The Influence of Environmental and Genetic Factors on Behavior Problems and Autistic Symptoms in Boys and Girls With  Fragile X Syndrome

Hessl, David; Dyer-Friedman, Jennifer; Glaser, Bronwyn; Wisbeck, Jacob M.; Barajas, R. Gabriela; Taylor, Annette K.; Reiss, Allan L.

doi:10.1542/peds.108.5.e88

Cited by 181 publications

(152 citation statements)

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“…Our behavioral data are thus consistent with the observations by Reiss and coworkers (58,59), indicating that environmental factors positively influence the behavioral outcome in children with FXS. Although further investigations are needed to elucidate the molecular mechanisms involved in the enrichment effects, our findings demonstrate that some mechanisms of neuronal plasticity are preserved in FMR1-KO mice and can be triggered by environmental stimulation.…”

Section: Discussionsupporting

confidence: 92%

Enriched environment promotes behavioral and morphological recovery in a mouse model for the fragile X syndrome

Restivo

Ferrari

Passino

et al. 2005

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

280

220

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Fragile X syndrome, the most frequent form of hereditary mental retardation, is due to a mutation of the fragile X mental retardation 1 (FMR1) gene on the X chromosome. Like fragile X patients, FMR1-knockout (FMR1-KO) mice lack the normal fragile X mental retardation protein (FMRP) and show both cognitive alterations and an immature neuronal morphology. We reared FMR1-KO mice in a C57BL͞6 background in enriched environmental conditions to examine the possibility that experience-dependent stimulation alleviates their behavioral and neuronal abnormalities. FMR1-KO mice kept in standard cages were hyperactive, displayed an altered pattern of open field exploration, and did not show habituation. Quantitative morphological analyses revealed a reduction in basal dendrite length and branching together with more immatureappearing spines along apical dendrites of layer five pyramidal neurons in the visual cortex. Enrichment largely rescued these behavioral and neuronal abnormalities while increasing ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor subunit 1 (GluR1) levels in both genotypes. Enrichment did not, however, affect FMRP levels in the WT mice. These data suggest that FMRP-independent pathways activating glutamatergic signaling are preserved in FMR1-KO mice and that they can be elicited by environmental stimulation.fragile X mental retardation protein ͉ mental retardation ͉ FMR1 gene ͉ AMPA receptor ͉ dendritic spines S everal genes associated with mental retardation have been mapped on the X chromosome and, among them is the fragile X mental retardation 1 (FMR1) gene. The fragile X mental retardation protein (FMRP) absence or mutation is responsible for the fragile X syndrome (FXS), which is the most common form of inherited mental retardation. Most of the individuals affected carry a trinucleotide repeat that, after methylation, leads to transcriptional silencing of the FMR1 gene (1). Patients with the FXS do not express FMRP and exhibit phenotypic traits ranging from severe (IQ 20) to moderate (IQ 60) mental retardation, defective attention, autistic behavior, and physical features including an elongated face, large ears, joint laxity, and macroorchidism (2-5).FMR1 is highly conserved between human and mouse, with a nucleotide and amino acid identity of 95% and 97%, respectively (6). The expression pattern of mouse FMR1 is similar to its human counterpart in both tissue specificity and timing (7). Interestingly, FMR1-knockout (FMR1-KO) mice, the mouse model for the FXS, lack the normal FMRP and show macroorchidism, hyperactivity, and mild learning deficits (8, 9) reminiscent of the human syndrome.One common brain feature of fragile X patients and of the mouse model for the syndrome is the presence of long and thin immature dendritic spines indicative of defective pruning during development (10)(11)(12)(13)(14). At the molecular level, it has been shown that protein synthesis triggered by the type I metabotropic glutamate receptor (mGluR1) agonist dihydroxyphenylglycine is dramati...

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Section: Discussionsupporting

confidence: 92%

Enriched environment promotes behavioral and morphological recovery in a mouse model for the fragile X syndrome

Restivo

Ferrari

Passino

et al. 2005

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

280

220

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“…In a longitudinal study of Ferdinand et al (2001), thought problems in childhood were associated with substance abuse (alcohol and tobacco) in young adulthood. Other studies showed TP in children to be associated with disorders, such as obsessive-compulsive disorder (OCD; Geller et al, 2004), multiple complex developmental disorder (MCDD;de Bruin et al, 2006) and fragile X syndrome (Hessel et al, 2006). The TP-syndrome also predicted DSM-III-R diagnoses of simple phobia, social phobia, separation anxiety disorder, mood disorders and psychotic disorders (Kasius et al, 1997).…”

mentioning

confidence: 99%

Genetic Influences on Thought Problems in 7-Year-Olds: A Twin-Study of Genetic, Environmental and Rater Effects

Abdellaoui¹,

Bartels

Hudziak³

et al. 2008

Twin Res Hum Genet

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T he Thought-Problem scale (TP) of the CBCL assesses symptoms such as hallucinations and strange thoughts/behaviors and has been associated with other behavioral disorders. This study uses parental reports to examine the etiology of variation in TP, about which relatively little is known, in 7-year-old twins. Parental ratings on TP were collected in 8,962 7-year-old twin pairs. Because the distribution of TP scores was highly skewed scores were categorized into 3 classes. The data were analyzed under a threshold liability model with genetic structural equation modeling. Ratings from both parents were simultaneously analyzed to determine the rater agreement phenotype (or common phenotype [TPc]) and the rater specific phenotype [TPs] that represents rater disagreement caused by rater bias, measurement error and/or a unique view of the parents on the child's behavior. Scores on the TP-scale varied as a function of rater (fathers rated fewer problems), sex (boys scored higher) and zygosity (DZ twins scored higher). The TPc explained 67% of the total variance in the parental ratings. Variation in TPc was influenced mainly by the children's genotype (76%). Variance in TPs also showed a contribution of genetic factors (maternal reports: 61%, paternal reports: 65%), indicating that TPs does not only represent rater bias. Shared environmental influences were only found in the TPs. No sex differences in genetic architecture were observed. These results indicate an important contribution of genetic factors to thought problems in children as young as 7 years.

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confidence: 99%

“…The gender of the individual with FRAX impacts significantly upon the expression of this syndrome due to the fact that FRAX is caused by a mutation on the X chromosome (Hessl et al, 2001). Females are protected from FRAX to some degree due to the presence of one unaffected X chromosome (Hessl et al, 2001). As a result, intellectual functioning in such females may not be impaired, with ID typically ranging from mild ID to no significant impairment (Bennetto & Pennington, 1996;Hagerman & Sobesky, 1989).…”

mentioning

confidence: 99%

An analysis of challenging behavior, comorbid psychopathology, and Attention-Deficit/Hyperactivity Disorder in Fragile X Syndrome

Newman

Leader

Chen

et al. 2015

Research in Developmental Disabilities

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CitationAn analysis of challenging behavior, comorbid psychopathology, and Attention-Deficit/Hyperactivity Disorder in Fragile X Syndrome. 2015, 38:7- Results revealed high levels of challenging behavior and AD/HD symptoms within the sample, with some participants exhibiting symptoms of comorbid psychopathology. Further analysis revealed that challenging behavior and comorbid psychopathology were positively correlated, with stereotypy correlating most strongly with comorbid psychopathology. In addition, ASD was found to predict challenging behavior, and gender was found to predict AD/HD symptoms. The implications of these findings are discussed.

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The Influence of Environmental and Genetic Factors on Behavior Problems and Autistic Symptoms in Boys and Girls With Fragile X Syndrome

Cited by 181 publications

References 31 publications

Enriched environment promotes behavioral and morphological recovery in a mouse model for the fragile X syndrome

Enriched environment promotes behavioral and morphological recovery in a mouse model for the fragile X syndrome

Genetic Influences on Thought Problems in 7-Year-Olds: A Twin-Study of Genetic, Environmental and Rater Effects

An analysis of challenging behavior, comorbid psychopathology, and Attention-Deficit/Hyperactivity Disorder in Fragile X Syndrome

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