scholarly journals Allopregnanolone Improves Locomotor Activity and Arousal in the Aged CGG Knock-in Mouse Model of Fragile X-Associated Tremor/Ataxia Syndrome

2021 ◽  
Vol 15 ◽  
Author(s):  
Jared J. Schwartzer ◽  
Dolores Garcia-Arocena ◽  
Amanda Jamal ◽  
Ali Izadi ◽  
Rob Willemsen ◽  
...  
Keyword(s):  
Adult Neurogenesis ◽  
Late Onset ◽  
Fragile X ◽  
Repetitive Behavior ◽  
Neurological Symptoms ◽  
Function Learning ◽  
Digging Behavior ◽  
Marble Burying ◽  
Brdu Labeling ◽  
Ataxia Syndrome

Carriers of the fragile X premutation (PM) can develop a variety of early neurological symptoms, including depression, anxiety and cognitive impairment as well as being at risk for developing the late-onset fragile X-associated tremor/ataxia syndrome (FXTAS). The absence of effective treatments for FXTAS underscores the importance of developing efficacious therapies to reduce the neurological symptoms in elderly PM carriers and FXTAS patients. A recent preliminary study reported that weekly infusions of Allopregnanolone (Allop) may improve deficits in executive function, learning and memory in FXTAS patients. Based on this study we examined whether Allop would improve neurological function in the aged CGG knock-in (CGG KI) dutch mouse, B6.129P2(Cg)-Fmr1tm2Cgr/Cgr, that models much of the symptomatology in PM carriers and FXTAS patients. Wild type and CGG KI mice received 10 weekly injections of Allop (10 mg/kg, s.c.), followed by a battery of behavioral tests of motor function, anxiety, and repetitive behavior, and 5-bromo-2′-deoxyuridine (BrdU) labeling to examine adult neurogenesis. The results provided evidence that Allop in CGG KI mice normalized motor performance and reduced thigmotaxis in the open field, normalized repetitive digging behavior in the marble burying test, but did not appear to increase adult neurogenesis in the hippocampus. Considered together, these results support further examination of Allop as a therapeutic strategy in patients with FXTAS.

scholarly journals Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes

2021 ◽  
Vol 22 (16) ◽  
pp. 8368
Author(s):  
Luis M. Valor ◽  
Jorge C. Morales ◽  
Irati Hervás-Corpión ◽  
Rosario Marín
Keyword(s):  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Fragile X ◽  
Endocrine System ◽  
Molecular Pathogenesis ◽  
Adult Women ◽  
Adult Men ◽  
Cgg Repeats ◽  
Reproductive Impairment ◽  
Ataxia Syndrome

Abnormal trinucleotide expansions cause rare disorders that compromise quality of life and, in some cases, lifespan. In particular, the expansions of the CGG-repeats stretch at the 5’-UTR of the Fragile X Mental Retardation 1 (FMR1) gene have pleiotropic effects that lead to a variety of Fragile X-associated syndromes: the neurodevelopmental Fragile X syndrome (FXS) in children, the late-onset neurodegenerative disorder Fragile X-associated tremor-ataxia syndrome (FXTAS) that mainly affects adult men, the Fragile X-associated primary ovarian insufficiency (FXPOI) in adult women, and a variety of psychiatric and affective disorders that are under the term of Fragile X-associated neuropsychiatric disorders (FXAND). In this review, we will describe the pathological mechanisms of the adult “gain-of-function” syndromes that are mainly caused by the toxic actions of CGG RNA and FMRpolyG peptide. There have been intensive attempts to identify reliable peripheral biomarkers to assess disease progression and onset of specific pathological traits. Mitochondrial dysfunction, altered miRNA expression, endocrine system failure, and impairment of the GABAergic transmission are some of the affectations that are susceptible to be tracked using peripheral blood for monitoring of the motor, cognitive, psychiatric and reproductive impairment of the CGG-expansion carriers. We provided some illustrative examples from our own cohort. Understanding the association between molecular pathogenesis and biomarkers dynamics will improve effective prognosis and clinical management of CGG-expansion carriers.

scholarly journals Case Report: Coexistence of Alzheimer-Type Neuropathology in Fragile X-Associated Tremor Ataxia Syndrome

2021 ◽  
Vol 15 ◽  
Author(s):  
Maria Jimena Salcedo-Arellano ◽  
Desiree Sanchez ◽  
Jun Yi Wang ◽  
Yingratana A. McLennan ◽  
Courtney Jessica Clark ◽  
...  
Keyword(s):  
Globus Pallidus ◽  
Late Onset ◽  
Fragile X ◽  
Amyloid Β ◽  
Middle Temporal Gyrus ◽  
Histopathological Study ◽  
Precentral Gyrus ◽  
Alzheimer Type ◽  
Mri Findings ◽  
Ataxia Syndrome

This case documents the co-occurrence of the fragile X-associated tremor ataxia syndrome (FXTAS) and Alzheimer-type neuropathology in a 71-year-old premutation carrier with 85 CGG repeats in the fragile X mental retardation 1 (FMR1) gene, in addition to an apolipoprotein E (APOE) ε4 allele. FXTAS and Alzheimer's Disease (AD) are late-onset neurodegenerative diseases that share overlapping cognitive deficits including processing speed, working memory and executive function. The prevalence of coexistent FXTAS-AD pathology remains unknown. The clinical picture in this case was marked with rapid cognitive decline between age 67 and 71 years in addition to remarkable MRI changes. Over the 16 months between the two clinical evaluations, the brain atrophied 4.12% while the lateral ventricles increased 26.4% and white matter hyperintensities (WMH) volume increased 15.6%. Other regions atrophied substantially faster than the whole brain included the thalamus (−6.28%), globus pallidus (−10.95%), hippocampus (−6.95%), and amygdala (−7.58%). A detailed postmortem assessment included an MRI with confluent WMH and evidence of cerebral microbleeds (CMB). The histopathological study demonstrated FXTAS inclusions in neurons and astrocytes, a widespread presence of phosphorylated tau protein and, amyloid β plaques in cortical areas and the hippocampus. CMBs were noticed in the precentral gyrus, middle temporal gyrus, visual cortex, and brainstem. There were high amounts of iron deposits in the globus pallidus and the putamen consistent with MRI findings. We hypothesize that coexistent FXTAS-AD neuropathology contributed to the steep decline in cognitive abilities.

scholarly journals Three Faces of Fragile X

2016 ◽  
Vol 96 (11) ◽  
pp. 1782-1790 ◽  
Author(s):  
Cornelia C.E. Lieb-Lundell
Keyword(s):  
Physical Therapy ◽  
Late Onset ◽  
Muscle Tone ◽  
Fragile X ◽  
Genetic Defect ◽  
Health Condition ◽  
Fmr1 Gene ◽  
Health Conditions ◽  
Motor Delay ◽  
Ataxia Syndrome

Abstract Fragile X syndrome (FXS) is the first of 3 syndromes identified as a health condition related to fragile X mental retardation (FMR1) gene dysfunction. The other 2 syndromes are fragile X–associated primary ovarian insufficiency syndrome (FXPOI) and fragile X–associated tremor/ataxia syndrome (FXTAS), which together are referred to as fragile X–associated disorders (FXDs). Collectively, this group comprises the 3 faces of fragile X. Even though the 3 conditions share a common genetic defect, each one is a separate health condition that results in a variety of body function impairments such as motor delay, musculoskeletal issues related to low muscle tone, coordination limitations, ataxia, tremor, undefined muscle aches and pains, and, for FXTAS, a late-onset neurodegeneration. Although each FXD condition may benefit from physical therapy intervention, available evidence as to the efficacy of intervention appropriate to FXDs is lacking. This perspective article will discuss the genetic basis of FMR1 gene dysfunction and describe health conditions related to this mutation, which have a range of expressions within a family. Physical therapy concerns and possible assessment and intervention strategies will be introduced. Understanding the intergenerational effect of the FMR1 mutation with potential life-span expression is a key component to identifying and treating the health conditions related to this specific genetic condition.

scholarly journals FXTAS is difficult to differentiate from neuronal intranuclear inclusion disease through skin biopsy: a case report

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Megumi Toko ◽  
Tomohiko Ohshita ◽  
Takashi Kurashige ◽  
Hiroyuki Morino ◽  
Kodai Kume ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Skin Biopsy ◽  
Trinucleotide Repeat ◽  
Late Onset ◽  
Fragile X ◽  
Brain Mri ◽  
Intranuclear Inclusion ◽  
Neuronal Intranuclear Inclusion ◽  
Cerebellar Peduncle ◽  
Ataxia Syndrome

Abstract Background Both fragile X-associated tremor/ataxia syndrome (FXTAS) and late-onset neuronal intranuclear inclusion disease (NIID) show CGG/GGC trinucleotide repeat expansions. Differentiating these diseases are difficult because of the similarity in their clinical and radiological features. It is unclear that skin biopsy can distinguish NIID from FXTAS. We performed a skin biopsy in an FXTAS case with cognitive dysfunction and peripheral neuropathy without tremor, which was initially suspected to be NIID. Case presentation The patient underwent neurological assessment and examinations, including laboratory tests, electrophysiologic test, imaging, skin biopsy, and genetic test. A brain MRI showed hyperintensity lesions along the corticomedullary junction on diffusion-weighted imaging (DWI) in addition to middle cerebellar peduncle sign (MCP sign). We suspected NIID from the clinical picture and the radiological findings, and performed a skin biopsy. The skin biopsy specimen showed ubiquitin- and p62-positive intranuclear inclusions, suggesting NIID. However, a genetic analysis for NIID using repeat-primed polymerase chain reaction (RP-PCR) revealed no expansion detected in the Notch 2 N-terminal like C (NOTCH2NLC) gene. We then performed genetic analysis for FXTAS using RP-PCR, which revealed a repeat CGG/GGC expansion in the FMRP translational regulator 1 (FMR1) gene. The number of repeats was 83. We finally diagnosed the patient with FXTAS rather than NIID. Conclusions For the differential diagnosis of FXTAS and NIID, a skin biopsy alone is insufficient; instead, genetic analysis, is essential. Further investigations in additional cases based on genetic analysis are needed to elucidate the clinical and pathological differences between FXTAS and NIID.

Low diagnostic accuracy of fragile X tremor/ataxia syndrome diagnostic criteria in late onset ataxia

2019 ◽  
Vol 34 (4) ◽  
pp. 582-583
Author(s):  
David José Dávila-Ortiz de Montellano ◽  
Aurelio Jara-Prado ◽  
Mayela Rodríguez-Violante ◽  
Alejandra Camacho-Molina ◽  
Alessandra Carnevale ◽  
...  
Keyword(s):  
Diagnostic Accuracy ◽  
Diagnostic Criteria ◽  
Late Onset ◽  
Fragile X ◽  
Ataxia Syndrome

scholarly journals Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome

2010 ◽  
Vol 429 (3) ◽  
pp. 545-552 ◽  
Author(s):  
Catherine Ross-Inta ◽  
Alicja Omanska-Klusek ◽  
Sarah Wong ◽  
Cedrick Barrow ◽  
Dolores Garcia-Arocena ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Fragile X ◽  
Mitochondrial Protein ◽  
Additional Treatment ◽  
Cgg Repeat ◽  
Cgg Repeats ◽  
Nitrative Stress ◽  
Ataxia Syndrome

FXTAS (fragile X-associated tremor/ataxia syndrome) is a late-onset neurodegenerative disorder that affects individuals who are carriers of premutation expansions (55–200 CGG repeats) in the 5′ untranslated region of the FMR1 (fragile X mental retardation 1) gene. The role of MD (mitochondrial dysfunction) in FXTAS was evaluated in fibroblasts and brain samples from premutation carriers with and without FXTAS symptoms, with a range of CGG repeats. This study resulted in several important conclusions: (i) decreased NAD- and FAD-linked oxygen uptake rates and uncoupling between electron transport and synthesis of ATP were observed in fibroblasts from premutation carriers; (ii) a lower expression of mitochondrial proteins preceded both in age and in CGG repeats the appearance of overt clinical involvement; (iii) the CGG repeat size required for altered mitochondrial protein expression was also smaller than that required to produce brain intranuclear inclusions from individuals with the premutation who died, suggesting that MD is an incipient pathological process occurring in individuals who do not display overt features of FXTAS; and (iv) on the basis of the CGG repeats, MD preceded the increase in oxidative/nitrative stress damage, indicating that the latter is a late event. MD in carriers of small CGG repeats, even when the allele size is not sufficient to produce FXTAS, may predispose them to other disorders (e.g. Parkinson's disease) that are likely to involve MD, and to environmental stressors, which may trigger the development of FXTAS symptoms. Detection of MD is of critical importance to the management of FXTAS, since it opens up additional treatment options for this disorder.

scholarly journals The fragile x-associated tremor and ataxia syndrome (FXTAS)

2010 ◽  
Vol 68 (5) ◽  
pp. 791-798 ◽  
Author(s):  
Leonardo Pires Capelli ◽  
Márcia Rúbia Rodrigues Gonçalves ◽  
Claudia C Leite ◽  
Egberto R Barbosa ◽  
Ricardo Nitrini ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Current Knowledge ◽  
Fragile X ◽  
Gait Ataxia ◽  
Intention Tremor ◽  
Full Mutation ◽  
Clinical Genetic ◽  
Diagnostic Aspects ◽  
Ataxia Syndrome

FXTAS (Fragile X-associated tremor and ataxia syndrome) is a late- onset neurodegenerative disorder affecting mainly men, over 50 years of age, who are carriers of the FMR1 gene premutation. The full mutation of this gene causes the fragile X syndrome (FXS), the most common cause of inherited mental retardation. Individuals affected by FXTAS generally present intention tremor and gait ataxia that might be associated to specific radiological and/or neuropathological signs. Other features commonly observed are parkinsonism, cognitive decline, peripheral neuropathy and autonomic dysfunction. Nearly a decade after its clinical characterization, FXTAS is poorly recognized in Brazil. Here we present a review of the current knowledge on the clinical, genetic and diagnostic aspects of the disease.

scholarly journals Late-onset Tremor and Ataxia Syndrome: Fragile X-Associated Tremor/Ataxia Syndrome and Neuroimaging Findings

2017 ◽  
Vol 23 (1) ◽  
pp. 32-33
Author(s):  
Levent Öcek ◽  
Onural Tümer ◽  
Figen Tokuçoğlu ◽  
Özgür Öztekin ◽  
Yaşar Zorlu
Keyword(s):  
Late Onset ◽  
Fragile X ◽  
Ataxia Syndrome

Men with FMR1 premutation alleles of less than 71 CGG repeats have low risk of being affected with fragile X-associated tremor/ataxia syndrome (FXTAS)

2021 ◽  
pp. jmedgenet-2021-107758
Author(s):  
Ellenore M Martin ◽  
Ying Zhu ◽  
Claudine M Kraan ◽  
Kishore R Kumar ◽  
David E Godler ◽  
...  
Keyword(s):  
Late Onset ◽  
Population Control ◽  
Fragile X ◽  
Control Group ◽  
Intention Tremor ◽  
Fmr1 Premutation ◽  
Onset Condition ◽  
Cgg Repeats ◽  
Ataxia Syndrome ◽  
Population Control Group

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset condition characterised by cerebellar ataxia and intention tremor, usually found in individuals with FMR1 premutation alleles (PM—CGG expansion of 55–199 repeats). Population studies estimate that between 1 in 250 and 1 in 1600 men have a PM, with up to 45% of these men suggested to develop FXTAS by age 80. We used a Bayesian approach to compare the probability of finding a specific PM genotype in an ataxia population to a population control group and found an estimated penetrance of <1% (0.031%; CI 0.007% to 0.141%) for men with ≤70 CGGs. These findings suggest that men with a PM of ≤70 CGGs, who comprise the vast majority of those with a PM, have a much lower risk of being affected with FXTAS than previously suggested. This is an issue of growing importance for accurate genetic counselling, as those with a PM of ≤70 CGGs are increasingly detected through community carrier screening or neurodevelopmental assessment programmes.

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