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The Trajectory of Cognitive Development in Males with Fragile X Syndrome
The Trajectory of Cognitive Development in Males with Fragile X Syndrome ELISABETH M. DYKENS, PH.D., ROBERT M. HODAPP, PH.D., SHARON ORT, R.N., BRENDA FINUCANE, M.S., LAURENCE R. SHAPIRO, M.D., AND JAMES F. LECKMAN, M.D. Abstract. The trajectory of cognitive development in males with fragile X syndrome was identified in a cross-sectional study of 56 males and in a smaller, longitudinal study of 10 fragile X males. Results from both studies indicated steady cognitive growth until late childhood and early adolescence (10 to 15 years of age), at which point mental age plateaued and IQ declined. Males with higher initial IQ scores manifested more IQ decline than those with initial lower levels of intelligence. The trajectories of IQ differ from those in other etiological groups and mixed groups of retarded individuals. Results have direct implications for intervention strategies with fragile X males. Parents and teachers should be informed about the possibility of an early plateau in mental age, the impact this may have on the child's academic performance, and that the plateau and IQ decline may not be apparent in the child's adaptive behaviors. J. Am. Acad. Child Adolesc. Psychiatry, 1989, 28, 3:422-426. Key Words: fragile X syndrome, IQ, cognitive development, trajectory. children remained unchanged over a 4-year span. Ross et al. (1985) found that the IQ scores for retarded individuals tested as children and again during middle-age "showed no meaningful increase over some 35 years" (p. 69). The stability noted in these short- and long-term longitudinal studies contrasts with the approach of many intervention programs that aim to increase the IQ scores of young retarded and at-risk children. Although the main effect of these programs appears to be in the promotion of school and work related adaptive skills (Berrueta-Clement et al., 1984; Seitz et al., 1985), an increase in IQ scores remains a primary goal of many intervention programs. Indeed, the view that IQ scores are malleable is common in the mental retardation field (e.g., Barnett, 1986). The issue ofIQ stability in the mentally retarded population is further complicated by the problem of etiology. A traditional perspective in the field of mental retardation claims that the etiology of the retarded person is irrelevant, that "it does not appear to matter how one gets to be a retardate ... the maturational results are the same" (Fisher and Zeaman, 1970, p. 164). Recent evidence, however, suggeststhat at least some specific etiological groups differ in their trajectories of intelligence. Down syndrome children appear to decline in their IQ scores from early childhood on, with gains in intellectual abilities occurring more slowlywith age (Gibson, 1978; Hodapp and Zigler, in press). It remains unclear whether this slowing of development occurs as a steady decline over time or whether Down syndrome children "lose ground" at each of several transition points (Kopp and McCall, 1982). In contrast to findings for children with Down syndrome, mentally retarded children with cerebral palsy do not appear to decline in their IQs as they get older. Several studies (e.g., Cruickshank et al., 1976; Fishman and Palkes, 1974; Klapper and Birch, 1967) have found that the IQ scores of retarded children with cerebral palsy remain stable over time and may even increase slightly. This difference in IQ trajectory among different groups confirms the importance of classifying research groups according to etiology of retardation rather than overall level of impairment (Burack et al., in press). In contrast to the IQ trajectory of retarded persons with Down syndrome or cerebral palsy, the trajectory of IQ in males with fragile X syndrome has not been extensively
The degree to which an individual's IQ remains stable over time has long been debated among researchers studying both nonretarded and retarded populations. A first line of research on the intellectual development of nonretarded individuals has shown that IQ scores are relatively stable, varying only slightly as a result of extremely good or poor environments (Cronbach, 1975; Gottesman, 1968; Zigler, 1970). These claims of IQ stability are substantiated with data from the Berkeley and Fels growth studies, two large longitudinal studies that followed nonretarded persons for spans of up to 50 years (Honzik and Macfarlane, 1973; McCall et al., 1973). Another body of research with nonretarded individuals suggests that IQ fluctuates considerably throughout development. Influenced by Skodak and Skeels' (1949) adoption study of institutionalized infants, modern proponents of this view (e.g., Hunt, 1971) claim that small changes in the child's environment can increase IQ scores by as much as 50 points. Workers associated with the Milwaukee Project (Garber and Herber, 1981), Abecedarian Project (Ramey, et al., 1984), and other early intervention programs have used this evidence to advance the belief that early intervention programs may bolster the IQ scores of at-risk children. Research with mentally retarded individuals also offers conflicting data regarding the long-term stability of intellectual abilities. In a longitudinal study, Silverstein (1982) reported that the IQ scores of educable mentally retarded Accepted December 14, 1988. Drs. Dykens. Hodapp. and Leckman and Ms. Ort are with the Child Study Center, Children ',I' Clinical Research Center, Yale University. Miss Finucane is with the Medical Department ofElwyn, Inc. Dr. Shapiro is with the Medical Genetics Unit, Westchester County Medical Center, Cornell University. This research was supported in part by the John Merck Fund, NIH grants RR00125 and llD03008. and NIMH grants MHI8268 and MH30929. The authors wish to thank Joseph Merighi, Sara Sparrow, Ed Zigler, Donald Cohen, Wendy Marans, Joel Bregman. and Fred Volkmar for their comments on an earlier draft ofthis manuscript. Request reprints from Dr. Leckman, Yale Child Study Center. 230 South Frontage Rd., P. O. Box 3333, New Haven, CT 06510. 0890-8567/89/2803-0422$02.00/0© 1989 by the American Academy of Child and Adolescent Psychiatry. 422
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studied. Fragile X syndrome is a recently identified X-linked disorder resulting in mental retardation, and characteristic physical and behavioral features. This syndrome is estimated to affect I in 2,000 males, making it the second most common genetic cause of mental retardation (Bregman et aI., 1987; Opitz, 1984). The genetic mechanisms responsible for fragile X syndrome remain to be illucidated, with some investigators postulating that multiple genes in the same chromosomal region may be affected (Laird, 1987). The mean IQ score of affected adult males is in the moderately retarded range (35 to 40). Some reports have noted, however, that the intellectual functioning of many younger boys with fragile X syndrome lies in the borderline or mildly retarded range, whereas adult males are more often severely or profoundly retarded (Hagerman et al., 1985; Opitz, 1984). Based on observations of six boys, Borghgraef et al. (1987) suggest that there may be a deterioration of IQ in fragile X males that is related to chronological age. Lachiewicz et al. (1987) found a steady decrease in the IQ scores of fragile X males throughout the childhood years. These authors concluded that the IQ trajectory of males with fragile X syndrome is similar to that seen in Down syndrome: highest in the early years, followed by an increasingly slower rate of development in childhood and adulthood. In contrast to Lachiewicz at al. (1987), our preliminary findings (Leckman and Paul, 1985) indicated that the trajectory of IQ in fragile X males does not involve a simple linear decline as found in the Down syndrome population. Thus, there are conflicting reports regarding the specific trajectory of IQ in this population, but some agreement that IQ scores eventually decline. The present study identified the trajectory of IQ in fragile X males in a large cross-sectional study (Study I) involving four separate fragile X clinics, and in a smaller, longitudinal study (Study 2) spanning the years from ages 5 to 20. In addition, a small number of subjects were examined longitudinally across the prepubertal years (before age 10). The combined cross-sectional and longitudinal approach of the present investigation helped control for possible confounding effects common to this type of research. In the cross-sectional study, for example, data from four medical centers helped control for the possibility that more severely impaired individuals were disproportionately represented in the older subjects, or that institutional effects caused spurious IQ declines. Other problems, such as the need to occasionally combine data from different types of IQ tests (e.g., child, adult, nonverbal), were addressed in the longitudinal study.
--~---,---~---.---~-----, I (,hronolll~H.._;11
-"1!l'
FIG. I. The trajectory of IQ in fragile X males: means and standard deviations at each 5-year interval.
residing at the Southbury Training School in Southbury, Connecticut. For each case record, data were collected concerning the subject's birthdate, date of testing, age at testing, name of intelligence test, and the overall IQ or Mental Age (MA) score. This information was gathered for each testing mentioned in each subject's records. The majority of IQ and MA scores (80%) were based on the Stanford-Binet Intelligence Scale (Terman and Merrill, 1973). Sixteen percent (16%) of the data points were based on either the Wechsler Adult Intelligence Scale (Wechsler, 1981), or the Wechsler Intelligence Scale for Children (Wechsler, 1973),leaving 5% of the subjects with IQ scores derived from either the Leiter International Performance Scale (Arthur, 1962) or the Slosson Intelligence Test for Children and Adults (Slosson, 1963). Results
The findings from all IQ tests from the cross-sectional records review are presented in Figures I and 2. Although these figures show the results with different individuals con-
Study 1
Method Subjects and procedures. For the cross-sectional study, the case records of 56 fragile X males, aged 3 to 35, were examined. Four mental retardation facilities in the northeast United States were involved: 13 records reviewed were from the Medical Genetics Unit at the Westchester County Medical Center in Valhalla, New York; 17 records were from the Genetics Clinic and Child Study Center at the Yale University Medical School in New Haven, Connecticut; 13 were from the Genetics Clinic at the Elywn Institutes in Elywn, Pennsylvania; and data were gathered from 13 fragile X subjects
+-_---L_----,---_---,---
2. The trajectory of mental age in fragile X males: means and standard deviations at each 5-year interval.
FIG.
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tributing different numbers of tests, the findings seem clear. Mean IQs fell from 53.6 during the 5- to 10-year period, to 43.6 from 10 to IS years, to 37.7 from IS to 20 years of age. IQ scores averaged 42.6 from 20 to 25 years, and 37.4 from 25 to 30. Corresponding MAs for this sample show a continual increase until the early teen years, followed by a plateauing that begins earlier than that found in the nonretarded population (i.e., from 16 to 18 years of age). To address the problem of different individuals contributing different numbers of test scores, further analyses were conducted using only the first test score noted for each fragile X subject. Forty-eight of the 56 subjects (86%) received the Stanford-Binet as their first test, four subjects (7%) were administered the Wechsler Intelligence Scale for Children, and the remaining four subjects (7%) received either the Leiter or Siosson as their first test. Results again show that IQ scores decline after approximately 10 years of age. A 2 x 4 (age cohort by center) design using analysis of variance, where age cohort consisted of subjects before age 10, and from 10 to 35, revealed a main effect for time of testing. Mean IQ scores decreased from 52.4 before 10 to 39.1 in the 10 to 35 year period, F(I, 55) = 8.61, p < 0.01. There was also a main effect for place of testing, with the sample from the large, state training school in Connecticut (mean IQ = 32.4) scoring lower than samples from each of the other three centers (mean IQ scores = 53.3, 50.8, and 46.8, respectively), F(3, 55) = 4.20, p < 0.05.
IQ scores and the differences in IQ between the initial IQ levels and the levels at the 10- to 15- and 15- to 20-year periods, respectively. Both of these correlations were significant: the pre-IO IQ and the 10- to IS-year change score correlation was rl.1 0) = 0.64, p < 0.05, and the pre-I 0 IQ and 15- and 20-year change score correlation was rl.1 0) = 0.66, p < 0.05. Thus, subjects who had higher IQ scores in the 5- to 10-year period showed greater losses in IQ during both the 10- to 15- and 15- to 20-year periods. Conversely, subjects with lower IQ scores before age 10 manifested less of a decline in subsequent IQ scores. In order to determine whether the changes in IQ trajectory beginning in the early teen years are not simply reflective of a general slowing of development beginning in infancy (as in Down syndrome), a matched t test was performed using six subjects for whom IQ scores were available before the age of 5 and from 5 to 10 years of age. Subjects included two of the 10 longitudinal subjects and four subjects from Study 1. Five subjects were administered the Stanford-Binet at each testing, and one subject received the Siosson and the Stanford-Binet, Results show that there does not appear to be a significant decline in IQ scores before age 10, t(5) = 0.08, NS. The mean IQ score before age 10 was 63.7, and the mean IQ from 5 to 10 was 63.5. Two subjects manifested a mean increase in IQ of 9 points from the earlier to later period, three subjects manifested a mean decrease in IQ of 5 points, and one subject stayed the same.
Study 2
Discussion
Method Subjects and procedures. In the second, longitudinal study, 10 males with fragile X syndrome were examined one or more times at three points: ( I) before age 10, (2) from 10 to IS, and (3) from IS to 20 years of age. For each subject, mean IQ scores were calculated from all tests administered within a given 5-year period. The mean number of tests given during each 5-year period was 1.7 (range = I to 4). Eight of the 10 subjects were administered Stanford-Binets at each testing, one subject received the Wechsler Intelligence Scale for Children at each testing, and one subject was administered a combination of Stanford-Binets and Siossons. All of the 10 subjects lived at home; eight boys were examined through the Yale Child Study Center and two were examined through programs of Elwyn Institutes. Results A one-way repeated measures ANDYA indicated that IQ scores differed significantly across the three age spans, F(2, 18) = 15.45, p < 0.001. IQ scores declined from a mean of 53.8 during the 5- to IO-year period, to 47.2 from 10 to IS years of age, to 40.6 from IS to 20. Post-hoc analyses (Newman-Keuls) revealed significant changes between the 5- to 10year level and each subsequent period, as well as a difference between the 10- to 15- and 15- to 20-year levels. Additional analyses were conducted to determine whether the IQ score obtained during the initial 5- to IO-year period predicted the degree to which subjects declined in IQ. Correlations were calculated between subjects' initial 5- to 10-year
Data from both the cross-sectional and longitudinal studies suggest a pattern of IQ trajectory in fragile X males of relative stability and steady growth until the ages of approximately 10 to 15, after which IQ declines and MA plateaus. The combined cross-sectional and longitudinal approach of the present study reduces the possibility that these findings are due to spurious changes in IQ scores resulting from subject or test selection factors. The finding of IQ stability and subsequent decline in fragile X males is consistent with the authors' preliminary observations (Leckman and Paul, 1985), yet contradicts other data pertaining to the trajectory of IQ in fragile X syndrome and in the retarded population in general. Unlike the linear decline ofIQ in Down syndrome children, it appears that IQ in males with fragile X syndrome shows stability and steady intellectual growth until late childhood or early adolescence. At this point, IQ declines and MA plateaus. This finding of IQ stability followed by decline in early adolescence contradicts Lachiewicz's et al. (1987) conclusion that the IQs of fragile X boys begin to decline in the early childhood years. In the Lachiewicz et al. (1987) study, however, only two of six children (33%) who received a post-test before age 10 showed significant decreases in IQ, while II of IS males (73%) tested after 10 years of age showed significant declines in IQ compared to their earlier (pre-IO) levels. The present study similarly found no significant declines in IQ scores among a small sample of children tested before age 5 and again at 5 to 10 years of age. Both the present investigation and the Lachiewicz et al. (1987) study concur, then, in finding that many fragile X males show a decline in IQ that begins during the late childhood and early adolescent years.
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Although it remains unclear why fragile X males display this stable, then falling trajectory of IQ, Leckman (unpublished data, 1988) observed that the earliest plateauing in cognitive development in these boys (8.5 to 9.5 years) appears to coincide with the earliest signs of pubertal development (testicular enlargement at 8 to 10 years). These preliminary findings suggest that the regulatory factors responsible for the initiation of puberty may play an important role in the plateauing of MA seen in these subjects. This hypothesis raises questions concerning the biologic mechanisms responsible for the normal plateauing of cognitive development that occurs in late adolescence . It may be that the plateauing observed in many fragile X males is a consequence of a precocious activation of these mechanisms. Results from the present study also suggest that the magnitude of IQ decline may be related to levels of IQ established in the early years. Children with higher IQ scores in the 5- to IO-year period showed greater losses in both the 10- to 15and 15- to 20-year periods, while subjects with lower initial IQs manifested less of a decline in their subsequent IQ scores. A similar finding is also apparent in the data published by Lachiewicz et al. (1987), although it was not discussed by these authors in this report . In a correlation calculated with Lachiewicz et al.'s (1987) data, a significant relationship emerged between the initial IQ test score and the difference from pretest to posttest, r(21) = 0.50, p < 0.05. Thus, findings from both the present study and Lachiewicz et al.'s (1987) data suggest that fragile X males with higher initial IQ estimates may manifest more of a decline in IQ scores than boys who initially function within the lower ranges of intelligence. The findings of IQ decline and MA plateau in the present cross-sectional and longitudinal studies have important implications for research with the retarded population in general and for intervention with fragile X males in particular. First, this study demonstrates the importance of using research samples that are based upon etiology of retardation. Although the current tendency is to classify research groups according to level of impairment (e.g., mild, moderate, etc.), this practice may obscure behavioral, cognitive and developmental differences between various etiological groups (Burack et al., 1988). Identifying these differences, including variations in the trajectory of IQ, will ultimately allow for more fine-tuned intervention efforts. Although it is too early to conclude that declines in IQ are an inevitable consequence of fragile X syndrome, findings from the present study may help in plann ing the tim ing and intensity of educational and vocational efforts with fragile X males; indeed these findings provide renewed impetus for the "earlier the better" focus of many intervention programs. In addition, these findings certainly do not imply that development in adaptive or vocational skills will also reach a premature developmental plateau . Indeed, recent research suggests that fragile X males generally exhibit adaptive skills that either exceed or are commensurate with their levels of cognitive abilities (Dykens et al., 1989). Thus, it may be helpful for parents and teachers of fragile X males to be informed about the possibility of an earlier than usual plateau in cognitive development, and that children doing comparatively well in their earlier years may ultimately perform lower on
IQ tests than previously thought. In addition, parents should be informed that this decline in IQ may not be apparent in their child's adaptive behavior. Further research that identifies the specific relationship between the trajectories of IQ and adaptive skills in males with fragile X syndrome is necessary. References Arthur, G. (1962), L eiter International Performance Scale-Author Adoption. New York: Psychological Services. Barnett , W. (1986), Definition and classification of mental retardation : a reply to Zigler, Balla, and Hodapp. Am. 1. Ment. Defic.. 91:111-116. Berrueta-Clement, J., Schweinhart, L., Barnett, W., Epstein, A. & Weikart, C. (1984), Changed lives: the effects of the Perry Preschool Program on youths through age 10. In: Monographs of the HighScope Educational Re search Foundation. Ypsilanti, MI: High/ Scope. Borghgraef M.• Fryns, J.. Dielkens, A.. Pyck, K. & Van Den Berghe, H. (1987). Fragile X syndrome: a stud y of the psychological profile in 23 patients. Clin . Genet.. 32:179-1 86. Bregman, J., Dykens, E., Watson. M., art, S. & Leckman , J. (1987), Fragile X syndrome: variability of phenotypic expression. 1. A m . A cad. Child Adolesc. Psychiatry, 26:461-471. Burack, J.. Hodapp, R. & Zigler, E. (1988), Issues in the classification of mental retardation: differentiating among organic etiologies. J. Child Psychol. Psychiatry, 29:765-779. Cronbach, L. (1975), Five decades of controversy over mental testing. American Psychologist 30:1-14. Cruickshank, W., Hallahan, D. & Bice, H. (1976), The evaluation of intelligence. In: Cerebral palsy: A dev elopmental di sab ility (3rd Ed.), ed. W. Cruickshank. Syracuse, NY: Syracuse Un iversity Press. Dykens, E. M., Hodapp, R. M. & Leckman , J. F. (1989). Adapti ve and maladaptive funct ioning of institut ionalized and non institutionalized fragile X males. J. Am. Acad. Child Adolesc. Psychiatry, 28:427-430. Fisher, M. & Zeaman, D. (1970), Growth and decline of retardate intelligence. International Review of R esearch in Mental Retardation 4:151-191. Fishman, M. & Palkes, H. (1974), The validity of psychometric testing in children with congenital malformations of the central nervous system . Dev. Med. Child Neurol., 16:180-185. Garber, H. & Herber, R. (1981), The efficacy of early intervention with family rehabilitation. In: Research to Practice in Mental Retardation (Vol. I), ed. P. Mittler. Baltimore, MD: Uni versity Park Press. Gibson, D. (1978), Down's Syndrome: Th e Psychology ofM ongolism. Cambridge, England : Cambridge University Press. Gottesman, I. (1968), Biogenetics of race and class. In: Social Class . Race and Psychological Development, ed. M. Deutch, I. Katz & A. Jensen . New York: Holt, Rinehart & Winston . Hagerman, R., Kemper, M. & Hudson, M. (1985), Learn ing disabilities and attentional problems in boys with fragile X syndrome. Am . J. Dis. Child., 139:674-678. Hodapp, R. & Zigler, E. (in press), Applying the developmental persepective to individuals with Down syndrome. In: Down Syndrome: The Developmental Perspective, ed. D. Cicchetti & M. Beechly. New York: Cambridge University Press. Honz ik, M. & MacFarlane, J. (1973), Personality development and intellectual functioning from 21 months to 40 years. In: Intellectual Fun ctioning in Adults, ed. L. Jarvik , C. Eisdorf & J. Blum. New York: Springer. Hunt, J. ( 1971), Parent and child centers: their basis in the behavioral and educational sciences. Am. J. Orth opsychiatry, 41:13-38 . Klapper, K. & Birch, H. (1967), A fourteen year follow-up study of cerebral palsy: intellectual change and stability. Am. J. Orthopsychiatry, 3:540- 547. Kopp , C. & McCall, R. (1982), Predict ing later mental performance for normal , at-risk, and handicapped infants. In: Lifespan Development and Behavior (Vol. 4), ed. P. Baltes & O. Brim. New York:
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Academic Press. Lachiewicz, A., Gullion, c., Spiridigliozzi, G. & Aylsworth, A. (1987), Declining IQs of males with fragile X syndrome. American Journal of Mental Retardation, 92:272-278. Laird, C. (1987), Proposed mechanism of inheritance and expression of the human fragile X syndrome of mental retardation. Genetics, 117:587-599. Leckman J. & Paul, R. (1985), Behavioral issues in fragile X syndrome. Paper presented to the University of Connecticut Symposium on Fragile X syndrome. Hartford, Conn. McCall, R., Appelbaum, M. & Hogarty, P. (1973), Developmental changes in mental performance. Monogr. Soc. Res. Child Dev., 38. Opitz, J. ed. (1984), Xslinked Mental Retardation. New York: Liss. Ramey, c., Campbell, F. & Finkelstein, N. (1984), Course and structure of intellectual development in children at high risk for mental retardation. In: Learning and Cognition in the Mentally Retarded, ed. P. Brooks, R. Sperber & C. McCauley. Hillsdale, NJ: Erlbaum. Ross, R., Begab, M., Dondis, E., Giampiccolo, J., & Meyers, C. (1985), Lives of the Mentally Retarded: A Forty-Year Follow-up
Study. Stanford, CA: Stanford University Press. Seitz, Y., Rosenbaum, L. & Apfel, N. (1985), Effects offamily support intervention. Child Dev., 56:376-391. Silverstein, A. (1982), Note on the constancy of IQ. Am. J. Ment. Defic., 87:227-228. Skodak, M. & Skeels, H. (1949), A final follow-up study of one hundred adopted children. J. Genet. Psychol., 74:84-125. Siosson, R. (1963), Slosson Intelligence Test for Children and Adults. New York: Siosson Educational Publications. Terman, L. & Merrill, M. (1973), Stanford-Binet Intelligence Scale: Manual for the third revision. Form L-M. Boston: HoughtonMimin. Wechsler, D. (1973), Wechsler Intelligence Scale for Children-Revised. New York: Psychological Corporation. - - (1981), Wechsler Adult Intelligence Scale-Revised. New York: Psychological Corporation. Zigler, E. (1970), The nature-nurture issue reconsidered. In: SocialCultural Aspects of Mental Retardation: Proceedings of the Peabody-NIMH Conference, ed. H. C. Haywood. New York, NY: Appleton-Century-Crofts.
The degree to which an individual's IQ remains stable over time has long been debated among researchers studying both nonretarded and retarded populations. A first line of research on the intellectual development of nonretarded individuals has shown that IQ scores are relatively stable, varying only slightly as a result of extremely good or poor environments (Cronbach, 1975; Gottesman, 1968; Zigler, 1970). These claims of IQ stability are substantiated with data from the Berkeley and Fels growth studies, two large longitudinal studies that followed nonretarded persons for spans of up to 50 years (Honzik and Macfarlane, 1973; McCall et al., 1973). Another body of research with nonretarded individuals suggests that IQ fluctuates considerably throughout development. Influenced by Skodak and Skeels' (1949) adoption study of institutionalized infants, modern proponents of this view (e.g., Hunt, 1971) claim that small changes in the child's environment can increase IQ scores by as much as 50 points. Workers associated with the Milwaukee Project (Garber and Herber, 1981), Abecedarian Project (Ramey, et al., 1984), and other early intervention programs have used this evidence to advance the belief that early intervention programs may bolster the IQ scores of at-risk children. Research with mentally retarded individuals also offers conflicting data regarding the long-term stability of intellectual abilities. In a longitudinal study, Silverstein (1982) reported that the IQ scores of educable mentally retarded Accepted December 14, 1988. Drs. Dykens. Hodapp. and Leckman and Ms. Ort are with the Child Study Center, Children ',I' Clinical Research Center, Yale University. Miss Finucane is with the Medical Department ofElwyn, Inc. Dr. Shapiro is with the Medical Genetics Unit, Westchester County Medical Center, Cornell University. This research was supported in part by the John Merck Fund, NIH grants RR00125 and llD03008. and NIMH grants MHI8268 and MH30929. The authors wish to thank Joseph Merighi, Sara Sparrow, Ed Zigler, Donald Cohen, Wendy Marans, Joel Bregman. and Fred Volkmar for their comments on an earlier draft ofthis manuscript. Request reprints from Dr. Leckman, Yale Child Study Center. 230 South Frontage Rd., P. O. Box 3333, New Haven, CT 06510. 0890-8567/89/2803-0422$02.00/0© 1989 by the American Academy of Child and Adolescent Psychiatry. 422
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studied. Fragile X syndrome is a recently identified X-linked disorder resulting in mental retardation, and characteristic physical and behavioral features. This syndrome is estimated to affect I in 2,000 males, making it the second most common genetic cause of mental retardation (Bregman et aI., 1987; Opitz, 1984). The genetic mechanisms responsible for fragile X syndrome remain to be illucidated, with some investigators postulating that multiple genes in the same chromosomal region may be affected (Laird, 1987). The mean IQ score of affected adult males is in the moderately retarded range (35 to 40). Some reports have noted, however, that the intellectual functioning of many younger boys with fragile X syndrome lies in the borderline or mildly retarded range, whereas adult males are more often severely or profoundly retarded (Hagerman et al., 1985; Opitz, 1984). Based on observations of six boys, Borghgraef et al. (1987) suggest that there may be a deterioration of IQ in fragile X males that is related to chronological age. Lachiewicz et al. (1987) found a steady decrease in the IQ scores of fragile X males throughout the childhood years. These authors concluded that the IQ trajectory of males with fragile X syndrome is similar to that seen in Down syndrome: highest in the early years, followed by an increasingly slower rate of development in childhood and adulthood. In contrast to Lachiewicz at al. (1987), our preliminary findings (Leckman and Paul, 1985) indicated that the trajectory of IQ in fragile X males does not involve a simple linear decline as found in the Down syndrome population. Thus, there are conflicting reports regarding the specific trajectory of IQ in this population, but some agreement that IQ scores eventually decline. The present study identified the trajectory of IQ in fragile X males in a large cross-sectional study (Study I) involving four separate fragile X clinics, and in a smaller, longitudinal study (Study 2) spanning the years from ages 5 to 20. In addition, a small number of subjects were examined longitudinally across the prepubertal years (before age 10). The combined cross-sectional and longitudinal approach of the present investigation helped control for possible confounding effects common to this type of research. In the cross-sectional study, for example, data from four medical centers helped control for the possibility that more severely impaired individuals were disproportionately represented in the older subjects, or that institutional effects caused spurious IQ declines. Other problems, such as the need to occasionally combine data from different types of IQ tests (e.g., child, adult, nonverbal), were addressed in the longitudinal study.
--~---,---~---.---~-----, I (,hronolll~H.._;11
-"1!l'
FIG. I. The trajectory of IQ in fragile X males: means and standard deviations at each 5-year interval.
residing at the Southbury Training School in Southbury, Connecticut. For each case record, data were collected concerning the subject's birthdate, date of testing, age at testing, name of intelligence test, and the overall IQ or Mental Age (MA) score. This information was gathered for each testing mentioned in each subject's records. The majority of IQ and MA scores (80%) were based on the Stanford-Binet Intelligence Scale (Terman and Merrill, 1973). Sixteen percent (16%) of the data points were based on either the Wechsler Adult Intelligence Scale (Wechsler, 1981), or the Wechsler Intelligence Scale for Children (Wechsler, 1973),leaving 5% of the subjects with IQ scores derived from either the Leiter International Performance Scale (Arthur, 1962) or the Slosson Intelligence Test for Children and Adults (Slosson, 1963). Results
The findings from all IQ tests from the cross-sectional records review are presented in Figures I and 2. Although these figures show the results with different individuals con-
Study 1
Method Subjects and procedures. For the cross-sectional study, the case records of 56 fragile X males, aged 3 to 35, were examined. Four mental retardation facilities in the northeast United States were involved: 13 records reviewed were from the Medical Genetics Unit at the Westchester County Medical Center in Valhalla, New York; 17 records were from the Genetics Clinic and Child Study Center at the Yale University Medical School in New Haven, Connecticut; 13 were from the Genetics Clinic at the Elywn Institutes in Elywn, Pennsylvania; and data were gathered from 13 fragile X subjects
+-_---L_----,---_---,---
2. The trajectory of mental age in fragile X males: means and standard deviations at each 5-year interval.
FIG.
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tributing different numbers of tests, the findings seem clear. Mean IQs fell from 53.6 during the 5- to 10-year period, to 43.6 from 10 to IS years, to 37.7 from IS to 20 years of age. IQ scores averaged 42.6 from 20 to 25 years, and 37.4 from 25 to 30. Corresponding MAs for this sample show a continual increase until the early teen years, followed by a plateauing that begins earlier than that found in the nonretarded population (i.e., from 16 to 18 years of age). To address the problem of different individuals contributing different numbers of test scores, further analyses were conducted using only the first test score noted for each fragile X subject. Forty-eight of the 56 subjects (86%) received the Stanford-Binet as their first test, four subjects (7%) were administered the Wechsler Intelligence Scale for Children, and the remaining four subjects (7%) received either the Leiter or Siosson as their first test. Results again show that IQ scores decline after approximately 10 years of age. A 2 x 4 (age cohort by center) design using analysis of variance, where age cohort consisted of subjects before age 10, and from 10 to 35, revealed a main effect for time of testing. Mean IQ scores decreased from 52.4 before 10 to 39.1 in the 10 to 35 year period, F(I, 55) = 8.61, p < 0.01. There was also a main effect for place of testing, with the sample from the large, state training school in Connecticut (mean IQ = 32.4) scoring lower than samples from each of the other three centers (mean IQ scores = 53.3, 50.8, and 46.8, respectively), F(3, 55) = 4.20, p < 0.05.
IQ scores and the differences in IQ between the initial IQ levels and the levels at the 10- to 15- and 15- to 20-year periods, respectively. Both of these correlations were significant: the pre-IO IQ and the 10- to IS-year change score correlation was rl.1 0) = 0.64, p < 0.05, and the pre-I 0 IQ and 15- and 20-year change score correlation was rl.1 0) = 0.66, p < 0.05. Thus, subjects who had higher IQ scores in the 5- to 10-year period showed greater losses in IQ during both the 10- to 15- and 15- to 20-year periods. Conversely, subjects with lower IQ scores before age 10 manifested less of a decline in subsequent IQ scores. In order to determine whether the changes in IQ trajectory beginning in the early teen years are not simply reflective of a general slowing of development beginning in infancy (as in Down syndrome), a matched t test was performed using six subjects for whom IQ scores were available before the age of 5 and from 5 to 10 years of age. Subjects included two of the 10 longitudinal subjects and four subjects from Study 1. Five subjects were administered the Stanford-Binet at each testing, and one subject received the Siosson and the Stanford-Binet, Results show that there does not appear to be a significant decline in IQ scores before age 10, t(5) = 0.08, NS. The mean IQ score before age 10 was 63.7, and the mean IQ from 5 to 10 was 63.5. Two subjects manifested a mean increase in IQ of 9 points from the earlier to later period, three subjects manifested a mean decrease in IQ of 5 points, and one subject stayed the same.
Study 2
Discussion
Method Subjects and procedures. In the second, longitudinal study, 10 males with fragile X syndrome were examined one or more times at three points: ( I) before age 10, (2) from 10 to IS, and (3) from IS to 20 years of age. For each subject, mean IQ scores were calculated from all tests administered within a given 5-year period. The mean number of tests given during each 5-year period was 1.7 (range = I to 4). Eight of the 10 subjects were administered Stanford-Binets at each testing, one subject received the Wechsler Intelligence Scale for Children at each testing, and one subject was administered a combination of Stanford-Binets and Siossons. All of the 10 subjects lived at home; eight boys were examined through the Yale Child Study Center and two were examined through programs of Elwyn Institutes. Results A one-way repeated measures ANDYA indicated that IQ scores differed significantly across the three age spans, F(2, 18) = 15.45, p < 0.001. IQ scores declined from a mean of 53.8 during the 5- to IO-year period, to 47.2 from 10 to IS years of age, to 40.6 from IS to 20. Post-hoc analyses (Newman-Keuls) revealed significant changes between the 5- to 10year level and each subsequent period, as well as a difference between the 10- to 15- and 15- to 20-year levels. Additional analyses were conducted to determine whether the IQ score obtained during the initial 5- to IO-year period predicted the degree to which subjects declined in IQ. Correlations were calculated between subjects' initial 5- to 10-year
Data from both the cross-sectional and longitudinal studies suggest a pattern of IQ trajectory in fragile X males of relative stability and steady growth until the ages of approximately 10 to 15, after which IQ declines and MA plateaus. The combined cross-sectional and longitudinal approach of the present study reduces the possibility that these findings are due to spurious changes in IQ scores resulting from subject or test selection factors. The finding of IQ stability and subsequent decline in fragile X males is consistent with the authors' preliminary observations (Leckman and Paul, 1985), yet contradicts other data pertaining to the trajectory of IQ in fragile X syndrome and in the retarded population in general. Unlike the linear decline ofIQ in Down syndrome children, it appears that IQ in males with fragile X syndrome shows stability and steady intellectual growth until late childhood or early adolescence. At this point, IQ declines and MA plateaus. This finding of IQ stability followed by decline in early adolescence contradicts Lachiewicz's et al. (1987) conclusion that the IQs of fragile X boys begin to decline in the early childhood years. In the Lachiewicz et al. (1987) study, however, only two of six children (33%) who received a post-test before age 10 showed significant decreases in IQ, while II of IS males (73%) tested after 10 years of age showed significant declines in IQ compared to their earlier (pre-IO) levels. The present study similarly found no significant declines in IQ scores among a small sample of children tested before age 5 and again at 5 to 10 years of age. Both the present investigation and the Lachiewicz et al. (1987) study concur, then, in finding that many fragile X males show a decline in IQ that begins during the late childhood and early adolescent years.
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Although it remains unclear why fragile X males display this stable, then falling trajectory of IQ, Leckman (unpublished data, 1988) observed that the earliest plateauing in cognitive development in these boys (8.5 to 9.5 years) appears to coincide with the earliest signs of pubertal development (testicular enlargement at 8 to 10 years). These preliminary findings suggest that the regulatory factors responsible for the initiation of puberty may play an important role in the plateauing of MA seen in these subjects. This hypothesis raises questions concerning the biologic mechanisms responsible for the normal plateauing of cognitive development that occurs in late adolescence . It may be that the plateauing observed in many fragile X males is a consequence of a precocious activation of these mechanisms. Results from the present study also suggest that the magnitude of IQ decline may be related to levels of IQ established in the early years. Children with higher IQ scores in the 5- to IO-year period showed greater losses in both the 10- to 15and 15- to 20-year periods, while subjects with lower initial IQs manifested less of a decline in their subsequent IQ scores. A similar finding is also apparent in the data published by Lachiewicz et al. (1987), although it was not discussed by these authors in this report . In a correlation calculated with Lachiewicz et al.'s (1987) data, a significant relationship emerged between the initial IQ test score and the difference from pretest to posttest, r(21) = 0.50, p < 0.05. Thus, findings from both the present study and Lachiewicz et al.'s (1987) data suggest that fragile X males with higher initial IQ estimates may manifest more of a decline in IQ scores than boys who initially function within the lower ranges of intelligence. The findings of IQ decline and MA plateau in the present cross-sectional and longitudinal studies have important implications for research with the retarded population in general and for intervention with fragile X males in particular. First, this study demonstrates the importance of using research samples that are based upon etiology of retardation. Although the current tendency is to classify research groups according to level of impairment (e.g., mild, moderate, etc.), this practice may obscure behavioral, cognitive and developmental differences between various etiological groups (Burack et al., 1988). Identifying these differences, including variations in the trajectory of IQ, will ultimately allow for more fine-tuned intervention efforts. Although it is too early to conclude that declines in IQ are an inevitable consequence of fragile X syndrome, findings from the present study may help in plann ing the tim ing and intensity of educational and vocational efforts with fragile X males; indeed these findings provide renewed impetus for the "earlier the better" focus of many intervention programs. In addition, these findings certainly do not imply that development in adaptive or vocational skills will also reach a premature developmental plateau . Indeed, recent research suggests that fragile X males generally exhibit adaptive skills that either exceed or are commensurate with their levels of cognitive abilities (Dykens et al., 1989). Thus, it may be helpful for parents and teachers of fragile X males to be informed about the possibility of an earlier than usual plateau in cognitive development, and that children doing comparatively well in their earlier years may ultimately perform lower on
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