986)
Mean IQ 5 104.08 6
No. Mean IQ of 86 6 16
differed significantly
N 5 50, women with
PKU. Age range is not
Waisbren &
25.2 6 3.8.
Control for IQ
PKU sample
Continued
Reference
Table I.
12.8, including subjects
in the borderline range.
Yes. Mean IQ 5 93.6 6
N 5 58, early-and
continuously treated
10-yr-old subjects.
N 5 34, early-and
continuously subjects,
Weglage et al.
(1992)
N 5 16 early and continuously
subjects.
subjects, and 2 untreated
IQ 5 105.47 6 8.64.
continuously treated
(1997)
children, ages 10–13.
Not reported. Mean
N 5 15, early- and
Griffiths et al.
Yes.
mentally deficient range.
13-yr-olds.
Disorders. Parent report.
Devereaux Scales of Mental
norms of the measure.
Compared to population
population norms by age 13.
significant differences from
provided, results indicate no
matched controls are not
Although comparisons to
confounded by IQ.
Probability of a Type II error
is $0.50. Results may be
prevalent in the PKU group.
was significantly more
No diagnosis or symptom
poorer control.
problems than those with
phe had fewer psychosocial
Patients with lower serum
at age 10 yrs.
differences between groups
Results indicate no
groups.
age differences between
confounded by significant
variables. Results may be
heterogeneous for important
informants is not provided.
epidemiological study.
a longitudinal
191 13-yr-old subjects in
sample of each measure.
from the standardization
Compared with subjects
sample of the PFK 9–14.
from standardization
218 10-yr-old subjects
None.
Unclear. Groups are
sensitivity.
(N 5 15), and parents
(N 5 28).
norms used have poor
noncarrier siblings
variables. The adolescent
heterogeneous for important
28), presumed
Unclear. Proband group is
Included presumed
carrier siblings ( N 5
report. Info on use of
Interview. Parent and child
Mannheimer Eltern-
Psychiatric interview, the
Yes.
13, including subjects in
N 5 60, early-and
continuously treated
Burgard et al.
(1994)
Inventory, the PFK 9–14, and
Mannheimer Biographic
PFK 9–14. Self-report.
FBI-R. Self-report.
No. Mean IQ 5 98 6
Yes.
Yes.
Young adolescents fall
ages 11–18 yrs.
12.6 (range: 85–115).
No. Mean IQ 5 96.4 6
age range for this measure.
resumed treatment may not
developmental delays.
represent truly off-diet patients.
outside the recommended
at least 5 yrs. Five subjects in
the second group who
because of
procedures. Norms used for
adolescents are not reported.
treated subjects and those who
been off-diet at some time for
subjects were diagnosed
nonstandard administration
MMPI. Self-report with
MMPI. Self-report.
excluded, 3 late-treated
treated subjects and 12 late-
Weglage et al.
Sample consisted of 6 earlytreated subjects, 7 late-treated
retarded subjects were
(1994)
No. Although mentally
N 5 28 subjects, ages
11–35.
Zaff (1994)
borderline range.
adolescent subjects.
Waisbren &
subjects with IQs in the
describes adult and
Mean IQ 5 98.4.
Sample included
N 5 15 subjects. Ages
not reported, but text
Fisch et al.
(1985)
294
gender-matched controls. This could be accomplished through the administration of standardized
psychiatric interviews, as well as measures of personality and psychological functioning using ageappropriate norms. Differences may be found using
both categorical assessments, as well as dimensional
measures of the frequency or severity of symptoms.
It also is important to consider the psychosocial
effects of chronic illness on behavior and personality development. Early epidemiological surveys
showed that children and adolescents with chronic
illnesses were at a significantly greater risk than
their healthy peers for developing psychosocial
problems (Pless, 1983). Current data cast doubt on
the assumption that chronic illness invariably leads
to emotional and behavioral disturbance. Although
findings related to significantly lower scores on
measures of self-concept have been frequently reported for this population, including disruption of
body image, problems with parents, school disruption, and impaired peer relations (Bussing, Burket,
& Kelleher, 1996; Nelms, 1989; Seigel, Golden,
Gough, Lashley, & Sacker, 1990; Zeltzer, Kellerman,
Ellenberg, Dash, & Rigler, 1980), a meta-analysis by
Lavigne and Faier-Routman (1992) demonstrated
that differences in self-concept are not statistically
significant when compared with carefully matched
controls. Furthermore, several studies have demonstrated that subjects with asthma, juvenile-onset diabetes, cystic fibrosis, and cancer do not appear to
differ from their age-mates in terms of self-concept
and general adjustment (Drotar et al., 1981; Hazzard & Angert, 1986; Kashani, Barbero, Wilfley,
Morris, & Shepperd, 1988; Kashani, König, Shepperd, Wilfley, & Morris, 1988; Kellerman, Zeltzer, Ellenberg, Dash, & Rigler, 1980; Smith, Treadwell, &
O’Grady, 1983).
Findings related to the incidence of behavioral
problems and full-blown clinical syndromes have
been mixed. When present, anxiety disorders (Bussing et al., 1996) and depressive symptomatology
appear to be the most common clinical features
(Bennett, 1994; Seigel et al., 1990). However, the
majority of studies indicate no differences in the
prevalence of diagnosable clinical disorders (Burke
et al., 1989; Kaplan, Busner, Weinhold, & Lenon,
1987; Kashani, Barbero, et al., 1988; Kashani, König,
et al., 1988; Kokkonen & Kokkonen, 1995; Tebbi,
Bromberg, & Mallon, 1988; Stawski et al., 1995).
Finally, with the exception of somatic symptoms
and concerns, the average personality profiles of
Sullivan and Chang
patients with chronic illnesses fall within the normal range (Geiss, Hobbs, Hammersley-Maercklein,
Kramer, & Henley, 1992).
Most current research converges upon a profile
of normality, indicating that concomitant psychological disturbance is not an inevitable consequence
of chronic disease and showing the adaptability of
these children and their families. However, some
studies indicate emotional and behavioral disturbance consistent with the historic view of maladaptation in chronically ill populations. This
inconsistency indicates the importance of examining cofactors that may be contributing to concomitant difficulties in some probands.
Rates of depression/anxiety and peer conflict/
social withdrawal in chronically ill children have
been found to covary with the absence of a parent,
low family income, low maternal education, and
younger maternal age at childbirth (Gortmaker,
Walker, Weitzman, & Sobol, 1990). These finds suggest that chronically ill children are typically welladjusted, but the presence of additional stressful circumstances may contribute to poorer adaptation.
Severity of illness may also be a contributing factor.
For example, differences in affective adjustment
and self-esteem disappeared when controlling for
functional status in asthmatics (Padur et al., 1995).
Thus, the more severe the physical and medical impairment of included subjects, the more impaired
psychological functioning appears to be. Furthermore, high social support from peers and family is
related to better adjustment in chronically ill and
handicapped children (Wallander & Varni, 1989).
Investigations that have not considered the impact
of illness severity, social support, and important
demographic variables on functioning contribute to
inconsistent conclusions regarding emotional and
behavioral functioning among and between chronically ill groups.
Treatment-related factors, including the necessity of maintaining a restrictive diet, regular blood
tests, frequent visits to the hospital, and daily problems managing treatment, may pose considerable
stress for children and adolescents with PKU (Weglage et al., 1994). In order to confidently attribute
observed difficulties specifically to PKU, it will be
necessary to examine the elements of the “PKU profile” that may be attributed to chronic disease. This
could be accomplished by comparing PKU-affected
individuals to those with other chronic illnesses
that are lifelong and demand daily compliance with
Emotional and Behavioral Functioning in PKU
295
Table II. Methodological Suggestions for Future Research
Topic
Size
Control for IQ
Suggestion
Maximum possible sample size to ensure sufficent power.
e.g., WAIS/WISC Full Scale IQs $ 85 would fall at least in normal range, controlling for standard error of measure
on these instruments.
Homogeneity
Control for treatment variables
Sample homogeneity for (1) socioeconomic status, (2) education, and (3) age or developmental phase.
Control of (1) onset of treatment (e.g., ,90 days), (2) duration of treatment, and (3) quality of treatment (e.g.,
average lifetime phenylalanine levels).
Biological variables to consider
(1) current phenylalanine levels, (2) current tyrosine levels, (3) neurotransmitter synthesis (e.g., dopamine and
serotonin), and (4) mutation type.
Comparison groups
Inclusion of matched controls (e.g., matched for age, gender, and IQ) and comparison to chronically ill controls
(e.g., matched controls with other lifelong illnesses that demand daily treatment and involve a genetic and
neuropsychological component).
Reliability and validity
Use of age-appropriate, standardized measures with adequate reliability and validity; report of administration
procedures, norms used, diagnostic criteria, etc.
Analyses
Appropriate analyses that measure strength of association (e.g., effect size) when possible
Emphasis
Longitudinal, collaborative emphasis.
dietary/medical therapies. Such a control group
could be composed of individuals with asthma, cystic fibrosis, or juvenile onset diabetes.
The current database is relatively underdeveloped with respect to critical issues and leaves many
questions unanswered regarding concomitant
psychological functioning in treated PKU. This indicates the need to pursue new lines of methodologically sound, clinically useful research. Table II
summarizes methodological suggestions for future
investigations. Such studies will contribute to the
debate regarding the utility of continued adherence
to dietary restrictions.
While some have concluded that there are protective effects of long-term dietary treatment, it is
possible that these studies have confounded the dependent variable with the treatment condition. Decisions to comply with treatment recommendations
reflect some degree of self-selection. Those who
have emotional and behavioral difficulties may fail
to maintain the diet, while those who are higherfunctioning continue to comply with treatment demands. The efficacy of extended treatment cannot
be established through randomized controlled trials; patients and their guardians cannot be prohibited from electing to terminate or continue with
treatment despite assignment to a particular condition. This decision may be related to SES, IQ, education, emotional and behavioral functioning of the
patient or parents, parenting style, family functioning, specific knowledge about PKU and diet-related
factors, and beliefs about treatment. Studies that in-
clude subjects who were advised to maintain the
diet throughout the lifecourse and compare those
who elect to comply with those who do not will be
able to investigate factors that influence treatment
compliance.
While disease-related issues such as phenylalanine control and compliance with treatment regimens are the focus of many care programs, the
impact of the illness on the family, social functioning, academic performance, and overall adjustment
should be considered in conjunction with physical
care. For example, while several investigations have
examined the impact of phenylketonuria on family,
parent, and marital functioning (Kazak, 1987; Kazak, Reber, & Carter, 1988; Reber, Kazak, & Himmelberg, 1987; Shulman, Fisch, Zempel, Gadish, &
Chang, 1991), it also is useful to consider these factors in conjunction with the quality of emotional
functioning in the affected individual.
Kazak, Reber, and Snitzer (1988) examined family structure, parental functioning, and child behavior in 45 families with children 6 years or younger
still maintaining the dietary regimen. No overall
differences were found for parental psychological
distress, parenting stress, or marital satisfaction.
These children were not rated as showing more internalizing, externalizing, or overall behavioral
problems; however, both mothers and fathers reported lower social competence for affected children than the parents of controls. Mothers reported
their families to be significantly more “separated”
and “rigid” than control families. These authors
296
hypothesized that a rigid family organization may
establish the necessary structure for maintaining
consistent dietary routines. However, this type of
family system may not be as adaptive at later stages
of development.
Pietz et al. (1997) found that overprotective and
restrictive styles of mothering were reported more
often by adult PKU-affected individuals than controls. Probands with restrictive-controlling mothers
were more likely to report functional and emotional
symptoms, indicating that parenting styles that are
adaptive for maintaining strict dietary control early
in life may have a detrimental effect on long-term
emotional development. Future investigations may
provide clarity regarding socioenvironmental factors that covary with measures of psychological
functioning across the lifespan of patients with
early and continuously treated PKU.
If significant psychiatric or behavioral disturbance is shown to be more prevalent in treated individuals with PKU than in the general population,
families and professionals working with PKU will
find this information important for establishing
preventative intervention programs. Within-group
analyses may identify factors that distinguish those
Sullivan and Chang
who not develop concomitant difficulties from
those who do. This information could be used to
identify risk and protective factors that will assist
with the development of programs designed to enhance positive outcomes.
A biopsychosocial approach requires the integration of information about medical status, cognitive ability, emotional and social functioning, and
environmental factors that may affect the diagnosis, treatment, and prognosis of behavioral and
emotional concomitants of this developmental disorder. Weglage et al. (1994) have demonstrated that
patients treated early and strictly do not show a
higher incidence of psychological maladjustment
compared with healthy controls at the age of 10
years. Continued collaborative, prospective, longitudinal research that examines the emergence and
course of emotional and behavioral disturbances in
this population may result in numerous practical
benefits to affected individuals, families, health care
professionals, and the scientific community.
Received March 10, 1998; revisions received July 22,
1998; accepted August 7, 1998
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