Abstract
Brain dysfunction is the most important sequelae of the fragile X (FMR-1) mutation, the most common heritable cause of developmental disability. Using magnetic resonance imaging (MRI) and quantitative morphometry, we have compared the neuroanatomy of 51 individuals with an FMR-1 mutation with matched controls and showed that subjects with an FMR-1 mutation have increased volume of the caudate nucleus and, in males, the lateral ventricle. Both caudate and lateral ventricular volumes are correlated with IQ. Caudate volume is also correlated with the methylation status of the FMR-1 gene. Neuroanatom-ical differences between two monozygotic twins with an FMR-1 mutation who are discordant for mental retardation are localized to the cerebellum, lateral ventricles and subcortical nuclei. These findings suggest that the FMR-1 mutation causing the fragile X syndrome leads to observable changes in neuroanatomy that may be relevant to the neurodevelopmental disability and behavioural problems observed in affected individuals.
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References
Sherman, S. Epidemiology. in The Fragile X Syndrome (eds Hagerman, R.J. & Cronister, A.C.) 69–86 (Johns Hopkins Univ. Press, Baltimore, 1991).
Reiss, A.L. et al. Frequency and stability of the fragile X premutation. Hum. molec. Genet. 3, 393–398 (1994).
Verkerk, A.J. et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905–914 (1991).
Curfs, L.M., Schreppers, T.G., Wiegers, A., Borghgraef, M. & Fryns, J.P. Intelligence and cognitive profile in the fra(X) syndrome: A longitudinal study in 18 fra(X) boys. J. med. Genet. 26, 443–446 (1989).
Dykens, E.M. et al. The trajectory of cognitive development in males with fragile X syndrome. J. Am. Acad. Child Adolesc. Psychiat. 28, 422–426 (1989).
Fisch, G.S., Simensen, R., Arinami, T., Borghgraef, M. & Fryns, J.P. Longitudinal changes in IQ among fragile X females: A preliminary multicenter analysis. Am. J. med. Genet. 51, 353–357 (1994).
Hagerman, R.J. et al. Longitudinal IQ changes in fragile X males. Am. J. med. Genet. 33, 513–518 (1989).
Lachiewicz, A.M., Gullion, C.M., Spiridigliozzi, G.A. & Aylsworth, A.S. Declining IQs of young males with the fragile X syndrome. Am. J. ment. Retard. 92, 272–278 (1987).
Pennington, B., Schreiner, R. & Sudhalter, V. Towards a neuropsychology of fragile X syndrome in The Fragile X Syndrome (eds Hagerman, R.J. & Cronister, A.C.) 173–201 (Johns Hopkins Univ. Press, Baltimore, 1991).
Baumgardner, T., Green, K. & Reiss, A.L. The psychological effects associated with fragile X syndrome. Curr. Opin. Pediat. 4, 609–615 (1992).
Bregman, J.D., Leckman, J.F. & Ort, S.I. Fragile X syndrome: Genetic predisposition to psychopathology. J. Autism. Dev. Disord. 18, 343–354 (1988).
Hagerman, R.J. Physical and behavioural phenotype. in Fragile X Syndrome (eds Hagerman, R.J. & Cronister, A.C.) 3–68 (Johns Hopkins Univ. Press, Baltimore, 1991).
Reiss, A. & Freund, L. Neuropsychiatric aspects of fragile X syndrome. Brain Dysfunct. 3, 9–22 (1990).
Reiss, A.L. & Freund, L. Behavioural phenotype of fragile X syndrome: DSM-III-R autistic behaviour in male children. Am. J. med. Genet. 43, 35–46 (1992).
Cohen, I.L. et al. Social gaze, social avoidance, and repetitive behaviour in fragile X males: a controlled study. Am. J. ment. Retard. 92, 436–446 (1988).
Baumgardner, T., Reiss, A.L., Freund, L. & Abrams, M. Specification of the neurobehavioural phenotype in males with fragile X syndrome. Pediatrics in the press.
Sudhalter, V., Scarborough, H.S. & Cohen, I.L. Syntactic delay and pragmatic deviance in the language of fragile X males. Am. J. med. Genet. 38, 493–497 (1991).
Cohen, I.L. et al. Why are autism and the fragile-X syndrome associated? Conceptual and methodological issues. Am. J. hum. Genet. 48, 195–202 (1991).
Freund, L.S. & Reiss, A.L. Cognitive profiles associated with the fra(X) syndrome in males and females. Am. J. med. Genet. 38, 542–547 (1991).
Kemper, M.B., Hagerman, R.J. & Altshul, S.D. Cognitive profiles of boys with the fragile X syndrome. Am. J. med. Genet. 30, 191–200 (1988).
Crowe, S.F. & Hay, D.A. Neuropsychological dimensions of the fragile X syndrome: Support for a non-dominant hemisphere dysfunction hypothesis. Neuropsychologia 28, 9–16 (1990).
Theobald, T.M., Hay, D.A. & Judge, C. Individual variation and specific cognitive deficits in the fra(X) syndrome. Am. J. med. Genet. 28, 1–11 (1987).
Lachiewicz, A.M. & Dawson, D.V. Behaviour problems of young girls with fragile X syndrome: Factor scores on the Conners' Parent's Questionnaire. Am. J. med. Genet. 51, 364–369 (1994).
Freund, L.S., Reiss, A.L. & Abrams, M.T. Psychiatric disorders associated with fragile X in the young female. Pediatrics 91, 321–329 (1993).
Freund, L.S. & Reiss, A.L. A neurocognitive phenotype of young males and females with fragile X. Dev. Neuropsych. in the press.
Prouty, L.A. et al. Fragile X syndrome: growth, development, and intellectual function. Am. J. med. Genet. 30, 123–142 (1988).
Hinton, V.J., Brown, W.T., Wisniewski, K. & Rudelli, R.D. Analysis of neocortex in three males with the fragile X syndrome. Am. J. med. Genet. 41, 289–294 (1991).
Rudelli, R.D. et al. Adult fragile X syndrome. Clinico-neuropathologic findings. Acta. neuropath. (Berl) 67, 289–295 (1985).
Reiss, A.L., Aylward, E., Freund, L.S., Joshi, P.K. & Bryan, R.N. Neuroanatomy of fragile X syndrome: the posterior fossa. Ann. Neurol. 29, 26–32 (1991).
Reiss, A.L., Lee, J. & Freund, L. Neuroanatomy of fragile X syndrome: The temporal lobe. Neurology 44, 1317–1324 (1994).
Reiss, A.L., Freund, L., Tseng, J.E. & Joshi, P.K. Neuroanatomy in fragile X females: The posterior fossa. Am. J. hum. Genet. 49, 279–288 (1991).
Bayley, N. Bayley Scales of Infant Development, Second Edition Manual (The Psychological Corporation, San Antonio, 1993).
Thorndike, R., Hagen, E. & Sattler, J. Guide for Administering and Scoring the Fourth Edition Stanford-Binet Intelligence Scale (Riverside, Chicago, 1986).
Wechsler, D. WISC-R Manual: Wechsler Intelligence Scale for Children-Revised (The Psychological Corporation, New York, 1974).
Filipek, P.A., Richelme, C., Kennedy, D.N. & Caviness, V.S. The young adult human brain: An MRI-based morphometric analysis. Cerebral Cortex in the press.
Abrams, M.T. et al. Molecular-neurobehavioural associations in females with the fragile X full mutation. Am. J. med. Genet. 51, 317–327 (1994).
Pieretti, M. et al. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 66, 817–822 (1991).
Jeffreys, A.J., Wilson, V. & Thein, S.L. Individual specific fingerprints of human DNA. Nature 316, 76–79 (1985).
Jack, C.R. MRI-based hippocampal volume measurements in epilepsy. Epilepsia 35, S21–S29 (1994).
Cote, L. & Crutcher, M.D. The basal ganglia. in Principles of Neural Science (eds Kandel, E.R., & Schwartz, J.H.) 647–659 (New York, New York, 1991).
Cummings, J.L. Frontal-subcortical circuits and human behaviour. Arch Neurol 50, 873–880 (1993).
Taylor, A.E., Saint, C.J. & Lang, A.E. Subcognitive processing in the fron-tocaudate “complex loop”: The role of the striatum. Alzheimer Dis. Assoc. Disord. 4, 150–160 (1990).
Mesulam, M.-M. Patterns in behavioural neuroanatomy: association areas, the limbic system, and hemispheric specialization. in Principles of Behavioural Neurology (eds Mesulam, M.-M.) 1–70 (Davis, Philadelphia, 1985).
Hodapp, R.M. et al. Developmental implications of changing trajectories of IQ in males with fragile X syndrome. J. Am. Acad. Child. Adolesc. Psychiat. 29, 214–219 (1990).
Rousseau, F., Heitz, D., Oberle, I. & Mandel, J.-L. Selection in blood cells from female carriers of the fragile X syndrome: Inverse correlation between age and proportion of active X chromosomes carrying the full mutation. J. med. Genet. 28, 830–836 (1991).
Siomi, H., Siomi, M.C., Nussbaum, R.L. & Dreyfuss, G. The protein product of the fragile X gene, FMR1, has characteristics of an RNA-binding protein. Cell 74, 291–298 (1993).
Gibson, T.J., Rice, P.M., Thompson, J.D. & Heringa, J. KH domains within the FMR1 sequence suggest that fragile X syndrome stems from a defect in RNA metabolism. Trends Biochem. Sci. 18, 331–333 (1993).
Verkerk, A.J. et al. Alternative splicing in the fragile X gene FMR1. Hum. molec. Genet. 2, 399–404 (1993).
Verheij, C. et al. Characterization and localization of the FMR-1 gene product associated with fragile X syndrome. Nature 363, 722–724 (1993).
Eichler, E.E., Richards, S., Gibbs, R.A. & Nelson, D.L. Fine structure of the human FMR1 gene. Hum. molec. Genet. 2, 1147–1153 (1993).
Ashley, C.T. et al. Human and murine FMR-1: alternative splicing and translational initiation downstream of the CGG-repeat. Nature Genet. 4, 244–251 (1993).
Margolis, R.L., Chuang, D.-M. & Post, R.M. Programmed cell death: implications for neuropsychiatric disorders. Biol. Psychiat. 35, 946–956 (1994).
Sugimoto, A., Friesen, P.D. & Rothman, J.H. Baculovirus p35 prevents developmentally programmed cell death and rescues a ced-9 mutant in the nematode Caenorhabditis elegans . EMBOJ. 13, 2023–2028 (1994).
Driscoll, M. Molecular genetics of cell death in the nematode Caenorhabditis elegans . J. Neurobiol. 23, 1327–1351 (1992).
Ellis, R.E., Yuan, J.Y. & Horvitz, H.R. Mechanisms and functions of cell death. Ann. Rev. Cell. Biol. 7, 663–698 (1991).
Hengartner, M.O. & Horvitz, H.R. C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell 76, 665–676 (1994).
Vaux, D.L., Weissman, I.L. & Kim, S.K. Prevention of programmed cell death in Caenorhabditis elegans by human bcl-2. Science 258, 1955–1957 (1992).
D'Mello, S.R., Anelli, R. & Calissano, P. Lithium induces apoptosis in immature cerebellar granule cells but promotes survival of mature neurons. Exp. Cell Res. 211, 332–338 (1994).
Oberle, I. et al. Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science 252, 1097–1102 (1991).
Reiss, A.L. et al. The effects of X monosomy on brain development: Monozygotic twins discordant for Turner's syndrome. Ann. Neurol. 34,
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Reiss, A., Abrams, M., Greenlaw, R. et al. Neurodevelopmental effects of the FMR-1 full mutation in humans. Nat Med 1, 159–167 (1995). https://doi.org/10.1038/nm0295-159
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DOI: https://doi.org/10.1038/nm0295-159
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