747 research outputs found
Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics
No full textFragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and is also linked to other neurologic and psychiatric disorders. FXS is caused by a triplet expansion that inhibits expression of the FMR1 gene; the gene product, FMRP, regulates mRNA metabolism in the brain and thus controls the expression of key molecules involved in receptor signaling and spine morphology. While there is no definitive cure for FXS, the understanding of FMRP function has paved the way for rational treatment designs that could potentially reverse many of the neurobiological changes observed in FXS. Additionally, behavioral, pharmacological, and cognitive interventions can raise the quality of life for both patients and their families.sponsorship: Randi Hagerman has received grant support from Roche, Novartis, Seaside Therapeutics, Forest, and Curemark to carry out clinical trials for fragile X and/or ASD. She has also consulted with Novartis regarding clinical trials in fragile X syndrome. Giovanni Neri received grant support from Novartis for an in vitro study of AFQ056.This work was supported by grants from VIB, Telethon (GGP10150), Compagnia San Paolo, PRIN 2008, Queen Elisabeth Foundation (NICHD HD036071, HD02274, and NCRR 3UL1 RR024146-04S4), Associazione Italiana Sindrome X Fragile, American National Fragile X, and FRAXA Foundations. We are grateful to Matthew Holt and Tilmann Achsel, and to members of our laboratories for critical reading of the manuscript. We thank Nicholas Rajan for helping with the figures. Due to space constraints, we apologize to our colleagues whose work has not been cited. Further, we limit our discussion to FXS in human and mouse models. (Roche, Novartis, Seaside Therapeutics, Forest, Curemark, VIB, Telethon|GGP10150, Compagnia San Paolo, PRIN, Queen Elisabeth Foundation|NICHD HD036071, Queen Elisabeth Foundation|HD02274, Queen Elisabeth Foundation|NCRR 3UL1 RR024146-04S4, Associazione Italiana Sindrome X Fragile Foundation, American National Fragile X Foundation, FRAXA Foundation)status: Publishe
Reduced FMR1 mRNA translation efficiency in fragile X patients with premutations
No full textThe Fragile X mental retardation ′gene (FMR1) contains a polymorphic trinucleotide CGG repeat in the 5 untranslated region (UTR) of the FMR1 messenger. We have characterized three lymphoblastoid cell lines derived from unrelated male carriers of a premutation that overexpress FMR1 mRNA and show reduced FMRP level compared to normal cells. The analysis of polysomes/mRNPs distribution of mRNA in the cell lines with a premutation shows that the polysomal association of FMR1 mRNA, which is high in normal cells, becomes progressively lower with increasing CGG repeat expansion. In addition, we could detect a very low level of FMR1 mRNA in a lymphoblastoid cell line from a patient with a full mutation. In this case, FMR1 mRNA is not at all associated with polysomes, in agreement with the complete absence of FMRP. The impairment of FMR1 mRNA translation in patients with the Fragile X syndrome with FMR1 premutation is the cause of the lower FMRP levels that leads to the clinical involvement
Fragile X and autism : intertwined at the molecular level leading to targeted treatments
No full textFragile X syndrome (FXS) is caused by an expanded CGG repeat (>200 repeats) in the 5’ un-translated portion of the fragile mental retardation 1 gene (FMR1) leading to deficiency or absence of the FMR1 protein (FMRP). FMRP is an RNA carrier protein that controls the translation of a number of other genes that regulate synaptic development and plasticity. Autism occurs in approximately 30% of FXS cases, and Pervasive Developmental Disorder, Not Otherwise Specified (PDD-NOS) occurs in an additional 30% of cases. Premutation repeat expansions (55 to 200 CGG repeats) may also give rise to autism spectrum disorders (ASD), including both autism and PDD-NOS, through a different molecular mechanism that involves a direct toxic effect of the expanded-CGG-repeat FMR1 mRNA. RNA toxicity can also lead to aging effects including tremor, ataxia and cognitive decline termed the fragile X-associated tremor ataxia syndrome (FXTAS) in premutation carriers in late life. In studies of mice bearing premutation expansions, there is evidence of early post-natal neuronal cell toxicity, manifest as reduced cell longevity, decreased dendritic arborization and altered synaptic morphology. There is also evidence of mitochondrial dysfunction in premutation carriers. Many of the problems with cellular dysregulation in both premutation and full mutation neurons also parallel the cellular abnormalities that have been documented in autism without fragile X mutations. Research regarding dysregulation of neurotransmitter systems in FXS, including metabotropic glutamate receptor 1/5 (mGluR1/5) pathway and GABAA pathways, have led to new targeted treatments for FXS. Preliminary evidence suggests that these new targeted treatments will also be beneficial in non-fragile X forms of autis
Curr Opin Psychiatry
No full textPurpose of reviewThis work reviews recent research regarding treatment of fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism spectrum disorder. The phenotype includes anxiety linked to sensory hyperarousal, hyperactivity, and attentional problems consistent with attention deficit hyperactivity disorder and social deficits leading to autism spectrum disorder in 60% of boys and 25% of girls with FXS.Recent findingsMultiple targeted treatments for FXS have rescued the phenotype of the fmr1 knockout mouse, but few have been beneficial to patients with FXS. The failure of the metabotropic glutamate receptor 5 antagonists falls on the heels of the failure of Arbaclofen\u2019s efficacy in children and adults with autism or FXS. In contrast, efficacy has been demonstrated in a controlled trial of minocycline in children with FXS. Minocycline lowers the abnormally elevated levels of matrix metalloproteinase 9 in FXS. Acamprosate and lovastatin have been beneficial in open-label trials in FXS. The first 5 years of life may be the most efficacious time for intervention when combined with behavioral and/or educational interventions.SummaryMinocycline, acamprosate, lovastatin, and sertraline are treatments that can be currently prescribed and have shown benefit in children with FXS. Use of combined medical and behavioral interventions will likely be most efficacious for the treatment of FXS.R40MC27701/PHS HHS/United States90DD0596/DD/NCBDD CDC HHS/United StatesU54 HD079125/HD/NICHD NIH HHS/United StatesU54HD079125/HD/NICHD NIH HHS/United StatesU50 DD000596/DD/NCBDD CDC HHS/United StatesR40MC22641/PHS HHS/United State
Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome
No full textFragile 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
Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome
No full textBrain Disord Ther
No full textFragile X syndrome (FXS) is the most common single gene cause of intellectual disability and it is characterized by a CGG expansion of more than 200 repeats in the FMR1 gene, leading to methylation of the promoter and gene silencing. The fragile X premutation, characterized by a 55 to 200 CGG repeat expansion, causes health problems and developmental difficulties in some, but not all, carriers. The premutation causes primary ovarian insufficiency in approximately 20% of females, psychiatric problems (including depression and/or anxiety) in approximately 50% of carriers and a neurodegenerative disorder, the fragile X-associated tremor ataxia syndrome (FXTAS), in approximately 40% of males and 16% of females later in life. Recent clinical studies in premutation carriers have expanded the health problems that may be seen. Advances in the molecular pathogenesis of the premutation have shown significant mitochondrial dysfunction and oxidative stress in neurons which may be amenable to treatment. Here we review the clinical problems of carriers and treatment recommendations.R01 HD036071/HD/NICHD NIH HHS/United StatesR01 MH078041/MH/NIMH NIH HHS/United StatesU50 DD000596/DD/NCBDD CDC HHS/United States2014-11-26T00:00:00Z25436181PMC424501
FXTAS: Pathophysiology and Management
No full textPURPOSE OF REVIEW: The purpose of this paper is to review the prevalence, pathophysiology, and management of FXTAS. RECENT FINDINGS: The pathophysiology of FXTAS involves RNA toxicity due to elevated levels of the premutation-expanded CGG-repeat FMR1 mRNA, which can sequester a variety of proteins important for neuronal function. A recent analysis of the inclusions in FXTAS demonstrates elevated levels of several proteins, including SUMO1/2, that target molecules for the proteasome, suggesting that some aspect(s) of proteasomal function may be altered in FXTAS. Recent neuropathological studies show that Parkinson disease and Alzheimer disease can sometimes co-occur with FXTAS. Lewy bodies can be found in 10% of the brains of patients with FXTAS. Microbleeds and iron deposition are also common in the neuropathology, in addition to white matter disease and atrophy. SUMMARY: The premutation occurs in 1:200 females and 1:400 males. Penetrance for FXTAS increases with age, though lower in females (16%) compared to over 60% of males by age 70. To diagnose FXTAS, an MRI is essential to document the presence of white matter disease, a primary component of the diagnostic criteria. Pain can be a significant feature of FXTAS and is seen in approximately 50% of patients
Proceeding from the 2009 genetic syndromes of the Ras/MAPK pathway: from bedside to bench and back
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