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In this study we aim to identify and characterize a potential neurophysiological biomarker by mapping functional networks of brain activity (Brain Network Activation, BNA) based on analysis of evoked response potential (ERP) signals in both asymptomatic FMR1 premutation carriers and in patients with various stages of FXTAS. Additionally correlations will be studied between these BNA scores and demographics (gender, age and disease duration) as well as genetic mutation and clinical scores.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive, late-onset (>50 years) multisystem neurodegenerative disorder, associated with an expansion in the 5ʹuntranslated region of the fragile X mental retardation 1 (FMR1) gene that consists of 55-200 CGG repeats, termed the FMR1 gene premutation. While the prevalence of the premutation is 1 in 150-300 females, and 1 in 400-850 males, the penetrance of FXTAS in male carriers is ~40% compared to less than 20% in females.
The mean age of onset of FXTAS is 60 years, presenting with intention tremor, cerebellar ataxia, neuropathic pain, memory and/or executive function deficits, parkinsonism, and psychiatric manifestations such as depression, anxiety and/or apathy.
There are typical MRI findings in FXTAS patients, including increased T2-weighted signal intensity in the middle cerebellar peduncles, cerebellar and cerebral atrophy and volume loss of the corpus callosum.
Currently, no definitive diagnostic tests exist for the symptomatic condition, FXTAS, in FMR1 premutation carriers, making it difficult to diagnose, particularly in the early stages of disease pathology. ElMindA, an Israeli company established in 2006, that focuses on the mapping of neuro-electrophysiological activity, has developed a novel method of mapping functional networks of brain activity (Brain Network Activation or BNA) based on analysis of evoked response potential (ERP) signals. Patients whose underlying disease involves impairment in brain circuitry and connectivity are expected to produce abnormal activity templates in response to the same paradigm, both as a result of failing to adhere to the normal pattern and of recruiting compensatory pathways and strategies to tackle the task. The essence of BNA analysis is the extraction of brain activity patterns common to a group of normal subjects, against which the brain activity of individual subjects may be compared. Patients with FXTAS have been found to exhibit executive and memory deficits along with altered prefrontal cortex activity in functional MRI studies and we suspect that patients with FXTAS and also FMR1 premutation carriers in the early phase of neurodegeneration (even before exhibiting overt clinical symptoms of FXTAS) may display abnormal BNA patterns. Accordingly, at Sheba medical center we have computed individual BNA scores for 30 healthy control subjects and thus defined the BNA patterns of healthy subjects to be used for comparison wit study subjects.
The goal of the study is to identify and characterize a potential neurophysiological biomarker for early stage FXTAS and for disease progression by evaluating the electrophysiological activity in both asymptomatic FMR1 Premutation carriers and in patients with various stages (duration) of FXTAS. Additionally correlations will be studied between these BNA data and demographics (gender, age and disease duration). length of the pathological CGG repeat expansion as well as FXTAS score, gait and posture abnormalities (obtained by instrumental timed up and go evaluation) and neuropsychological status.
Characterization of neuro-electrophysiological biomarkers may be important to detect early transformation from asymptomatic carriership to neurodegeneration and FXTAS and to enable early interventions and monitoring of response to treatment
Observational Model: Case-Only, Time Perspective: Cross-Sectional
Fragile X Associated Tremor-ataxia Syndrome
Not yet recruiting
Sheba Medical Center
Published on BioPortfolio: 2016-10-19T02:38:21-0400
The purpose of this study is to determine if memantine is effective in treating symptoms of Fragile X-associated Tremor Ataxia Syndrome.
The purpose of this study is to examine the safety and efficacy of Allopregnanolone as a possible treatment for symptoms of Fragile X-associated Tremor/Ataxia Syndrome (FXTAS).
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Mosaicism for FMR1 premutation (PM: 55-199 CGG)/full mutation (FM: >200 CGG) alleles or the presence of unmethylated FM (UFM) have been associated with a less severe fragile X syndrome (FXS) phenotype...
Sellier et al. (2017) show that translation of expanded CGG repeats in fragile X-associated tremor/ataxia syndrome is initiated at an upstream ACG near-cognate start codon. The resulting polyglycine-...
Fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI) are definitely related to the fragile X mental retardation 1 (FMR1) premutation (PM)....
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder typically affecting male premutation carriers with 55-200 CGG trinucleotide repeat expansions in the FMR1...
Specific loci that show up during KARYOTYPING as a gap (an uncondensed stretch in closer views) on a CHROMATID arm after culturing cells under specific conditions. These sites are associated with an increase in CHROMOSOME FRAGILITY. They are classified as common or rare, and by the specific culture conditions under which they develop. Fragile site loci are named by the letters "FRA" followed by a designation for the specific chromosome, and a letter which refers to which fragile site of that chromosome (e.g. FRAXA refers to fragile site A on the X chromosome. It is a rare, folic acid-sensitive fragile site associated with FRAGILE X SYNDROME.)
Incoordination of voluntary movements that occur as a manifestation of CEREBELLAR DISEASES. Characteristic features include a tendency for limb movements to overshoot or undershoot a target (dysmetria), a tremor that occurs during attempted movements (intention TREMOR), impaired force and rhythm of diadochokinesis (rapidly alternating movements), and GAIT ATAXIA. (From Adams et al., Principles of Neurology, 6th ed, p90)
A RNA-binding protein that is found predominately in the CYTOPLASM. It helps regulate GENETIC TRANSLATION in NEURONS and is absent or under-expressed in FRAGILE X SYNDROME.
An increased number of contiguous trinucleotide repeats in the DNA sequence from one generation to the next. The presence of these regions is associated with diseases such as FRAGILE X SYNDROME and MYOTONIC DYSTROPHY. Some CHROMOSOME FRAGILE SITES are composed of sequences where trinucleotide repeat expansion occurs.
An autosomal recessive condition characterized by recurrent myoclonic and generalized seizures, ATAXIA, slowly progressive intellectual deterioration, dysarthria, and intention tremor. Myoclonic seizures are severe and continuous, and tend to be triggered by movement, stress, and sensory stimuli. The age of onset is between 8 and 13 years, and the condition is relatively frequent in the Baltic region, especially Finland. (From Menkes, Textbook of Child Neurology, 5th ed, pp109-110)
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