The neuroanatomy and neuroendocrinology of fragile X syndrome
Abstract
Fragile X syndrome (FXS), caused by a single gene mutation on the X chromosome, offers a unique opportunity for investigation of gene-brain-behavior relationships. Recent advances in molecular genetics, human brain imaging, and behavioral studies have started to unravel the complex pathways leading to the cognitive, psychiatric, and physical features that are unique to this syndrome. In this article, we summarize studies focused on the neuroanatomy and neuroendocrinology of FXS. A review of structural imaging studies of individuals with the full mutation shows that several brain regions are enlarged, including the hippocampus, amygdala, caudate nucleus, and thalamus, even after controlling for overall brain volume. These regions mediate several cognitive and behavioral functions known to be aberrant in FXS such as memory and learning, information and sensory processing, and social and emotional behavior. Two regions, the cerebellar vermis, important for a variety of cognitive tasks and regulation of motor behavior, and the superior temporal gyrus, involved in processing complex auditory stimuli, are reported to be reduced in size relative to controls. Functional imaging, typically limited to females, has emphasized that individuals with FXS do not adequately recruit brain regions that are normally utilized by unaffected individuals to carry out various cognitive tasks, such as arithmetic processing or visual memory tasks. Finally, we review a number of neuroendocrine studies implicating hypothalamic dysfunction in FXS, including abnormal activation of the hypothalamic-pituitary-adrenal (HPA) axis. These studies may help to explain the abnormal stress responses, sleep abnormalities, and physical growth patterns commonly seen in affected individuals. In the future, innovative longitudinal studies to investigate development of neurobiologic and behavioral features over time, and ultimately empirical testing of pharmacological, behavioral, and even molecular genetic interventions using MRI are likely to yield significant positive changes in the lives of persons with FXS, as well as increase our understanding of the development of psychiatric and learning problems in the general population.
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Several lines of investigation point to dysregulation of the oxytocin system in fragile X syndrome.
“Although the available data do not help differentiate between these two possibilities, several lines of investigation point to dysregulation of the OT system in FXS:”
From Effects of intranasal oxytocin on social anxiety in males with fragile X syndrome (2012) · cites this paper as Hessl et al., 2004
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Self-citation
- Authors
- Hessl, D., Rivera, S. M., & Reiss, A. L.
- Affiliations
- University of California, Davis (US)
- Stanford Medicine (US)
- Corresponding author
- Reiss, Allan L.
- Venue
- Mental Retardation and Developmental Disabilities Research Reviews
- Publisher
- Wiley
- Published
- 2004-02
- Volume
- 10
- Issue
- 1
- Pages
- 17-24
- ISSN
- 1080-4013 (ISSN-L)
- 1098-2779
- OpenAlex
- W2058528988
- Cited by
- 165
- References
- 74
- Citations by year
- 2025: 2 · 2024: 5 · 2023: 2 · 2021: 2 · 2020: 5 · 2019: 5 · 2018: 5 · 2017: 13 · 2016: 7 · 2015: 2 · 2014: 9 · 2013: 11 · 2012: 13
- FWCI
- 1.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Mental Retardation and Developmental Disabilities Research Reviews (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Williams Syndrome Research
- Keywords
- fragile X syndrome, neuroanatomy, neuroendocrinology, hippocampus, amygdala, caudate nucleus, thalamus, cerebellar vermis, superior temporal gyrus, functional neuroimaging, hypothalamic dysfunction, hypothalamic-pituitary-adrenal axis, stress response, sleep abnormalities, growth patterns, gene-brain-behavior relationship
- MeSH terms
- Adolescent, Adult, Brain, Child, Endocrine Glands, Female, Fragile X Syndrome, Humans, Hydrocortisone, Magnetic Resonance Imaging, Male, Nervous System, Saliva, Cluster Analysis
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