Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome
TL;DR: To define the extent to which the mechanisms contributing toFXTAS also contribute to other neurodegenerative and medical disorders, and to redefine FXTAS in view of its differing presentations and associated features, are emerging.
Abstract: Summary Fragile X syndrome, the most common heritable form of cognitive impairment, is caused by epigenetic silencing of the fragile X ( FMR1 ) gene owing to large expansions (>200 repeats) of a non-coding CGG-repeat element. Smaller, so-called premutation expansions (55–200 repeats) can cause a family of neurodevelopmental phenotypes (attention deficit hyperactivity disorder, autism spectrum disorder, seizure disorder) and neurodegenerative (fragile X-associated tremor/ataxia syndrome [FXTAS]) phenotypes through an entirely distinct molecular mechanism involving increased FMR1 mRNA production and toxicity. Results of basic cellular, animal, and human studies have helped to elucidate the underlying RNA toxicity mechanism, while clinical research is providing a more nuanced picture of the range of clinical manifestations. Advances of knowledge on both mechanistic and clinical fronts are driving new approaches to targeted treatment, but two important necessities are emerging: to define the extent to which the mechanisms contributing to FXTAS also contribute to other neurodegenerative and medical disorders, and to redefine FXTAS in view of its differing presentations and associated features.
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TL;DR: Fragile X syndrome (FXS) is the leading inherited form of intellectual disability and autism spectrum disorder, and patients can present with severe behavioural alterations, including hyperactivity, impulsivity and anxiety, in addition to poor language development and seizures as mentioned in this paper.
Abstract: Fragile X syndrome (FXS) is the leading inherited form of intellectual disability and autism spectrum disorder, and patients can present with severe behavioural alterations, including hyperactivity, impulsivity and anxiety, in addition to poor language development and seizures. FXS is a trinucleotide repeat disorder, in which >200 repeats of the CGG motif in FMR1 leads to silencing of the gene and the consequent loss of its product, fragile X mental retardation 1 protein (FMRP). FMRP has a central role in gene expression and regulates the translation of potentially hundreds of mRNAs, many of which are involved in the development and maintenance of neuronal synaptic connections. Indeed, disturbances in neuroplasticity is a key finding in FXS animal models, and an imbalance in inhibitory and excitatory neuronal circuits is believed to underlie many of the clinical manifestations of this disorder. Our knowledge of the proteins that are regulated by FMRP is rapidly growing, and this has led to the identification of multiple targets for therapeutic intervention, some of which have already moved into clinical trials or clinical practice.
514 citations
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29 Sep 2017
TL;DR: Fragile X syndrome (FXS) is the leading inherited form of intellectual disability and autism spectrum disorder, and patients can present with severe behavioural alterations, including hyperactivity, impulsivity and anxiety, in addition to poor language development and seizures as mentioned in this paper.
Abstract: Fragile X syndrome (FXS) is the leading inherited form of intellectual disability and autism spectrum disorder, and patients can present with severe behavioural alterations, including hyperactivity, impulsivity and anxiety, in addition to poor language development and seizures. FXS is a trinucleotide repeat disorder, in which >200 repeats of the CGG motif in FMR1 leads to silencing of the gene and the consequent loss of its product, fragile X mental retardation 1 protein (FMRP). FMRP has a central role in gene expression and regulates the translation of potentially hundreds of mRNAs, many of which are involved in the development and maintenance of neuronal synaptic connections. Indeed, disturbances in neuroplasticity is a key finding in FXS animal models, and an imbalance in inhibitory and excitatory neuronal circuits is believed to underlie many of the clinical manifestations of this disorder. Our knowledge of the proteins that are regulated by FMRP is rapidly growing, and this has led to the identification of multiple targets for therapeutic intervention, some of which have already moved into clinical trials or clinical practice.
387 citations
TL;DR: Current molecular classification of NDDs is summarized, focusing on the most relevant biochemical and morphological aspects, to support better prediction of prognosis and stratification of patients for therapy trials.
Abstract: Neurodegenerative diseases (NDDs) are characterized by selective dysfunction and loss of neurons associated with pathologically altered proteins that deposit in the human brain but also in peripheral organs. These proteins and their biochemical modifications can be potentially targeted for therapy or used as biomarkers. Despite a plethora of modifications demonstrated for different neurodegeneration-related proteins, such as amyloid-β, prion protein, tau, α-synuclein, TAR DNA-binding protein 43 (TDP-43), or fused in sarcoma protein (FUS), molecular classification of NDDs relies on detailed morphological evaluation of protein deposits, their distribution in the brain, and their correlation to clinical symptoms together with specific genetic alterations. A further facet of the neuropathology-based classification is the fact that many protein deposits show a hierarchical involvement of brain regions. This has been shown for Alzheimer and Parkinson disease and some forms of tauopathies and TDP-43 proteinopathies. The present paper aims to summarize current molecular classification of NDDs, focusing on the most relevant biochemical and morphological aspects. Since the combination of proteinopathies is frequent, definition of novel clusters of patients with NDDs needs to be considered in the era of precision medicine. Optimally, neuropathological categorizing of NDDs should be translated into in vivo detectable biomarkers to support better prediction of prognosis and stratification of patients for therapy trials.
206 citations
Cites background from "Advances in clinical and molecular ..."
...Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s disease, is a slowly progressive motor neuronopathy, which is X-linked and is caused by an expansion of the CAG repeat in the androgen receptor (AR) gene [225] and fragile X-associated tremor and ataxia syndrome (FXTAS), which is associated with CGG repeats in the FMR1 gene, also show neuronal intranuclear inclusions [226]....
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TL;DR: The complexities involved in the clinical management of fragile X-associated tremor/ataxia syndrome are reviewed and how targeted treatment for these clinical features of FXTAS will result from advances in the understanding of the molecular mechanisms that underlie this neurodegenerative disorder are considered.
Abstract: Many physicians are unaware of the many phenotypes associated with the fragile X premutation, an expansion in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene that consists of 55-200 CGG repeats. The most severe of these phenotypes is fragile X-associated tremor/ataxia syndrome (FXTAS), which occurs in the majority of ageing male premutation carriers but in fewer than 20% of ageing women with the premutation. The prevalence of the premutation is 1 in 150-300 females, and 1 in 400-850 males, so physicians are likely to see people affected by FXTAS. Fragile X DNA testing is broadly available in the Western world. The clinical phenotype of FXTAS at presentation can vary and includes intention tremor, cerebellar ataxia, neuropathic pain, memory and/or executive function deficits, parkinsonian features, and psychological disorders, such as depression, anxiety and/or apathy. FXTAS causes brain atrophy and white matter disease, usually in the middle cerebellar peduncles, the periventricular area, and the splenium and/or genu of the corpus callosum. Here, we review the complexities involved in the clinical management of FXTAS and consider how targeted treatment for these clinical features of FXTAS will result from advances in our understanding of the molecular mechanisms that underlie this neurodegenerative disorder. Such targeted approaches should also be more broadly applicable to earlier forms of clinical involvement among premutation carriers.
201 citations
TL;DR: It is shown that phosphorylation of the mRNA 5′ cap binding protein, eukaryotic initiation factor 4E (eIF4E), is elevated concomitant with increased expression of matrix metalloproteinase 9 (MMP-9) protein, which opens the possibility of new treatment avenues for the diverse neurological and psychiatric aspects of FXS.
167 citations
Cites background from "Advances in clinical and molecular ..."
...Many CGG repeats in the FMR1 gene induce its hypermethylation, transcriptional silencing, and loss of fragile X mental retardation protein (FMRP) expression (Verkerk et al., 1991; Hagerman and Hagerman, 2013)....
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...mental retardation protein (FMRP) expression (Verkerk et al., 1991; Hagerman and Hagerman, 2013)....
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References
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TL;DR: The specificity of C9RANT for c9FTD/ALS is a potential biomarker for this most common cause of FTD and ALS and have significant implications for treatment strategies directed at RAN-translated peptides and their aggregation and the RNA structures necessary for their production.
961 citations
TL;DR: In this article, the authors reported five elderly men with the fragile X premutation who had a progressive action tremor associated with executive function deficits and generalized brain atrophy, and they had elevated fragile X mental retardation 1 gene (FMR1) messenger RNA and normal or borderline levels of FMR1 protein.
Abstract: 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.
817 citations
TL;DR: Current results support a mechanism of involvement in premutation carriers, in which reduced translational efficiency is at least partially compensated through increased transcriptional activity in the full-mutation range as the FMR1 gene is silenced.
Abstract: Summary Fragile-X syndrome is a trinucleotide-repeat–expansion disorder in which the clinical phenotype is believed to result from transcriptional silencing of the fragile-X mental retardation 1 ( FMR1 ) gene as the number of CGG repeats exceeds ∼200. For premutation alleles (∼55–200 repeats), no abnormalities in FMR1 -gene expression have been described, despite growing evidence of clinical involvement in premutation carriers. To address this (apparent) paradox, we have determined, for 16 carrier males (55–192 repeats), the relative levels of leukocyte FMR1 mRNA, by use of automated fluorescence-detection reverse transcriptase–PCR, and the percent of lymphocytes that are immunoreactive for FMR1 protein (FMRP). For some alleles with >100 repeats, there was a reduction in the number of FMRP-positive cells. Unexpectedly, FMR1 mRNA levels were elevated at least fivefold within this same range. No significant increase in FMR1 mRNA stability was observed in a lymphoblastoid cell line (160 repeats) derived from one of the carrier males, suggesting that the increased message levels are due to an increased rate of transcription. Current results support a mechanism of involvement in premutation carriers, in which reduced translational efficiency is at least partially compensated through increased transcriptional activity. Thus, diminished translational efficiency may be important throughout much of the premutation range, with a mechanistic switch occurring in the full-mutation range as the FMR1 gene is silenced.
731 citations
TL;DR: The clinical presentation of these patients, coupled with a specific lesion visible on magnetic resonance imaging and with neuropathological findings, affords a more complete delineation of this fragile X premutation-associated tremor/ataxia syndrome and distinguishes it from other movement disorders.
Abstract: We present a series of 26 patients, all >50 years of age, who are carriers of the fragile X premutation and are affected by a multisystem, progressive neurological disorder. The two main clinical features of this new syndrome are cerebellar ataxia and/or intention tremor, which were chosen as clinical inclusion criteria for this series. Other documented symptoms were short-term memory loss, executive function deficits, cognitive decline, parkinsonism, peripheral neuropathy, lower limb proximal muscle weakness, and autonomic dysfunction. Symmetrical regions of increased T2 signal intensity in the middle cerebellar peduncles and adjacent cerebellar white matter are thought to be highly sensitive for this neurologic condition, and their presence is the radiological inclusion criterion for this series. Molecular findings include elevated mRNA and low-normal or mildly decreased levels of fragile X mental retardation 1 protein. The clinical presentation of these patients, coupled with a specific lesion visible on magnetic resonance imaging and with neuropathological findings, affords a more complete delineation of this fragile X premutation–associated tremor/ataxia syndrome and distinguishes it from other movement disorders.
711 citations
TL;DR: It is demonstrated that older male carriers of premutation alleles of the FMR1 gene are at high risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), and older men with ataxia and intention tremor should be screened for the F MR1 mutation.
Abstract: ContextPremutation expansions (55-200 CGG repeats) of the fragile X mental
retardation 1 (FMR1) gene are frequent in the general
population, with estimated prevalences of 1 per 259 females and 1 per 813
males. Several articles have recently described the presence of late-onset
neurological symptoms in male carriers of premutation (FMR1) alleles. The main clinical features described in this newly identified
syndrome are cerebellar ataxia and intention tremor. Additional documented
symptoms include short-term memory loss, executive functional deficits, cognitive
decline, parkinsonism, peripheral neuropathy, lower-limb proximal muscle weakness,
and autonomic dysfunction.ObjectiveTo study the penetrance of the fragile X–associated tremor/ataxia
syndrome (FXTAS) among premutation carriers.Design, Setting, and ParticipantsFamily-based study of 192 individuals (premutation carriers and controls)
whose families belong to the Northern or Southern California Fragile X Associations.
Data were collected (March 2002-April 2003) through a survey and a standardized
neurological examination, which was videotaped and subsequently scored in
a blinded fashion.Main Outcome MeasuresPenetrance of intention tremor and ataxia among adult carriers (aged
≥50 years) of premutation expansions of the FMR1 gene.ResultsData from the survey of 192 individuals demonstrated an age-related
penetrance of the combination of reported intention tremor and gait ataxia
in male carriers (17%, 38%, 47%, and 75% [lower-bound estimates] for participants
aged 50-59, 60-69, 70-79, and ≥80 years, respectively). The male carrier
group had an age-adjusted 13-fold increased risk (95% confidence interval,
3.9-25.4; P = .003) of combined intention tremor
and gait ataxia when compared with male controls. The clinical examination
data from 93 individuals demonstrated that male carriers experienced more
difficulties on each of 3 standardized neurological rating scales compared
with controls (P<.05). Female carrier scores were
also higher than those of female controls (P<.05)
on 2 of the 3 neurological rating scales, but no participant was identified
with probable or definite FXTAS.ConclusionsThe study demonstrates that older male carriers of premutation alleles
of the FMR1 gene are at high risk of developing FXTAS.
Since male premutation carriers are relatively common in the general population,
older men with ataxia and intention tremor should be screened for the FMR1 mutation, especially if these signs are accompanied
by parkinsonism, autonomic dysfunction, or cognitive decline, regardless of
family history.
589 citations