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Note on “Some observations on thedietary treatment of phenylketonuria”
798
November, 1968 T h e Journal of P E D I A T R I C S
Letters to the Editor
Do~n :r syndrome, hypothyroidism, and diabetes mellitus To the Editor: The purpose of this letter is to report another child with the combination of Down's syndrome, hypothyroidism, and diabetes mellitus similar to the one reported by Daniels and Simon in the May, 1968, issue of the JOURNAL OF PEDIATRICS. The patient was the result of the first pregnancy of a 38-year-old woman. At birth, he had classical stigmata of Down's syndrome, and chromosomal studies done at U C L A Medical Center showed trisomy 21. At 13 months of age the child was hospitalized at Childrens Hospital of Los Angeles with progressive weakness and coma. The diagnosis of diabetes meltitus was established by hyperglycemia and glycosuria. After control with' insulin therapy, an intern, for unknown reasons, drew a PBI which was 1.8 /~g per cent. Repeat PBI was also low. I -lal uptake was 8 per cent in 24 hours. After 3 days of thyrotropic hormone ( T S H ) , the uptake was 9 per cent, confirming the diagnosis of primary hypothyroidism. At the present time the child is 18 months old aad receiving t grain of thyroid a day, plus a combination of ultralente and regular insulin. The mother recently delivered a normal infant. NEIL N. LITI~IAN, M.D. CHILDRENS I~[EDICAL GROUP 5 8 3 0 OVERHILL DR. LOS ANGELES, CALIF. 9 0 0 4 3
Note on "Some observations on the dietary treatmenl of [ ben;ylketon uria"
This report was facilitated by a research grant from the National Institute of Child Health and Human Development (HD 0143).
Vol. 73, No. 5, pp. 798-802
To the Editor: For at least 15 years 1, ~ a specially prepared fornmla low in phenylalanine has been available for the treatment of phenylketonuria, Its use aims at reduction not only of the plasma phenylalanine level but also of the phenylpyruvic acid that is excreted in the urine by such patients. Clinical evidence and research reports have tended to agree a-5 that the I.Q. of such patients can increase significantly, presumably as a byproduct of such diminution. There is also evidence that the earlier the diet is begun the greater such increases will be. 3 The question has been raised, however, as to whether such increases may be attributable solely to adherence to the rigid diet. e, r Birch and Tizard, 6 for example, have criticized the report of Berman, Waisman, and Graham s on the grounds that selective bias may be in operation when patients selected from a variety of sources are grouped together. They point out that affected children in whom the diagnosis is first made because they are suspected of being retarded may represent a group different from those who are discovered by screening programs or because they have relatives with the disorder. Birch and Tizard proposed that the first group will naturaIly tend to have lower initial I.Q.'s than those in the latter 2 groups. They also indicated that the changes in scores may be influenced by the group from which the sample is taken in addition to any effects the diet may have. Other differences between institutionalized and noninstitutionalized retardates which probably have bearing on conclusions to be drawn from such samples have been enumerated elsewhere. Steisel r emphasized that children in institutions tend to be from lower socioeconomic levels and to have less social competency and lower initial I.Q.'s than those who do not require institutianalization. Further, he asserted that institutionalization itself may adversely affect a child's intelligence level. Most recently O'Flynn and Hsia 5 presented data derived from 37 children in their care who were begun on the diet at various ages and who were tested a number of times, These. authors
Volume 73 Number 5
Letters- to the editor
state t h a t because of the great range of scores it is not possible to demonstrate statistical significance to the increases from the first to. last testing. a But reference to standard statistical testbooks s, 9 will reveal a n u m b e r of analytic methods with which such data can be examined to test various hypotheses.
T a b l e I. C o m p a r i s o n of first a n d last I . Q . tests of 37 p h e n y l k e t o n u r i c c h i l d r e n b a s e d o n a g e of s t a r t i n g d i e t ( F r o m O ' F l y n n a n d Hsia, ~ Table II)
Age of I patient start- t Intelligence quotients Case ing diet 1st test t Last test I Change No. (months) Treated before 2 months 1 2 3 4 5 6 7 8 9
1 1 1 1 1~2 6 6 7 8
week week week week week weeks weeks weeks weeks
83 100 57 77 103 81 87 62 96
10.0 101 84 75 91 84 82 40 83
+17 + 1 +27 - 2 -12 + 3 - 5 -22 -13
52 26 68 16
+16 + 6 +11 + 2
20 90 61 62 46 105 101 85 49 54 57 120 20 94 20 51
-19 +19 + 6 +23 + 4 +48 +71 - 9 + 4 +i6 +24 +68 - 3 +50 - 3 + 3
88 63 57 97 42 40 71 51
+38 +I8 + 7 +35 + 2 +10 +22 +2i
Treated between 3 and 11 months 1
4
2 3 4
7 9 11
36 20 58 14
Treated between 12 and 24 months 1
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
12 12 13 14 16 17 18 18 18 19 20 20 21 22 23 24
39 71 55 39 42 57 30 94 45 38 33 52 23 44 17 48
Treated between 25 and 60 months 1
2 3 4 5 6 7 8
28 30 34 36 36 42 54 60
50 45 50 62 40 30 49 30
7 99
T o contribute to the discussion on the effect of the diet on I.Q., statistical analyses were carried out on the data provided by O ' F l y n n and Hsia in their Table II. Aside from omitting the age at which the children were tested, their data are presented in T a b l e I here. I t is noteworthy that the authors indicate in a footnote to the original table that in their estimation " . . . obviously inaccurate changes" were shown in the following Cases: No. 2 (in whom diet began between 3 and 11 m o n t h s ) ; and Nos. 13 and 15 (for both of whom treatm e n t was begun between the ages of 25 and 60 m o n t h s ) . It would be most helpful if the authors h a d specified the reasons for this judgm e n t for these m a y be i m p o r t a n t in evaluating any results obtained. A n u m b e r of the other increases are quite sizeable; e.g., 71 points in Case No. 7, 68 in Case No. 12, and 50 in Case No. 14 (all of whom began t r e a t m e n t between the ages of 12 and 24 m o n t h s ) . M y clinical experience suggests that such m a r k e d changes as these are quite rare. T h e clinical impressions of the psychoIogist(s) at either or both testings would be i m p o r t a n t additional information supporting or qualifying such changes in I.Q. T h e first question which may be weighed from these data is whether a statistically significant increase in the I.Q.'s has occurred in this group of children between the first and last testing, T h e m e a n increase in I.Q. is 13.08 which (with a t test for related measures s) yields a t value of 3.69; this difference is greater than zero (p < 0.01, df = 36). One can be reasonably sure that changes in these scores have occurred. A problem arises in testing whether early t r e a t m e n t results in significantly greater increase, t h a n late institution of the diet. "Early" a n d "late," b o t h relative terms, ought to be specified be/ore the data are examined to avoid "stacking" of the results. If one has an a priori hypothesis based on clinical intuition or published findings, this will help determine the way the data are analyzed. I n this instance "early" was arbitrarily defined as comprising the top half of the group in Table I and " l a t e " as the lower. Two slightly different combinations were utilized owing to the fact that O ' F l y n n and Hsia report on an odd n u m b e r of subjects and that the exclusion of one pair of values may alter the final outcome. I n comparing the first 19 (early) subjects with the 18 who began the t r e a t m e n t "late," one obtains the following: insignificant changes be-
800
Letters to the editor
The Journal of Pediatrics November 1968
tween first and last testing in the former group (mean I.Q. increase o~ 5.79; t of 1.47; df -~ 18), but highly signfiicant changes in the latter group (mean increase in I.Q. of 20.77; t of 3.74; df = 17; and p < 0.01). If we consider the first 18 children as "early" dieters and the last 19 as "late," we again find insignificant increases between first and last tests in the former group (mean change of 3.44; t of 1.039; df = 17), whereas significant changes occur if the diet is begun "late" (mean difference of 22.21; t of 4.08; df -= 18; p < 0.01). These results suggesting that "late" dieting is more efficacious than "early" dieting axe most surprising, and at variance with clinical impressions as well as previous reports, s They await further data and perhaps other analyses for confirmation or refutation. Summary. Data presented in a recent paper of O'Flynn and Hsia s were anlyzed to determine whether the reported I.Q. changes following institution of diet in children with phenylketonuria are significantly greater than zero. Utilizing one of a number of techniques available (t test for related measures) it was found that the average increase in the I.Q. of 13.08 is statistically significant. On the other hand, arbitrarily defining "early" institution of diet as applicable to the first half of the patients reported and "late" as the last half, yielded divergent results. Although the "late" dieters' I.Q.'s increased significantly, the changes in I.Q. for the "early" ones may be attributable to chance. Such findings are not congruent with either clinical impressions or punished reports, becloud an already hazy as well as heated issue, and are of no comfort to the practicing pediatrician. The author wishes to express his appreciation to Miss Elizabeth Baker for the statistical calculations. IRA M.STEISEL~ PH.D. ST. C H R I S T O P H E R ' S HOSPITAL trOR CHILDREN AND T H E DEPARTMENT
OF
PSYCHIATRY
OF T E M P L E UNIVERSITY
SCHOOL OF MEDICINE
2600 N. LAWRENCE PHILADELPHIA, PA. 19133 REFERENCES 1. Bickel, tI.: Influence of phenylalanine intake on phenylketonuria, Lancet 3: 812, 1953. 2. Woolf, L. I., Griffiths, R., and Monerieff, A.: Treatment of phenylketonurla with a diet low in phenylalanine, Brit. M. J. h 57, 1955. 3. Knox, W. E.: An evaluation of the treatment
4.
3. 6. 7.
8. 9.
of phenylketonuria with diets low in phenylalanine, Pediatrics 26: 1, 1960. Berman, P. W., Waisman, H. A., and Graham, F. K.: Intelligence in treated phenylketonuric children: A development study, Child Develop. 37: 731, 1966. O'Flynn, M. E., and Hsia, D. Y. Y.: Some observation on the dietary treatment of phenylketonuria, J. PEDIAT.72: 260, 1968. Birch, H. G., and Tizard, J.: The dietary treatment of phenylketonuria, Develop. Med. & Child Neurol. 9: 9, 1967. Steisel, I. M.: Psychological and social variables and phenylketonuria, Presented at the Conference of the American Association on Mental Deficiency, May 4, 1968. Winer, B. J.: Statistical principles in experimental design, New York, 1962, McGraw-Hill Book Company. Siegel, S.: Nonparametric statistics for the behavioral sciences, New York, 1956, McGrawHill Book Company.
Reply To the Editor: In replying to the note by Steisel, we would like to emphasize the historical background of the current dialogue. In 1966, Berman, Waisman, and Graham ~ described changes in intelligence of 22 diet-treated phenylketonuHc children. They found that children treated early attained higher intelligence levels than children treated later and suggested that the former group may have suffered less impairment at the time treatment was instituted. Birch and Tizard 2 challenged these conclusions by pointing out that there are biases of selection inherent in the methods of ascertainment. Children selected for biochemical study because they have already been noted to be mentally retarded will upon examination be found to have low I.Q.'s when compared with those setected at younger ages through affected relatives or screening programs. They suggested that if one compared the first and last test while on treatment, the ultimate results of treatment are based on the initial mental status, and that the dietary treatment of phenylketonuria has had no effect on the I.Q. of such children. Using our own material and tabulating them in the same manner, O'Flynn and Hsia a found that there was an increase of 20 points between the mean I.Q. on the first test and last test in those treated from 12 to 24 months of age and those treated from 25 to 60 months, but this effect could not be found in those treated before 2 months of age and in those treated between 3 and 11 months. While there was obviously
November, 1968 T h e Journal of P E D I A T R I C S
Letters to the Editor
Do~n :r syndrome, hypothyroidism, and diabetes mellitus To the Editor: The purpose of this letter is to report another child with the combination of Down's syndrome, hypothyroidism, and diabetes mellitus similar to the one reported by Daniels and Simon in the May, 1968, issue of the JOURNAL OF PEDIATRICS. The patient was the result of the first pregnancy of a 38-year-old woman. At birth, he had classical stigmata of Down's syndrome, and chromosomal studies done at U C L A Medical Center showed trisomy 21. At 13 months of age the child was hospitalized at Childrens Hospital of Los Angeles with progressive weakness and coma. The diagnosis of diabetes meltitus was established by hyperglycemia and glycosuria. After control with' insulin therapy, an intern, for unknown reasons, drew a PBI which was 1.8 /~g per cent. Repeat PBI was also low. I -lal uptake was 8 per cent in 24 hours. After 3 days of thyrotropic hormone ( T S H ) , the uptake was 9 per cent, confirming the diagnosis of primary hypothyroidism. At the present time the child is 18 months old aad receiving t grain of thyroid a day, plus a combination of ultralente and regular insulin. The mother recently delivered a normal infant. NEIL N. LITI~IAN, M.D. CHILDRENS I~[EDICAL GROUP 5 8 3 0 OVERHILL DR. LOS ANGELES, CALIF. 9 0 0 4 3
Note on "Some observations on the dietary treatmenl of [ ben;ylketon uria"
This report was facilitated by a research grant from the National Institute of Child Health and Human Development (HD 0143).
Vol. 73, No. 5, pp. 798-802
To the Editor: For at least 15 years 1, ~ a specially prepared fornmla low in phenylalanine has been available for the treatment of phenylketonuria, Its use aims at reduction not only of the plasma phenylalanine level but also of the phenylpyruvic acid that is excreted in the urine by such patients. Clinical evidence and research reports have tended to agree a-5 that the I.Q. of such patients can increase significantly, presumably as a byproduct of such diminution. There is also evidence that the earlier the diet is begun the greater such increases will be. 3 The question has been raised, however, as to whether such increases may be attributable solely to adherence to the rigid diet. e, r Birch and Tizard, 6 for example, have criticized the report of Berman, Waisman, and Graham s on the grounds that selective bias may be in operation when patients selected from a variety of sources are grouped together. They point out that affected children in whom the diagnosis is first made because they are suspected of being retarded may represent a group different from those who are discovered by screening programs or because they have relatives with the disorder. Birch and Tizard proposed that the first group will naturaIly tend to have lower initial I.Q.'s than those in the latter 2 groups. They also indicated that the changes in scores may be influenced by the group from which the sample is taken in addition to any effects the diet may have. Other differences between institutionalized and noninstitutionalized retardates which probably have bearing on conclusions to be drawn from such samples have been enumerated elsewhere. Steisel r emphasized that children in institutions tend to be from lower socioeconomic levels and to have less social competency and lower initial I.Q.'s than those who do not require institutianalization. Further, he asserted that institutionalization itself may adversely affect a child's intelligence level. Most recently O'Flynn and Hsia 5 presented data derived from 37 children in their care who were begun on the diet at various ages and who were tested a number of times, These. authors
Volume 73 Number 5
Letters- to the editor
state t h a t because of the great range of scores it is not possible to demonstrate statistical significance to the increases from the first to. last testing. a But reference to standard statistical testbooks s, 9 will reveal a n u m b e r of analytic methods with which such data can be examined to test various hypotheses.
T a b l e I. C o m p a r i s o n of first a n d last I . Q . tests of 37 p h e n y l k e t o n u r i c c h i l d r e n b a s e d o n a g e of s t a r t i n g d i e t ( F r o m O ' F l y n n a n d Hsia, ~ Table II)
Age of I patient start- t Intelligence quotients Case ing diet 1st test t Last test I Change No. (months) Treated before 2 months 1 2 3 4 5 6 7 8 9
1 1 1 1 1~2 6 6 7 8
week week week week week weeks weeks weeks weeks
83 100 57 77 103 81 87 62 96
10.0 101 84 75 91 84 82 40 83
+17 + 1 +27 - 2 -12 + 3 - 5 -22 -13
52 26 68 16
+16 + 6 +11 + 2
20 90 61 62 46 105 101 85 49 54 57 120 20 94 20 51
-19 +19 + 6 +23 + 4 +48 +71 - 9 + 4 +i6 +24 +68 - 3 +50 - 3 + 3
88 63 57 97 42 40 71 51
+38 +I8 + 7 +35 + 2 +10 +22 +2i
Treated between 3 and 11 months 1
4
2 3 4
7 9 11
36 20 58 14
Treated between 12 and 24 months 1
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
12 12 13 14 16 17 18 18 18 19 20 20 21 22 23 24
39 71 55 39 42 57 30 94 45 38 33 52 23 44 17 48
Treated between 25 and 60 months 1
2 3 4 5 6 7 8
28 30 34 36 36 42 54 60
50 45 50 62 40 30 49 30
7 99
T o contribute to the discussion on the effect of the diet on I.Q., statistical analyses were carried out on the data provided by O ' F l y n n and Hsia in their Table II. Aside from omitting the age at which the children were tested, their data are presented in T a b l e I here. I t is noteworthy that the authors indicate in a footnote to the original table that in their estimation " . . . obviously inaccurate changes" were shown in the following Cases: No. 2 (in whom diet began between 3 and 11 m o n t h s ) ; and Nos. 13 and 15 (for both of whom treatm e n t was begun between the ages of 25 and 60 m o n t h s ) . It would be most helpful if the authors h a d specified the reasons for this judgm e n t for these m a y be i m p o r t a n t in evaluating any results obtained. A n u m b e r of the other increases are quite sizeable; e.g., 71 points in Case No. 7, 68 in Case No. 12, and 50 in Case No. 14 (all of whom began t r e a t m e n t between the ages of 12 and 24 m o n t h s ) . M y clinical experience suggests that such m a r k e d changes as these are quite rare. T h e clinical impressions of the psychoIogist(s) at either or both testings would be i m p o r t a n t additional information supporting or qualifying such changes in I.Q. T h e first question which may be weighed from these data is whether a statistically significant increase in the I.Q.'s has occurred in this group of children between the first and last testing, T h e m e a n increase in I.Q. is 13.08 which (with a t test for related measures s) yields a t value of 3.69; this difference is greater than zero (p < 0.01, df = 36). One can be reasonably sure that changes in these scores have occurred. A problem arises in testing whether early t r e a t m e n t results in significantly greater increase, t h a n late institution of the diet. "Early" a n d "late," b o t h relative terms, ought to be specified be/ore the data are examined to avoid "stacking" of the results. If one has an a priori hypothesis based on clinical intuition or published findings, this will help determine the way the data are analyzed. I n this instance "early" was arbitrarily defined as comprising the top half of the group in Table I and " l a t e " as the lower. Two slightly different combinations were utilized owing to the fact that O ' F l y n n and Hsia report on an odd n u m b e r of subjects and that the exclusion of one pair of values may alter the final outcome. I n comparing the first 19 (early) subjects with the 18 who began the t r e a t m e n t "late," one obtains the following: insignificant changes be-
800
Letters to the editor
The Journal of Pediatrics November 1968
tween first and last testing in the former group (mean I.Q. increase o~ 5.79; t of 1.47; df -~ 18), but highly signfiicant changes in the latter group (mean increase in I.Q. of 20.77; t of 3.74; df = 17; and p < 0.01). If we consider the first 18 children as "early" dieters and the last 19 as "late," we again find insignificant increases between first and last tests in the former group (mean change of 3.44; t of 1.039; df = 17), whereas significant changes occur if the diet is begun "late" (mean difference of 22.21; t of 4.08; df -= 18; p < 0.01). These results suggesting that "late" dieting is more efficacious than "early" dieting axe most surprising, and at variance with clinical impressions as well as previous reports, s They await further data and perhaps other analyses for confirmation or refutation. Summary. Data presented in a recent paper of O'Flynn and Hsia s were anlyzed to determine whether the reported I.Q. changes following institution of diet in children with phenylketonuria are significantly greater than zero. Utilizing one of a number of techniques available (t test for related measures) it was found that the average increase in the I.Q. of 13.08 is statistically significant. On the other hand, arbitrarily defining "early" institution of diet as applicable to the first half of the patients reported and "late" as the last half, yielded divergent results. Although the "late" dieters' I.Q.'s increased significantly, the changes in I.Q. for the "early" ones may be attributable to chance. Such findings are not congruent with either clinical impressions or punished reports, becloud an already hazy as well as heated issue, and are of no comfort to the practicing pediatrician. The author wishes to express his appreciation to Miss Elizabeth Baker for the statistical calculations. IRA M.STEISEL~ PH.D. ST. C H R I S T O P H E R ' S HOSPITAL trOR CHILDREN AND T H E DEPARTMENT
OF
PSYCHIATRY
OF T E M P L E UNIVERSITY
SCHOOL OF MEDICINE
2600 N. LAWRENCE PHILADELPHIA, PA. 19133 REFERENCES 1. Bickel, tI.: Influence of phenylalanine intake on phenylketonuria, Lancet 3: 812, 1953. 2. Woolf, L. I., Griffiths, R., and Monerieff, A.: Treatment of phenylketonurla with a diet low in phenylalanine, Brit. M. J. h 57, 1955. 3. Knox, W. E.: An evaluation of the treatment
4.
3. 6. 7.
8. 9.
of phenylketonuria with diets low in phenylalanine, Pediatrics 26: 1, 1960. Berman, P. W., Waisman, H. A., and Graham, F. K.: Intelligence in treated phenylketonuric children: A development study, Child Develop. 37: 731, 1966. O'Flynn, M. E., and Hsia, D. Y. Y.: Some observation on the dietary treatment of phenylketonuria, J. PEDIAT.72: 260, 1968. Birch, H. G., and Tizard, J.: The dietary treatment of phenylketonuria, Develop. Med. & Child Neurol. 9: 9, 1967. Steisel, I. M.: Psychological and social variables and phenylketonuria, Presented at the Conference of the American Association on Mental Deficiency, May 4, 1968. Winer, B. J.: Statistical principles in experimental design, New York, 1962, McGraw-Hill Book Company. Siegel, S.: Nonparametric statistics for the behavioral sciences, New York, 1956, McGrawHill Book Company.
Reply To the Editor: In replying to the note by Steisel, we would like to emphasize the historical background of the current dialogue. In 1966, Berman, Waisman, and Graham ~ described changes in intelligence of 22 diet-treated phenylketonuHc children. They found that children treated early attained higher intelligence levels than children treated later and suggested that the former group may have suffered less impairment at the time treatment was instituted. Birch and Tizard 2 challenged these conclusions by pointing out that there are biases of selection inherent in the methods of ascertainment. Children selected for biochemical study because they have already been noted to be mentally retarded will upon examination be found to have low I.Q.'s when compared with those setected at younger ages through affected relatives or screening programs. They suggested that if one compared the first and last test while on treatment, the ultimate results of treatment are based on the initial mental status, and that the dietary treatment of phenylketonuria has had no effect on the I.Q. of such children. Using our own material and tabulating them in the same manner, O'Flynn and Hsia a found that there was an increase of 20 points between the mean I.Q. on the first test and last test in those treated from 12 to 24 months of age and those treated from 25 to 60 months, but this effect could not be found in those treated before 2 months of age and in those treated between 3 and 11 months. While there was obviously