Article

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: 5.63). 01/2007; 22(2):203-6. DOI: 10.1002/mds.21252
Source: PubMed

ABSTRACT 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.
    American Journal of Medical Genetics Part A 10/2012; 158A(10):2473-81. DOI:10.1002/ajmg.a.35569 · 2.05 Impact Factor
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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.
    Current Gerontology and Geriatrics Research 05/2011; 2011(1687-7063):484713. DOI:10.1155/2011/484713
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    • "This further supports the influence of the CGG repeat number on the severity of clinical involvement. Past studies found particularly strong correlation of the CGG repeats with the FXTAS phenotypes including overall motor impairment (Leehey et al., 2007), the age of onset of tremor and ataxia (Tassone et al., 2007), severity of white matter disease and degree of brain atrophy (Loesch et al., 2005; Cohen et al., 2006), severity of neuropathic signs (Berry-Kravis et al., 2007b), degree of neuropathy as measured by nerve conduction studies (Soontarapornchai et al., 2008), reduced cerebellar volume (Adams et al., 2007), the percent of inclusions and age at death (Greco et al., 2006), and the Figure 5 Progressive grey matter (GM) loss correlated with the severity of FXTAS. (A) Significant negative correlation with a clinical scale for assessment of the FXTAS severity in the vermis (shown in the blue circles). "
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    ABSTRACT: Fragile X-associated tremor/ataxia syndrome is a neurodegenerative disorder that primarily affects older male premutation carriers of the fragile X mental retardation gene. Although its core symptoms are mainly characterized by motor problems such as intention tremor and gait ataxia, cognitive decline and psychiatric problems are also commonly observed. Past radiological and histological approaches have focused on prominent neurodegenerative changes in specific brain structures including the cerebellum and limbic areas. However, quantitative investigations of the regional structural abnormalities have not been performed over the whole brain. In this study, we adopted the voxel-based morphometry method together with regions of interest analysis for the cerebellum to examine the pattern of regional grey matter change in the male premutation carriers with and without fragile X-associated tremor/ataxia syndrome. In a comparison with healthy controls, we found striking grey matter loss of the patients with fragile X-associated tremor/ataxia syndrome in multiple regions over the cortical and subcortical structures. In the cerebellum, the anterior lobe and the superior posterior lobe were profoundly reduced in both vermis and hemispheres. In the cerebral cortex, clusters of highly significant grey matter reduction were found in the extended areas in the medial surface of the brain, including the dorsomedial prefrontal cortex, anterior cingulate cortex and precuneus. The other prominent grey matter loss was found in the lateral prefrontal cortex, orbitofrontal cortex, amygdala and insula. Although the voxel-wise comparison between the asymptomatic premutation group and healthy controls did not reach significant difference, a regions of interest analysis revealed significant grey matter reduction in anterior subregions of the cerebellar vermis and hemisphere in the asymptomatic premutation group. Correlation analyses using behavioural scales of the premutation groups showed significant associations between grey matter loss in the left amygdala and increased levels of obsessive-compulsiveness and depression, and between decreased grey matter in the left inferior frontal cortex and anterior cingulate cortex and poor working memory performance. Furthermore, regression analyses revealed a significant negative effect of CGG repeat size on grey matter density in the dorsomedial frontal regions. A significant negative correlation with the clinical scale for the severity of fragile X-associated tremor/ataxia syndrome was found in a part of the vermis. These observations reveal the anatomical patterns of the neurodegenerative process that underlie the motor, cognitive and psychiatric problems of fragile X-associated tremor/ataxia syndrome, together with incipient structural abnormalities that may occur before the clinical onset of this disease.
    Brain 03/2011; 134(Pt 3):863-78. DOI:10.1093/brain/awq368 · 10.23 Impact Factor
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