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Sonia Merino, Nekane Ibarluzea, Hiart Maortua, Begoña Prieto, Idoia Rouco, Maria-Asunción López-Aríztegui, Maria-Isabel Tejada
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). Additional medical problems have also been associated with the PM, such as fibromyalgia, endocrine, and psychiatric disorders. To improve our understanding in the field, we reviewed all PM carriers and their reasons for any medical referrals from 104 fragile X families molecularly diagnosed in our laboratory and living in the Spanish Basque Country...
October 21, 2016: Genes
M I Alvarez-Mora, L Rodriguez-Revenga, I Madrigal, M Guitart-Mampel, G Garrabou, M Milà
Mitochondrial involvement plays an important role in neurodegenerative diseases. At least one-third of adult carriers of a FMR1 premutation (55-200 CGG repeats) are at risk of presenting an adult-onset neurodegenerative disorder known as fragile X-associated tremor/ataxia syndrome (FXTAS). In an attempt to provide new insights into the mechanisms involved in the pathogenesis of FXTAS, we characterized mitochondrial function and dynamics by the assessment of oxidative respiratory chain function, mitochondrial content, oxidative stress levels, and mitochondrial network complexity...
October 22, 2016: Molecular Neurobiology
Amy Krans, Michael G Kearse, Peter K Todd
OBJECTIVE: Repeat associated non-AUG (RAN) translation drives production of toxic proteins from pathogenic repeat sequences in multiple untreatable neurodegenerative disorders. Fragile X-associated tremor/ataxia syndrome (FXTAS) is one such condition, resulting from a CGG trinucleotide repeat expansion in the 5' leader sequence of the FMR1 gene. RAN proteins from the CGG repeat accumulate in ubiquitinated inclusions in FXTAS patient brains and elicit toxicity. In addition to the CGG repeat, an antisense mRNA containing a CCG repeat is also transcribed from the FMR1 locus...
October 19, 2016: Annals of Neurology
Indhu-Shree Rajan-Babu, Samuel S Chong
Fragile X syndrome (FXS) is the most common monogenic cause of intellectual disability and autism. Molecular diagnostic testing of FXS and related disorders (fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS)) relies on a combination of polymerase chain reaction (PCR) and Southern blot (SB) for the fragile X mental retardation 1 (FMR1) CGG-repeat expansion and methylation analyses. Recent advancements in PCR-based technologies have enabled the characterization of the complete spectrum of CGG-repeat mutation, with or without methylation assessment, and, as a result, have reduced our reliance on the labor- and time-intensive SB, which is the gold standard FXS diagnostic test...
October 14, 2016: Genes
Yun Tae Hwang, Solange Mabel Aliaga, Marta Arpone, David Francis, Xin Li, Belinda Chong, Howard Robert Slater, Carolyn Rogers, Lesley Bretherton, Matthew Hunter, Robert Heard, David Eugeny Godler
CGG repeat expansion >200 within FMR1, termed full mutation (FM), has been associated with promoter methylation, consequent silencing of gene expression and fragile X syndrome (FXS)-a common cause of intellectual disability and co-morbid autism. Unmethylated premutation (55-199 repeats) and FM alleles have been associated with fragile X related tremor/ataxia syndrome (FXTAS), a late onset neurodegenerative disorder. Here we present a 33-year-old male with FXS, with white matter changes and progressive deterioration in gait with cerebellar signs consistent with probable FXTAS; there was no evidence of any other cerebellar pathology...
October 1, 2016: American Journal of Medical Genetics. Part A
Atefeh Entezari, Mahmoud Shekari Khaniani, Tayyeb Bahrami, Sima Mansoori Derakhshan, Hossein Darvish
Male carriers of an expansion of CGG alleles (with 55-200 CGG repeats) in the FMR1 gene are affected with Fragile X-associated tremor/ataxia syndrome (FXTAS). On the other hand, individuals with Parkinson's disease (PD) or Parkinsonism spectrum disorders may have some clinical features that overlap with FXTAS. To investigate the possible association between PD and FMR1 expanded alleles, we screened a total of 154 male PD patients and 190 gender- and age-matched healthy control subjects from Iran. Eleven intermediate allele carriers (7...
October 1, 2016: Neurological Sciences
Andreea L Seritan, Kyoungmi Kim, Ian Benjamin, Ioana Seritan, Randi J Hagerman
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disease with motor, psychiatric, and cognitive manifestations that occurs in carriers of the fragile X mental retardation 1 (FMR1) gene premutations. This was a retrospective chart review of 196 individuals (127 men and 69 women) with FXTAS. Forty-six (23%) participants were cognitively impaired, of whom 19 (10%) had dementia. Risk factors for dementia were examined (CGG repeat size; alcohol, benzodiazepine, and opioid use; diabetes; hyperlipidemia; hypertension; hypothyroidism; obesity; sleep apnea; surgeries with general anesthesia; depression; family history of dementia)...
September 19, 2016: Journal of Geriatric Psychiatry and Neurology
Danuta Z Loesch, Sarah J Annesley, Nicholas Trost, Minh Q Bui, Sui T Lay, Elsdon Storey, Shawn W De Piazza, Oana Sanislav, Lisa M Francione, Eleanor M Hammersley, Flora Tassone, David Francis, Paul R Fisher
BACKGROUND: The need for accessible cellular biomarkers of neurodegeneration in carriers of the fragile X mental retardation 1 (FMR1) premutation (PM) alleles. OBJECTIVE: To assess the mitochondrial status and respiration in blood lymphoblasts from PM carriers manifesting the fragile X-associated tremor/ataxia syndrome (FXTAS) and non-FXTAS carriers, and their relationship with the brain white matter lesions. METHODS: Oxygen consumption rates (OCR) and ATP synthesis using a Seahorse XFe24 Extracellular Flux Analyser, and steady-state parameters of mitochondrial function were assessed in cultured lymphoblasts from 16 PM males (including 11 FXTAS patients) and 9 matched controls...
September 8, 2016: Neuro-degenerative Diseases
Rustam Esanov, Nadja S Andrade, Sarah Bennison, Claes Wahlestedt, Zane Zeier
Fragile X syndrome (FXS) results from a repeat expansion mutation near the FMR1 gene promoter and is the most common form of heritable intellectual disability and autism. Full mutations larger than 200 CGG repeats trigger FMR1 heterochromatinization and loss of gene expression, which is primarily responsible for the pathological features of FXS . In contrast, smaller pre-mutations of 55-200 CGG are associated with FMR1 overexpression and Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative condition...
September 5, 2016: Human Molecular Genetics
Sylwia Olimpia Rzońca, Monika Gos, Daniel Szopa, Danuta Sielska-Rotblum, Aleksandra Landowska, Agnieszka Szpecht-Potocka, Michał Milewski, Jolanta Czekajska, Anna Abramowicz, Ewa Obersztyn, Dorota Maciejko, Tadeusz Mazurczak, Jerzy Bal
The article summarizes over 20 years of experience of a reference lab in fragile X mental retardation 1 gene (FMR1) molecular analysis in the molecular diagnosis of fragile X spectrum disorders. This includes fragile X syndrome (FXS), fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS), which are three different clinical conditions with the same molecular background. They are all associated with an expansion of CGG repeats in the 5'UTR of FMR1 gene...
2016: Genes
Cecilia Giulivi, Eleonora Napoli, Flora Tassone, Julian Halmai, Randi Hagerman
Premutation carriers have a 55-200 CGG expansion in the fragile X mental retardation 1 (FMR1) gene. Currently, 1.5 million individuals are affected in the United States, and carriers are at risk of developing the late-onset neurodegenerative disorder Fragile X-associated tremor ataxia syndrome (FXTAS). Limited efforts have been made to develop new methods for improved early patient monitoring, treatment response, and disease progression. To this end, plasma metabolomic phenotyping was obtained for 23 premutation carriers and 16 age- and sex-matched controls...
2016: Frontiers in Molecular Neuroscience
Cecilia Giulivi, Eleonora Napoli, Flora Tassone, Julian Halmai, Randi Hagerman
Carriers of premutation CGG expansions in the fragile X mental retardation 1 ( FMR1 ) gene are at higher risk of developing a late-onset neurodegenerative disorder named Fragile X-tremor ataxia syndrome (FXTAS). Given that mitochondrial dysfunction has been identified in fibroblasts, PBMC and brain samples from carriers as well as in animal models of the premutation and that mitochondria are at the center of intermediary metabolism, the aim of this study was to provide a complete view of the metabolic pattern by uncovering plasma metabolic perturbations in premutation carriers...
August 23, 2016: Biochemical Journal
Erin E Robertson, Deborah A Hall, Andrew R McAsey, Joan A O'Keefe
OBJECTIVE: The purpose of this paper is to review the typical cognitive and motor impairments seen in fragile X-associated tremor/ataxia syndrome (FXTAS), essential tremor (ET), Parkinson disease (PD), spinocerebellar ataxias (SCAs), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) in order to enhance diagnosis of FXTAS patients. METHODS: We compared the cognitive and motor phenotypes of FXTAS with each of these other movement disorders. Relevant neuropathological and neuroimaging findings are also reviewed...
August 2016: Clinical Neuropsychologist
Marina de Tommaso, Miriam Kunz, Massimiliano Valeriani
INTRODUCTION: Neurodegenerative diseases are increasing in parallel to the lengthening of survival. The management of Alzheimer's disease (AD) and other dementias, Parkinson's disease (PD) and PD-related disorders, and motor neuron diseases (MND), is mainly targeted to motor and cognitive impairment, with special care for vital functions such as breathing and feeding. AREAS COVERED: The present review focuses on chronic pain in main neurodegenerative diseases, addressing current evidence on pain therapeutic management, pain frequency and clinical features, and possible pathophysiological mechanisms...
July 26, 2016: Expert Review of Neurotherapeutics
C M Kraan, K M Cornish, Q M Bui, X Li, H R Slater, D E Godler
Fragile X tremor ataxia syndrome (FXTAS) is a late-onset disorder manifesting in a proportion of FMR1 premutation individuals (PM: 55-199 CGG triplet expansions). FXTAS is associated with elevated levels of FMR1 mRNA which are toxic. In this study, relationships between neurocognitive and intra-step gait variability measures with mRNA levels, measured in blood samples, were examined in 35 PM and 35 matched control females. The real-time PCR assays measured FMR1 mRNA, and previously used internal control genes: β-Glucuronidase (GUS), Succinate Dehydrogenase 1 (SDHA) and Eukaryotic Translation Initiation Factor 4A (EI4A2)...
2016: Scientific Reports
Gyu Song, Eleonora Napoli, Sarah Wong, Randi Hagerman, Siming Liu, Flora Tassone, Cecilia Giulivi
A 55-200 expansion of the CGG nucleotide repeat in the 5'-UTR of the fragile X mental retardation 1 gene (FMR1) is the hallmark of the triplet nucleotide disease known as the "premutation" as opposed to those with >200 repeats, known as the full mutation or fragile X syndrome. Originally, premutation carriers were thought to be free of phenotypic traits; however, some are diagnosed with emotional and neurocognitive issues and, later in life, with the neurodegenerative disease fragile X-associated tremor/ataxia syndrome (FXTAS)...
June 30, 2016: Molecular Medicine
Jim Grigsby
OBJECTIVES: To provide an historical perspective and overview of the phenotypes, mechanism, pathology, and epidemiology of the fragile X-associated tremor/ataxia syndrome (FXTAS) for neuropsychologists. METHODS: Selective review of the literature on FXTAS. RESULTS: FXTAS is an X-linked neurodegenerative disorder of late onset. One of several phenotypes associated with different mutations of the fragile X mental retardation 1 gene (FMR1), FXTAS involves progressive action tremor, gait ataxia, and impaired executive functioning, among other features...
August 2016: Clinical Neuropsychologist
Christopher M Filley
OBJECTIVE: Fragile X tremor ataxia syndrome (FXTAS) is an inherited neurodegenerative disease in which dementia is common and disabling. The pathogenesis of dementia in FXTAS is poorly understood, but the salience of executive dysfunction and slowed processing speed, the frequent presence of the middle cerebellar peduncle sign on magnetic resonance imaging (MRI), and striking neuropathological alterations of white matter all suggest that myelinated tracts are significantly involved. This paper considers the role of white matter disease in FXTAS dementia, particularly with regard to the concept of white matter dementia (WMD)...
August 2016: Clinical Neuropsychologist
Molly M Foote, Milo Careaga, Robert F Berman
OBJECTIVE: To describe in this review how research using mouse models developed to study the Fragile X premutation (PM) and Fragile X-associated tremor/ataxia syndrome (FXTAS) have contributed to understanding these disorders. PM carriers bear an expanded CGG trinucleotide repeat on the Fragile X Mental Retardation 1 (FMR1) gene, and are at risk for developing the late onset neurodegenerative disorder FXTAS. CONCLUSIONS: Much has been learned about these genetic disorders from the development and study of mouse models...
August 2016: Clinical Neuropsychologist
Rachael Cherie Birch, Darren Robert Hocking, Julian Norman Trollor
OBJECTIVE: To examine the prevalence and predictors of subjective memory complaints among a cohort of male FMR1 premutation (PM) carriers with and without fragile X-associated tremor ataxia syndrome (FXTAS). METHOD: Twenty-two PM males (ages 26-80, 7 with FXTAS) and 24 matched controls with normal FMR1 alleles (ages 26-77) completed cross-sectional assessments of subjective memory complaints (memory complaints questionnaire, MAC-Q), objective memory function (Logical Memory subtest from the Wechsler Memory Scale, third edition), and psychiatric symptoms (Depression, Anxiety, and Stress Scales; the Structured Clinical Interview for DSM-IV-TR Axis I Disorders)...
August 2016: Clinical Neuropsychologist
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