A neuropsychological profile of attention deficits in young males with fragile X syndrome

Munir, Fehmidah; Cornish, Kim; Wilding, John

doi:10.1016/s0028-3932(00)00036-1

Cited by 168 publications

(188 citation statements)

References 30 publications

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“…Because accuracy and RTs on the Go͞NoGo condition were similar in both groups, the anomalous pattern of brain activation observed in our study may reflect aberrant neuronal organization in fraX. Our results also suggest that females with fraX may have the capacity to overcome executive functioning weaknesses (10,27), particularly in simple tasks like the one used in our study.…”

Section: Discussionsupporting

confidence: 50%

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: Discussionsupporting

confidence: 50%

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

View full text Add to dashboard Cite

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“…Attention-deficit hyperactive disorder (ADHD) symptoms are more prevalent in children with FXS compared to the general population, or with other disorders with intellectual disabilities (Munir et al, 2000;Backes et al, 2000;Cornish et al, 2005). FXS patients under the age of 5 years old are particularly difficult to treat, as stimulants that are routinely used to treat older patients are not as effective (Hagerman and Hagerman, 2002).…”

Section: Diagnostic and Statistical Manual Of Mental Disorders Fourtmentioning

confidence: 99%

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

et al. 2010

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The purpose of this study was to examine the expression of GABAergic proteins in Fmr1 knockout mice during brain maturation and to assess behavioural changes potentially linked to perturbations in the GABAergic system. Quantitative western blotting of the forebrain revealed that compared to wild-type mice, the GABA A receptor α1, β2, and δ subunits, and the GABA catabolic enzymes GABA transaminase and SSADH were down-regulated during postnatal development, while GAD65 was up-regulated in the adult knockout mouse forebrain. In tests of locomotor activity, the suppressive effect on motor activity of the GABA A β2/3 subunit-selective drug loreclezole was impaired in the mutant mice. In addition, sleep time induced by the GABA A β2/3-selective anaesthetic drug etomidate was decreased in the knockout mice. Our results indicate that disruptions in the GABAergic system in the developing brain may result in behavioural consequences in adults with fragile X syndrome.iii

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“…Investigators have reported that individuals with FXS experience weaknesses in executive function, visual memory, visual-spatial relationships, and arithmetic, with relatively less severe impairments in verbal skills (Bennetto et al 2001;Cornish et al 2004;Fisch 2006;Freund and Reiss 1991;Kemper et al 1986;Mazzocco et al 1992;Miezejeski et al 1986;Munir et al 2000). While this profile appears similar for both genders, females with FXS experience significantly and substantially less severe deficits than males, presumably because of their status as heterozygotes for the FMR1 mutation, with resulting higher FMRP levels.…”

mentioning

confidence: 99%

Longitudinal Changes in Intellectual Development in Children with Fragile X Syndrome

Hall

Burns

Lightbody

et al. 2008

J Abnorm Child Psychol

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Structural equation modeling (SEM) was used to examine the development of intellectual functioning in 145 school-age pairs of siblings. Each pair included one child with Fragile X syndrome (FXS) and one unaffected sibling. All pairs of children were evaluated on the Wechsler Intelligence Scale for Children-Third Edition (WISC-III) at time 1 and 80 pairs of children received a second evaluation at time 2 approximately 4 years later. Compared to their unaffected siblings, children with FXS obtained significantly lower percentage correct scores on all subtests of the WISC at both time points. During the time between the first and second assessments, the annual rate of intellectual development was approximately 2.2 times faster in the unaffected children compared to the children with FXS. Levels of the fragile X mental retardation protein (FMRP) were highly associated with intellectual ability scores of the children with FXS at both time points (r=0.55 and 0.64 respectively). However, when gender, age, and the time between assessments were included as covariates in the structural equation model, FMRP accounted for only 5% of the variance in intellectual ability scores at time 1 and 13% of the variance at time 2. The results of this study suggest that slower learning contributes to the low and declining standardized IQ scores observed in children with FXS. KeywordsFragile X syndrome; Structural equation modeling; Intellectual functioning; IQ; FMRP Fragile X syndrome occurs in approximately 1 in every 4,000 live births and is the most common inherited form of cognitive and behavioral disability. In 1991, Verkerk and colleagues reported that a single gene on the X chromosome (locus Xq27.3), FMR1, was associated with the symptoms of FXS (Verkerk et al. 1991). Subsequent research revealed that persons with FXS had increased numbers of triplet (CGG) repeats within FMR1. In normal alleles, the CGG repeats vary from 6 to 50, whereas expansions of ~50-200 repeats are associated with the "premutation" form of the gene seen in carrier females and males. The probability of having a child with the full mutation increases as the length of the mothers' CGG repeat length increases-a phenomenon known as genetic anticipation. Larger expansions (200 to thousands) of CGG repeats are considered "full mutations" and are typically associated with excessive methylation of cytosines in the FMR1 promoter. This hallss@stanford.edu. HHS Public AccessAuthor manuscript J Abnorm Child Psychol. Author manuscript; available in PMC 2016 April 04. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript modification extinguishes transcription of the FMR1 gene into mRNA, thus stopping translation of the fragile X mental retardation protein (FMRP). FMRP plays an important role in the development of synaptic function, maturation, and plasticity during development, and possibly, on an ongoing basis throughout adult life as well (Reiss et al. 1995).Investigators have reported that individuals with FXS experience weaknesses in executi...

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A neuropsychological profile of attention deficits in young males with fragile X syndrome

Cited by 168 publications

References 30 publications

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

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

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

Longitudinal Changes in Intellectual Development in Children with Fragile X Syndrome

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