A neuropsychological investigation of male premutation carriers of fragile X syndrome

It is currently thought that fragile X syndrome (FraX; the most common inherited form of learning disability) results from having more than 200 cytosine–guanine–guanine (CGG) trinucleotide repeats, with consequent methylation of the fragile X mental retardation (FMR1) gene and loss of FMR1 protein (FMRP). It was also considered that premutation carriers (with 55–200 CGG repeats) are unaffected, although a tremor/ataxia syndrome has recently been described in older adult male carriers. We reported that premutation expansion of CGG trinucleotide repeats affects brain anatomy, which, together with other studies, indicates that the molecular model for FraX needs modification. However, there are few studies on the cognitive ability of adult male premutation carriers. Thus, we selected 20 male premutation carriers on the basis of their genetic phenotype, and compared them to 20 male controls matched on age, IQ and handedness. We investigated intellectual functioning, executive function, memory, attention, visual and spatial perception, and language and pragmatics. The premutation carriers had significant impairments on tests of executive function (Verbal Fluency, Trail Making Test and Tower of London) and memory (Names sub-test of the Doors and People, Verbal Paired Associates Immediate Recall and Visual Paired Associates Delayed Recall sub-tests of the WMS-R, and Category Fluency Test for natural kinds). We therefore suggest that CGG trinucleotide repeats in the premutation range affect specific neuronal circuits that are concordant with specific neuropsychological deficits; and that these deficits reflect an emerging neuropsychological phenotype of premutation FraX.     

FMR1 alleles in Parkinson's disease: relation to cognitive decline and hallucinations, a longitudinal study

Carriers of expanded alleles of the fragile X mental retardation (FMR1) gene may display parkinsonism, cognitive decline, and behavioral changes. The authors screened 2 male groups of patients affected with Parkinson's disease (PD) (n = 137). One group (n = 56) was followed longitudinally for up to 12 years. Length of CGG repeats in PD patients was compared with healthy controls (n = 310). In addition, the association of the number of CGG repeats with cognitive decline or hallucinations was studied in the longitudinally followed PD group. The authors found no repeats in the premutation range (55-200 CGG repeats) and no significant difference in the proportion of intermediate-size (41-54 CGG repeats) carriers between the PD and the control groups. Using linear regression, the number of CGG repeats was not related to motor or cognitive progression. However, the marked cognitive decline in 2 patients carrying intermediate-size alleles points to a possible association. More studies with larger PD samples are warranted.     

CGG trinucleotide repeat length modulates neural plasticity and spatiotemporal processing in a mouse model of the fragile X premutation

The fragile X premutation is a CGG repeat expansion on the FMR1 gene between 55 and 200 repeats in length. It has been proposed that impaired spatiotemporal function underlies cognitive deficits in genetic disorders, including the fragile X premutation. This study characterized the role of the premutation for cognitive function by demonstrating CGG KI mice with 70–198 CGG repeats show deficits across tasks requiring spatial and temporal pattern separation. To elucidate mechanisms whereby CGG repeats affect spatiotemporal processing, hippocampal slices were evaluated for LTP, LTD, and mGluR1/5 LTD. Increasing CGG repeat length modulated the induction of LTP, LTD, and mGluR1/5 LTD, as well as behavioral tasks emphasizing spatiotemporal processing. Despite the deficits in the induction of all forms of plasticity, there were no differences in expression of plasticity once evoked. These data provide evidence for a neurocognitive endophenotype in the CGG KI mouse model of the premutation in which CGG repeat length negatively modulates plasticity and spatiotemporal attention. © 2012 Wiley Periodicals, Inc.     

Motor deficits on a ladder rung task in male and female adolescent and adult CGG knock-in mice

The fragile X premutation is a tandem CGG trinucleotide repeat expansion on the FMR1 gene between 55 and 200 repeats in length. A CGG knock-in (CGG KI) mouse with CGG trinucleotide repeat lengths between 70 and 350 has been developed and used to model the histopathology and cognitive deficits reported in carriers of the fragile X premutation. Previous studies have shown that CGG KI mice show progressive deficits in processing spatial and temporal information. To characterize the motor deficits associated with the fragile X premutation, male and female CGG KI mice ranging from 2 to 16 months of age with trinucleotide repeats ranging from 72 to 240 CGG in length were tested for their ability to perform a skilled ladder rung walking test. The results demonstrate that both male and female CGG KI mice showed a greater number of foot slips as a function of increased CGG repeat length, independent of the age of the animal or general activity level.     

Phenobarbital use and neurological problems in FMR1 premutation carriers

Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by a CGG expansion in the FMR1 gene located at Xq27.3. Patients with the premutation in FMR1 present specific clinical problems associated with the number of CGG repeats (55–200 CGG repeats). Premutation carriers have elevated FMR1 mRNA expression levels, which have been associated with neurotoxicity potentially causing neurodevelopmental problems or neurological problems associated with aging. However, cognitive impairments or neurological problems may also be related to increased vulnerability of premutation carriers to neurotoxicants, including phenobarbital. Here we present a study of three sisters with the premutation who were exposed differentially to phenobarbital therapy throughout their lives, allowing us to compare the neurological effects of this drug in these patients.     

Fragile X-associated disorders: a clinical overview

Fragile X Syndrome (FraX) is the most common inherited cause of learning disability worldwide. FraX is an X-linked neuro-developmental disorder involving an unstable trinucleotide repeat expansion of cytosine guanine guanine (CGG). Individuals with the full mutation of FraX have >200 CGG repeats with premutation carriers having 55–200 CGG repeats. A wide spectrum of physical, behavioural, cognitive, psychiatric and medical problems have been associated with both full mutation and premutation carriers of FraX. In this review, we detail the clinical profile and examine the aetiology, epidemiology, neuropathology, neuroimaging findings and possible management strategies for individuals with both the full mutation and premutation of FraX.     

Spatiotemporal processing deficits in female CGG KI mice modeling the fragile X premutation

The fragile X premutation is a tandem CGG trinucleotide repeat expansion in the fragile X mental retardation 1 (FMR1) gene between 55 and 200 repeats in length. A CGG knock-in (CGG KI) mouse has been developed that models the neuropathology and cognitive deficits reported in fragile X premutation carriers. It has been suggested that carriers of the premutation demonstrate a spatiotemporal hypergranularity, or reduced resolution of spatial and temporal processing. A temporal ordering of spatial locations task was used to evaluate the ability of CGG KI mice to process temporal and spatial information with either high or low levels of spatial interference. The results indicate that CGG KI mice showed difficulty performing a spatial novelty detection task when there were high levels of spatial interference, but were able to perform the novelty detection task when there was low spatial interference. These data suggest that CGG KI mice show reduced spatial and temporal resolution that are modulated by the dosage of the Fmr1 gene mutation, such that when behavioral tasks require mice to overcome high levels of either spatial or temporal interference, the CGG KI mice perform increasingly poorly as the CGG repeat length increases.     

Impairment in the cognitive functioning of men with fragile X-associated tremor/ataxia syndrome (FXTAS)

Disorders associated with fragile X syndrome involve a trinucleotide (CGG) repeat expansion in the FMR1 gene. Recently, a progressive movement disorder (fragile X-associated tremor/ataxia syndrome [FXTAS]) has been identified in premutation carriers, persons with 55 to 200 CGG repeats. In addition to ataxia, action tremor, and Parkinsonism, early case reports suggested that FXTAS involves impaired cognition, but the precise nature of the impairment has not been elucidated. In this first, preliminary study of the subject, circumscribed aspects of cognitive functioning were examined in 25 men with FXTAS. Subjects' performance on the cognitive tests was compared with normative data. Scores on two measures of executive cognitive functioning showed a high prevalence of substantial impairment. Capacity for inhibition was severely affected in one-quarter of this highly educated sample; information processing speed was profoundly impaired in most subjects. Although mean verbal and performance IQ scores were not significantly different from the general population, they were quite low given the sample's educational level. Cognitive and functional impairment was greater for men with more CGG repeats, although number of repeats was not associated with age of onset of either tremor or ataxia. The results provide evidence that FXTAS involves marked impairment of executive cognitive abilities.     

Visual motion processing deficits in infants with the fragile X premutation

Background

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).

Methods

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.

Results

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.

Conclusions

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.     

Investigation of amygdala volume in men with the fragile X premutation

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.     

Wisconsin Card Sorting Test performance over time in schizophrenia. Preliminary evidence from clinical follow-up and neuroleptic reduction studies.

Two groups of schizophrenic patients took the Wisconsin Card Sorting Test (WCST) in separate follow-up studies; a naturalistic clinical follow-up (n = 12, study 1) and a neuroleptic reduction study (n = 10, study 2). 11 of 22 subjects (50%) performed well on the task at one or both time points. In each study no group differences were found between time 1 and time 2 performance on three WCST variables. However, correlational analyses revealed considerable within-subject variation on the WCST in the study 1 sample, which was composed of younger and more acute patients than those in study 2. This variation was present despite within-subject stability on the WAIS-R Vocabulary and Block Design subtests. For the sample combined, a trend was found (p = 0.12) linking better WCST performance at either time period with higher WAIS-R Vocabulary scores. This intra-subject variability may reflect fluctuations in neuropsychological performance in schizophrenics who maintain the residual capacity to do the task. These findings highlight the importance of longitudinal studies of neuropsychological functioning in schizophrenia. Studies of larger samples are needed to confirm these initial results.     

Spatial cognition in males with Fragile-X syndrome: evidence for a neuropsychological phenotype.

Spatial performance in a group of young Fragile-X syndrome males with FMR-1 full mutation was compared to a learning disabled control group comprising young Down's syndrome males and two control groups of mainstream schoolchildren. Performance was assessed across a wide range of spatial tasks including visuo-construction, visuo-spatial memory, visuo-motor, and visuo-perception. The findings indicate a task-specific rather than global deficit in spatial performance in Fragile-X males with visuo-constructive and visuo-motor skills most vulnerable. Molecular analysis of the lymphocyte DNA found minimal evidence for a correlation between CGG expansion size and spatial performance, although tasks with a visuo-perceptual component correlated negatively with expansion size indicating that the further away the number of repeats are from the 200 threshold the poorer the performance.     

Parkinsonism, FXTAS, and FMR1 premutations.

The presence of late-onset neurological symptoms in male carriers of premutation expansions of the fragile X mental retardation 1 (FMR1) gene has been described recently. One of the clinical symptoms in this fragile X-associated tremor/ataxia syndrome (FXTAS) is parkinsonism. To test the possible association between expanded FMR1 alleles and Parkinson's disease (PD), we determined the size of the FMR1 CGG repeat in 414 male cases of clinically diagnosed parkinsonism, the majority of whom had PD. None of our patients had expanded FMR1 repeats within the premutation range (55-200 CGG repeats). Five patients (1.2%) carry intermediate-size alleles (41-54 CGG repeats). Expansions within the FMR1 gene are not associated with PD in our study.     

Personality profile and neuropsychological test performance in chronic cocaine-abusers.

Little is known about the association between personality disorders and neuropsychological test performance in chronic cocaine users. The aims of the present study were to (1) pinpoint the specific neuropsychological characteristics of chronic cocaine abusers, (2) analyze their personality profile, and (3) explore the association between personality traits and neuropsychological test performance. A sample of 42 drug-abusers (mean age = 34.15; SD = 6.73; mean educational level = 11.44; SD = 2.01) was selected from a state rehabilitation facility and was compared to a control group (mean age = 34.53; SD = 9.01; mean educational level = 12.29; SD = 1.31). The following information was collected for each subject: (1) A clinical history adapted from Horton (1996). (2) The Personality Assessment Inventory (PAI) (Morey, 1991). (3) A neuropsychological test battery including: Arithmetic and Digits subtests from the WAIS-R, California Verbal Learning Test, Trial Making Test, Verbal Fluency tests, Rey-Osterrieth Complex Figure, Wisconsin Card Sorting Test, Benton Visual Retention Test, Stroop Neurological Screening Test and Hooper Visual Organization. Thirty-seven of the drug-dependent subjects obtained an abnormal score in at least one PAI scale. The personality profile of the drug-dependent subjects found via the PAI pointed to a Borderline/Antisocial personality, frequently associated with mania features. In six of the drug-abusers, a normal personality profile was observed. Neuropsychological test performance scores were within the low average or borderline range. The most abnormal scores were observed in attention, memory, and executive functioning tests. The results did not show any robust association between personality profile and neuropsychological test performance.     

Neuropsychological Functioning in Depressed Versus Nondepressed Participants with Alzheimer's Disease

Differences in cognitive functioning between participants with Alzheimer's Disease (AD) reporting depressive symptomatology (AD-Dep; n = 37) and a control group of nondepressed participants with AD (AD-Con; n = 98) were investigated based on hypothesized impairments of attention/concentration, psychomotor speed, and simple motor speed. Groups did not differ in age, education, overall severity of dementia, auditory comprehension, or use of psychotropic medications. AD-Dep participants performed significantly more poorly than AD-Con participants on 3 of the 13 measures on which they were hypothesized to exhibit greater impairment (WAIS-R Block Design, WAIS-R Digit Symbol, and speeded motor programming); and there were trends toward poorer performance on four additional measures (WAIS-R Object Assembly, WAIS-R Picture Arrangement, WAIS-R Digit Span-backward, and letter fluency). There was only one significant effect for the 13 measures on which no group differences were hypothesized; the AD-Dep participants unexpectedly obtained better WMS-R Logical Memory delayed recall scores than the AD-Con participants. Finally, AD-Dep participants exhibited an unexpected pattern of greater right hand advantage on the Finger Tapping Test.     

Neuropsychological functioning in depressed versus nondepressed participants with Alzheimer's disease

Differences in cognitive functioning between participants with Alzheimer's Disease (AD) reporting depressive symptomatology (AD-Dep; n = 37) and a control group of nondepressed participants with AD (AD-Con; n = 98) were investigated based on hypothesized impairments of attention/concentration, psychomotor speed, and simple motor speed. Groups did not differ in age, education, overall severity of dementia, auditory comprehension, or use of psychotropic medications. AD-Dep participants performed significantly more poorly than AD-Con participants on 3 of the 13 measures on which they were hypothesized to exhibit greater impairment (WAIS-R Block Design, WAIS-R Digit Symbol, and speeded motor programming); and there were trends toward poorer performance on four additional measures (WAIS-R Object Assembly, WAIS-R Picture Arrangement, WAIS-R Digit Span-backward, and letter fluency). There was only one significant effect for the 13 measures on which no group differences were hypothesized; the AD-Dep participants unexpectedly obtained better WMS-R Logical Memory delayed recall scores than the AD-Con participants. Finally, AD-Dep participants exhibited an unexpected pattern of greater right hand advantage on the Finger Tapping Test.     

Tremor and ataxia in fragile X premutation carriers: blinded videotape study

Fragile X premutation carriers do not have typical fragile X syndrome (FXS) although late-onset progressive action tremor and gait disorder with CNS atrophy was recently reported in male carriers. We compared tremor, gait disorder and parkinsonian signs in FXS premutation subjects (age 50 or more) and a similar control population, using a standardized videotaping protocol. Videotapes were rated using standard scales for tremor (CRST), ataxia (ICARS), and parkinsonian signs (UPDRS) by an investigator blinded to premutation status. Compared to all other groups pooled (n = 30), the male premutation carrier group (n = 7) had significantly higher scores on the CRST (p = 0.0008), ICARS (p = 0.001), and UPDRS (p = 0.0094). On the CRST, rest, postural and kinetic tremor scores were all higher in the male carriers. The elevated total UPDRS and ICARS scores mainly resulted from markedly higher scores for tremor and limb ataxia, respectively. The female carrier (n = 14) and control groups (n = 8) did not differ on any measure. The FMR1 premutation is associated with increased levels of CGG repeat-containing FMR1 mRNA, which may predispose to these symptoms by interfering with nuclear mechanisms. Given the relatively high population frequency of the FMR1 premutation, this mutation may be a significant cause of late-onset "idiopathic" progressive tremor.     

Molecular genetic analysis of mentally retarded males with features of the fragile-X syndrome

The fragile-X [fra(X)] or Martin-Bell syndrome is the most common familial cause of mental retardation and is characterized by the presence of an Xq27.3 chromosome fragile site. Unstable DNA sequences representing large increases in the number of CGG trinucleotide DNA base repeats of the FMR-1 gene are located at the fragile site and responsible for the fra(X) syndrome. In order to identify whether cytogenetically normal yet mentally retarded males without 3 known cause of their retardation had expansion of the CGG repeat segment of the FMR-1 gene, molecular genetic studies using Southern hybridization were Performed with two DNA probes (fxa24l and Ox1.9) following digestion of genomic DNA from each patient with restriction enzymes PstI and EcoRI/EagI, respectively. DNA studies were performed on 20 (12.3%) out of 162 (122 white and 40 black people) cytogenetically normal mentally retarded males without a known cause of their retardation, but with high anthropometric discriminant values and/or clinical checklist scores identified previously and consistent with the fra(X) syndrome. None of the 20 males showed expansion of the CGG repeat of the FMR-1 gene detectable with the two probes used in this study. While heterogeneous single base pair substitutions, or small deletions or insertions in the FMR-1 gene could exist in our patients, aberrations in other X-tinked mental retardation genes, not identified to date but whose gene product can produce a phenotype similar to fra(X), either independently or in conjunction with the recently identified FMR-1 protein, should be considered and are under investigation. Our study supports the idea that major FMR-1 gene expansion detectable with Southern hybridization is rare in cytogenetically normal mentally retarded males, including those with physical and behavioural features seen in the fra(X) syndrome.     

Reelin gene alleles and susceptibility to autism spectrum disorders

A polymorphic trinucleotide repeat (CGG/GCC) within the human Reelin gene (RELN) was examined as a candidate gene for autism spectrum disorders (ASDs). This gene encodes a large extracellular matrix protein that orchestrates neuronal positioning during corticogenesis. The CGG-repeat within the 5' untranslated region of RELN exon 1 was examined in 126 multiple-incidence families. The number of CGG repeats varied from three to 16 in affected individuals and controls, with no expansion or contraction observed during maternal (n = 291) or paternal (n = 287) transmissions in families with autistic probands. Although the frequencies of the RELN alleles and genotypes in affected children were not different from those in the comparison group, a family-based association test (FBAT) showed that the larger RELN alleles (> or = 11 repeats) were transmitted more often than expected to affected children (S = 43, E(S) = 34.5, P = 0.035); this was particularly the case for the 13-repeat RELN allele (S = 22, E(S) = 16, P = 0.034). Affected sib-pair (ASP) analysis found no evidence of excess sharing of RELN alleles in affected siblings. The impact of genotypes with large alleles (> or = 11 repeats) on the phenotypes in individuals with ASD was analyzed by ANOVA in a subset of the families for which results of the Autism Diagnostic Interview-Revised were available. Children with large RELN alleles did not show any difference in scores for questions related to the core symptoms of autistic disorder, but there was a tendency for children with at least one large RELN allele to have an earlier age at first phrase (chi(2) = 3.538, P = 0.06). Thus, although the case-control and affected sib-pair findings did not support a role for RELN in susceptibility to ASD, the more powerful family-based association study demonstrated that RELN alleles with larger numbers of CGG repeats may play a role in the etiology of some cases of ASD, especially in children without delayed phrase speech.