Neurodevelopmental effects of the FMR-1 full mutation in humans
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. Neuroanatomical 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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MRI studies have found that individuals with Fragile X syndrome have enlarged lateral ventricles and increased caudate nucleus volumes relative to control subjects.
“MRI studies have found that individuals with FXS have enlarged lateral ventricles and increased caudate nucleus volumes relative to control subjects (Reiss et al., 1995).”
From Oxytocin and vasopressin systems in genetic syndromes and neurodevelopmental disorders (2014) · cites this paper as Reiss et al., 1995
Cites
Verkerk, A. J. M. H., Pieretti, M., Sutcliffe, J. S., Fu, Y.-H., Kuhl, D. P. A., Pizzuti, A., Reiner, O., Richards, S., Victoria, M. F., Zhang, F., et al. (1991) · Cell · doi:10.1016/0092-8674(91)90397-h · Cited by 3,481 · see citing works
Calabrese, V. P. (1992) · JAMA · doi:10.1001/jama.1992.03490230111048 · Cited by 2,517 · see citing works
Frontal-subcortical circuits and human behavior
Cummings, J. L. (1993) · Archives of Neurology · doi:10.1001/archneur.1993.00540080076020 · Cited by 2,262 · see citing works
Individual-specific ‘fingerprints’ of human DNA
Jeffreys, A. J., Wilson, V., & Thein, S. L. (1985) · Nature · doi:10.1038/316076a0 · Cited by 2,172 · see citing works
Mechanisms and Functions of Cell Death
Ellis, R. E., Yuan, J., & Horvitz, H. R. (1991) · Annual Review of Cell Biology · doi:10.1146/annurev.cb.07.110191.003311 · Cited by 2,063 · see citing works
Instability of a 550-Base Pair DNA Segment and Abnormal Methylation in Fragile X Syndrome
Oberlé, I., Rousseau, F., Heitz, D., Kretz, C., Devys, D., Hanauer, A., Boué, J., Bertheas, M. F., & Mandel, J. L. (1991) · Science · doi:10.1126/science.252.5009.1097 · Cited by 1,499 · see citing works
Absence of expression of the FMR-1 gene in fragile X syndrome
Pieretti, M., Zhang, F., Fu, Y.-H., Warren, S. T., Oostra, B. A., Caskey, C. T., & Nelson, D. L. (1991) · Cell · doi:10.1016/0092-8674(91)90125-i · Cited by 1,476 · see citing works
Hengartner, M. O., & Horvitz, H. R. (1994) · Cell · doi:10.1016/0092-8674(94)90506-1 · Cited by 1,167 · see citing works
The Young Adult Human Brain: An MRI-based Morphometric Analysis
Filipek, P. A., Richelme, C., Kennedy, D. N., & Caviness, V. S. (1994) · Cerebral Cortex · doi:10.1093/cercor/4.4.344 · Cited by 643 · see citing works
The protein product of the fragile X gene, FMR1, has characteristics of an RNA-binding protein.
Siomi, H., Siomi, M. C., Nussbaum, R. L., & Dreyfuss, G. (1993) · Cell · doi:10.1016/0092-8674(93)90420-u · Cited by 641 · see citing works
Prevention of Programmed Cell Death in Caenorhabditis elegans by Human bcl-2
Vaux, D. L., Weissman, I. L., & Kim, S. K. (1992) · Science · doi:10.1126/science.1470921 · Cited by 614 · see citing works
Analysis of neocortex in three males with the Fragile X syndrome
Hinton, V. J., Brown, W. T., Wisniewski, K., & Rudelli, R. D. (1991) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320410306 · Cited by 527 · see citing works
Adult fragile X syndrome: Clinico-neuropathologic findings
Rudelli, R. D., Brown, W. T., Wisniewski, K., Jenkins, E. C., Laure-Kamionowska, M., Connell, F., & Wisniewski, H. M. (1985) · Acta Neuropathologica · doi:10.1007/bf00687814 · Cited by 362 · see citing works
Characterization and localization of the FMR-1 gene product associated with fragile X syndrome
Verheij, C., Bakker, C. E., de Graaff, E., Keulemans, J., Willemsen, R., Verkerk, A. J. M. H., Galjaard, H., Reuser, A. J. J., Hoogeveen, A. T., & Oostra, B. A. (1993) · Nature · doi:10.1038/363722a0 · Cited by 343 · see citing works
Ashley, C. T., Sutcliffe, J. S., Kunst, C. B., Leiner, H. A., Eichler, E. E., Nelson, D. L., & Warren, S. T. (1993) · Nature Genetics · doi:10.1038/ng0793-244 · Cited by 269 · see citing works
Specification of the Neurobehavioral Phenotype in Males with Fragile X Syndrome
Baumgardner, T. L., Reiss, A. L., Freund, L. S., & Abrams, M. T. (1995) · PEDIATRICS · doi:10.1542/peds.95.5.744 · Cited by 245 · see citing works
Self-citationMRI‐Based Hippocampal Volume Measurements in Epilepsy
Jack, C. R. (1994) · Epilepsia · doi:10.1111/j.1528-1157.1994.tb05986.x · Cited by 224 · see citing works
Sugimoto, A., Friesen, P. D., & Rothman, J. H. (1994) · The EMBO Journal · doi:10.1002/j.1460-2075.1994.tb06475.x · Cited by 201 · see citing works
Psychiatric Disorders Associated With Fragile X in the Young Female
Freund, L. S., Reiss, A. L., & Abrams, M. T. (1993) · PEDIATRICS · doi:10.1542/peds.91.2.321 · Cited by 199 · see citing works
Self-citationNeuroanatomy of fragile X syndrome
Reiss, A. L., Lee, J. C., & Freund, L. S. (1994) · Neurology · doi:10.1212/wnl.44.7.1317 · Cited by 189 · see citing works
Self-citationCognitive profiles associated with the fra(X) syndrome in males and females
Freund, L. S., & Reiss, A. L. (1991) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320380409 · Cited by 189 · see citing works
Self-citationFine structure of the human FMR1 gene
Eichler, E. E., Richards, S., Gibbs, R. A., & Nelson, D. L. (1993) · Human Molecular Genetics · doi:10.1093/hmg/2.8.1147 · Cited by 188 · see citing works
Neuroanatomy of fragile X syndrome: The posterior fossa
Reiss, A. L., Aylward, E., Freund, L. S., Joshi, P. K., & Bryan, R. N. (1991) · Annals of Neurology · doi:10.1002/ana.410290107 · Cited by 173 · see citing works
Self-citationThe effects of X monosomy on brain development: Monozygotic twins discorcant for Turner's syndrome
Reiss, A. L., Freund, L. S., Plotnick, L., Baumgardner, T. L., Green, K., Sozer, A. C., Reader, M. J., Boehm, C. D., & DENCKLA, M. B. (1993) · Annals of Neurology · doi:10.1002/ana.410340117 · Cited by 156 · see citing works
Self-citationFragile X syndrome: genetic predisposition to psychopathology
Bregman, J. D., Leckman, J. F., & Ort, S. I. (1988) · Journal of Autism and Developmental Disorders · doi:10.1007/bf02212191 · Cited by 150 · see citing works
Programmed cell death: Implications for neuropsychiatric disorders
Margolis, R. L., Chuang, D., & Post, R. M. (1994) · Biological Psychiatry · doi:10.1016/0006-3223(94)91241-6 · Cited by 144 · see citing works
Social gaze, social avoidance, and repetitive behavior in fragile X males: a controlled study.
Cohen, I. L., Fisch, G. S., Sudhalter, V., Wolf‐Schein, E. G., Hanson, D., Hagerman, R. J., Ec, J., & Brown, W. T. (1988) · PubMed · Cited by 138 · see citing works
Behavioral phenotype of fragile X syndrome: DSM‐III‐R autistic behavior in male children
Reiss, A. L., & Freund, L. S. (1992) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320430106 · Cited by 138 · see citing works
Self-citationAlternative splicing in the fragile X gene FMR1
Verkerk, A. J. M. H., de Graaff, E., Boulle, K. D., Eichler, E. E., Konecki, D. S., Reyniers, E., Manca, A., Poustka, A., Willems, P. J., Nelson, D. L., et al. (1993) · Human Molecular Genetics · doi:10.1093/hmg/2.8.1348 · Cited by 138 · see citing works
Cognitive profiles of boys with the fragile X syndrome
Kemper, M. B., Hagerman, R. J., & Altshul‐Stark, D. (1988) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320300118 · Cited by 134 · see citing works
Why are autism and the fragile-X syndrome associated? Conceptual and methodological issues.
Cohen, I. L., Sudhalter, V., Pfadt, A., et al. (1991) · PubMed · Cited by 120 · see citing works
D’Mello, S. R., Anelli, R., & Calissano, P. (1994) · Experimental Cell Research · doi:10.1006/excr.1994.1095 · Cited by 118 · see citing works
Molecular‐neurobehavioral associations in females with the fragile X full mutation
Abrams, M. T., Reiss, A. L., Freund, L. S., Baumgardner, T. L., Chase, G. A., & DENCKLA, M. B. (1994) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320510407 · Cited by 112 · see citing works
Self-citationRousseau, F., Heitz, D., Oberlé, I., & Mandel, J. (1991) · Journal of Medical Genetics · doi:10.1136/jmg.28.12.830 · Cited by 110 · see citing works
The Trajectory of Cognitive Development in Males with Fragile X Syndrome
Dykens, E. M., Hodapp, R. M., Ort, S., Finucane, B. M., SHAPIRO, L. R., & Leckman, J. F. (1989) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/00004583-198905000-00020 · Cited by 106 · see citing works
Alternative splicing in the fragile X gene FMR1
Verkerk, A. J. M. H., de Graaff, E., Boulle, K. D., Eichler, E. E., Konecki, D. S., Reyniers, E., Manca, A., Poustka, A., Willems, P. J., Nelson, D. L., et al. (1993) · Human Molecular Genetics · doi:10.1093/hmg/2.4.399 · Cited by 101 · see citing works
Longitudinal IQ changes in fragile X males
Hagerman, R. J., Schreiner, R. A., Kemper, M. B., Wittenberger, M. D., Zahn, B., & Habicht, K. (1989) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320330422 · Cited by 89 · see citing works
Neuroanatomy in fragile X females: the posterior fossa.
Reiss, A. L., Freund, L. S., Tseng, J. E., & Joshi, P. K. (1991) · PubMed · Cited by 87 · see citing works
Self-citationDeclining IQs of young males with the fragile X syndrome.
Lachiewicz, A. M., Gullion, C. M., Spiridigliozzi, G. A., & Aylsworth, A. S. (1987) · PubMed · Cited by 86 · see citing works
Developmental Implications of Changing Trajectories of IQ in Males with Fragile X Syndrome
Hodapp, R. M., Dykens, E. M., Hagerman, R. J., Schreiner, R. A., Lachiewicz, A. M., & Leckman, J. F. (1990) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/00004583-199003000-00009 · Cited by 84 · see citing works
Syntactic delay and pragmatic deviance in the language of fragile X males
Sudhalter, V., Scarborough, H. S., & Cohen, I. L. (1991) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320380270 · Cited by 83 · see citing works
Frequency and stability of the fragile X premutation
Reiss, A. L., Kazazian, H. H., Krebs, C. M., McAughan, A., Boehm, C. D., Abrams, M. T., & Nelson, D. L. (1994) · Human Molecular Genetics · doi:10.1093/hmg/3.3.393 · Cited by 81 · see citing works
Self-citationMolecular genetics of cell death in the nematode Caenorhabditis elegans
Driscoll, M. (1992) · Journal of Neurobiology · doi:10.1002/neu.480230919 · Cited by 78 · see citing works
Crowe, S. F., & Hay, D. A. (1990) · Neuropsychologia · doi:10.1016/0028-3932(90)90082-y · Cited by 77 · see citing works
Gibson, T. J., Rice, P. M., Thompson, J., & Heringa, J. (1993) · Trends in Biochemical Sciences · doi:10.1016/0968-0004(93)90068-x · Cited by 67 · see citing works
Fragile X syndrome: Growth, development, and intellectual function
Prouty, L. A., Rogers, R. C., Stevenson, R. E., Dean, J. H., Palmer, K. K., Simensen, R. J., Coston, G. N., & Schwartz, C. E. (1988) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320300111 · Cited by 62 · see citing works
Individual variation and specific cognitive deficits in the fra(X) syndrome
Theobald, T. M., Hay, D. A., Judge, C., et al. (1987) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320280102 · Cited by 56 · see citing works
Lachiewicz, A. M., & Dawson, D. V. (1994) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320510413 · Cited by 43 · see citing works
Subcognitive Processing in the Frontocaudate “Complex Loop”
Taylor, A. E., Saint‐Cyr, J. A., & Lang, A. E. (1990) · Alzheimer Disease & Associated Disorders · doi:10.1097/00002093-199040300-00003 · Cited by 17 · see citing works
Neuropsychiatric Aspects of Fragile X Syndrome.
Levitas, A. S. (1996) · PubMed · doi:10.1053/scnp00100154 · Cited by 17 · see citing works
Intelligence and cognitive profile in the fra(X) syndrome: a longitudinal study in 18 fra(X) boys.
Curfs, L., Schreppers-Tijdink, G. A. J., Wiegers, A. M., et al. (1989) · Journal of Medical Genetics · doi:10.1136/jmg.26.7.443 · Cited by 14 · see citing works
Longitudinal changes in IQ among fragile X females: A preliminary multicenter analysis
Fisch, G. S., Simensen, R. J., Arinami, T., et al. (1994) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320510411 · Cited by 13 · see citing works
The psychological effects associated with fragile X syndrome
Baumgardner, T. L., Green, K., & Reiss, A. L. (1992) · Current Opinion in Pediatrics · doi:10.1097/00008480-199208000-00008 · Cited by 6 · see citing works
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D'Hooge, R., Nagels, G., Franck, F., Bakker, C. E., Reyniers, E., Storm, K., Kooy, R. F., Oostra, B. A., Willems, P. J., & De Deyn, P. P. (1997) · Neuroscience · doi:10.1016/s0306-4522(96)00224-2 · Cited by 208 · see citing works
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“Several studies suggest the existence of similar pathophysiological and anatomical mechanisms in ASD and FXS, particularly in the sensory processing domain (Belmonte and Bourgeron, 2006; Feinstein and Reiss, 1998; Hagerman, 2006; Pickett and London, 2005; Reiss et al., 1995).”
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- Authors
- Reiss, A. L., Abrams, M. T., Greenlaw, R., Freund, L., & Denckla, M. B.
- Affiliations
- Kennedy Krieger Institute (US)
- Venue
- Nature Medicine
- Published
- 1995-02
- Volume
- 1
- Issue
- 2
- Pages
- 159-167
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2082078122
- Cited by
- 242
- References
- 53
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 4 · 2022: 1 · 2021: 2 · 2020: 5 · 2019: 2 · 2018: 2 · 2017: 4 · 2016: 5 · 2015: 7 · 2014: 10 · 2013: 10 · 2012: 6
- FWCI
- 8.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p50hd025806-05)
- National Institute of Mental Health (MH01142, K02MH001142)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD24061, HD25806, P30HD024061)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- fragile X syndrome, neurodevelopmental disorders, caudate nucleus volume, lateral ventricle volume, cerebellum, IQ, monozygotic twins, brain structure
- MeSH terms
- Adolescent, Adult, Age Factors, Brain, Child, Child, Preschool, Diseases in Twins, DNA, Female, Fragile X Syndrome, Humans, Intelligence, Magnetic Resonance Imaging, Male, Intellectual Disability, Methylation, Mutation, Nerve Tissue Proteins, Sex Factors, Twins, Monozygotic, Matched-Pair Analysis, RNA-Binding Proteins, Fragile X Messenger Ribonucleoprotein 1
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