Neurodevelopmental effects of the FMR-1 full mutation in humans

Reiss, Allan L.; Abrams, Michael T.; Greenlaw, Ronald; Freund, Lisa S.; Denckla, Martha B.

doi:10.1038/nm0295-159

Cited by 220 publications

(189 citation statements)

References 45 publications

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“…Correlation of FMR1 gene inactivation with caudate volume further supports the validity and relevance of aberrant volumes of these neuroanatomical regions in individuals with fraX. For TD subjects, larger caudate size is associated with higher IQ, whereas in subjects with fraX, larger caudate size is correlated with lower IQ (2). This finding suggests that the developmental increases in caudate volume in individuals with fraX reflect aberrant neuronal organization.…”

Section: Discussionmentioning

confidence: 57%

“…Specific areas in the basal ganglia that showed such a relation included the dorsal caudate, putamen, and ventral striatum. Several brain imaging studies have established an association between reduced FMRP and morphological abnormalities in the basal ganglia (2,(6)(7)(8)(42)(43)(44). Here, our prior finding that caudate volumes are increased in individuals with fraX is of particular interest.…”

Section: Discussionmentioning

confidence: 65%

“…Disturbances of these frontal subcortical circuits are known to produce problems in executive function, motor programming, regulation of affect, social behavior, impulse control, and flexibility in response to environmental cues (45,46). Accordingly, dysfunction of neuroanatomical circuits involving prefrontal striatal regions would be consistent with some of the cognitive and behavioral abnormalities observed in fraX including attention deficit hyperactivity, stereotypic and perseverative language and motor behavior, and problems with impulse control (2,47).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, the study of individuals with homogeneous genetic abnormalities and neurocognitive dysfunction can potentially serve as a prototype for advancing our knowledge of specific associations among genetic, neurobiological, and behavioral variables (1,2). In this study, we used functional MRI (fMRI) to study deficits in executive function among females with fragile X syndrome (fraX).…”

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confidence: 99%

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Frontostriatal deficits in fragile X syndrome: Relation to FMR1 gene expression

Menon

Leroux

White

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

127

105

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Fragile X syndrome (fraX) is the most common known cause of inherited developmental disability. fraX is associated with a CGG expansion in the FMR1 gene on the long arm of the X chromosome. Behavioral deficits, including problems with impulse control and distractibility, are common in fraX. We used functional brain imaging with a Go͞NoGo task to examine the neural substrates of response inhibition in females with fraX (ages 10 -22) and age-and gendermatched typically developing subjects. Although subjects with fraX had significantly lower IQ scores, as a group their performance on the Go͞NoGo task was equivalent to that of the typically developing group. However, females with fraX showed abnormal activation patterns in several cortical and subcortical regions, with significantly reduced activation in the supplementary motor area, anterior cingulate and midcingulate cortex, basal ganglia, and hippocampus. An important finding of our study is that neural responses in the right ventrolateral prefrontal cortex (PFC) and the left and right striatum were correlated with the level of FMR1 gene expression. Our findings support the hypothesis that frontostriatal regions typically associated with response inhibition are dysfunctional in females with fraX. In addition to task-related activation deficits, reduced levels of ''deactivation'' were observed in the ventromedial PFC, and, furthermore, these reductions were correlated with the level of FMR1 gene expression. The ventromedial PFC is a key node in a ''default mode'' network that monitors mental and physiological states; we suggest that self-monitoring processes may be aberrant in fraX.genetic ͉ Go͞NoGo ͉ response inhibition ͉ prefrontal cortex ͉ basal ganglia T he effect of genetic factors on human brain function is a topic of increasing interest within the field of cognitive neuroscience. In particular, the study of individuals with homogeneous genetic abnormalities and neurocognitive dysfunction can potentially serve as a prototype for advancing our knowledge of specific associations among genetic, neurobiological, and behavioral variables (1, 2). In this study, we used functional MRI (fMRI) to study deficits in executive function among females with fragile X syndrome (fraX).fraX occurs in 1 of every 2,000-5,000 live births and is the most common known cause of inherited developmental disability. fraX affects both males and females. However, because the mutation occurs in an X chromosome gene, males are more uniformly and severely affected as opposed to females, who show a considerably wider spectrum of severity. Thus we chose to study females to more accurately elucidate the spectrum of neurobiological effects associated with fraX and reduced fragile X mental retardation protein (FMRP). In individuals with fraX, the cytogenetic fragile site on the long arm of the X chromosome, from which the syndrome derives its name, is typically caused by a mutation in which Ͼ200 (up to 2,000) cytosineguanine-guanine (CGG) triplet repeats occur within the promoter region of the ...

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Frontostriatal deficits in fragile X syndrome: Relation to FMR1 gene expression

Menon

Leroux

White

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

127

105

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“…Several MRI studies have been performed in individuals with fragile X syndrome, as well as in fragile X mice. In human brains, most findings are related to small deviations such as abnormalities in the hippocampus, 28 the amygdala 29 and the ventricular system. 30 Gross volumetric changes were found in the underdevelopment of the cerebellar vermis.…”

Section: Discussionmentioning

confidence: 99%

Craniofacial characteristics of fragile X syndrome in mouse and man

Heulens

Suttie²,

Постнов

et al. 2012

Eur J Hum Genet

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For a disorder as common as fragile X syndrome, the most common hereditary form of cognitive impairment, the facial features are relatively ill defined. An elongated face and prominent ears are the most commonly accepted dysmorphic hallmarks. We analysed 3D facial photographs of 51 males and 15 females with full FMR1 mutations and 9 females with a premutation using dense-surface modelling techniques and a new technique that forms a directed graph with normalized face shapes as nodes and edges linking those with closest dysmorphism. In addition to reconfirming known features, we confirmed the occurrence of some at an earlier age than previously recorded. We also identified as yet unrecorded facial characteristics such as reduced facial depth, hypoplasticity of the nasal bone-cartilage interface and narrow mid-facial width exaggerating ear prominence. As no consistent craniofacial abnormalities had been reported in animal models, we analysed micro-CT images of the fragile X mouse model. Results indicated altered dimensions in the mandible and both outer and inner skull, with the latter potentially reflecting differences in neuroanatomy. We extrapolated the mouse results to face shape differences of the human fragile X face.

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Connecting Genes to Brain in the Autism Spectrum Disorders

Abrahams¹,

Geschwind²

2010

Arch Neurol

174

115

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he autism spectrum disorders (ASDs) are a complex group of neuropsychiatric conditions involving language, social communication, and mental flexibility. Here, we attempt to place recent genetic advances within a developmental and anatomical context. Recent progress in identifying ASD candidate genes supports involvement of multiple brain regions, including the frontal lobes, anterior temporal lobes, caudate, and cerebellum. Understanding genetic data within an anatomical context will be critical to explain how individual risk factors operate to shape phenotypic presentation in patients.

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Neurodevelopmental effects of the FMR-1 full mutation in humans

Cited by 220 publications

References 45 publications

Frontostriatal deficits in fragile X syndrome: Relation to FMR1 gene expression

Frontostriatal deficits in fragile X syndrome: Relation to FMR1 gene expression

Craniofacial characteristics of fragile X syndrome in mouse and man

Connecting Genes to Brain in the Autism Spectrum Disorders

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