Mutations of the fragile X mental retardation 1 (FMR1) gene are the genetic cause of fragile X syndrome (FXS). Expanded CGG trinucleotide repeat (> 200 repeats) result in transcriptional silencing of the FMR1 gene and deficiency/absence of the FMR1 protein (FMRP). Carriers with a premutation allele (55–200 CGG repeats) are often associated with mildly reduced levels of FMRP and/or elevated levels of FMR1 mRNA, and are associated with the risk of developing a neurodegenerative disorder known as fragile X-associated tremor/ataxia syndrome (FXTAS). While impairments in numerical processing have been well documented in FXS, recent behavioral research suggests that premutation carriers also present with subtle but significant impairments in numerical processing. Using fMRI, the current study examined whether asymptomatic adults with the premutation would show aberrant neural correlates of magnitude estimation processing in the fronto-parietal area. Using a magnitude estimation task, we demonstrated that activity in the intraparietal sulcus and inferior frontal gyrus, associated with magnitude estimation processing, was significantly attenuated in premutation carriers compared to their neurotypical counterparts despite their comparable behavioral performance. Further, multiple regression analysis using CGG repeat size and FMR1 mRNA indicated that increased CGG repeat size is a primary factor for the decreased fronto-parietal activity, suggesting that reduced FMRP, rather than a toxic gain-of-function effect from elevated mRNA, contributes to altered neural activity of magnitude estimation processing in premutation carriers. In conclusion, we provide the first evidence on the aberrant neural correlates of magnitude estimation processing in premutation carriers accounted for by their FMR1 gene expression.
Approximately 40% of males with the fragile X premutation develop fragile X-associated tremor/ataxia syndrome after age 50. Although the thalamus and basal ganglia play a crucial role in movement disorders, their involvement in fragile X premutation carriers has not been systematically investigated.
The current study characterized structural abnormalities associated with fragile X premutation carriers (with and without fragile X-associated tremor/ataxia syndrome) in the thalamus, caudate nucleus, putamen, and globus pallidus using T1-weighted and diffusion tensor imaging.
Male premutation carriers with fragile X-associated tremor/ataxia syndrome showed significant volume atrophy and diffusion-weighted signal loss in all 4 structures compared to the control group. They also exhibited volume atrophy and diffusion-weighted signal loss in the thalamus and striatum compared to the premutation carriers without fragile X-associated tremor/ataxia syndrome. Importantly, many of the measurements exhibited robust correlations with symptom severity, with volume and DWI measurements displaying negative correlations and fractional anisotropy measurements displaying positive correlations.
The current study demonstrated involvement of all 4 subcortical gray matter structures in fragile X-associated tremor/ataxia syndrome, with significant volume atrophy, and possibly iron deposition indicated by the diffusion-weighted signal loss. The significant correlation between the subcortical measurements and symptom severity suggests the benefits of tracking structural changes in the subcortical gray matter in future longitudinal studies for early detection and disease monitoring.
neurodegeneration; iron dysregulation; genetic disorder; diffusion tensor imaging; diffusion weighted imaging
Individuals with the fragile X premutation express expanded CGG repeats (repeats 55–200) in the FMR1 gene and elevated FMR1 messenger RNA (mRNA) levels, both of which may underlie the occurrence of the late-onset neurodegenerative disorder fragile X–associated tremor/ataxia syndrome (FXTAS). Because the core feature of FXTAS is motor impairment, determining the influence of FMR1 mRNA levels on structural connectivity of motor fiber tracts is critical for a better understanding of the pathologic features of FXTAS.
To examine the associations of CGG repeat and FMR1 mRNA with motor-related fiber tracts in males with premutation alleles.
DESIGN AND SETTING
A case-control study conducted at the University of California, Davis, from April 1, 2008, through August 31, 2009. All data were collected masked to the carrier status of the FMR1 gene.
Thirty-six male premutation carriers with FXTAS and 26 male premutation carriers without FXTAS were recruited through their family relationships with children affected by fragile X syndrome. The controls were 34 unaffected family members and healthy volunteers from the local community.
MAIN OUTCOMES AND MEASURES
The CGG repeat lengths and FMR1 mRNA expression levels in peripheral blood lymphocytes, motor functioning, and white matter structural integrity that were estimated using diffusion tensor imaging. After data collection, we selected 4 motor tracts to reconstruct using diffusion tensor tractography, namely, the middle and superior cerebellar peduncles, descending motor tracts (containing the corticospinal, corticobulbar, and corticopontine tracts), and the anterior body of the corpus callosum.
All fiber tracts exhibited weaker structural connectivity in the FXTAS group (decreased 5%–53% from controls, P ≤ .02). Genetic imaging correlation analysis revealed negative associations of CGG repeat length and FMR1 mRNA with connectivity strength of the superior cerebellar peduncles in both premutation groups (partial r2 = 0.23–0.33, P ≤ .004). In addition, the measurements from the corpus callosum and superior cerebellar peduncles revealed a high correlation with motor functioning in all 3 groups (r between partial least square predicted and actual test scores = 0.41–0.56, P ≤ .04).
CONCLUSIONS AND RELEVANCE
Distinct pathophysiologic processes may underlie the structural impairment of the motor tracts in FXTAS. Although both the corpus callosum and superior cerebellar peduncles were of great importance to motor functioning, only the superior cerebellar peduncles exhibited an association with the elevated RNA levels in the blood of fragile X premutation carriers.
Carriers of the fragile X premutation allele (fXPCs) have an expanded CGG trinucleotide repeat size within the FMR1 gene and are at increased risk of developing fragile x-associated tremor/ataxia syndrome (FXTAS). Previous research has shown that male fXPCs with FXTAS exhibit cognitive decline, predominantly in executive functions such as inhibitory control and working memory. Recent evidence suggests fXPCs may also exhibit impairments in processing temporal information. The attentional blink (AB) task is often used to examine the dynamics of attentional selection, but disagreements exist as to whether the AB is due to excessive or insufficient attentional control. In this study, we used a variant of the AB task and neuropsychological testing to explore the dynamics of attentional selection, relate AB performance to attentional control, and determine whether fXPCs exhibited temporal and/or attentional control impairments. Participants were adult male fXPCs, aged 18–48 years and asymptomatic for FXTAS (n = 19) and age-matched male controls (n = 20). We found that fXPCs did not differ from controls in the AB task, indicating that the temporal dynamics of attentional selection were intact. However, they were impaired in the letter-number sequencing task, a test of executive working memory. In the combined fXPC and control group, letter-number sequencing performance correlated positively with AB magnitude. This finding supports models that posit the AB is due to excess attentional control. In our two-pronged analysis approach, in control participants we replicated a previously observed effect and demonstrated that it persists under more stringent theoretical constraints, and we enhance our understanding of fXPCs by demonstrating that at least some aspects of temporal processing may be spared.
fragile X; FMR1 gene; attentional blink; attention; temporal processing; executive function; inhibition; letter number sequencing
To examine the effects of premutation alleles on major brain fiber tracts in males.
Cross-sectional study performed in 2007–2009.
Fifteen younger (18–45 years old) carriers, 11 older (>45 years old) unaffected carriers, and 15 older carriers with fragile X–associated tremor/ataxia syndrome, together with 19 younger and 15 older controls matched by age and educational level.
Main Outcome Measures
Diffusion tensor imaging was performed on all study participants. Eleven fiber tracts important for motor, social, emotional, and cognitive functions were reconstructed and quantified. Complementary tract-based spatial statistical analyses were performed in core white matter.
In the younger carriers, premutation status was associated with a greater age-related connectivity decline in the extreme capsule. Among older carriers, unaffected individuals did not display structural alterations, whereas the affected carriers showed connectivity loss in 5 fiber tracts and exhibited greater age-related connectivity decline in all 11 tracts compared with the controls. In addition, 9 fiber tracts showed significantly higher variability relative to the controls, and symptom severity explained the variability in 6 measurements from the superior cerebellar peduncle, corpus callosum, and cingulum.
The findings revealed widespread alterations in structural connectivity associated with fragile X–associated tremor/ataxia syndrome and preserved or subtle changes in structural connectivity in unaffected carriers. Diffusion tensor imaging is sensitive to pathologic changes in the white matter associated with this neurodegenerative disorder.
Wang et al examine the effects of premutation alleles on major brain fiber tracts in males, who are at risk of developing fragile X-associated tremor/ataxia syndrome and may manifest subtle cognitive, social, and emotional disturbances before clinical involvement.
Minocycline can rescue the dendritic spine and synaptic structural abnormalities in the fragile X knock-out mouse. This is a review and preliminary survey to document side effects and potential outcome measures for minocycline use in the treatment of individuals with fragile X syndrome. We surveyed 50 patients with fragile X syndrome who received minocycline for at least 2 weeks and found that the most common reported side effect is gastrointestinal difficulty, including loss of appetite. The families reported an improvement in language and behavioral areas. Outcome measures in the design of future randomized clinical trials should include both behavioral and language measures. As with any other treatments, we emphasize that randomized clinical trials are needed to determine the efficacy of minocycline in fragile X syndrome.
Premutation fragile X carriers have a CGG repeat expansion (55 to 200 repeats) in the promoter region of the fragile X mental retardation 1 (FMR1) gene. Amygdala dysfunction has been observed in premutation symptomatology, and recent research has suggested the amygdala as an area susceptible to the molecular effects of the premutation. The current study utilizes structural magnetic resonance imaging (MRI) to examine the relationship between amygdala volume, CGG expansion size, FMR1 mRNA, and psychological symptoms in male premutation carriers without FXTAS compared with age and IQ matched controls. No significant between group differences in amygdala volume were found. However, a significant negative correlation between amygdala volume and CGG was found in the lower range of CGG repeat expansions, but not in the higher range of CGG repeat expansions.
Fragile X premutation; Amygdala; FMR1; mRNA; Structural MRI
Minocycline rescued synaptic abnormalities and improved behavior in the fragile X mouse model. Prior open-label human studies demonstrated benefits in individuals with fragile X syndrome (FXS); however, its efficacy in patients with FXS has not been assessed in a controlled trial.
Randomized, double-blind, placebo-controlled, crossover trial in individuals with FXS, ages 3.5-16 years (n=55, mean age 9.2 (SD 3.6 years)). Participants were randomized to minocycline or placebo for three months, then switched to the other treatment.
Sixty-nine subjects were screened and 66 were randomized. Fifty-five subjects (83.3%) completed at least the first period and 48 (72.7%) completed the full trial. Intention-to-treat analysis demonstrated significantly greater improvements in one primary outcome, Clinical Global Impression Scale-Improvement after minocycline compared to placebo (2.49 ±0.13, 2.97 ±0.13, respectively, p 0.0173) and greater improvement in ad hoc analysis of anxiety and mood-related behaviors on the Visual Analoge Scale (minocycline 5.26 cm ±0.46 cm, placebo 4.05 cm±0.46cm; p 0.0488). Side effects were not significantly different during the minocycline and placebo treatments. No serious adverse events occurred on minocycline. Results may be potentially biased by study design weaknesses, including unblinding of subjects when they completed the study, drug-related side effects unblinding and preliminary efficacy analysis results known to investigators.
Minocycline treatment for three months in children with FXS resulted in greater global improvement than placebo. Treatment for three months appears safe; however, longer trials are indicated to further assess benefits, side effects, and factors associated with a clinical response to minocycline.
Fragile X Syndrome; Intellectual Disability; Minocycline; Matrix Metalloproteinase 9
Fragile X-associated tremor/ataxia syndrome is a neurodegenerative disorder that primarily affects older male premutation carriers of the fragile X mental retardation gene. Although its core symptoms are mainly characterized by motor problems such as intention tremor and gait ataxia, cognitive decline and psychiatric problems are also commonly observed. Past radiological and histological approaches have focused on prominent neurodegenerative changes in specific brain structures including the cerebellum and limbic areas. However, quantitative investigations of the regional structural abnormalities have not been performed over the whole brain. In this study, we adopted the voxel-based morphometry method together with regions of interest analysis for the cerebellum to examine the pattern of regional grey matter change in the male premutation carriers with and without fragile X-associated tremor/ataxia syndrome. In a comparison with healthy controls, we found striking grey matter loss of the patients with fragile X-associated tremor/ataxia syndrome in multiple regions over the cortical and subcortical structures. In the cerebellum, the anterior lobe and the superior posterior lobe were profoundly reduced in both vermis and hemispheres. In the cerebral cortex, clusters of highly significant grey matter reduction were found in the extended areas in the medial surface of the brain, including the dorsomedial prefrontal cortex, anterior cingulate cortex and precuneus. The other prominent grey matter loss was found in the lateral prefrontal cortex, orbitofrontal cortex, amygdala and insula. Although the voxel-wise comparison between the asymptomatic premutation group and healthy controls did not reach significant difference, a regions of interest analysis revealed significant grey matter reduction in anterior subregions of the cerebellar vermis and hemisphere in the asymptomatic premutation group. Correlation analyses using behavioural scales of the premutation groups showed significant associations between grey matter loss in the left amygdala and increased levels of obsessive–compulsiveness and depression, and between decreased grey matter in the left inferior frontal cortex and anterior cingulate cortex and poor working memory performance. Furthermore, regression analyses revealed a significant negative effect of CGG repeat size on grey matter density in the dorsomedial frontal regions. A significant negative correlation with the clinical scale for the severity of fragile X-associated tremor/ataxia syndrome was found in a part of the vermis. These observations reveal the anatomical patterns of the neurodegenerative process that underlie the motor, cognitive and psychiatric problems of fragile X-associated tremor/ataxia syndrome, together with incipient structural abnormalities that may occur before the clinical onset of this disease.
fragile X-associated tremor/ataxia syndrome; movement disorder; voxel based morphometry; cerebellum; atrophy
Premutation alleles of the fragile X mental retardation 1 gene (FMR1) are associated with the risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder that involves neuropsychiatric problems and executive and memory deficits. Although abnormal elevation of FMR1 mRNA has been proposed to underlie these deficits, it remains unknown which brain regions are affected by the disease process of FXTAS and genetic molecular mechanisms associated with the FMR1 premutation. This study used functional magnetic resonance imaging (fMRI) to identify deficient neural substrates responsible for altered executive and memory functions in some FMR1 premutation individuals. We measured fMRI BOLD signals during the performance of verbal working memory from 15 premutation carriers affected by FXTAS (PFX+), 15 premutation carriers unaffected by FXTAS (PFX−), and 12 matched healthy control individuals (HC). We also examined correlation between brain activation and FMR1 molecular variables (CGG repeat size and mRNA levels) in premutation carriers. Compared with HC, PFX+ and PFX− showed reduced activation in the right ventral inferior frontal cortex and left premotor/dorsal inferior frontal cortex. Reduced activation specific to PFX+ was found in the right premotor/dorsal inferior frontal cortex. Regression analysis combining the two premutation groups demonstrated significant negative correlation between the right ventral inferior frontal cortex activity and the levels of FMR1 mRNA after excluding the effect of disease severity of FXTAS. These results indicate altered prefrontal cortex activity that may underline executive and memory deficits affecting some individuals with FMR1 premutation including FXTAS patients.
Previous functional MRI (fMRI) studies have shown that fragile X mental retardation 1 (FMR1) fragile X premutation allele carriers (FXPCs) exhibit decreased hippocampal activation during a recall task and lower inferior frontal activation during a working memory task compared to matched controls. The molecular characteristics of FXPCs includes 55–200 CGG trinucleotide expansions, increased FMR1 mRNA levels, and decreased FMRP levels especially at higher repeat sizes. In the current study, we utilized MRI to examine differences in hippocampal volume and function during an encoding task in young male FXPCs. While no decreases in either hippocampal volume or hippocampal activity were observed during the encoding task in FXPCs, FMRP level (measured in blood) correlated with decreases in parahippocampal activation. In addition, activity in the right dorsolateral prefrontal cortex during correctly encoded trials correlated negatively with mRNA levels. These results, as well as the established biological effects associated with elevated mRNA levels and decreased FMRP levels on dendritic maturation and axonal growth, prompted us to explore functional connectivity between the hippocampus, prefrontal cortex, and parahippocampal gyrus using a psychophysiological interaction analysis. In FXPCs, the right hippocampus evinced significantly lower connectivity with right ventrolateral prefrontal cortex (VLPFC) and right parahippocampal gyrus. Furthermore, the weaker connectivity between the right hippocampus and VLPFC was associated with reduced FMRP in the FXPC group. These results suggest that while FXPCs show relatively typical brain response during encoding, faulty connectivity between frontal and hippocampal regions may have subsequent effects on recall and working memory.
fragile X premutation; memory; prefrontal cortex; psychophysiological interaction analysis
The fragile X mental retardation 1 (FMR1) gene plays an important role in the development and maintenance of neuronal circuits that are essential for cognitive functioning. We explored the functional linkage(s) among lymphocytic FMR1 gene expression, brain structure, and working memory in healthy adult males. We acquired T1-weighted and diffusion tensor imaging from 34 males (18–80 years, mean ± SD = 43.6 ± 18.4 years) with normal FMR1 alleles and performed genetic and working memory assessments. Brain measurements were obtained from fiber tracts important for working memory (i.e. the arcuate fasciculus, anterior cingulum bundle, inferior longitudinal fasciculus, and the genu and anterior body of the corpus callosum), individual voxels, and whole brain. Both FMR1 mRNA and protein (FMRP) levels exhibited significant associations with brain measurements, with FMRP correlating positively with gray matter volume and white matter structural organization, and FMR1 mRNA negatively with white matter structural organization. The correlation was widespread, impacting rostral white matter and 2 working-memory fiber tracts for FMRP, and all cerebral white matter areas except fornix and cerebellar peduncles and all 4 fiber tracts for FMR1 mRNA. In addition, the levels of FMR1 mRNA as well as the fiber tracts demonstrated significant correlation with working memory performance. While FMR1 mRNA exhibited negative correlation with working memory, fiber tract structural organization showed positive correlation. These findings suggest that the FMR1 gene is a genetic factor in common for both working memory and the brain structure, and has implications for our understanding of the transmission of intelligence and brain structure.
FMR1; Diffusion tensor imaging; Working memory; Cognition; White matter; Tractography
Fragile X syndrome (FXS) results from a trinucleotide repeat expansion (full mutation >200 cytosine-guanine-guanine (CGG) repeats) in the FMR1 gene, leading to a reduction or absence of the gene’s protein product, fragile X mental retardation protein (FMRP), ultimately causing cognitive and behavioral impairments that are characteristic of the syndrome. In our previous work with infants and toddlers with FXS, we have been able to describe much about their cognitive and visual processing abilities. In light of recent work on the mild cognitive deficits and functional and structural brain differences that are present in adults with the fragile X (FX) premutation, in the present study we examined whether some of the low-level visual processing deficits we have observed in infants with FXS would also be present in infants with the FX premutation (55–200 CGG repeats).
We chose a contrast detection task using second-order motion stimuli on which infants with FXS previously showed significantly increased detection thresholds (Vision Res 48:1471–1478, 2008). Critically, we also included a developmental delay comparison group of infants with Down syndrome (DS), who were matched to infants with FXS on both chronological and mental age, to speak to the question of whether this second-order motion processing deficit is a FX-specific phenomenon.
As reported previously, infants with the FX full mutation showed motion contrast detection threshold levels that were significantly higher than age-matched typically developing control infants. Strikingly, the motion detection contrast levels of FX premutation infants were also significantly higher than typically developing (TD) infants and not significantly different from the group of infants with FXS or with DS.
These results, which are in keeping with a growing body of evidence on the mild cognitive and perceptual processing deficits and functional and structural brain differences that are present in adults and older children with the FX premutation, underscore the pressing need to study and describe the processing capabilities of infants and toddlers with the FX premutation.
Premutation; Visual processing deficits; Fragile X syndrome; Contrast detection
The fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting a subset of carriers of the FMR1 (fragile X mental retardation 1) premutation. Penetrance and expression appear to be significantly higher in males than females. Although the most obvious aspect of the phenotype is the movement disorder that gives FXTAS its name, the disorder is also accompanied by progressive cognitive impairment. In this review, we address the cognitive neuropsychological and neurophysiological phenotype for males and females with FXTAS, and for male and female unaffected carriers. Despite differences in penetrance and expression, the cognitive features of the disorder appear similar for both genders, with impairment of executive functioning, working memory, and information processing the most prominent. Deficits in these functional systems may be largely responsible for impairment on other measures, including tests of general intelligence and declarative learning. FXTAS is to a large extent a white matter disease, and the cognitive phenotypes observed are consistent with what some have described as white matter dementia, in contrast to the impaired cortical functioning more characteristic of Alzheimer’s disease and related disorders. Although some degree of impaired executive functioning appears to be ubiquitous among persons with FXTAS, the data suggest that only a subset of unaffected carriers of the premutation - both female and male - demonstrate such deficits, which typically are mild. The best-studied phenotype is that of males with FXTAS. The manifestations of cognitive impairment among asymptomatic male carriers, and among women with and without FXTAS, are less well understood, but have come under increased scrutiny.
Fragile X-associated tremor/ataxia syndrome; FXTAS; FMR1; Fragile X; Executive function; Cognition disorders; Fragile X premutation
Recent evidence suggests those with autism may be generally impaired in visual motion perception. To examine this, we investigated both coherent and biological motion processing in adolescents with autism employing both psychophysical and fMRI methods. Those with autism performed as well as matched controls during coherent motion perception but had significantly higher thresholds for biological motion perception. The autism group showed reduced posterior Superior Temporal Sulcus (pSTS), parietal and frontal activity during a biological motion task while showing similar levels of activity in MT+/V5 during both coherent and biological motion trials. Activity in MT+/V5 was predictive of individual coherent motion thresholds in both groups. Activity in dorsolateral prefrontal cortex (DLPFC) and pSTS was predictive of biological motion thresholds in control participants but not in those with autism. Notably, however, activity in DLPFC was negatively related to autism symptom severity. These results suggest that impairments in higher-order social or attentional networks may underlie visual motion deficits observed in autism.
Our visual world is dynamic in nature. The ability to encode, mentally represent, and track an object's identity as it moves across time and space is critical for integrating and maintaining a complete and coherent view of the world. Here we investigated dynamic object processing in typically developing (TD) infants and infants with fragile X syndrome (FXS), a single-gene disorder associated with deficits in dorsal stream functioning. We used the violation of expectation method to assess infants’ visual response to expected versus unexpected outcomes following a brief dynamic (dorsal stream) or static (ventral stream) occlusion event. Consistent with previous reports of deficits in dorsal stream-mediated functioning in individuals with this disorder, these results reveal that, compared to mental age-matched TD infants, infants with FXS could maintain the identity of static, but not dynamic, object information during occlusion. These findings are the first to experimentally evaluate visual object processing skills in infants with FXS, and further support the hypothesis of dorsal stream difficulties in infants with this developmental disorder.
object tracking; occlusion; motion; dorsal/ventral visual streams; attention
Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and non-idiopathic autism. Individuals with FXS present with a behavioral phenotype of specific and selective deficits in an array of cognitive skills. Disruption of number processing and arithmetic abilities in higher-functioning adults and female adolescents with FXS has been well established. Still, both numerical skills and developmentally antecedent cognitive processes have just begun to be investigated in toddlers with FXS. The goal of the current study was to assess how very young children with FXS respond to ordinal relationships among numerical magnitudes.
Infrared eye-tracking was used to explore infants’ novelty recognition during passive viewing of ordinal numerical sequences; t-tests were used to analyze group differences in looking time.
Ordinal recognition of numerical magnitudes is significantly impaired in young toddlers with FXS.
This study is the first to experimentally evaluate early number sense and ordinal recognition in toddlers with FXS, and our findings reveal that ordinal recognition of numerical magnitudes is significantly impaired in young toddlers with FXS, suggesting that later arithmetic impairments associated with FXS may have their origins in a developmental impairment of this more basic aspect of numerical cognition.
Approximate number system; Development; Magnitude
Fragile X syndrome is the most common cause of inherited intellectual impairment and the most common single-gene cause of autism. Individuals with fragile X syndrome present with a neurobehavioural phenotype that includes selective deficits in spatiotemporal visual perception associated with neural processing in frontal–parietal networks of the brain. The goal of the current study was to examine whether reduced resolution of spatial and/or temporal visual attention may underlie perceptual deficits related to fragile X syndrome. Eye tracking was used to psychophysically measure the limits of spatial and temporal attention in infants with fragile X syndrome and age-matched neurotypically developing infants. Results from these experiments revealed that infants with fragile X syndrome experience drastically reduced resolution of temporal attention in a genetic dose-sensitive manner, but have a spatial resolution of attention that is not impaired. Coarse temporal attention could have significant knock-on effects for the development of perceptual, cognitive and motor abilities in individuals with the disorder.
crowding; flicker; magnocellular; Mooney; contrast sensitivity
The fragile X premutation provides a unique opportunity for the study of genetic and brain mechanisms of behavior and cognition in the context of neurodevelopment and neurodegeneration. Although the neurodegenerative phenotype, fragile X-associated tremor/ataxia syndrome (FXTAS), is well described, evidence of a causal link between the premutation and psychiatric disorder earlier in life, clear delineation of a behavioral/cognitive phenotype, and characterization of the physiological basis of observed symptoms have been elusive.
We completed functional magnetic resonance imaging (fMRI) targeting the amygdala with an emotion-matching task and concurrent infra-red eyetracking, FMR1 molecular genetic testing, and neuropsychological assessment in 23 men with the premutation (mean age = 32.9 years) and 25 male controls (mean age = 30.1).
Premutation carriers had significantly smaller left and right amygdala volume and reduced right amygdala activation during the task relative to controls. Although both elevated FMR1 mRNA and reduced FMR1 protein (FMRP) were associated with the reduced activation, multiple regression analysis suggested that reduced FMRP is the primary factor. Premutation carriers also had higher ratings of autism spectrum symptoms than controls that were associated with the reduced amygdala response.
Although prior studies have emphasized a toxic gain-of-function effect of elevated mRNA associated with the premutation, the current results point to the role of reduced FMRP in alterations of brain activity and behavior.
FMR1; fragile X; premutation; amygdala; insula; FXTAS
A previous study reported preliminary results of enhanced processing of simple visual information in the form of faster reaction times, in female fragile X premutation carriers (fXPCs). In this study, we assessed manual and oral motor reaction times in 30 female fXPCs and 20 neurotypical (NT) controls. Participants completed two versions of the reaction time task; one version required a manual motor response and the other version required an oral motor response. Results revealed that the female fXPCs displayed faster reaction times for both manual and oral motor responses relative to NT controls. Molecular measures including CGG repeat length, FMR1 mRNA levels, and age were not associated with performance in either group. Given previously reported age and CGG repeat modulated performance on a magnitude comparison task in this same group of premutation carriers, results from the current study seem to suggest that female fXPCs may have spared basic psychomotor functionality.
Psychomotor performance; Anxiety; Cortiospinal tract; Corticopontine tract; Motor cortex; X-linked genetic disease
Older male premutation carriers of the FMR1 gene are associated with the risk of developing a late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Although previous postmortem and in vivo MRI studies have indicated white matter pathology, the regional selectivity of abnormalities, as well as their relationship with molecular variables of the FMR1 gene, has not been investigated. In this study, we used diffusion tensor imaging (DTI) to study male premutation carriers with and without FXTAS and healthy gender-matched controls. We performed a tract of interest analysis for fractional anisotropy (FA), axial and radial diffusivities of major white matter tracts in the cerebellar-brainstem and limbic systems. Compared with healthy controls, patients with FXTAS showed significant reductions of FA in multiple white matter tracts, including the middle cerebellar peduncle (MCP), superior cerebellar peduncle, cerebral peduncle, and the fornix and stria terminalis. Significant reduction of FA in these tracts were confirmed by a voxel-wise analysis using Tract-Based Spatial Statistics. Analysis of axial and radial diffusivities showed significant elevation of these measures in MCP even among premutation carriers without FXTAS. Furthermore, regression analyses demonstrated clear inverted U-shaped relationship between CGG repeat size and axial and radial diffusivities in MCP. These results provide new evidence from DTI for white matter abnormalities in the cerebellar-brainstem and limbic systems among individuals with the fragile X premutation, and suggest the involvement of molecular mechanisms related to the FMR1 gene in their white matter pathology.
DTI; cerebellum; FMR1; FXTAS
Young children with fragile X syndrome (FXS) often experience anxiety, irritability, and hyperactivity related to sensory hyperarousal. However, there are no medication recommendations with documented efficacy for children under 5 years old of age with FXS. We examined data through a chart review for 45 children with FXS, 12–50 months old, using the Mullen Scales of Early Learning (MSEL) for baseline and longitudinal assessments. All children had clinical level of anxiety, language delays based on MSEL scores, and similar early learning composite (ELC) scores at their first visit to our clinic. Incidence of autism spectrum disorder (ASD) was similar in both groups. There were 11 children who were treated with sertraline, and these patients were retrospectively compared to 34 children who were not treated with sertraline by chart review. The baseline assessments were done at ages ranging from 18 to 44 months (mean 26.9, SD 7.99) and from 12 to 50 months (mean 29.94, SD 8.64) for treated and not treated groups, respectively. Mean rate of improvement in both expressive and receptive language development was significantly higher in the group who was treated with sertraline (P < 0.0001 and P = 0.0071, resp.). This data supports the need for a controlled trial of sertraline treatment in young children with FXS.
The high frequency of the fragile X premutation in the general population and its emerging neurocognitive implications highlight the need to investigate the effects of the premutation on lifespan cognitive development. Until recently, cognitive function in fragile X premutation carriers (fXPCs) was presumed to be unaffected by the mutation. Here we show that young adult female fXPCs show subtle, yet significant, age- and FMR1 gene mutation-modulated cognitive impairments as tested by a quantitative magnitude comparison task. Our results begin to define the neurocognitive endophenotype associated with the premutation in adults, who are at risk for developing a neurodegenerative disorder associated with the fragile X premutation. Results from the present study may potentially be applied toward the design of early interventions wherein we might be able to target premutation carriers most at risk for degeneration for preventive treatment.
fragile X premutation carrier; adult; women; parietal lobe; magnitude; numerical; spatial
Conscious visual perception of the constantly changing environment is one of the brain’s most critical functions. In virtually every moment of every daily activity, the visual system is confronted with the task of accurately representing and interpreting scenes that change rapidly over time. Adults can judge the identity and order of changing images presented at a rate of up to 10 Hz (~50 ms per image); this limit reflects a finite temporal resolution of attention. In the research reported here, although 6- to 15-month-old infants could detect the presence of rapid flicker without difficulty, their ability to segment individual alternating states within the flicker was severely limited: Fifteen-month-old infants had a temporal resolution of attention approximately one order of magnitude lower than that of adults (~1 Hz). Coarse temporal resolution constrains how infants perceive and utilize dynamic visual information and may play a role in the visual processing deficits found in individuals with neurodevelopmental disorders.
temporal individuation; Gestalt flicker fusion; contrast sensitivity
A previous study reported enhanced psychomotor speed, and subtle but significant cognitive impairments, modulated by age and by mutations in the fragile X mental retardation 1 (FMR1) gene in adult female fragile X premutation carriers (fXPCs). Because male carriers, unlike females, do not have a second, unaffected FMR1 allele, male fXPCs should exhibit similar, if not worse, impairments. Understanding male fXPCs is of particular significance because of their increased risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS).
Male fXPCs (n = 18) and healthy control (HC) adults (n = 26) aged less than 45 years performed two psychomotor speed tasks (manual and oral) and two visuospatial tasks (magnitude comparison and enumeration). In the magnitude comparison task, participants were asked to compare and judge which of two bars was larger. In the enumeration task, participants were shown between one and eight green bars in the center of the screen, and asked to state the total number displayed. Enumeration typically proceeds in one of two modes: subitizing, a fast and accurate process that works only with a small set of items, and counting, which requires accurate serial-object detection and individuation during visual search. We examined the associations between the performance on all tasks and the age, full-scale intelligent quotient, and CGG repeat length of participants.
We found that in the magnitude comparison and enumeration tasks, male fXPCs exhibited slower reaction times relative to HCs, even after controlling for simple reaction time.
Our results indicate that male fXPCs as a group show impairments (slower reaction times) in numerical visuospatial tasks, which are consistent with previous findings. This adds to a growing body of literature characterizing the phenotype in fXPCs who are asymptomatic for FXTAS. Future longitudinal studies are needed to determine how these impairments relate to risk of developing FXTAS.
X-linked genetic disease; Psychomotor performance; FMR1