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Biomedical subjects

P J Hagerman

Publications and source records attributed to P J Hagerman.

At least 19 recordsLinked to original sources
PubMed2006

Molecular and imaging correlates of the fragile X-associated tremor/ataxia syndrome.

OBJECTIVES: To assess changes in regional brain volumes associated with the fragile X-associated tremor/ataxia syndrome (FXTAS) and the molecular correlates of these changes. METHODS: We administered molecular, MRI, and neurocognitive tests to 36 male premutation carriers (ages 51 to 79), 25 affected and 11 unaffected with FXTAS, and to 21 control subjects of similar age and education. RESULTS: We found differences among the three groups in whole brain, cerebrum, cerebellum, ventricular volume, and whole-brain white matter hyperintensity, with the affected group showing significantly more pathology than the control and unaffected groups. Brainstem volume was significantly smaller in the unaffected group vs controls but did not differ from the affected group. Within the premutation sample, CGG repeat length correlated with reductions in IQ and cerebellar volume and increased ventricular volume and whole-brain white matter hyperintensity. CONCLUSIONS: The current findings, coupled with recent evidence linking the degree of neuropathology (numbers of intranuclear inclusions) to the size of the premutation allele, provide evidence that the neurodegenerative phenotype in the fragile X-associated tremor/ataxia syndrome is a consequence of the CGG repeat expansion.

Aged↗
PubMed2006

Prevalence of FMR1 repeat expansions in movement disorders. A systematic review.

We reviewed prevalence rates of fragile X mental retardation gene (FMR1) repeat expansions in movement disorder populations. Inclusion criteria included published epidemiological studies from systematic searches of Medline, Pubmed, Cochrane Databases and Web Science. Thirteen cross-sectional studies were carried out between 2003 and 2005. Subjects with ataxia showed higher than expected rates while those with essential tremor and parkinsonism showed lower rates. The heterogeneous design of the studies, inclusion criteria and mean age of subjects may have led to underestimation of FMR1 repeat expansion prevalence rates.

Cross-Sectional Studies↗
PubMed2005

Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS).

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects carriers, principally males, of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Clinical features of FXTAS include progressive intention tremor and gait ataxia, accompanied by characteristic white matter abnormalities on MRI. The neuropathological hallmark of FXTAS is an intranuclear inclusion, present in both neurons and astrocytes throughout the CNS. Prior to the current work, the nature of the associations between inclusion loads and molecular measures (e.g. CGG repeat) was not defined. Post-mortem brain and spinal cord tissue has been examined for gross and microscopic pathology in a series of 11 FXTAS cases (males, age 67-87 years at the time of death). Quantitative counts of inclusion numbers were performed in various brain regions in both neurons and astrocytes. Inclusion counts were compared with specific molecular (CGG repeat, FMR1 mRNA level) and clinical (age of onset, age of death) parameters. In the current series, the three most prominent neuropathological characteristics are (i) significant cerebral and cerebellar white matter disease, (ii) associated astrocytic pathology with dramatically enlarged inclusion-bearing astrocytes prominent in cerebral white matter and (iii) the presence of intranuclear inclusions in both brain and spinal cord. The pattern of white matter pathology is distinct from that associated with hypertensive vascular disease and other diseases of white matter. Spongiosis was present in the middle cerebellar peduncles in seven of the eight cases in which those tissues were available for study. There is inclusion formation in cranial nerve nucleus XII and in autonomic neurons of the spinal cord. The most striking finding is the highly significant association between the number of CGG repeats and the numbers of intranuclear inclusions in both neurons and astrocytes, indicating that the CGG repeat is a powerful predictor of neurological involvement in males, both clinically (age of death) and neuropathologically (number of inclusions).

Age of Onset↗
PubMed2005

Protein composition of the intranuclear inclusions of FXTAS.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by premutation expansions (55-200 CGG repeats) in the fragile X mental retardation 1 (FMR1) gene. The pathologic hallmark of FXTAS is the ubiquitin-positive intranuclear inclusion found in neurons and astrocytes in broad distribution throughout the brain. The pathogenesis of FXTAS is likely to involve an RNA toxic gain-of-function mechanism, and the FMR1 mRNA has recently been identified within the inclusions. However, little is known about the proteins that mediate the abnormal cellular response to the expanded CGG repeat allele. As one approach to identify the protein mediators, we have endeavoured to define the protein complement of the inclusion itself. Fluorescence-activated flow-based methods have been developed for the efficient purification of inclusions from the post-mortem brain tissue of FXTAS patients. Mass spectrometric analysis of the entire protein complement of the isolated inclusions, combined with immunohistochemical analysis of both isolated nuclei and tissue sections, has been used to identify inclusion-associated proteins. More than 20 inclusion-associated proteins have been identified on the basis of combined immunohistochemical and mass spectrometric analysis, including a number of neurofilaments and lamin A/C. There is no dominant protein species in the inclusions, and ubiquitinated proteins represent only a minor component; thus, inclusion formation is not likely to reflect a breakdown in proteasomal degradation of nuclear proteins. The list of proteins includes at least two RNA binding proteins, heterogeneous nuclear ribonucleoprotein A2 and muscle blind-like protein 1, which are possible mediators of the RNA gain-of-function in FXTAS.

Aged↗
PubMed2005

Initial diagnoses given to persons with the fragile X associated tremor/ataxia syndrome (FXTAS).

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a newly described disorder that occurs in premutation carriers of the fragile X mental retardation 1 (FMR1) gene. Fifty-six patients with FXTAS were given 98 prior diagnoses: most were in the categories of parkinsonism, tremor, ataxia, dementia, or stroke. Data from this study and others were used to develop guidelines for FMR1 diagnostic testing for FXTAS.

Age Factors↗
PubMed2004

Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation.

We describe five female carriers of the FMR1 premutation who presented with symptoms of tremor and ataxia and who received a diagnosis of definite or probable fragile-X-associated tremor/ataxia syndrome (FXTAS). Unlike their male counterparts with FXTAS, none of the women had dementia. Females had not been reported in previous studies of FXTAS, suggesting that they may be relatively protected from this disorder. Brain tissue was available from one of the five subjects, a women who died at age 85 years; microscopic examination revealed intranuclear neuronal and astrocytic inclusions, in accord with the findings previously reported in males with FXTAS. The work-up of families with the FMR1 mutation should include questions regarding neurological symptoms in both older male and female carriers, with the expectation that females may also manifest the symptoms of FXTAS, although more subtly and less often than their male counterparts.

Adult↗
PubMed2004

Aging in individuals with the FMR1 mutation.

Individuals with fragile X mental retardation 1 (FMR1) premutation (55 to 200 CGG repeats) are typically unaffected by fragile X syndrome. However, a subgroup of older males with the premutation have developed a neurological syndrome, which usually begins between 50 and 70 years and is associated with a progressive intention tremor and/or ataxia manifested by balance problems, frequent falling, and Parkinsonian symptoms, such as masked facies, intermittent resting tremor, and mild rigidity. This finding has been termed the fragile X-associated tremor/ataxia syndrome (FXTAS) and has brought focus to the aging process in individuals with the FMR1 mutation. The premutation is associated with elevated messenger RNA levels leading to the formation of intranuclear inclusions in neurons and astrocytes associated with FXTAS. This review is a summary of our experience with FXTAS in male carriers of the premutation.

Aged↗
PubMed2003

Expression of the FMR1 gene.

Fragile X syndrome is a trinucleotide repeat disorder in which a (CGG)n element located within the 5' untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene expands to more than 200 copies (full mutation) and becomes hypermethylated. Such expansions are accompanied by the failure to produce FMR1 protein (FMRP), resulting in the fragile X phenotype. For smaller (premutation) expansions (approximately 55-200 repeats), FMR1 mRNA and FMRP levels had been assumed to be normal; however, our group and others have recently demonstrated that FMR1 mRNA levels are elevated in cells harboring premutation alleles. Moreover, mRNA levels remain elevated in fragile X males with partially methylated full mutation alleles. Finally, some fragile X males with hypermethylated, full mutation alleles continue to produce FMR1 mRNA, despite the expectation that those genes should be silent. These observations all point to a complex mechanism of expression of the FMR1 gene, one that provides a more consistent foundation for the spectrum of clinical involvement. An FMRP deficit is observed in all categories of fragile X individuals, including carriers of the premutation and partially methylated full mutation alleles. These results demonstrate that lowered FMRP levels, in the absence of methylation-coupled silencing of the FMR1 gene, are not caused by reduced transcriptional activity, but rather by a reduced efficiency of translation.

DNA Methylation↗
PubMed2003

A cerebellar tremor/ataxia syndrome among fragile X premutation carriers.

Fragile X syndrome is a neurodevelopmental disorder that is not known to have any progressive neurological sequelae in adulthood. However, a neurological condition involving intention tremor, ataxia, and cognitive decline has recently been identified among older male carriers of premutation alleles of the FMR1 gene. This condition is clinically distinct from fragile X syndrome and arises through a different molecular mechanism involving the same gene (FMR1). Characteristic findings on magnetic resonance imaging include cerebral and cerebellar volume loss and altered signal intensities of the middle cerebellar peduncles. A striking feature of this fragile X-associated tremor/ataxia syndrome is the presence of ubiquitin-positive neuronal and astroglial intranuclear inclusions. Unlike the CAG repeat expansion diseases, which lead to altered protein products, there is no known protein abnormality among FMR1 premutation carriers. Thus, inclusion formation may reflect a gain-of-function effect of the FMR1 mRNA or the CGG repeat itself. Finally, since this syndrome may represent one of the more common single-gene causes of tremor, ataxia, and dementia among older males, FMR1 DNA testing should be considered when evaluating adult patients with tremor/ataxia.

Cerebellar Ataxia↗
PubMed2002

Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers.

A neurological syndrome involving progressive action tremor with ataxia, cognitive decline and generalized brain atrophy has been described recently in some adult males with pre-mutation alleles of the fragile X syndrome (FXS) fragile X mental retardation gene (FMR1). Neurohistological studies have now been performed on the brains of four elderly premutation carriers, not reported previously, who displayed the neurological phenotype. Eosinophilic, intranuclear inclusions were present in both neuronal and astrocytic nuclei of the cortex in all four individuals. Systematic analysis of the brains of two of these carriers demonstrated the presence of the intranuclear inclusions throughout the cerebrum and brainstem, being most numerous in the hippocampal formation. The cerebellum displayed marked dropout of Purkinje cells, Purkinje axonal torpedoes and Bergmann gliosis. Intranuclear inclusions were absent from Purkinje cells, although they were present in a small number of neurones in the dentate nucleus and diffusely in cerebellar astrocytes. The presence of inclusions in the brains of all four FXS carriers with the neurological findings provides further support for a unique clinical entity associated with pre-mutation FMR1 alleles. The origin of the inclusions is unknown, although elevated FMR1 mRNA levels in these pre-mutation carriers may lead to the neuropathological changes.

Aged↗
PubMed2001

The 5'-untranslated region of the FMR1 message facilitates translation by internal ribosome entry.

Fragile X syndrome, the leading heritable form of mental impairment, is generally caused by large expansions of a CGG repeat in the promoter region of the FMR1 gene followed by transcriptional silencing. However, there is growing evidence that translation of the FMR1 message is also impaired, presumably because of the expanded CGG element in the 5'-untranslated region (5'-UTR) of the FMR1 message. To study the properties of the FMR1 5'-UTR, deletions were generated within a normal 5'-UTR with 16 CGG repeats for both monocistronic and dicistronic (luciferase) reporter constructs. Transient transfection experiments revealed a approximately 20-nucleotide region upstream of the CGG repeat element that functions as an internal ribosome entry site (IRES). The normal CGG element itself does not appear to influence the efficiency of IRES-mediated stimulation of downstream reporter activity (approximately 18-fold over controls). Additional controls indicate that the enhanced activity of the downstream reporter is not due to readthrough from the upstream cistron, nor is it due to translation of cryptic monocistronic transcripts. The role of the FMR1 IRES element is not known at present; however, by analogy to other IRES-containing mRNAs expressed in neurons, the FMR1 IRES element may help to promote translation in dendrites.

5' Untranslated Regions↗
PubMed2001

Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X.

The authors report five elderly men with the fragile X premutation who had a progressive action tremor associated with executive function deficits and generalized brain atrophy. These individuals had elevated fragile X mental retardation 1 gene (FMR1) messenger RNA and normal or borderline levels of FMR1 protein. The authors propose that elevations of FMR1 messenger RNA may be causative for a neurodegenerative syndrome in a subgroup of elderly men with the FMR1 premutation.

Aged↗
PubMed2001

Structural studies of the tRNA domain of tmRNA.

tmRNA is a small, stable prokaryotic RNA. It rescues ribosomes that have become stalled during the translation of mRNA fragments lacking stop codons, or during periods of tRNA scarcity. It derives its name from the presence of two separate domains, one that functions as a tRNA, and another that serves as an mRNA. We have carried out modeling and transient electric birefringence studies to determine the angle between the acceptor stem and anticodon stem of the tRNA domain of Eschericia coli tmRNA. The results of the modeling studies yielded an interstem angle of 110 degrees, in agreement with the lower end of the range of angles (111 degrees -137 degrees ) determined experimentally for various solution conditions. The range of experimental angles is greater than the angles observed for any of the tRNA crystal structures, in line with the presence of a shortened D stem. The secondary structure of the tRNA domain is conserved for all known tmRNA sequences, so we propose that the angle is also conserved. These results also suggest that the region of tmRNA between P2a and P2b may interact with the decoding site of the ribosome.

Anticodon↗
PubMed2001

A majority of fragile X males with methylated, full mutation alleles have significant levels of FMR1 messenger RNA.

FMR1 mRNA levels were determined in peripheral blood leucocytes for 48 fragile X males with methylated, full mutation alleles that are resistant to cleavage by methylation sensitive enzymes. Using quantitative (fluorescence) RT-PCR, we observed that more than half of these males produce FMR1 mRNA, with some mRNA levels approaching those found in normal subjects. In none of the samples analysed was there any evidence of premutation alleles. These results suggest that the assumed relationship between enzyme resistance and FMR1 gene silencing may not be generally valid. Despite the presence of FMR1 mRNA in some subjects, no FMRP production was detected by either immunocytochemistry or western blotting. The low/absent FMRP levels are probably a reflection of a post-trancriptional effect such as a defect in translation.

Alleles↗
PubMed2001

[Fragile X syndrome: a model of gene-brain-behaviour relationships].

INTRODUCTION: Sequencing of the fragile X mental retardation 1 (FMR1) gene and the measurements of the gene product FMRP, have enabled protein quantification of variations within the FMR1 gene and FMRP-clinical correlations. DEVELOPMENT: This paper will review our knowledge of the regulation of FMR1 gene expression and the genotype-phenotype relationships. The clinical variability is related to several factors including: 1) molecular variations at FMR1 leading to a range of FMRP levels, 2) the combined effect of background genes interacting directly or indirectly with FMRP, 3) environmental factors which can either enhance or impede development and the degree of dysfunction which ensues. CONCLUSION: Advances in neuroimaging, neurosciences, and knockout mice further our understanding of the gene-brain-behavior relationships in Fragile X Syndrome.

Animals↗
PubMed2000

Fragile X males with unmethylated, full mutation trinucleotide repeat expansions have elevated levels of FMR1 messenger RNA.

Fragile X syndrome normally arises as a consequence of large expansions (n >200) of a (CGG)(n) trinucleotide repeat in the promoter region of the FMR1 gene. The clinical phenotype is thought to result from hypermethylation of the repeat and adjacent upstream elements, with consequent down-regulation of transcription (transcriptional silencing). However, the relationship between repeat expansion and transcription has not been defined in the full mutation range. Using the method of quantitative (fluorescence) reverse transcriptase polymerase chain reaction, we demonstrated previously that FMR1 mRNA levels are substantially elevated in premutation (55 </= n < 200) male carriers. In the current work, we report that in fragile X males with unmethylated alleles in the full mutation range (n > 200), FMR1 mRNA levels remain significantly elevated (mean 3.5-fold elevation; P = 6.7 x 10(-3)) relative to normal controls, even for alleles exceeding 300 repeats. This conclusion is independent of any assumption regarding the transcriptional activity of methylated alleles. However, if it were assumed that all methylated alleles were transcriptionally silent, the FMR1 mRNA levels for cells with unmethylated alleles would be even higher (mean 4.5-fold elevation; P = 2.1 x 10(-4)). These observations show that the full-mutation CGG expansion per se is not a strong impediment to transcription and that the apparent up-regulation of the FMR1 locus remains active in at least some cells with full-mutation alleles.

Alleles↗