scholarly journals Evidence for Three Subgroups of Female FMR1 Premutation Carriers Defined by Distinct Neuropsychiatric Features: A Pilot Study

2022 ◽  
Vol 15 ◽  
Author(s):  
Lauren M. Schmitt ◽  
Kelli C. Dominick ◽  
Rui Liu ◽  
Ernest V. Pedapati ◽  
Lauren E. Ethridge ◽  
...  
Keyword(s):  
Pilot Study ◽  
Fragile X ◽  
Executive Dysfunction ◽  
Self Report ◽  
Oscillatory Activity ◽  
Cluster Solution ◽  
Cgg Repeat ◽  
Fmr1 Premutation ◽  
Variable Expression ◽  
Increased Risk

Over 200 Cytosine-guanine-guanine (CGG) trinucleotide repeats in the 5′ untranslated region of the Fragile X mental retardation 1 (FMR1) gene results in a “full mutation,” clinically Fragile X Syndrome (FXS), whereas 55 – 200 repeats result in a “premutation.” FMR1 premutation carriers (PMC) are at an increased risk for a range of psychiatric, neurocognitive, and physical conditions. Few studies have examined the variable expression of neuropsychiatric features in female PMCs, and whether heterogeneous presentation among female PMCs may reflect differential presentation of features in unique subgroups. In the current pilot study, we examined 41 female PMCs (ages 17–78 years) and 15 age-, sex-, and IQ-matched typically developing controls (TDC) across a battery of self-report, eye tracking, expressive language, neurocognitive, and resting state EEG measures to determine the feasibility of identifying discrete clusters. Secondly, we sought to identify the key features that distinguished these clusters of female PMCs. We found a three cluster solution using k-means clustering. Cluster 1 represented a psychiatric feature group (27% of our sample); cluster 2 represented a group with executive dysfunction and elevated high frequency neural oscillatory activity (32%); and cluster 3 represented a relatively unaffected group (41%). Our findings indicate the feasibility of using a data-driven approach to identify naturally occurring clusters in female PMCs using a multi-method assessment battery. CGG repeat count and its association with neuropsychiatric features differ across clusters. Together, our findings provide important insight into potential diverging pathophysiological mechanisms and risk factors for each female PMC cluster, which may ultimately help provide novel and individualized targets for treatment options.

scholarly journals Family history of FXTAS is associated with age-related cognitive-linguistic decline among mothers with the FMR1 premutation

2022 ◽  
Vol 14 (1) ◽  
Author(s):  
Jessica Klusek ◽  
Amanda Fairchild ◽  
Carly Moser ◽  
Marsha R. Mailick ◽  
Angela John Thurman ◽  
...  
Keyword(s):  
Family History ◽  
Neurodegenerative Disease ◽  
Cognitive Skills ◽  
Fragile X ◽  
Repeat Length ◽  
Syntactic Complexity ◽  
Cgg Repeat ◽  
Age Related ◽  
Increased Risk ◽  
History Of

Abstract Background Women who carry a premutation allele of the FMR1 gene are at increased vulnerability to an array of age-related symptoms and disorders, including age-related decline in select cognitive skills. However, the risk factors for age-related decline are poorly understood, including the potential role of family history and genetic factors. In other forms of pathological aging, early decline in syntactic complexity is observed and predicts the later onset of neurodegenerative disease. To shed light on the earliest signs of degeneration, the present study characterized longitudinal changes in the syntactic complexity of women with the FMR1 premutation across midlife, and associations with family history of fragile X-associated tremor/ataxia syndrome (FXTAS) and CGG repeat length. Methods Forty-five women with the FMR1 premutation aged 35–64 years at study entry participated in 1–5 longitudinal assessments spaced approximately a year apart (130 observations total). All participants were mothers of children with confirmed fragile X syndrome. Language samples were analyzed for syntactic complexity and participants provided information on family history of FXTAS. CGG repeat length was determined via molecular genetic testing. Results Hierarchical linear models indicated that women who reported a family history of FXTAS exhibited faster age-related decline in syntactic complexity than those without a family history, with that difference emerging as the women reached their mid-50 s. CGG repeat length was not a significant predictor of age-related change. Conclusions Results suggest that women with the FMR1 premutation who have a family history of FXTAS may be at increased risk for neurodegenerative disease, as indicated by age-related loss of syntactic complexity. Thus, family history of FXTAS may represent a personalized risk factor for age-related disease. Follow-up study is needed to determine whether syntactic decline is an early indicator of FXTAS specifically, as opposed to being a more general age-related cognitive decline associated with the FMR1 premutation.

scholarly journals Genotoxicity in Patients on Long-term Proton Pump Inhibitor Therapy in Korea: A Nested Case-control, Prospective, Pilot Study

2020 ◽  
Vol 20 (1) ◽  
pp. 47-53 ◽  
Author(s):  
Youn I Choi ◽  
Jun-Won Chung ◽  
Dong Kyun Park ◽  
Kyoung Oh Kim ◽  
Kwang An Kwon ◽  
...  
Keyword(s):  
Pilot Study ◽  
Medical History ◽  
Proton Pump ◽  
Serum Levels ◽  
Self Report ◽  
Healthy Controls ◽  
Control Subjects ◽  
Increased Risk ◽  
Healthy Control

Background/Aims: Although proton pump inhibitors (PPIs) remain a mainstay for the suppression of gastric acid secretion, long-term PPI use is associated with side effects. However, the genotoxicity associated with long-term PPI use is unclear.Materials and Methods: This prospective observational pilot study enrolled patients who had been on PPIs for >1 year and healthy controls from July 2015 to August 2016. The subjects completed self-report questionnaires pertaining to their drug and medical history, and only those with no medical history and a ≥2-year wash-out period (for drugs other than PPIs) were included. We collected peripheral-blood lymphocytes from long-term PPI users and healthy controls and analyzed the genotoxicity by using the cytokinesis-block micronucleus cytome assay; we also determined the fasting serum levels of pyridoxine, folate, cobalamin, and homocysteine.Results: Ten long-term PPI users and 40 healthy control subjects were enrolled. The median serum pyridoxine, folate, cobalamin, and homocysteine levels were not significantly different between the groups. The median frequencies of micronuclei (MNi), nucleoplasmic bridges (NPBs), and nuclear buds (Nbuds) per 1,000 binucleated cells, in long-term PPI users and healthy controls, were 30.3 and 16.3 (<i>P</i><0.005), 2.5 and 1.8 (<i>P</i><0.005), and 9.3 and 5.0 (<i>P</i><0.005), respectively. Even after adjustment for confounding factors, the OR of the MNi, NPBs, and Nbuds for long-term PPI users compared with healthy control subjects were 14.1 (<i>P</i><0.001), 2.0 (<i>P</i>=0.001), and 1.3 (<i>P</i>=0.3), respectively.Conclusions: Long-term PPI use was significantly associated with an increased risk of genotoxicity after adjustment for age, sex, body mass index, medical history, drug history, and the serum levels of vitamins.

P–514 RAN-Translation in Fragile X associated Premature Ovarian Insufficiency (FXPOI): FMRpolyG as a predictive tool

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
X P Nguyen ◽  
B Messmer ◽  
J E Dietrich ◽  
K Hinderhofer ◽  
T Strowitzki ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Fragile X ◽  
Human Lymphocytes ◽  
Predictive Tool ◽  
Ovarian Insufficiency ◽  
Glass Coverslip ◽  
Cgg Repeat ◽  
Fmr1 Premutation ◽  
The Impact ◽  
Ran Translation

Abstract Study question Does repeat-associated non-AUG (RAN) translation lead to accumulation of polyglycine- containing protein (FMRpolyG) in human lymphocytes and mural granulosa cells of FMR1 premutation carriers? Summary answer Lymphocytes and granulosa cells from FMR1 premutation carriers contain intracellular inclusions that stain positive for both FMRpolyG and ubiquitin. What is known already: Fragile-X-associated-Primary-Ovarian-Insufficiency (FXPOI) is characterized by oligo/amenorrhea and hypergonadotropic hypogonadism associated with the expansion of CGG-repeats in the 5’UTR of FMR1, called premutation (PM) (n: 55–200). Approximately 20% of women carrying a FMR1-premutation (PM) allele develop FXPOI. RAN-translation dependent on variable CGG-repeat length is hypothesized to cause FXPOI due to the production of a polyglycine-containing FMR1-protein, FMRpolyG. Recently, FMRpolyG inclusions were found in neuronal brain cells of FXTAS patients and stromal cells of the ovary of an FXPOI patient. Study design, size, duration: Lymphocytes and granulosa cells (GCs) from women with PM (6) and women without PM (10) (controls) were analyzed by immunofluorescence (IF) staining for the presence of inclusions positive for ubiquitin and FMRpolyG. Cell lysis and protein extraction samples were subjected to Fluorescent Western Blot (WB) analysis to detect FMRP and FMRpolyG Participants/materials, setting, methods Human GCs were obtained from follicular fluid after oocyte retrieval and lymphocytes were isolated from peripheral blood using Ficoll-Paque. Cells suspended in PBS were adhered to a glass-coverslip placed at the bottom of the 6-well culture plate, via gravity sedimentation. Adhered cells were fixed, IF staining for FMRpolyG and ubiquitin was performed and analyzed by fluorescence microscopy. Fluorescent WB was used to demonstrate the expression of FMRP, FMRpolyG in extracted protein from lymphocytes and GCs. Main results and the role of chance FMRP was successfully detected by fluorescence WB in both lymphocytes and GCs. FMRP is mainly present in cytoplasm and was expressed in greater amount in GCs than in leukocytes. Moreover, FMRP expression was significantly decreased in GCs from FMR1-PM compared with controls. Lymphocytes from PM-carriers and controls were immunostained for FMRpolyG and ubiquitin. In PM-carriers, FMRpolyG was present as aggregates, whereas in controls only a weak signal without inclusions was detectable. The expression pattern of FMRpolyG in GCs was similar to that in lymphocytes with a significant increase in PM-carriers. There, the FMRpolyG-aggregates additionally demonstrated as ubiquitin-positive inclusions. These may resemble the toxic potential of these protein fractions involved the ovarian damage in developing FXPOI. Limitations, reasons for caution More patients are needed to support the present findings. Further investigation into the possible consequences of these FMRpolyG-positive inclusions in PM-carriers is also advisable. Wider implications of the findings: We found for the first time FMRpolyG-accumulation in lymphocytes and GCs from FMR1-PM-carriers in ubiquitin-positive inclusions. Future experiments evaluating consistency in more patients and elucidating the impact on fertility and prospective value for individual ovarian reserve are therefore in preparation. Trial registration number Not applicable

scholarly journals Family as a Context for Child Development: Mothers with the FMR1 Premutation and Their Children with Fragile X Syndrome

2021 ◽  
Vol 42 (04) ◽  
pp. 277-286
Author(s):  
Katherine Bangert ◽  
Carly Moser ◽  
Laura Friedman ◽  
Jessica Klusek
Keyword(s):  
Fragile X Syndrome ◽  
Family Environment ◽  
Fragile X ◽  
Genetic Disorder ◽  
Challenging Behaviors ◽  
Fmr1 Gene ◽  
Fmr1 Premutation ◽  
Children And Parents ◽  
Increased Risk ◽  
Outcomes For Children

AbstractFragile X syndrome (FXS) is a genetic disorder caused by changes of the FMR1 gene that is passed along among families. A range of developmental processes may be impacted with wide variation in abilities across individuals with FXS. Mothers of children with FXS are often carriers of a “premutation” expansion on the FMR1 gene, which is associated with its own clinical phenotype. These maternal features may increase individual and family vulnerabilities, including increased risk for depression and anxiety disorders and difficulties in social and cognitive ability. These characteristics may worsen with age, and potentially interact with a child's challenging behaviors and with family dynamics. Thus, families of children with FXS may experience unique challenges related to genetic risk, manifested across both children and parents, that should be considered in therapeutic planning to optimize outcomes for children and their families. In this article, we review core features of the FMR1 premutation as expressed in mothers and aspects of the family environment that interface with developmental outcomes of children with FXS. Recommendations for family-centered support services are discussed.

scholarly journals Refining the risk for fragile X–associated primary ovarian insufficiency (FXPOI) by FMR1 CGG repeat size

2021 ◽  
Author(s):  
Emily Graves Allen ◽  
Krista Charen ◽  
Heather S. Hipp ◽  
Lisa Shubeck ◽  
Ashima Amin ◽  
...  
Keyword(s):  
High Resolution ◽  
Fragile X ◽  
Primary Ovarian Insufficiency ◽  
Ovarian Insufficiency ◽  
Cgg Repeat ◽  
Repeat Size ◽  
Cgg Repeats ◽  
Increased Risk ◽  
Personalized Risk Assessment ◽  
Current Risk

Abstract Purpose Approximately 20–30% of women with an FMR1 premutation experience fragile X–associated primary ovarian insufficiency (FXPOI); however, current risk estimates based on repeat size only identify women with the midrange of repeats to be at the highest risk. Methods To better understand the risk by repeat size, we collected self-reported reproductive histories on 1,668 women and divided them into high-resolution repeat size bins of ~5 CGG repeats to determine a more accurate risk for FXPOI in relation to CGG repeat length. Results As previously reported, women with 70–100 CGG repeats were at the highest risk for FXPOI using various statistical models to compare average age at menopause and risk of FXPOI, with women with 85–89 repeats being at the highest risk. Importantly, women with <65 repeats or >120 repeats did not have a significantly increased risk for FXPOI compared to women with <45 repeats. Conclusion Using a large cross-section study on 1,668 women, we have provided more personalized risk assessment for FXPOI using high-resolution repeat size bins. Understanding the variability in risk has important implications for family planning and overall health among women with a premutation.

scholarly journals Inhibition deficits are modulated by age and CGG repeat length in carriers of the FMR1 premutation allele who are mothers of children with fragile X syndrome

2020 ◽  
Vol 139 ◽  
pp. 105511 ◽  
Author(s):  
Jessica Klusek ◽  
Jinkuk Hong ◽  
Audra Sterling ◽  
Elizabeth Berry-Kravis ◽  
Marsha R. Mailick
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Repeat Length ◽  
Cgg Repeat ◽  
Fmr1 Premutation ◽  
Premutation Allele

scholarly journals Neuropathology of FMR1-premutation carriers presenting with dementia and neuropsychiatric symptoms

2021 ◽  
Author(s):  
Anke A Dijkstra ◽  
Saif Haify ◽  
Niek A Verwey ◽  
Niels D Prins ◽  
Esmay C van der Toorn ◽  
...  
Keyword(s):  
Fragile X ◽  
Neuropsychiatric Symptoms ◽  
White Matter Lesions ◽  
Neuropsychiatric Disorders ◽  
Vascular Lesions ◽  
Intranuclear Inclusions ◽  
Cgg Repeat ◽  
Fmr1 Premutation ◽  
Ataxia Syndrome ◽  
The Brain

Abstract CGG repeat expansions within the premutation range (55-200) of the FMR1 gene can lead to Fragile-X associated tremor/ataxia syndrome and Fragile-X associated neuropsychiatric disorders. These CGG repeats are translated into a toxic polyglycine-containing protein, FMRpolyG. Pathology of Fragile-X associated tremor/ataxia syndrome and Fragile-X associated neuropsychiatric disorders comprise FMRpolyG- and p62-positive intranuclear inclusions. Diagnosing a FMR1-premutation carrier remains challenging, as the clinical features overlap with other neurodegenerative diseases. Here, we describe two male cases with Fragile-X associated neuropsychiatric disorders related symptoms and mild movement disturbances and novel pathological features that can attribute to the variable phenotype. Macroscopically, both donors did not show characteristic white matter lesions on MRI, however, vascular infarcts in cortical- and subcortical regions were identified. Immunohistochemistry analyses revealed a high number of FMRpolyG intranuclear inclusions throughout the brain, which were also positive for p62. Importantly, we identified a novel pathological vascular phenotype with inclusions present in pericytes and endothelial cells. Although these results need to be confirmed in more cases, we propose that these vascular lesions in the brain could contribute to the complex symptomology of FMR1-premutation carriers. Overall, our report suggests that Fragile-X associated tremor/ataxia syndrome and Fragile-X associated neuropsychiatric disorders may present diverse clinical involvements resembling other types of dementia, and in the absence of genetic testing, FMRpolyG can be used post-mortem to identify premutation carriers.

Ethical Issues Relevant to the Assessment of Suicide Risk in Nonclinical Research Settings

Crisis ◽  
2012 ◽  
Vol 33 (1) ◽  
pp. 54-59 ◽  
Author(s):  
Carolyn M. Wilson ◽  
Bruce K. Christensen
Keyword(s):  
Undergraduate Students ◽  
Suicide Risk ◽  
Ethical Issues ◽  
Current Paper ◽  
Self Report ◽  
Ethical Guidelines ◽  
Schizotypal Personality ◽  
Increased Risk ◽  
Genetic Features ◽  
Conducting Research

Background: Our laboratory recently confronted this issue while conducting research with undergraduate students at the University of Waterloo (UW). Although our main objective was to examine cognitive and genetic features of individuals with schizotypal personality disorder (SPD), the study protocol also entailed the completion of various self-report measures to identify participants deemed at increased risk for suicide. Aims and Methods: This paper seeks to review and discuss the relevant ethical guidelines and legislation that bear upon a psychologist’s obligation to further assess and intervene when research participants reveal that they are at increased risk for suicide. Results and Conclusions: In the current paper we argue that psychologists are ethically impelled to assess and appropriately intervene in cases of suicide risk, even when such risk is revealed within a research context. We also discuss how any such obligation may potentially be modulated by the research participant’s expectations of the role of a psychologist, within such a context. Although the focus of the current paper is on the ethical obligations of psychologists, specifically those practicing within Canada, the relevance of this paper extends to all regulated health professionals conducting research in nonclinical settings.

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