24
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      The cognitive neuropsychological phenotype of carriers of the FMR1 premutation

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          The fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting a subset of carriers of the FMR1 (fragile X mental retardation 1) premutation. Penetrance and expression appear to be significantly higher in males than females. Although the most obvious aspect of the phenotype is the movement disorder that gives FXTAS its name, the disorder is also accompanied by progressive cognitive impairment. In this review, we address the cognitive neuropsychological and neurophysiological phenotype for males and females with FXTAS, and for male and female unaffected carriers. Despite differences in penetrance and expression, the cognitive features of the disorder appear similar for both genders, with impairment of executive functioning, working memory, and information processing the most prominent. Deficits in these functional systems may be largely responsible for impairment on other measures, including tests of general intelligence and declarative learning. FXTAS is to a large extent a white matter disease, and the cognitive phenotypes observed are consistent with what some have described as white matter dementia, in contrast to the impaired cortical functioning more characteristic of Alzheimer’s disease and related disorders. Although some degree of impaired executive functioning appears to be ubiquitous among persons with FXTAS, the data suggest that only a subset of unaffected carriers of the premutation - both female and male - demonstrate such deficits, which typically are mild. The best-studied phenotype is that of males with FXTAS. The manifestations of cognitive impairment among asymptomatic male carriers, and among women with and without FXTAS, are less well understood, but have come under increased scrutiny.

          Related collections

          Most cited references67

          • Record: found
          • Abstract: found
          • Article: not found

          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.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates.

            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.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Cerebral white matter: neuroanatomy, clinical neurology, and neurobehavioral correlates.

              Lesions of the cerebral white matter (WM) result in focal neurobehavioral syndromes, neuropsychiatric phenomena, and dementia. The cerebral WM contains fiber pathways that convey axons linking cerebral cortical areas with each other and with subcortical structures, facilitating the distributed neural circuits that subserve sensorimotor function, intellect, and emotion. Recent neuroanatomical investigations reveal that these neural circuits are topographically linked by five groupings of fiber tracts emanating from every neocortical area: (1) cortico-cortical association fibers; (2) corticostriatal fibers; (3) commissural fibers; and cortico-subcortical pathways to (4) thalamus and (5) pontocerebellar system, brain stem, and/or spinal cord. Lesions of association fibers prevent communication between cortical areas engaged in different domains of behavior. Lesions of subcortical structures or projection/striatal fibers disrupt the contribution of subcortical nodes to behavior. Disconnection syndromes thus result from lesions of the cerebral cortex, subcortical structures, and WM tracts that link the nodes that make up the distributed circuits. The nature and the severity of the clinical manifestations of WM lesions are determined, in large part, by the location of the pathology: discrete neurological and neuropsychiatric symptoms result from focal WM lesions, whereas cognitive impairment across multiple domains--WM dementia--occurs in the setting of diffuse WM disease. We present a detailed review of the conditions affecting WM that produce these neurobehavioral syndromes, and consider the pathophysiology, clinical effects, and broad significance of the effects of aging and vascular compromise on cerebral WM, in an attempt to help further the understanding, diagnosis, and treatment of these disorders.
                Bookmark

                Author and article information

                Contributors
                Journal
                J Neurodev Disord
                J Neurodev Disord
                Journal of Neurodevelopmental Disorders
                BioMed Central
                1866-1947
                1866-1955
                2014
                30 July 2014
                : 6
                : 1
                : 28
                Affiliations
                [1 ]Department of Psychology, University of Colorado Denver, Denver, CO, USA
                [2 ]Department of Medicine; Division of Health Care Policy and Research, University of Colorado School of Medicine, Aurora, CO, USA
                [3 ]School of Psychology & Psychiatry; Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia
                [4 ]Olga Tennison Autism Research Centre, School of Psychological Science, La Trobe University, Melbourne, Victoria, Australia
                [5 ]Center for Mind and Brain, University of California, Davis, CA, USA
                [6 ]Department of Neurology, University of California, Davis, Sacramento, CA, USA
                [7 ]Department of Psychology, University of California-Davis, Sacramento, CA, USA
                [8 ]MIND Institute, University of California-Davis Medical Center, Sacramento, CA, USA
                [9 ]Department of Human Genetics, Emory University, Atlanta, GA, USA
                [10 ]Department of Pediatrics, University of California, Davis, Sacramento, CA, USA
                Article
                1866-1955-6-28
                10.1186/1866-1955-6-28
                4135346
                25136377
                237a9d57-f062-46a9-9d5b-42c4c82ad1a8
                Copyright © 2014 Grigsby et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 31 October 2013
                : 27 January 2014
                Categories
                Review

                Neurosciences
                fragile x-associated tremor/ataxia syndrome,fxtas,fmr1,fragile x,executive function,cognition disorders,fragile x premutation

                Comments

                Comment on this article