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Fragile X-associated tremor ataxia syndrome in FMR1 gray zone allele carriers.

ABSTRACT: Carriers of fragile X mental retardation 1 (FMR1) repeat expansions in the premutation range (55-200 CGG repeats) often develop a syndrome of kinetic tremor, cerebellar ataxia, and parkinsonism; designated the fragile X-associated tremor ataxia syndrome (FXTAS). Neurological signs have not been reported in carriers of gray zone (45-54 CGG repeats) expansions.We describe 3 patients with FMR1 gray zone alleles who meet diagnostic criteria for FXTAS.Our cases suggest that the definition of the FXTAS may need to be broadened to include individuals with FMR1 repeat expansions in the gray zone. These neurological signs may be due to elevated levels of expanded CGG repeat FMR1 mRNA in the gray zone carriers, similar to the changes seen in premutation carriers with FXTAS.

SUBMITTER: Hall D

PROVIDER: S-EPMC4286243 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Fragile X-associated tremor ataxia syndrome in FMR1 gray zone allele carriers.

Hall Deborah D Tassone Flora F Klepitskaya Olga O Leehey Maureen M

Movement disorders : official journal of the Movement Disorder Society 20111211 2

<h4>Background</h4>Carriers of fragile X mental retardation 1 (FMR1) repeat expansions in the premutation range (55-200 CGG repeats) often develop a syndrome of kinetic tremor, cerebellar ataxia, and parkinsonism; designated the fragile X-associated tremor ataxia syndrome (FXTAS). Neurological signs have not been reported in carriers of gray zone (45-54 CGG repeats) expansions.<h4>Methods/results</h4>We describe 3 patients with FMR1 gray zone alleles who meet diagnostic criteria for FXTAS.<h4>Co ...[more]

PMID: 22161987

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Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation.

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Project description: Not available

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Altered Bioenergetics in Primary Dermal Fibroblasts from Adult Carriers of the FMR1 Premutation Before the Onset of the Neurodegenerative Disease Fragile X-Associated Tremor/Ataxia Syndrome.

Project description:Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder, characterized by tremors, ataxia, impaired coordination, and cognitive decline. While all FXTAS individuals are carriers of a 55-200 CGG expansion at the 5'-UTR of the fragile X mental retardation gene (FMR1), also known as premutation, not all carriers develop FXTAS symptoms and some display other types of psychological/emotional disorders (e.g., autism, anxiety). The goal of this study was to investigate whether the mitochondrial dysfunction previously observed in fibroblasts from older premutation individuals (>60 years) was already present in younger (17-48 years), non-FXTAS-affected carriers and to identify the type and severity of the bioenergetic deficit. Since FXTAS affects mostly males, while females account for a small part of the FXTAS-affected population displaying less severe symptoms, only fibroblasts from males were evaluated in this study. Based on polarographic and enzymatic measurements, a generalized OXPHOS deficit was noted accompanied by increases in the matrix biomarker citrate synthase, oxidative stress (as increased mtDNA copy number and deletions), and mitochondrial network disruption/disorganization. Some of the outcomes (ATP-linked oxygen uptake, coupling, citrate synthase activity, and mitochondrial network organization) strongly correlated with the extent of the CGG expansion, with more severe deficits observed in cell lines carrying higher CGG number. Furthermore, mitochondrial outcomes can identify endophenotypes among carriers and are robust predictors of the premutation diagnosis before the onset of FXTAS, with the potential to be used as markers of prognosis and/or as readouts of pharmacological interventions.

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Fragile X-associated Tremor/Ataxia Syndrome in an Adolescent Female.

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Tremorography in fragile X-associated tremor/ataxia syndrome, Parkinson's disease and essential tremor.

Project description:BackgroundFragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disease affecting carriers of a 55-200 CGG repeat in the fragile X mental retardation 1 gene, may receive an initial diagnosis of Parkinson's disease (PD) or essential tremor (ET) due to overlapping motor symptoms. Therefore, tremor and bradykinesia were compared in these disorders using quantitative tremorography.MethodsThe inertial sensor based Kinesia ™ system was used to quantify upper extremity tremor and bradykinesia in participants with FXTAS (n = 25), PD (n = 23), ET (n = 18) and controls (n = 20) and regression analysis was performed to determine whether tremorography measures distinguished between the groups. The FXTAS Rating scale (FXTAS-RS) was administered to determine whether sub-score items on the clinician rated scale correlated with tremorography variables.ResultsFXTAS participants had reduced finger tap speed compared to those with ET, and ET had increased kinetic tremor compared to PD. Higher kinetic tremor distinguished FXTAS from PD (p = .02), and lower finger tap speed distinguished FXTAS from ET (p = .004). FXTAS-RS tremor and bradykinesia items correlated with tremorography measures (p = .005 to <0.0001).ConclusionsThis is the first quantitative study to compare tremor and bradykinesia in FXTAS, PD and ET. Kinetic tremor and bradykinesia measures using a quantitative inertial sensor system distinguished FXTAS from PD and ET, respectively. Such technologies may be useful for detecting precise tremor and bradykinesia abnormalities and distinguishing the tremor and bradykinesia profiles in each of these disorders.

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