Advances in research on the fragile X syndrome

Mazzocco, Michèle M.M.

doi:10.1002/1098-2779(2000)6:2<96::aid-mrdd3>3.0.co;2-h

Cited by 106 publications

(48 citation statements)

References 101 publications

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“…Studies in attention-deficit hyperactivity disorder suggest that the disease has a negative impact on parenting behaviors and that there are improvements in children's behavior when mothers are treated (34,35). Also, mothers with fragile X syndrome have a greater predisposition to anxiety and depression, and this predisposition may affect the postnatal environment of their children (36,37). The model of dual transmission of risk factors described here indicates that the overall effects of risk alleles can 78; P = 0.060, trend only; Distance: F 3,26 = 3.72; P = 0.023; *, P < 0.05) (n = 6-9) and have reduced immobility in the FST (ANOVA: F 3,46 = 24.56; P < 0.000001; ***, P < 0.0005; n = 11-14).…”

Section: Discussionmentioning

confidence: 99%

The serotonin _1A receptor gene as a genetic and prenatal maternal environmental factor in anxiety

Gleason

Liu²,

Bruening³

et al. 2010

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

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Low serotonin 1A receptor (5-HT 1A R) binding is a risk factor for anxiety and depression, and deletion of the 5-HT 1A R results in anxiety-like behavior in mice. Here we show that anxiety-like behavior in mice also can be caused, independently of the offspring's own 5-HT 1A R genotype, by a receptor deficit in the mother: a nongenetic transmission of a genetic defect. Some of the nongenetically transmitted anxiety manifestations were acquired prenatally and linked to a delay in dentate gyrus maturation in the ventral hippocampus of the offspring. Both the developmental delay and the anxiety-like phenotype were phenocopied by the genetic inactivation of p16 ink4a encoding a cyclin-dependent kinase inhibitor implicated in neuronal precursor differentiation. No maternal 5-HT 1A R genotype-dependent anxiety developed when the strain background was switched from Swiss Webster to C57BL/6, consistent with the increased resilience of this strain to early adverse environment. Instead, all anxiety manifestations were caused by the offspring's own receptor deficiency, indicating that the genetic and nongenetic effects converge to common anxiety manifestations. We propose that 5-HT 1A R deficit represents a dual risk for anxiety and that vulnerability to anxiety associated with genetic 5-HT 1A R deficiency can be transmitted by both genetic and nongenetic mechanisms in a population. Thus, the overall effect of risk alleles can be higher than estimated by traditional genetic assays and may contribute to the relatively high heritability of anxiety and psychiatric disorders in general.genetic risk | heritability | cross-fostering S tudies have identified mutant/polymorphic variants of genes, each with a relatively small contribution to the risk of depression, anxiety, schizophrenia, and other psychiatric diseases. However, demonstrable genetic influences explain only a small fraction of estimated heritability in psychiatric conditions. This "missing heritability" could be caused by a large number of undiscovered alleles or by mechanisms that amplify the effect of risk alleles but are not genetic in nature. We tested the hypothesis that mutant/polymorphic variants can have a larger effect if, besides their purely genetic effect, they have an additional "environmental" effect. For example, gene variants could influence maternal physiology, affecting the developmental program of the offspring, and consequently also increasing the risk for psychopathology. Indeed, adverse prenatal maternal and/or postnatal environment increases vulnerability to various diseases, including psychiatric disorders, in adulthood (1, 2), and one may extrapolate these findings to an abnormal maternal/parental environment related to disease-associated genes/gene variants.One of the few candidate genes whose function has been associated with anxiety and depression encodes the serotonin 1A receptor (5-HT 1A R) (3). Reduced binding or binding potential in the 5-HT 1A R has been linked to posttraumatic stress and panic disorders (3) and depression (4), and a...

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Section: Discussionmentioning

confidence: 99%

The serotonin _1A receptor gene as a genetic and prenatal maternal environmental factor in anxiety

Gleason

Liu²,

Bruening³

et al. 2010

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

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“…Females with FXS are usually less severely affected at the phenotypic level and demonstrate more variable outcomes than their male counterparts (Mazzocco, 2000). Because of the lower prevalence rates and this more variable phenotypic presentation in females with FXS, studies of females have been infrequent, with very few focused on language.…”

Section: Noncomprehension Signaling In Girls With Fxsmentioning

confidence: 99%

Noncomprehension Signaling in Males and Females With Fragile X Syndrome

Thurman

Kover

Brown

et al. 2017

J Speech Lang Hear Res

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a,bPurpose: This study used a prospective longitudinal design to evaluate the trajectory and predictors of noncomprehension signaling in male and female youth with fragile X syndrome (FXS). Method: A direction-following task in which some of the directions were inadequate was administered. Participants were 52 youth (36 boys, 16 girls) with FXS. Upon study entry, participants ranged from 10 to 16 years. The average number of annual assessments per participant was 3.65 (range = 1-4), providing 198 data points for analysis. Results: Participants with FXS were less likely to signal noncomprehension than younger, typically developing, cognitively matched children. The average rate of change in noncomprehension signaling was not significantly different from 0 for either boys or girls, suggesting a plateau. Both FMRP and nonverbal IQ were significant independent predictors of noncomprehension signaling for boys. Variability in noncomprehension signaling among girls was not explained by any of the predictors, but trends similar to those observed for boys were observed. Conclusions: Noncomprehension signaling appears to be an area of weakness for individuals with FXS. Because the failure to signal noncomprehension can have negative, cumulative effects on comprehension, the results suggest a need for interventions targeting the requisite cognitive skills.

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“…64 The clinical phenotype associated with the syndrome has since been widened to include a variety of cognitive, physical, and behavioral characteristics (reviewed in Mazzocco). 65 Almost all males with the full mutation exhibit some clinical features of the fragile X syndrome. Also, most 43 provided a range, not a point estimate.…”

Section: Disease(s)mentioning

confidence: 99%

FMR1 and the fragile X syndrome: Human genome epidemiology review

Crawford

Acuña

Sherman

2001

Genetics in Medicine

578

391

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The fragile X syndrome, an X-linked dominant disorder with reduced penetrance, is one of the most common forms of inherited mental retardation. The cognitive, behavioral, and physical phenotype varies by sex, with males being more severely affected because of the X-linked inheritance of the mutation. The disorder-causing mutation is the amplification of a CGG repeat in the 5' untranslated region of FMR1 located at Xq27.3. The fragile X CGG repeat has four forms: common (6 -40 repeats), intermediate (41-60 repeats), premutation (61-200 repeats), and full mutation (Ͼ200 -230 repeats). Population-based studies suggest that the prevalence of the full mutation, the disorder-causing form of the repeat, ranges from 1/3,717 to 1/8,918 Caucasian males in the general population.The full mutation is also found in other racial/ethnic populations; however, few population-based studies exist for these populations. No population-based studies exist for the full mutation in a general female population. In contrast, several large, population-based studies exist for the premutation or carrier form of the disorder, with prevalence estimates ranging from 1/246 to 1/468 Caucasian females in the general population. For Caucasian males, the prevalence of the premutation is~1/1,000. Like the full mutation, little information exists for the premutation in other populations. Although no effective cure or treatment exists for the fragile X syndrome, all persons affected with the syndrome are eligible for early intervention services. The relatively high prevalence of the premutation and full mutation genotypes coupled with technological advances in genetic testing make the fragile X syndrome amenable to screening. The timing as well as benefits and harms associated with the different screening strategies are the subject of current research and discussion. Genet Med 2001:3(5):359 -371.

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Advances in research on the fragile X syndrome

Cited by 106 publications

References 101 publications

The serotonin _1A receptor gene as a genetic and prenatal maternal environmental factor in anxiety

The serotonin _1A receptor gene as a genetic and prenatal maternal environmental factor in anxiety

Noncomprehension Signaling in Males and Females With Fragile X Syndrome

FMR1 and the fragile X syndrome: Human genome epidemiology review

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Advances in research on the fragile X syndrome

Cited by 106 publications

References 101 publications

The serotonin 1A receptor gene as a genetic and prenatal maternal environmental factor in anxiety

The serotonin 1A receptor gene as a genetic and prenatal maternal environmental factor in anxiety

Noncomprehension Signaling in Males and Females With Fragile X Syndrome

FMR1 and the fragile X syndrome: Human genome epidemiology review

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The serotonin _1A receptor gene as a genetic and prenatal maternal environmental factor in anxiety

The serotonin _1A receptor gene as a genetic and prenatal maternal environmental factor in anxiety