PubMed Health⌕ Search

Biomedical subjects

Randi J Hagerman

Publications and source records attributed to Randi J Hagerman.

At least 19 recordsLinked to original sources
PubMed2007

Neuropathic features in fragile X premutation carriers.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurological condition occurring in fragile X premutation carriers, predominantly males, and resulting in CNS dysfunction including tremor, ataxia, Parkinsonism, and cognitive decline. Neuropathic signs have also been described. The objective of this study was to compare neuropathic signs in fragile X premutation carriers versus controls and determine the relationship of these signs to CGG repeat length and tremor/ataxia. A neuropathy scale was utilized to compare distal tendon reflexes and vibration sense in subjects from a large cohort of carriers and controls undergoing neurological exam and structured videotaping sessions for movement disorder rating. The male carrier group displayed more impairment on total neuropathy, vibration and reflex scores than the corresponding control group, while female carriers were not significantly different from controls. In males, after correction for age effects, there was a correlation between CGG repeat length and both total neuropathy and reflex impairments. Age-adjusted partial correlation analyses showed an association between neuropathy scores and severity of ataxia but not tremor in carrier males and females. These data suggest that neuropathic signs are associated with the fragile X premutation, presumably occurring through the same mechanism proposed for CNS disease, namely, toxicity from expanded-CGG-repeat FMR1 mRNA.

Female↗
PubMed2007

Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1.

Recent advances in our understanding of the clinical and molecular features of the fragile-X mental-retardation 1 gene, FMR1, highlight the importance of single-gene disorders. 15 years after its discovery, FMR1 continues to reveal new and unexpected clinical presentations and molecular mechanisms. Loss of function of FMR1 is a model for neurodevelopmental and behavioural disorders, including mental retardation, autism, anxiety, and mood instability. In addition, overexpression and CNS toxicity of FMR1 mRNA causes a late-onset neurodegenerative disorder, the fragile-X-associated tremor/ataxia syndrome (FXTAS). A similar mechanism is probably involved in premature ovarian failure, which affects up to 20% of female carriers of an altered FMR1 gene.

Adult↗
PubMed2006

Amygdala dysfunction in men with the fragile X premutation.

Premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene are associated with autism spectrum disorder in childhood, premature ovarian failure, and the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS, and perhaps the other clinical presentations among carriers, are thought to be due to toxic gain-of-function of elevated levels of the expanded-repeat FMR1 mRNA. Previous structural MRI studies have implicated the amygdala as a potential site of dysfunction underlying social deficits and/or risk for FXTAS. As a preliminary investigation of this possible association, adult males with the premutation, and male controls matched for IQ, age and education, completed three protocols that probe amygdala and sympathetic function: (i) a functional MRI paradigm that measures brain response to fearful faces; (ii) a fear-potentiated startle paradigm that differentiates responses to fearful faces and fearful non-social images and (iii) measurement of skin conductance level during a brief social encounter. Compared with controls, men with the FMR1 premutation demonstrated diminished brain activation in the amygdala and several brain areas that mediate social cognition while viewing fearful faces. The reduced amygdala activation in the premutation group was significantly associated with self-report of psychological symptoms on the Symptom Checklist-90--Revised. These men also displayed a lack of startle potentiation while viewing fearful faces and showed reduced skin conductance response when greeting an unfamiliar experimenter in comparison with the control group. The current findings may be related to social cognition deficits reported previously in children and adults with the premutation. The aetiology for this dysfunction may be elevated FMR1 mRNA or reduced FMR1 protein that occurs in carriers with higher premutation CGG repeat alleles.

Adult↗
PubMed2006

The FMR1 premutation and reproduction.

OBJECTIVE: To update clinicians on the reproductive implications of premutations in FMR1 (fragile X mental retardation 1). Fragile X syndrome, a cause of mental retardation and autism, is due to a full mutation (>200 CGG repeats). Initially, individuals who carried the premutation (defined as more than 55 but less than 200 CGG repeats) were not considered at risk for any clinical disorders. It is now recognized that this was incorrect, specifically with respect to female reproduction. DESIGN AND SETTING: Literature review and consensus building at two multidisciplinary scientific workshops. CONCLUSION(S): Convincing evidence now relates the FMR1 premutation to altered ovarian function and loss of fertility. An FMR1 mRNA gain-of-function toxicity may underlie this altered ovarian function. There are major gaps in knowledge regarding the natural history of the altered ovarian function in women who carry the FMR1 premutation, making counseling about reproductive plans a challenge. Women with premature ovarian failure are at increased risk of having an FMR1 premutation and should be informed of the availability of fragile X testing. Specialists in reproductive medicine can provide a supportive environment in which to explain the implications of FMR1 premutation testing, facilitate access to testing, and make appropriate referral to genetic counselors.

Adolescent↗
PubMed2006

Transcript levels of the intermediate size or grey zone fragile X mental retardation 1 alleles are raised, and correlate with the number of CGG repeats.

BACKGROUND: Grey zone or intermediate alleles are one of the three recognised classes of the X-linked fragile X mental retardation 1 (FMR1) gene showing intergenerational instability. These classes are defined according to the number of CGG repeats in the FMR1 5'-untranslated region. Although large CGG expansions (>200 repeats) cause a neurodevelopmental anomaly through silencing of the gene, resulting in a deficit of FMR1 specific protein, smaller expansions (approximately 55-200 repeats) are associated with an increased transcription and late-onset specific phenotypes. Those alleles with a CGG repeat number ranging between approximately 41 and 55 are relatively poorly defined with regard to both transcriptional and translational activity, and also potential phenotypic effects. METHODS AND RESULTS: Based on a sample of 33 males carrying FMR1 alleles within the grey zone range, defined here as 41-60 CGGs, we show an increased transcriptional activity relative to that seen in common alleles (5-40 CGGS). This is the first study to report a significant relationship between FMR1 mRNA levels and CGG repeat number within the grey zone range (p<0.001). From a piecewise linear regression model, the threshold for onset of the increase in mRNA levels as a function of CGG repeat size has been determined at approximately 39 repeats (standard error (SE) 3.24), and that for the reduction in the rate of this increase at approximately 54 repeats (SE 4.27). CONCLUSIONS: The ambiguities associated with the definition and transcription dynamics of the FMR1 gene within the grey zone range are dealt with. There may be specific phenotypes associated with the toxic "gain-of-function" effect of raised mRNA.

5' Untranslated Regions↗
PubMed2006

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.

Aged↗
PubMed2006

Size bias of fragile X premutation alleles in late-onset movement disorders.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS), caused by premutation expansions (55-200 CGG repeats) of the FMR1 gene, shares clinical features with other movement disorders, particularly in the domains of gait ataxia, intention tremor and parkinsonism. However, the prevalence of FXTAS within other diagnostic categories is not well defined. METHODS: A meta-analysis was conducted of all published (n = 14) genetic screens for expanded FMR1 alleles to assess the prevalence and CGG-repeat size bias of FMR1 premutation alleles in those populations. RESULTS: In men with late-onset cerebellar ataxia, the prevalence of premutation alleles (1.5%; 16/1049) was 13 times greater than expected based on its prevalence in the general population (2%; 16/818 for age of onset >50 years; odds ratio 12.4; 95% confidence interval 1.6 to 93.5). Meta-analysis of CGG-repeat data for screened patients with premutation alleles shows a shift to larger repeat size than in the general population (p<0.001). 86% (19/22) of premutation alleles were larger than 70 repeats in the patients screened, whereas only approximately 22% of premutation alleles are larger than 70 repeats in the general population. CONCLUSIONS: Expanded FMR1 alleles contribute to cases of late-onset sporadic cerebellar ataxia, suggesting that FMR1 genetic testing should be carried out in such cases. The biased distribution of FMR1 allele sizes has substantial implications for genetic counselling of carriers with smaller alleles who are at a low risk of developing FXTAS, and suggests that the estimated prevalence of FXTAS among men >50 years of age in the general population may be two to threefold lower than the initial figure of 1 in 3000.

Adult↗
PubMed2006

Symptomatic treatment in the fragile X-associated tremor/ataxia syndrome.

There is no established treatment for the neurological features of the recently discovered fragile X-associated tremor/ataxia syndrome (FXTAS). Fifty-six patients with FXTAS completed a questionnaire to determine whether any medications had been effective for neurological symptoms. Of 11 subjects with definite FXTAS, 8 (70%) were on medications for their neurological symptoms, whereas most subjects with possible or probable FXTAS, 31 (70%) of 45 subjects, were not on medications. Although no therapy was uniformly effective for intention tremor, ataxia, Parkinsonism, memory loss, or anxiety, some subjects with intention tremor or Parkinsonism reported improvement with medications frequently used in other movement disorders. Overall, all 22 subjects on medications reported improvement in one or more symptoms. Lack of insight, recall bias, and cognitive impairment may have resulted in an underestimation of the beneficial effect of medical therapy. This study suggests that patients with FXTAS can derive improvement from medication treatment for some of their symptoms.

Adrenergic beta-Antagonists↗
PubMed2006

Lessons from fragile X regarding neurobiology, autism, and neurodegeneration.

The fragile X mental retardation 1 gene (FMR1) mutation causes two disorders: fragile X syndrome (FXS) in those with the full mutation and the fragile X-associated tremor/ataxia syndrome (FXTAS) in some older individuals with the premutation. FXS is caused by a deficiency of the FMR1 protein (FMRP) leading to dysregulation of many genes that create a phenotype with ADHD, anxiety, and autism. FXTAS is caused by the elevation of FMR1-mRNA to levels 2 to 8 times normal in the premutation. This causes an RNA gain of function toxicity leading to brain atrophy, white matter disease, neuronal and astrocytic inclusion formation, and subsequent ataxia, intention tremor, peripheral neuropathy, and cognitive decline. The neurobiology and pathophysiology of FXS and FXTAS are described in detail.

Adult↗
PubMed2006

Cognitive impairment in a 65-year-old male with the fragile X-associated tremor-ataxia syndrome (FXTAS).

OBJECTIVE: This is the first case report of a comprehensive neuropsychologic examination of an older man with the fragile X-associated tremor-ataxia syndrome (FXTAS). BACKGROUND: FXTAS, a newly identified phenotype affecting older male carriers of the fragile X premutation allele, is a progressive disorder marked by gait ataxia, action tremor, peripheral neuropathy, executive cognitive deficits, generalized brain atrophy, and neuronal and astrocytic intranuclear inclusion bodies throughout the brain. The patient previously had undergone neurologic evaluation, molecular analysis, and magnetic resonance imaging. METHOD: The patient was administered a neuropsychologic examination, assessing motor and somatosensory functioning, visual and spatial functioning, speech and language, attention, executive abilities, learning and memory, and reasoning. RESULTS: The patient showed a pattern of cognitive impairment characterized by essentially normal speech and language, moderately impaired control of attention, and moderate to severe deficits in working memory, executive functioning, and both declarative and procedural learning. Visual and spatial abilities were relatively unimpaired, and verbal reasoning was only mildly deficient. CONCLUSIONS: The findings suggest that a cognitive disorder, with especially marked executive cognitive function and memory deficits, accompanies FXTAS. The findings in FXTAS are compared with those in several other neurodegenerative disorders.

Aged↗
PubMed2006

Psychiatric phenotype of the fragile X-associated tremor/ataxia syndrome (FXTAS) in males: newly described fronto-subcortical dementia.

OBJECTIVE: The authors describe and quantify the neuropsychiatric symptoms present in a cohort of males with the fragile X mental retardation 1 (FMR1) premutation allele who have developed fragile X-associated tremor/ataxia syndrome (FXTAS). METHOD: Fourteen male carriers of the FMR1 premutation who had clinical manifestations of the FXTAS syndrome and 14 age- and education-matched controls were assessed with the Neuropsychiatric Inventory (NPI), formal cognitive testing, and genetic analysis. RESULTS: Males with FXTAS had significantly higher total NPI scores (p < .004) and significantly higher scores on the agitation/aggression (p < .004), depression (p < .004), apathy (p < .004), disinhibition (p < .004), and irritability (p < .004) scales, compared with controls. Cognitive performances on the Mini-Mental State Examination did not correlate with severity of symptoms on the NPI. CONCLUSIONS: The neuropsychiatric manifestations of FXTAS, based on this preliminary report, appear to cluster as a fronto-subcortical dementia. Clinicians encountering patients with clinical dementia with motor symptoms suggesting FXTAS should consider genetic testing to determine whether the patient's dementia syndrome is secondary to a fragile X premutation carrier status.

Aged↗
PubMed2005

Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutation.

Until recently, individuals with premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene were believed to be psychologically unaffected. However, the recent documentation of abnormal elevation of FMR1 mRNA, discovery of fragile X-associated tremor/ataxia syndrome (FXTAS), and reports of psychiatric disorders in children and adults with the premutation have suggested a pathogenic gene-brain-behavior mechanism. In a large collaborative study, 68 men and 144 women with the FMR1 premutation completed a psychological symptoms checklist and FMR1 genetic testing, including determination of CGG repeat size, percentage of FMR1 protein (FMRP)-positive lymphocytes, and FMR1 mRNA levels. Relative to published norms, men and women with FXTAS symptoms reported higher levels of several types of psychological symptoms. In addition, men and women with the premutation and no overt evidence of FXTAS reported higher levels of obsessive-compulsive symptoms. Elevated FMR1 mRNA, but not CGG repeat size or reduced FMRP (as measured by immunocytochemistry), was significantly associated with increased psychological symptoms, predominantly obsessive-compulsive symptoms and psychoticism, in premutation men with and without FXTAS symptoms. There was no relationship between CGG repeat size, FMR1 mRNA or FMRP and psychological symptoms in premutation women unless the sample was restricted to those with skewed X-activation ratio toward >50% active premutation alleles. The results of this study support the hypothesis that FMR1 function is associated with psychological difficulties in individuals with the premutation, and provide evidence concordant with an RNA toxic gain-of-function model in a neuropsychiatric phenotype.

Female↗
PubMed2005

Neural progenitor cells from an adult patient with fragile X syndrome.

BACKGROUND: Currently, there is no adequate animal model to study the detailed molecular biochemistry of fragile X syndrome, the leading heritable form of mental impairment. In this study, we sought to establish the use of immature neural cells derived from adult tissues as a novel model of fragile X syndrome that could be used to more fully understand the pathology of this neurogenetic disease. METHODS: By modifying published methods for the harvest of neural progenitor cells from the post-mortem human brain, neural cells were successfully harvested and grown from post-mortem brain tissue of a 25-year-old adult male with fragile X syndrome, and from brain tissue of a patient with no neurological disease. RESULTS: The cultured fragile X cells displayed many of the characteristics of neural progenitor cells, including nestin and CD133 expression, as well as the biochemical hallmarks of fragile X syndrome, including CGG repeat expansion and a lack of FMRP expression. CONCLUSION: The successful production of neural cells from an individual with fragile X syndrome opens a new avenue for the scientific study of the molecular basis of this disorder, as well as an approach for studying the efficacy of new therapeutic agents.

Adult↗
PubMed2005

Recent advances in fragile X: a model for autism and neurodegeneration.

PURPOSE OF REVIEW: This review will describe recent developments in the neurobiology of fragile X syndrome (FXS), the association between FXS and autism, and involvement in premutation carriers. RECENT FINDINGS: Metabotropic glutamate receptor 5 (mGluR5)-coupled pathways are dysregulated in individuals with FXS and this is thought to relate to the FXS phenotype. The mGluR5 model suggests that mGluR5 antagonists, including downstream effectors such as lithium, could be useful for treating FXS. Two forms of clinical involvement associated with the fragile X mental retardation 1 (FMR1) gene, autism and fragile X-associated tremor/ataxia syndrome (FXTAS), have received additional attention during the past year. One study has found that approximately 30% of individuals with FXS have autism; those with autism have lowered cognitive abilities, language problems, and behavioral difficulties compared to those with FXS alone. Furthermore, evidence is mounting that autism also occurs in some young males who have premutation alleles. Finally, males and occasional females with premutation alleles may develop a neurological syndrome with aging that consists of tremor, ataxia, peripheral neuropathy, and cognitive deficits. Significant brain atrophy and white-matter disease is usually seen. This new disorder (FXTAS) is thought to be related to elevated levels of abnormal FMR1 mRNA. SUMMARY: Full-mutation forms of the gene (> 200 repeats) can cause autism, learning disabilities, anxiety disorders, and mental retardation. Disorders associated with premutation forms of the gene (55-200 repeats) include, in addition to autism, FXTAS in older males and females, and premature ovarian failure.

Journal Article↗
PubMed2005

GRAND ROUNDS: an atypical progressive dementia in a male carrier of the fragile X premutation: an example of fragile X-associated tremor/ataxia syndrome.

This case study describes a 65-year-old man initially diagnosed with an atypical rapidly progressive dementia who subsequently participated in a research project at the MIND Institute at the University of California-Davis, where he was diagnosed with a recently identified neurodegenerative syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS). He was a carrier of the fragile X premutation and in later life developed tremor, gait ataxia, parkinsonism, and cognitive deficits that progressed very rapidly. This case study provides a detailed description of the individual's history, presenting symptoms, neuropsychological test results, and postmortem neuropathological analysis. Pathological findings showed diagnostic features of both FXTAS and Alzheimer's disease, which might help to explain the rapid progression of his dementia.

Aged↗
PubMed2004

The effect of pre-mutation of X chromosome CGG trinucleotide repeats on brain anatomy.

Expanded trinucleotide repeats are associated with several neuropsychiatric disorders, including fragile X syndrome (FraX) which is the most common inherited form of mental retardation. It is currently thought that FraX results from having >200 CGG trinucleotide repeats, with consequent methylation of the fragile X mental retardation gene (FMR1) and loss of FMR1 protein (FMRP). Pre-mutation carriers of FraX (with 55-200 CGG trinucleotide repeats) were originally considered unaffected, although recent studies challenge this view. However, there are few studies on the effect of pre-mutation trinucleotide repeat expansion on the male human brain using quantitative MRI. Also the results of prior investigations may be confounded because people were selected on the basis of clinical and neurological features, and not genetic phenotype. We compared the brain anatomy of 20 adult male pre-mutation members of known FraX families with 20 healthy male controls. The two groups did not differ significantly in age, intelligence quotient (IQ) or handedness. We also investigated whether any observed effects were associated with: (i) ageing; (ii) expansion of pre-mutation CGG trinucleotide repeats; (iii) reduction in the percentage of lymphocytes staining with anti-FMRP antibodies [%FMRP(+) lymphocytes]; and (iv) elevation of FMR1 mRNA levels. Male pre-mutation carriers of FraX, compared with matched controls, had significantly less voxel density in several brain regions, including the cerebellum, amygdalo-hippocampal complex and thalamus. Within pre-mutation carriers of FraX, ageing, increases in the number of CGG trinucleotide repeats and decreases in %FMRP(+) lymphocytes were associated with decreasing voxel density of regions previously identified as decreased relative to controls. Regional grey and white matter density is significantly affected in male pre-mutation carriers of FraX recruited on the basis of genetic, not clinical, phenotype. The association of voxel density reduction and ageing is consistent with observations of a subgroup of older pre-mutation males who present with cognitive decline. Moreover, our findings suggest, for the first time, an association between voxel density reduction and genetic variation in FraX.

Adolescent↗
PubMed2004

Paternal transmission of fragile X syndrome.

We present a family in which a fragile X mosaic male, who carries both premutation and full mutation alleles in his peripheral blood leukocytes, has a daughter with both premutation and partially methylated full mutation alleles and a significant developmental disability. To our knowledge, this is the first report of such an occurrence and it challenges current thinking about the expansion and transmission of unstable FMR1 alleles from men to their daughters. It is currently accepted that neither males with premutations nor full mutations are at risk for having daughters with full mutations and fragile X syndrome. The sperm cells of full mutation males are thought to carry only premutation alleles. These alleles, when transmitted through a male, regardless of his cognitive status, are thought to be unable to expand to full mutations in the next generation. In effect, the expansion from premutation to full mutation has only been observed through female meioses. The sperm cells in the father in this family have been shown to contain only alleles in the premutation range. Since his daughter has both premutation and full mutation alleles the expansion to full mutation in this case must have occurred postzygotically.

Alleles↗