Abstract
Fragile X Associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder affecting carriers of premutation alleles (PM) of the X-linked FMR1 gene, which contain CGG repeat expansions of 55–200 range in a non-coding region. This late-onset disorder is characterised by the presence of tremor/ataxia and cognitive decline, associated with the white matter lesions throughout the brain, especially involving the middle cerebellar peduncles. Nearly half of older male and ~ 20% of female PM carriers develop FXTAS. While there is evidence for mitochondrial dysfunction in neural and some peripheral tissues from FXTAS patients (though less obvious in the non-FXTAS PM carriers), the results from peripheral blood mononuclear cells (PBMC) are still controversial. Motor, cognitive, and neuropsychiatric impairments were correlated with measures of mitochondrial and non-mitochondrial respiratory activity, AMPK, and TORC1 cellular stress-sensing protein kinases, and CGG repeat size, in a sample of adult FXTAS male and female carriers. Moreover, the levels of these cellular measures, all derived from Epstein- Barr virus (EBV)- transformed and easily accessible blood lymphoblasts, were compared between the FXTAS (N = 23) and non-FXTAS (n = 30) subgroups, and with baseline data from 33 healthy non-carriers. A significant hyperactivity of cellular bioenergetics components as compared with the baseline data, more marked in the non-FXTAS PMs, was negatively correlated with repeat numbers at the lower end of the CGG-PM distribution. Significant associations of these components with motor impairment measures, including tremor-ataxia and parkinsonism, and neuropsychiatric changes, were prevalent in the FXTAS subgroup. Moreover, a striking elevation of AMPK activity, and a decrease in TORC1 levels, especially in the non-FXTAS carriers, were related to the size of CGG expansion. The bioenergetics changes in blood lymphoblasts are biomarkers of the clinical status of FMR1 carriers. The relationship between these changes and neurological involvement in the affected carriers suggests that brain bioenergetic alterations are reflected in this peripheral tissue. A possible neuroprotective role of stress sensing kinase, AMPK, in PM carriers, should be addressed in future longitudinal studies. A decreased level of TORC1—the mechanistic target of the rapamycin complex, suggests a possible future approach to therapy in FXTAS.
Highlights
Fragile X premutations, which are small expansions of CGG repeat ranging from 55 to 200 in the non-coding region of the Fragile X Mental Retardation 1 (FMR1) X-linked gene, are associated with the variety of abnormal conditions [1]
The two genetic groups (33 normal controls and 53 FMR1 PM carriers) bore alleles of the CGG trinucleotide repeat in the FMR1 locus that were either in the normal size range (20– 40, control group), or in the premutation range (55–199, PM group)
For the purpose of this study, the PM carriers were classified into non-Fragile X Associated Tremor/Ataxia Syndrome (FXTAS) (N = 30, including 12 females), and FXTAS (n = 23, including 3 females) subgroups, with individuals in the latter subgroup diagnosed on the basis of the revised clinical criteria [57]
Summary
Fragile X premutations, which are small expansions of CGG repeat ranging from 55 to 200 in the non-coding region of the Fragile X Mental Retardation 1 (FMR1) X-linked gene, are associated with the variety of abnormal conditions [1]. The most severe premutation-associated disorder affecting carriers of the FMR1 premutation allele is the late onset progressive neurodegenerative condition termed Fragile X Associated Tremor/Ataxia Syndrome (FXTAS), affecting 40−50% of male carriers after the age of 55, and 8–16.5% female carriers in the same age group [2–4]. The much lower risk of FXTAS in females than in males may be, at least partly, attributed to the protective role of the normal FMR1 allele on the second X chromosome [5], but the existence of other sex-limited protective factors has recently been postulated [6]. The standard diagnostic (core) features of FXTAS require one or more of the following pathological changes: intention tremor; cerebellar ataxia; and white matter disease in the middle cerebellar peduncles (MCP sign) seen on magnetic resonance imaging (MRI) [7, 8]; white matter disease in the splenium of the corpus callosum [9] has more recently been considered another core FXTAS feature. Typical FXTAS neuropathological changes are of widespread ubiquitin-positive intranuclear inclusions abundant in neurones and astrocytes [15], extending to autonomic nervous and neuroendocrine systems and myocardial cells [16–18]
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