Aging Symptom Trajectories in Mother Carriers of the FMR1 Premutation

FMR1 前突变母携带者的衰老症状轨迹

基本信息

批准号：
10445687
负责人：
Jessica Klusek
金额：
$ 60.67万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10445687
关键词：
Activities of Daily Living Adopted Adult Advocate Affect Age Aging Anxiety Autoimmune Autonomic Dysfunction Autonomic nervous system Biological Biological Factors Caring Characteristics Child Child Rearing Classification Clinical Clinical Management Cross-Sectional Studies DNA Sequence Alteration Data Development Environmental Risk Factor Executive Dysfunction Eye FMR1 FMR1 Premutation FMRP Family Fragile X Syndrome Functional disorder Future Gene Abnormality Genes Genetic Genetic Predisposition to Disease Genotype Glean Goals Growth Heart Rate High Prevalence Impairment Individual Infertility International Investigation Life Long-Term Effects Mental Depression Mental Health Messenger RNA Modeling Molecular Abnormality Molecular Genetics Mothers Mutate Neurodegenerative Disorders Outcome Parents Partner in relationship Phenotype Physiological Play Premature Menopause Prevention Process Public Health Risk Risk Factors Role Sinus Arrhythmia Statistical Methods Stress Symptoms Testing Time United States Woman Work age related aged chronic painful condition clinical risk disability disorder risk executive function experience human old age (65+)improved improved outcome innovation longitudinal design men middle age premature respiratory social social communication social deficits social skills stressor

项目摘要

PROJECT SUMMARY/ABSTRACT About 1 in 151 women in the US are carriers of a genetic abnormality called the FMR1 premutation (FXpm). Mothers who carry the FXpm are at risk for passing the mutated gene to their children, which may result in fragile X syndrome. The FXpm is also associated with substantially increased risk for disease, including neurodegenerative disease, premature menopause, psychiatric involvement, and executive and social deficits. New evidence suggests that FXpm carrier mothers may experience premature age-related decline across multiple symptom domains. The aging expression of FXpm phenotype is particularly concerning when applied within the context of fragile X families because these symptoms impact not only the carrier mother, but also her ability to care and advocate for her children with fragile X syndrome. However, almost all evidence of age- related decline in this group has been gleaned from cross-sectional data that are insufficient for drawing robust longitudinal trajectories. This represents a substantial barrier to effective clinical management, as we lack the data needed to understand the long-term effects of the FXpm genotype and its implications for families. This proposal seeks to determine the stability of key FXpm phenotypes (mental health, executive, social) across midlife and early old age in FXpm carrier mothers compared to healthy controls (Aim 1); investigate autonomic and molecular-genetic factors associated with age-related symptom expression and their interface with parenting stress (Aim 2); and evaluate functional limitations associated with FXpm symptoms across age (Aim 3). We will accomplish these aims by adopting an accelerated longitudinal design to track age-related change occurring across 45-80 years in 75 FXpm carrier mothers compared to 75 control mothers. The over- arching goal is to inform the critical age periods and risk factors in age-related decline, as well as to lay the groundwork for future mechanistic studies. This work is necessary to develop strategies to ameliorate FXpm symptoms, which will improve outcomes for both FXpm carrier mothers and their children with fragile X syndrome.

项目概要/摘要在美国，大约每 151 名女性就有 1 名携带 FMR1 前突变基因异常（FXpm）。携带 FXpm 的母亲有将突变基因遗传给孩子的风险，这可能会导致脆性 X 综合征。 FXpm 还与疾病风险大幅增加相关，包括神经退行性疾病、过早绝经、精神障碍以及执行和社交缺陷。新证据表明，FXpm 携带者母亲可能会经历与年龄相关的过早衰退多个症状域。 FXpm 表型的衰老表达在应用时尤其令人担忧在脆弱的 X 家庭中，因为这些症状不仅影响携带者母亲，还影响她有能力照顾和倡导患有脆性 X 综合症的孩子。然而，几乎所有年龄的证据—— 该组的相关下降是从横截面数据中收集到的，这些数据不足以绘制稳健的图纵向轨迹。这对有效的临床管理构成了巨大障碍，因为我们缺乏需要数据来了解 FXpm 基因型的长期影响及其对家庭的影响。该提案旨在确定关键 FXpm 表型（心理健康、执行力、社交）的稳定性与健康对照组相比，FXpm 携带者母亲的中年和早年情况（目标 1）；调查与年龄相关症状表达及其界面相关的自主和分子遗传因素承受养育压力（目标 2）；并评估与跨年龄 FXpm 症状相关的功能限制（目标 3）。我们将通过采用加速纵向设计来跟踪与年龄相关的数据来实现这些目标与 75 名对照母亲相比，75 名 FXpm 携带者母亲在 45-80 年间发生的变化。过度首要目标是了解与年龄相关的衰退的关键年龄阶段和风险因素，并奠定基础为未来的机理研究奠定基础。这项工作对于制定改善 FXpm 的策略是必要的症状，这将改善 FXpm 携带者母亲及其患有脆性 X 病的孩子的结果综合症。