Prevalence and characterisation of FMR1 gene's premutation carriers amongst older males presenting with tremor/ataxia

出现震颤/共济失调的老年男性中 FMR1 基因前突变携带者的患病率和特征

• 批准号: nhmrc : 330400
• 负责人: Dr Danuta Loesch
• 金额: $ 13.3万
• 依托单位: La Trobe University
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2005
• 资助国家: 澳大利亚
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/prevalence-characterisation-fmr1-presenting-tremorataxia/95237
• 关键词: Prevalence; characterisation; FMR1; gene; premutation

The study concerns a novel form of progressive neurological disorder associated with tremor and body imbalance occurring in older males and caused by a small expansion of the trinucleotide (CGG) repeat in a fragile X (FMR1) gene. This expansion is termed 'premutation', in contrast with the full mutation, where a large expansion of the CGG repeat in this gene causes Fragile X Syndrome, a common form of intellectual disability. While brain anomaly in the full mutation is caused by a deficit of the FMR1 specific protein product (FMRP), the pathways from premutation to a neurological disorder are unknown. In this disorder, neurological dysfunction is associated with brain atrophy visible in magnetic resonance (MRI) images. Molecular studies showed increased levels of 'messenger' RNA (mRNA), which indicates overexpression of FMR1 gene . Our own study showed significantly increased (41.7%) prevalence of neurological involvement in male premutation carriers aged >50, compared with age-matched norms. Moreover, a screening of patients with two neurological disorders associated with tremor showed a significant increase of premutation carriers (5%- 22%). The aim of this study is to test hypotheses about the association of late-onset neurological disorders of unknown cause presenting tremor and imbalance, with a fragile X premutation in males, by screening for the presence of this premutation; and then conducting a full assessment of the identified premutation carriers, including detailed neurological, neuropsychological and MRI tests, to establish the spectrum of neurological involvement. This involvement will be correlated with the molecular (DNA, mRNA, FMRP) findings. The results will contribute to understanding the mechanisms of neurological involvement caused by this premutation. Moreover, estimation of the prevalence of this premutation in relevant neurological disorders will impact on standard diagnostic, and possibly future treatment approaches in neurology clinics.

该研究涉及一种新形式的进行性神经系统疾病，与老年男性中发生的震颤和身体不平衡有关，由脆性X（FMR 1）基因中三核苷酸（CGG）重复序列的小幅扩展引起。这种扩展被称为“前突变”，与完全突变相反，其中该基因中CGG重复序列的大量扩展导致脆性X综合征，这是一种常见的智力残疾形式。虽然全突变中的大脑异常是由FMR1特异性蛋白产物（FMRP）的缺陷引起的，但从前突变到神经系统疾病的途径尚不清楚。在这种疾病中，神经功能障碍与磁共振（MRI）图像中可见的脑萎缩相关。分子生物学研究表明，“信使”RNA（mRNA）水平增加，表明FMR 1基因过表达。我们自己的研究显示，与年龄匹配的正常人相比，50岁男性前突变携带者神经系统受累的患病率显著增加（41.7%）。>此外，对患有两种与震颤相关的神经系统疾病的患者进行的筛查显示，前突变携带者显着增加（5%-22%）。本研究的目的是通过筛查男性脆性X前突变的存在来检验关于不明原因的迟发性神经系统疾病（表现为震颤和失衡）与该前突变相关的假设;然后对已识别的前突变携带者进行全面评估，包括详细的神经学、神经心理学和MRI检查，以确定神经系统受累的范围。这种参与将与分子（DNA，mRNA，FMRP）结果相关。这一结果将有助于理解这种前突变引起的神经系统受累的机制。此外，估计这种前突变在相关神经系统疾病中的患病率将影响标准诊断，并可能影响神经科诊所未来的治疗方法。