EurJ Pediatr (1990) 149 [Suppl 1]: S 34-S 38 European Journal of

Pediatrics �9 Springer-Verlag 1990

Results of psychological testing of patients aged 3-6 years Ute Michel, E. Schmidt, and U. Batzler*

Ruprecht-Karls-Universitfit Heidelberg, Kinderklinik, Im Neuenheimer Feld 150, D-6900 Heidelberg, Federal Republic of Germany

Abstract. Cognitive development of early treated PKU children (132) was investigated by intelligence tests, tests for visual perception, motor and language development. Deviations from test norms occurred at 5 years of age con- cerning performance IQ, mathematical thinking, and vi- sual perception. With the exception of mathematical thinking, "normal" results were obtained at the age of 6 years. Correlation with levels of plasma Phe revealed a relation between qualitiy of dietary control and perfor- mance IQ. Results are discussed in light of methodologi- cal aspects and with respect to treatment consequence.

Key words: Phenylketonuria - Intelligence quotient - Dietary control - Longitudinal study - Psychometric test results

Introduction

The success of PKU treatment can be determined on the basis of various aspects of psychological function. The main assessment of cognitive development of PKU patients is based on IQ tests. The choice of test was made in view of the global t reatment aim, namely to prevent severe mental handicap. Furthermore it is possible to examine the dis- turbance of specific cognitive functions, such as visual- motor and language abilities. Various studies [4-6] support the hypothesis that metabolic disturbances caused by PKU reduce specific cognitive functions rather than the general level of cognitive ability. Since the illness directly or indi- rectly influences the emotional and social behaviour of children [2, 8-10], behavioural, personal and social devel- opment of the patients should also be studied. The preven- tion of mental handicap can already be seen as a success of treatment. At present, however, it is not unjustified to ex- pect that early and strict treatment of PKU patients may even result in normal development without any signs of dis- turbance becoming apparent.

* On behalf of a group of psychologists cooperating for the PKU study: D. Awiszus, S. B6rner, B. Granitzny, R. Matthaei, A. Stachiw, I. Unger, J. Weglage, and H. Weyhreter

The outcome of treatment can be determined either by making cross-sectional measurements at various ages or longitudinally following the development over a certain age range. The present investigation, being conceived as a longitudinal study, permits both types of measurements.

A wide variety of psychodiagnostic tools has been ap- plied in the PKU study. Within the first 7 years of life, cog- nitive development has been the focus of psychological re- search. It is proposed to include tests of personal and social development. In this contribution only the results of the age range from 3.5 to 6.5 years will be reported. The Denver Development Test results will be discussed sepa- rately.

Methods

The psychological tests were administered by clinical psy- chologists in the centres participating in the study. All tests took place in the morning and, whenever possible, before medical intervention. The group of clinical psychologists has more or less remained unchanged since the beginning of the study and has met every 6 months to clarify the problems which came up in connection with the test pro- cedures. In this way the group took the responsibility for the study design as far as the psychological tests are con- cerned.

The psycho-diagnostic tests are given in Table 1. The "Columbia Mental Maturity Scale" (CMM) is a

test used for screening general intelligence. The tasks in- cluded in this test establish the child's ability to think logi- cally and abstractly. The child is shown cards on which three to six objects are printed and then has to pick out the one object which logically does not fit the group. The re- sults of the test are based on norms established in 1972 [1].

The "Hannover Wechsler Intelligenztest fiir das Vor- schulalter" (HAWIVA) is an extension toward a younger age range of the well-known "Hamburg-Wechsler-Intelli- genztest ftir Kinder" (HAWIK). The HAWIVA measures both, verbal and performance IQ, however, not general IQ. Part of the test concerning verbal ability contains sec- tions called "General Knowledge", "Comprehension" and "Vocabulary". The performance scale concerning

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Table 1. Psychological tests used to determine the success of treat- ment up to the age of 6 years

Age Test procedures (years)

1.6

3.6

4.6

5.0

5.6

6.0

6.6

Denver Entwicklungsskalen

Denver Entwicklungsskalen IQ: Columbia Mental Maturity Scale (CMM)

IQ: Columbia Mental Maturity Scale (CMM) Language Development: Psycholinguistischer Entwicklungstest (PET)

IQ: Hannover-Wechsler-Intelligenz-Test ftir das Vorschulalter (HAWIVA) Visual Perception: Frostig's Entwicklungstest der visuellen Wahrnehmung (FEW)

Motor Development: Lincoln-Oseretzky-Skala (LOS ~ 18) IQ: Hannover-Wechsler-Intelligenz-Test fiir das Vorschulalter (HAWIVA)

Visual Perception: Frostig's Entwicklungstest der visuellen Wahrnehmung (FEW) Motor Development: Lincoln-Oseretzky-Skala (LOS KF 18)

perception and visual-motor coordination, comprises sections called "Figure Drawing", "Puzzle-Test" and "Maze". In addition a special procedure under the head- ing "Mathematical Ability" examines the child's com- prehension of relations between mass, size, and number. Another procedure under the heading "Animal House" determines the ability to match colours as well as the time taken to complete the task. The norms of this test were determined in 1972-1974. In this test, in contrast to the CCM, social class was taken into consideration to estab- lish the norms.

The "Coloured Progressive Matrices" (CPM) also measures general intelligence. Since the solutions to prob- lems do not require language capabilities, this test was used in examining children with a language other than German as a mother tongue. The child is asked to com- plete "correctly" a geometric figure. The CPM tests the ability to differentiate between similar and equal designs, the recognition of connections within figures and the ability to make logical inferences. The norms for this test have been established during the 1970 s, taking into ac- count social class, school attendance and residential area.

The "Psycholinguistischer Entwicklungstest" (PET) is a German version of the "Illinois Test of Psycholinguistic Abilities" (ITAP). It is designed to measure linguistic de- velopment and to recognise difficulties in communication. For the purpose of this study only 4 out of the 12 sub-tests have been used:

- understanding of words (auditory understanding); - completion of sentences (making inferences on the basis of auditory material); - description of objects (the ability to put thoughts into words); - grammar test (the ability to use the structure of the lan- guage automatically).

The norms for this test were established 1973, taking sex, residential area, and social class into account.

The "Lincoln-Oseretzky-Skala" (LOS KF 18) assesses motor development. The tasks include coordination, speed of movement as well as precision in performing a movement. The norms were established separately for normal and mentally retarded children at the end of the 1960s.

The "Fortigs Entwicklungstest der visuellen Wahrneh- mung" (FEW) examines perceptual skills required for learning to read and write. The results of four subscales are added to a global score. Norms for this test were estab- lished in 1974.

Patients

This contribution is based on the results of those patients who could be classified into response types I and II, need- ing dietetic treatment, following their protein challenge [7]; this group comprised 139 patients. Four of the pa- tients' parents refused all psychological tests and 3 of the patients could not be assessed with the above mentioned tests, because of mental retardation which was inde- pendent of PKU. Therefore, the sample was reduced to 132 patients, 80% of whom were of German and 20% of other origin. Since not all the children have yet reached their 5th and 6th year, results are not available for the whole group. However, for the largest part, the test results are complete. For example, 74% of the expected results gathered with the HAWIVA at the age of 5 will be re- ported in this contribution. Of the test results 11% have not been collected by the stipulated data, the drop-out rate was 12%. Of the total children, 3% could not be tested because of disabilities unrelated to PKU.

R e s u l t s

The cross-sectional results of the intelligence tests are given in Table 2.

The CMM test results in PKU children aged 3.5 and 4.5 years showed no significant differences compared with normal children. However, at the ages of 5 and 6 years ap- plying the HAWIVA test, the picture changed. At 5 years of age there was a significant difference ( p < 0.05) be- tween normal and PKU groups in the performance scale of the HAWIVA and in the additional test concerning mathematical thinking. At 6 years of age there was no longer any statistically significant difference between the two groups with regard to their performance IQ. How- ever, mathematical abilities still showed deficits in the PKU group.

As mentioned earlier, the CPM test had only been ap- plied to the group of PKU children of non-German origin. Comparing the results with normal children, deficits be- came apparent. If, however, the social class is taken into account it appeared that no significant differences exist between the two groups; the fathers of 73% of the non- German PKU patients are manual workers of a very low social class.

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Table 2. Psychological test results of PKU and normal children

Test Age PKU group Normal group Signifi- (years) cance*

CMM 3.6 n = 97 n = 116 M= 30.6 M= 31.2 NS

SD= 9.6 SD= 12.4

CMM 4.6 n - 111 n = 152 M= 42.2 M= 40.2 NS

SD= 13.0 SD= 15.2

HAWIVA 5 n = 72 n = 239 verbal scale M= 40.2 M= 41.7 NS

SD= 9.9 SD= 11.3

HAWIVA 5 n = 73 n = 239 performance M = 23.0 M = 26.0 P< 0.05 scale SD= 9.7 S D - 9.6

HAWIVA 5 n = 74 n = 239 mathematical M= 9.3 M= 10.1 P< 0.05 thinking SD= 2.8 SD= 3.7

HAWIVA 5 n = 74 n = 239 animal houses M= 16.6 M= 17.5 NS

SD= 7.1 SD= 6.6

RAVEN- 5 n = 21 n - 106 CPM M = 13.5 M low. class = 13.5 NS

M mid. class = 15.0 P < 0.05 M upp. class = 15.9 P<0.05

SD= 3.2 SD= 3.1

HAWIVA 6 n 56 n= 47 verbal scale M= 50.6 M= 51.2 NS

SD= 10.8 SD= 10.2

HAWIVA 6 n= 57 n= 47 performance M= 35.9 M= 37.0 NS scale SD= 10.3 SD= i0.3

HAWIVA 6 n= 57 n= 47 mathematical M= 11.3 M= 12.6 P<0.05 thinking SD= 2.7 SD= 3.1

HAWIVA 6 n= 57 n= 47 animal houses M= 24.4 M= 24.9 NS

SD= 7.3 SD= 7.3

* One-sided t-test n = number of subjects; M = mean of test deviation; NS = not significant

results; SD =standard

The long i tud ina l resul ts of in te l l igence are shown in Table 3.

In te l l igence tests were a d m i n i s t e r e d for each child four t imes dur ing the t ime span of 3 .5-6 years , thus pe rmi t t i ng analysis of in te l l igence deve lopmen t . Ove r this wide age range two d i f ferent I Q tests had to be app l i ed n a m e l y C M M and H A W I V A for ch i ld ren of G e r m a n and C P M for those of o t h e r origin.

Since the resul ts of the H A W I V A p e r f o r m a n c e scale c o m p a r e m o r e f avourab ly with those of CMM, only this pa r t i cu la r pa r t of the H A W I V A has b e e n chosen for the long i tud ina l analysis. F u r t h e r m o r e , the ind iv idua l test re- sults of each child and test p r o c e d u r e had to be stan- da rd i s ed for the i n t e r p r e t a t i o n of the long i tud ina l devel - o p m e n t of in te l l igence. Since it is cus tomary to def ine a m e a n of 100 and a s t anda rd dev ia t ion of 15 by this s tan- dard i sa t ion , the resul ts of the P K U pa t ien ts b e c a m e com- pa r ab l e wi th the n o r m a l d is t r ibut ion. F o r this long i tud ina l

eva lua t ion only those 45 pa t ien ts con t r ibu t ed for w h o m the resul ts of the to ta l of 4 tests were avai lable .

The resul ts suggest tha t P K U chi ldren at 5 years of age devia te f rom n o r m a l d e v e l o p m e n t in the i r in te l l igence. However , at the ear l ie r and la te r examina t ions the intel- l igence of P K U ch i ld ren was c o m p a r a b l e to the n o r m a l group.

In add i t i on the tes t resul ts of the fol lowing specific abil- i t ies were ob ta ined : m o t o r de ve lopme n t , pe r c e p tua l de- v e l o p m e n t and l anguage deve lopmen t .

N e i t he r at 5 nor at 6 years of age could the P K U group be d i f fe ren t i a t ed f rom the n o r m a l g roup in the resul ts of the L O S test, measu r ing m o t o r de ve lopme n t . In the tes t of visual p e r c e p t i o n ( F E W ) , however , the re was a g roup dif- f e rence at 5, bu t not at 6 years of age (Table 4).

In cont ras t to all o the r tests t he re are no stat is t ical norms concern ing l anguage d e v e l o p m e n t (PET) . H o w - ever, the t -value can be accep ted as an equiva lent . The n o r m a l r ange c ompa r i son t -value is 50 + 1 SD. Us ing this m e t h o d of eva lua t ion , values for P K U chi ldren are nor- mal. I f one s tudies the specific tests of l anguage deve lop- ment , P K U chi ldren are at leas t average in all tests wi th the excep t ion of the sub-scale " O b j e c t Desc r ip t ion" . In this case the m e a n t -value is lower t han 50 at 4 and 6 yea r s bu t still wi th in the n o r m a l range. However , the ques t ion of w he the r this resul t shows a r e t a r d a t i o n in express ive abil- ities, pe rhaps due to psychic conflicts, has to be e x a m i n e d in fur ther s tudies (Table 5).

Summar i s ing all results, the fol lowing can be s tated:

- dev ia t ion of P K U chi ldren f rom n o r m a l ch i ld ren cannot be speci f ied be fo re the 5 th b i r thday ; - P K U chi ld ren ' s weaknesses lie in the areas of ma the - ma t i ca l th ink ing and non -ve rba l aspects of in te l l igence; - the abi l i t ies of P K U ch i ld ren s eem to improve at the age of 6 years .

The re la t ionsh ip b e t w e e n onse t of t r ea tmen t , p l a sma Phe levels, educa t iona l level of pa r e n t s and test results of the P K U - c h i l d r e n was assessed in o r d e r to eva lua te w h e t h e r t r e a t m e n t factors (e.g. onse t of t r ea tmen t , qual i ty of di- e ta ry control ) or p a r e n t a l level of educa t ion could exp la in some of the dev ia t ions f rom n o r m a l chi ldren. The da t a of m a t h e m a t i c a l abi l i ty at 5 and 6 years , the H A W I V A per- fo rmance scale and the F E W at 5 years were cons idered .

A s ta t is t ical ly s ignif icant co r re l a t ion b e t w e e n the age of the P K U pa t i en t at the beg inn ing of t r e a t m e n t and test resul ts could not be es tabl ished. In this group the onse t of t r e a t m e n t r anged b e t w e e n the 4 th and 46 th day of life with a m e d i a n of 16 days.

A s far as the qual i ty of d ie ta ry cont ro l is concerned , the m e d i a n Phe values of every 6 -month p e r i o d (i. e. 12 in

T a b l e 3. Longitudinal mean values of PKU children measured four times over 2.5 years (n = 45)

IQtest Age(years) PKUmeasures Normaldistribution

CMM 3.6 Mean = 100.4 Mean = 100 CMM 4.6 Mean = 106.0 HAWIVA 5 Mean = 91.0 HAWIVA 6 Mean = 98.0

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Table 4. Psychological test results of PKU and normal children con- cerning their motor development (LOS) and their visual perception (FEW)

Test Age PKU group Normal group Significance* (years)

LOS 5.5 n = 74 n = 50 M= 4.15 M= 4.44 NS

SD = 2.27 SD= 1.74

LOS 6.5 n = 67 n : 59 M= 6.67 M= 7.02 NS

SD= 3.11 SD= 2.87

FEW 5 n = 57 n = 150 M = 32.2 M = 35.8 P < 0.05

SD= 9.2 SD= 11.8

FEW 6.5 n = 64 n = 150 M = 51.6 M = 50.5 NS

SD= 9.7 SD= 8.7

* One-sided t-test n = number of subjects; dard deviation; NS = not

M = mean of the test results; SD = stan- significant

Table 5. Psychological test results (t-values) of PKU and normal children concerning their language development (PET)

Test Age PKU group Age PKU group Normal (years) group

PET

Word under- 4.5 standing

Sentence 4.5 completion

Object 4.5 description

Grammar 4.5

n = 78 6 n = 54 M = 53.7 M = 52.6 M = 50.0

SD = 11.5 SD = 10.7 SD = 10.0

n : 78 6 n = 53 M = 50.6 M = 53.6 M = 50.0

SD = 9.2 SD = 9.6 SD =10.0

n = 78 6 n = 53 M = 48.8 M = 45.5 M = 50.0

SD= 7.6 SD= 9.2 SD=10.0

n = 78 6 n = 53 M = 52.5 M = 50.7 M = 50.0

SD = 10.1 SD = 11.5 SD = 10.0

6 years) as well as the means of all median Phe values col- lected until the date of test were calculated and sub- sequent ly corre la ted with the test results [12]. The mean value of the 6-month median values served as a measure for the quality of dietary control over a p ro longed period. A statistically significant re la t ion be tween this long- term pa ramete r and the test results could only be established for the H A W I V A per fo rmance scale at 5 years. The corre- lation is - 0.35 and is significant ( P = 0.004). If the 6-month median values are considered, a relat ion exists be tween the plasma Phe concent ra t ion taken at 2 years and the H A W I V A test results at 5 years. For all o ther psychologi- cal measures no relat ion could be established be tween plasma Phe concent ra t ion and test results. The impor- tance of dietary control for the H A W I V A per fo rmance IQ is also suppor ted by a compar i son of ex t reme groups, the 25% of children having obta ined the best results versus the 25% having obta ined the worst results in psychologi- cal tests. Only in the H A W I V A per fo rmance scale was a relat ion be tween the quality of dietary control and the test

results. The same was true when, in a vice-versa approach, children who were assigned to a g roup with subopt imal dietary m a n a g e m e n t were compared to those children who were classified as "well t rea ted" [12]. The criteria for subopt imal control were two medians of p lasma Phe con- centrat ions higher than 9.5 mg/dl. Only such a threshold has a negative effect on pe r fo rmance of IQ.

In contrast the relatively poor result of the P K U chil- dren in the mathemat ica l test could not be explained by their dietary control .

As to be expected, t rea tment parameters in P K U chil- dren who have been t rea ted strictly and at an early age are not the only and perhaps not even the major influence on their intelligence and specific menta l abilities. Our results conf i rm the well known fact in psychology of the correla- t ion be tween parental level of educat ion and their chil- dren's ability to pe r fo rm the test well. The correlat ion is a round 0.30. Since, however, there was no statistically sig- nificant correlat ion be tween level of parental educa t ion and quali ty of dietary control , we can infer that bo th fac- tors, namely the plasma Phe concent ra t ion and parenta l education, influence the intellectual ability of P K U chil- dren.

Discussion and summary

Most of the tests concerning cognitive abilities show nor- mal results for P K U children in the age range f rom 3.5 to 6 years. The deficits which became apparent be tween P K U patients and normal children were not significant. Differences which appeared in some of the tests were subtle and not conspicuous, a l though statistically signifi- cant. In P K U children general IQ is not lower than in the compar i son groups. The minor deficits are apparent in some aspects of intelligent behaviour namely mathemat i - cal thinking, visual percept ion and performance. This re- sult cor responds to the findings of the Uni ted States col- laborat ive study. Also "learning disorders" have been found in some children despite of normal IQ [3]. We agree with the conclusion that intelligence test results are im- por tan t to exclude menta l handicap but are not sufficient to evaluate the special quali ty of cognitive deve lopment in children with PKU.

The experience with P K U children who were t rea ted too late or who were under insufficient dietary control for longer periods of t ime shows that factors as onset of treat- men t and quality of dietary control are impor tan t deter- minants of intellectual ou tcome [11]. In the West G e r m a n collaborat ive s tudy there is no significant correlat ion be- tween initiation of t rea tment and test pe r fo rmance since all of the patients s tar ted with the Phe restricted diet at a very early age.

A n influence of poor dietary control could only be es- tablished for the results of the H A W I V A per fo rmance scale. This test requires higher cognitive opera t ions with a main focus on visual perception, visual encoding and con- centration. Children with good dietary control up to the age of 5 (median plasma Phe level below 9.5 mg/dl) scored bet ter in this test than children with higher median Phe levels. In the light of these results it seems promising to

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further investigate the cognitive operations with this test approach.

In 5- and 6-year-old P K U children mathematical abil- ities do not reach the norm. This result is not related to the long-term quality of dietary control. A similar result has been obtained by the United States collaborative study showing deficits in mathematical abilities independent of the patients ' dietary control. There are perhaps other rea- sons to take into consideration. One possibility which seems to be supported by results of neuropsychological computer-based investigations is that there is a negative influence of higher plasma Phe concentrations on the day of testing. However, this hypothesis has not yet been examined systematically, neither with respect to mathe- matical abilities nor to other aspects of intelligence.

The same is true for the FEW which measures visual perceptual skills. In accordance with the United States collaborative study there is a deficit in the P K U group at the age of 5 years which is not related to the plasma Phe concentrations in the years before testing.

Of course, one has to take for granted that the results are reliable and effects of measurement on scores are neg- ligible. But there is some doubt concerning the " improve- ment" from the age of 5 to 6 years concerning the FEW and H A W I V A performance scale. Perhaps these tests are too easy for children of 6 years and lack differentiation. On the one hand it cannot be ruled out that the change in results f rom age 5 to 6 is due to the fact that test results of PKU children are interpreted in comparison to a different normal group at each age point and for each test. On the other hand it can not be ruled out that retarded develop- ment exists in PKU patients which is compensated by its catch-up at the age of 6 years.

Further investigations of the development process will help to clarify these issues and contribute to the results collected so far.

Even if only the psychodiagnostic tool chosen to evalu- ate cognitive development in PKU children, namely the HAWIVA performance scale, reflects differences in di-

etary control, this seems to be reason enough to advise strict dietary t reatment with plasma Phe levels at least below 10 mg/dl.

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