scholarly journals Delineating the Relationships Between Motor, Cognitive-Executive and Psychiatric Symptoms in Female FMR1 Premutation Carriers

2021 ◽  
Vol 12 ◽  
Author(s):  
Darren R. Hocking ◽  
Danuta Z. Loesch ◽  
Paige Stimpson ◽  
Flora Tassone ◽  
Anna Atkinson ◽  
...  
Keyword(s):  
Executive Functioning ◽  
Response Inhibition ◽  
Rating Scales ◽  
Psychiatric Symptoms ◽  
Fragile X ◽  
Fmr1 Premutation ◽  
Symptom Dimensions ◽  
Cgg Repeats ◽  
Cerebellar Peduncles ◽  
Ataxia Syndrome

Introduction: Premutation expansions (55–200 CGG repeats) of the Fragile X Mental Retardation 1 (FMR1) gene on the X chromosome are associated with a range of clinical features. Apart from the most severe - Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) - where the most typical white matter changes affect cerebellar peduncles, more subtle changes may include impairment of executive functioning, affective disorders and/or subtle motor changes. Here we aimed to examine whether performance in selected components of executive functioning is associated with subclinical psychiatric symptoms in non-FXTAS, adult females carrying the FMR1 premutation.Methods and Sample: A total of 47 female premutation carriers (sub-symptomatic for FXTAS) of wide age range (26–77 years; M = 50.3; SD = 10.9) were assessed using standard neuropsychological tests, three motor rating scales and self-reported measures of psychiatric symptoms using the Symptom Checklist-90-Revised (SCL-90-R).Results: After adjusting for age and educational level where appropriate, both non-verbal reasoning and response inhibition as assessed on the Stroop task (i.e., the ability to resolve cognitive interference) were associated with a range of primary psychiatric symptom dimensions, and response inhibition uniquely predicted some primary symptoms and global psychiatric features. Importantly, lower scores (worse performance) in response inhibition were also strongly correlated with higher (worse) scores on standard motor rating scales for tremor-ataxia and for parkinsonism.Conclusion: These results provide evidence for the importance of response inhibition in the manifestation of psychiatric symptoms and subtle tremor-ataxia motor features, suggestive of the presence of early cerebellar changes in female premutation carriers.

scholarly journals Dementia in Fragile X-associated Tremor/Ataxia Syndrome

2010 ◽  
Vol 4 (1) ◽  
pp. 79-83 ◽  
Author(s):  
Ricardo Nitrini ◽  
Márcia Rúbia R. Gonçalves ◽  
Leonardo P. Capelli ◽  
Egberto Reis Barbosa ◽  
Cláudia Sellitto Porto ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Fragile X ◽  
Gait Ataxia ◽  
Action Tremor ◽  
Fmr1 Premutation ◽  
Cerebellar Peduncles ◽  
History Of ◽  
Diagnostic Hypothesis ◽  
Ataxia Syndrome ◽  
Lateral Sclerosis

Abstract Fragile X-associated tremor/ataxia syndrome (FXTAS) is a cause of movement disorders and cognitive decline which has probably been underdiagnosed, especially if its prevalence proves similar to those of progressive supranuclear palsy and amyotrophic lateral sclerosis. We report a case of a 74-year-old man who presented with action tremor, gait ataxia and forgetfulness. There was a family history of tremor and dementia, and one of the patient's grandsons was mentally deficient. Neuropsychological evaluation disclosed a frontal network syndrome. MRI showed hyperintensity of both middle cerebellar peduncles, a major diagnostic hallmark of FXTAS. Genetic testing revealed premutation of the FMR1 gene with an expanded (CGG)90 repeat. The diagnosis of FXTAS is important for genetic counseling because the daughters of the affected individuals are at high risk of having offspring with fragile X syndrome. Tremors and cognitive decline should raise the diagnostic hypothesis of FXTAS, which MRI may subsequently reinforce, while the detection of the FMR1 premutation can confirm the condition.

scholarly journals Neuroimaging Insight Into Fragile X-Associated Neuropsychiatric Disorders: Literature Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Andrea Elias-Mas ◽  
Maria Isabel Alvarez-Mora ◽  
Conxita Caro-Benito ◽  
Laia Rodriguez-Revenga
Keyword(s):  
Brain Function ◽  
Psychiatric Symptoms ◽  
Fragile X ◽  
Clinical Manifestations ◽  
Neuropsychiatric Disorders ◽  
Psychiatric Symptomatology ◽  
Cgg Repeat ◽  
Cgg Repeats ◽  
Ataxia Syndrome ◽  
Insight Into

FMR1 premutation is defined by 55–200 CGG repeats in the Fragile X Mental Retardation 1 (FMR1) gene. FMR1 premutation carriers are at risk of developing a neurodegenerative disease called fragile X-associated tremor/ataxia syndrome (FXTAS) and Fragile X-associated primary ovarian insufficiency (FXPOI) in adulthood. In the last years an increasingly board spectrum of clinical manifestations including psychiatric disorders have been described as occurring at a greater frequency among FMR1 premutation carriers. Herein, we reviewed the neuroimaging findings reported in relation with psychiatric symptomatology in adult FMR1 premutation carriers. A structured electronic literature search was conducted on FMR1 premutation and neuroimaging yielding a total of 3,229 articles examined. Of these, 7 articles were analyzed and are included in this review. The results showed that the main radiological findings among adult FMR1 premutation carriers presenting neuropsychiatric disorders were found on the amygdala and hippocampus, being the functional abnormalities more consistent and the volumetric changes more inconsistent among studies. From a molecular perspective, CGG repeat size, FMR1 mRNA and FMRP levels have been investigated in relation with the neuroimaging findings. Based on the published results, FMRP might play a key role in the pathophysiology of the psychiatric symptoms described among FMR1 premutation carriers. However, additional studies including further probes of brain function and a broader scope of psychiatric symptom measurement are required in order to obtain a comprehensive landscape of the neuropsychiatric phenotype associated with the FMR1 premutation.

scholarly journals Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications

2020 ◽  
Vol 21 (12) ◽  
pp. 4391
Author(s):  
Ana Maria Cabal-Herrera ◽  
Nattaporn Tassanakijpanich ◽  
Maria Jimena Salcedo-Arellano ◽  
Randi J. Hagerman
Keyword(s):  
Neurodegenerative Disorder ◽  
Fragile X ◽  
Cgg Repeats ◽  
Mri Features ◽  
Fmr1 Mrna ◽  
Cerebellar Peduncles ◽  
History Of ◽  
Ataxia Syndrome ◽  
Psychiatric Problems ◽  
Female Carriers

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in older premutation (55–200 CGG repeats) carriers of FMR1. The premutation has excessive levels of FMR1 mRNA that lead to toxicity and mitochondrial dysfunction. The clinical features usually begin in the 60 s with an action or intention tremor followed by cerebellar ataxia, although 20% have only ataxia. MRI features include brain atrophy and white matter disease, especially in the middle cerebellar peduncles, periventricular areas, and splenium of the corpus callosum. Neurocognitive problems include memory and executive function deficits, although 50% of males can develop dementia. Females can be less affected by FXTAS because of a second X chromosome that does not carry the premutation. Approximately 40% of males and 16% of female carriers develop FXTAS. Since the premutation can occur in less than 1 in 200 women and 1 in 400 men, the FXTAS diagnosis should be considered in patients that present with tremor, ataxia, parkinsonian symptoms, neuropathy, and psychiatric problems. If a family history of a fragile X mutation is known, then FMR1 DNA testing is essential in patients with these symptoms.

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.

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 CGG repeats in RNA modulate expression of TDP-43 in mouse and fly models of fragile X tremor ataxia syndrome

2014 ◽  
Vol 23 (22) ◽  
pp. 5906-5915 ◽  
Author(s):  
Jocelyn N. Galloway ◽  
Chad Shaw ◽  
Peng Yu ◽  
Deena Parghi ◽  
Mickael Poidevin ◽  
...  
Keyword(s):  
Fragile X ◽  
Cgg Repeats ◽  
Ataxia Syndrome

scholarly journals Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome

Neuron ◽  
2017 ◽  
Vol 93 (2) ◽  
pp. 331-347 ◽  
Author(s):  
Chantal Sellier ◽  
Ronald A.M. Buijsen ◽  
Fang He ◽  
Sam Natla ◽  
Laura Jung ◽  
...  
Keyword(s):  
Fragile X ◽  
Cgg Repeats ◽  
Ataxia Syndrome

scholarly journals Mothball ingestion as a manifestation of pica, leading to paradichlorobenzene CNS toxicity

2020 ◽  
Vol 20 (2) ◽  
pp. 932-935
Author(s):  
Joon Yau Leong ◽  
Margarita Gianniosis ◽  
Saman Zafar ◽  
Yan Zhang
Keyword(s):  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Fragile X ◽  
Hypochromic Anemia ◽  
High Index ◽  
Deficiency Anemia ◽  
Neurological Assessment ◽  
Cerebellar Peduncles ◽  
Ataxia Syndrome ◽  
High Index Of Suspicion

Background: Pica is a poorly understood psychiatric disorder that presents with the ingestion of non-nutritious substances for unclear reasons. A high index of suspicion for unusual toxin exposure aids in the diagnosis of pica patients presenting with unexplained neurodegenerative features. Methods: We present a 47-year-old female with worsening gait over the past year. Prior to this, she was fully independent with activities of daily living, but is now mostly housebound due to frequent falls. Past medical history is significant for menorrhagia, iron deficiency anemia and pica. CBC and iron studies revealed iron deficiency with microcytic hypochromic anemia. MRI brain demonstrated symmetrical T2 hyperintensities within the middle cerebellar peduncles. Results: Differential diagnoses for her clinical deficits and imaging, including Spinocerebellar Ataxia, Multiple System At- rophy and Fragile X Tremor-Ataxia Syndrome, were excluded based on neurological assessment, family history and genetic PCR testing. Collateral history revealed a regular habit of mothball ingestion and serum paradichlorobenzene levels were elevated to 15mcg/mL. The patient was treated with iron replacement therapy and her symptoms gradually improved over several months. Conclusion: Iron deficiency anemia is commonly associated with pica, which can lead to toxin ingestion. A high index of suspicion for toxin ingestion in pica patients can immensely aid in the diagnosis. Mothball abuse secondary to pica may affect the CNS and can present with nonspecific neurodegenerative changes. To our knowledge, there have been no reported cases in the literature with paradichlorobenzene neurotoxicity predominantly affecting the middle cerebellar peduncles. Keywords: Mothball; paradichlorobenzene; PDCB; toxicity; pica; middle cerebellar peduncles.

scholarly journals Near-cognate initiation generates FMRpolyG from CGG repeats in Fragile X associated Tremor Ataxia Syndrome

2020 ◽  
Author(s):  
Yuan Zhang ◽  
M. Rebecca Glineburg ◽  
Venkatesha Basrur ◽  
Kevin Conlon ◽  
Deborah A. Hall ◽  
...  
Keyword(s):  
Fragile X ◽  
Model Systems ◽  
Initiation Factor ◽  
Amino Terminal ◽  
Human Samples ◽  
Cgg Repeats ◽  
Cellular Environment ◽  
Ataxia Syndrome ◽  
Signature Peptides ◽  
Ran Translation

AbstractRepeat associated non-AUG (RAN) translation of FMR1 5’ UTR CGG repeats produces toxic homo-polymeric proteins that accumulate within ubiquitinated inclusions in Fragile X-associated tremor/ataxia syndrome (FXTAS) patient brains and model systems. The most abundant RAN product, FMRpolyG, initiates predominantly at an ACG codon located just 5’ to the repeat. Methods to accurately measure FMRpolyG in FXTAS patients are lacking. Here we used data dependent acquisition (DDA) and parallel reaction monitoring (PRM) mass spectrometry coupled with stable isotope labeled standard peptides (SIS) to identify potential signature FMRpolyG fragments in patient cells and tissues. Following immunoprecipitation (IP) enrichment, we detected FMRpolyG signature peptides by PRM in transfected cells, FXTAS human samples and patient derived stem cells, but not in controls. Surprisingly, we identified two amino-terminal peptides: one beginning with methionine (Ac-MEAPLPGGVR) initiating at an ACG, and a second beginning with threonine (Ac-TEAPLPGGVR), initiating at a GUG. Abundance of the threonine peptide was enhanced relative to the methionine peptide upon activation of the integrated stress response. In addition, loss of the eIF2 alternative factor, eIF2A, or enhanced expression of initiation factor eIF1, preferentially suppressed GUG initiated FMRpolyG synthesis. These data demonstrate that FMRpolyG is quantifiable in human samples and that RAN translation on FMR1 initiates at specific near cognate codons dependent on available initiation factors and cellular environment.

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