Progression of tremor and ataxia in male carriers of the FMR1 premutation

Department of Pediatrics, University of California, Davis, Davis, California, United States
Movement Disorders (Impact Factor: 5.68). 01/2007; 22(2):203-6. DOI: 10.1002/mds.21252
Source: PubMed


Premutation alleles of the fragile X mental retardation 1 (FMR1) gene give rise to a late-onset movement disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), characterized by progressive intention tremor and gait ataxia, with associated dementia and global brain atrophy. The natural history of FXTAS is largely unknown. To address this issue, a family-based, retrospective, longitudinal study was conducted with a cohort of 55 male premutation carriers. Analysis of the progression of the major motor signs of FXTAS, tremor and ataxia, shows that tremor usually occurs first, with median onset at approximately 60 years of age. From the onset of the initial motor sign, median delay of onset of ataxia was 2 years; onset of falls, 6 years; dependence on a walking aid, 15 years; and death, 21 years. Preliminary data on life expectancy are variable, with a range from 5 to 25 years.

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    • "The prevalence of the premutation allele is 1 in 130–259 women and 1 in 250–813 men in the general population [Rousseau et al., 1995; Hagerman, 2008; Fernandez-Carvajal et al., 2009]. Several disorders are associated with the premutation allele; including fragile X-associated primary ovarian insufficiency (FXPOI; cessation of menses before age 40) [Murray et al., 1995; Uzielli et al., 1999; Sullivan et al., 2005]; fragile X-associated tremor/ataxia syndrome (FXTAS) [Hagerman et al., 2001; Leehey et al., 2007]; psychiatric dysfunction, including depression and anxiety [Roberts et al., 2009; Bourgeois et al., 2010]; and hypertension [Coffey et al., 2008; Hamlin et al., 2012]. Recently, immune-mediated disorders (IMDs), specifically autoimmune thyroid disorder (AITD) and fibromyalgia, were found to be associated with the premutation in women with FXTAS compared to age-matched controls [Coffey et al., 2008]. "
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    ABSTRACT: The relative risk of immune-mediated disorders (IMDs) among women carriers of premutation alleles is estimated by a survey for IMDs among 344 carrier women (age 19-81 years; mean 46.35 and SD 12.60) and 72 controls (age 18-87 years; mean 52.40 and SD 15.40). One hundred fifty four (44.77%) women carrier had at least one IMD, as did 20 controls (27.78%). Among women carriers, autoimmune thyroid disorder was the most common (24.4%), then fibromyalgia (10.2%), irritable bowel syndrome (IBS; 9.9%), Raynaud's phenomenon (7.6%), rheumatoid arthritis (RA; 3.8%), Sjögren syndrome (2.6%), systemic lupus erythematosus (SLE; 2.03%), multiple sclerosis (1.74%). Of 55 carriers age 40 or older with FXTAS, 72.73% had at least one IMD, compared to 46.54% of those without FXTAS (n = 159), and 31.58% of controls (n = 57). The estimated odds ratio (OR) for IMD is 2.6 (95% CI 1.2-5.6, P = 0.015) for women with FXTAS relative to those without FXTAS; the likelihood of IMD in carriers without or with FXTAS was also significantly higher than for controls (OR 2.1, 95% CI 1.1-4.2, P = 0.034; OR 5.5, 95% CI 2.4-12.5, P < 0.001, respectively). Similarly, the odds of having an IMD among carriers with FXPOI is about 2.4 times higher when compared to carriers without FXPOI (95% CI 1.1-5.0; P = 0.021). The likelihood of IMD in carriers with or without FXPOI is greater (OR 2.4, 95% CI 1.1-5.0; P = 0.021) compared to that of controls. © 2012 Wiley Periodicals, Inc.
    Full-text · Article · Oct 2012 · American Journal of Medical Genetics Part A
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    • "FXTAS was first reported in 2001 (Hagerman et al. 2001) with five case reports of the onset of an intention tremor initially followed by ataxia and evidence of brain atrophy and white matter disease on T2 imaging. Further studies documented involvement of autonomic function including impotence, hypertension, orthostatic hypotension, and eventually urinary and bowel incontinence, neuropathy symptoms (particularly pain), parkinsonism, executive function deficits, cognitive decline with eventual dementia in 50% of people, and emotional difficulties including irritability, apathy, and depression (Grigsby et al. 2008; Jacquemont et al. 2003, 2007; Bacalman et al. 2006; Seritan et al. 2008; Berry-Kravis et al. 2007; Allen et al. 2008; Soontarapornchai et al. 2008; Aguilar et al. 2008; Leehey et al. 2007). MRI features include global brain atrophy and white matter disease with spongiosis involving the MCP sign, periventricular regions, subcortical regions, and pons (Adams et al. 2007, 2010; Cohen et al. 2006; Brunberg et al. 2003). "
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    ABSTRACT: Fragile X syndrome (FXS) is caused by an expanded CGG repeat (>200 repeats) in the 5' un-translated portion of the fragile X mental retardation 1 gene (FMR1) leading to a deficiency or absence of the FMR1 protein (FMRP). FMRP is an RNA-binding protein that regulates the translation of a number of other genes that are important for synaptic development and plasticity. Furthermore, many of these genes, when mutated, have been linked to autism in the general population, which may explain the high comorbidity that exists between FXS and autism spectrum disorders (ASD). Additionally, premutation repeat expansions (55 to 200 CGG repeats) may also give rise to ASD through a different molecular mechanism that involves a direct toxic effect of FMR1 mRNA. It is believed that RNA toxicity underlies much of the premutation-related involvement, including developmental concerns like autism, as well as neurodegenerative issues with aging such as the fragile X-associated tremor ataxia syndrome (FXTAS). RNA toxicity can also lead to mitochondrial dysfunction, which is common in older premutation carriers both with and without FXTAS. Many of the problems with cellular dysregulation in both premutation and full mutation neurons also parallel the cellular abnormalities that have been documented in idiopathic autism. Research regarding dysregulation of neurotransmitter systems caused by the lack of FMRP in FXS, including metabotropic glutamate receptor 1/5 (mGluR1/5) pathway and GABA pathways, has 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 autism.
    Full-text · Article · May 2011 · Journal of Neurodevelopmental Disorders
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    • "Clinically noticeable tremor and ataxia typically begins in the early 60s, although some symptoms can be seen as early as the 40s [13]. Brain imaging studies, nerve conduction, psychiatric, and neuropsychological assessments suggest that there are early subclinical features of the premutation [3, 14– 17]. "
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    ABSTRACT: The fragile X-associated tremor/ataxia syndrome (FXTAS) is a relatively common cause of balance problems leading to gait disturbances in older males (40%) with the premutation. FXTAS is less common in females. We utilized the CATSYS system, a quantitative measure of movement, in 23 women with FXTAS (mean age 62.7; SD 12.3), 90 women with the premutation without FXTAS (mean age 52.9; SD 9.4), and 37 controls (mean age 56.53; SD 7.8). CATSYS distinguished differences between carriers with and without FXTAS in postural tremor, postural sway, hand coordination, and reaction time tasks. Differences were also seen between carriers without FXTAS and controls in finger tapping, reaction time, and one postural sway task. However, these differences did not persist after statistical correction for multiple comparisons. Notably, there were no differences across groups in intention tremor. This is likely due to the milder symptoms in females compared to males with FXTAS.
    Full-text · Article · May 2011 · Current Gerontology and Geriatrics Research
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