American Journal of Medical Genetics zyx 43:2&34 (1992) Longitudinal Changes in I& Among Fragile X Males: zy Clinical Evidence of More Than One Mutation? G.S. Fisch, L.R. Shapiro, R. Simensen, C.E. Schwartz, J.P. Fryns, M. Borghgraef, L.M. Curfs, P.N. Howard-Peebles, T. Arinami, and A. Mavrou zyxwvu Department zyxwvutsrqpo of Psychiatry, Kings County Hospital, SUNYIHealth Science Center, Brooklyn, New York zyxw (G.S.F.)'; Departments of Pediatrics and Pathology, New York Medical College and Westchester County Hospital, Valhalla, New York, Regional Medical Genetics Laboratory, Thiells, New York (L.R.S.); Greenwood Genetics Center, Self Memorial Hospital, Greenwood, South Carolina (R.S., C.E.S.); Centre for Human Genetics, Leuven, Belgium (J.P.F., M.B., L.M.C.); Genetics and NF Institute, Fairfax, and Medical College of Virginia, Richmond, Virginia (P.N.H.-P.); Institute of Basic Medical Science, Ibaraki, Japan (TAJ; Aghia Sophia Children's Hospital, Athens, Greece (A.M.) Longitudinal changes in IQ among mentally retarded (MR) fragile X [fra(x)] males have been reported previously. While age is associated with decline in IQ, not all males are so affected. This suggests that there may be more than one subtype of affected fra(X) male. Therefore, we examined the distribution of standardized difference scores (Zdiff) in IQ to determine if subjects were from an admixture of at least 2 populations. Cluster analysis of Zdiff scores was used to partition subjects into 2 groups. Goodness-of-fit tests indicated that scores were more likely to come from an admixture. Discriminant functions (DF) were calculated to determine predictive validity of Zdiff scores. To eliminate the effect of skewing, a power transform was applied to Zdiff scores and DFs recomputed. Zdiff and transformed scores provided similar results. The mean and variance for one group showed no differences in test- retest scores as would be expected from examining any population while the mean for the second group indicated significant decline in IQ nearly 4 standard errors below the first test score. These results suggest that there may be clinical evidence for 2 types of fra(X) mutation: One which causes MR but is static, and a second mutation which causes MR but is dynamic and contributes to an apparent longitudinal decline in cognitive function. zyx KEY WORDS: heterogeneity, admixture analysis, cognitive development, X-linked mental retardation INTRODUCTION Previously, researchers have found longitudinal changes in IQ among fra(X) males. Lachiewicz et d. [1987] and Hagerman et zyx al. [1989] found significant declines in IQ while Fisch et al. [1991] found both significant increases and decreases. Although age has been identified as a salient factor in IQ decline, not all males appear to be so affected. Moreover, factors ~ Receivedfor publication September 30, 1991; revision received January 30, 1992. 'Address reprint requests to: Gene S. Fisch, Ph.D., Director of Research, Division of Child/Adolescent Psychiatry, Kings County Hospital, 451 Clarkson Ave., Brooklyn, NY 11203. zyxwv 0 1992 Wiley-Liss, Inc.