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

这项研究涉及一种新形式的进行性神经疾病，与震颤和身体失衡有关，发生在老年男性中，由脆性X(FMR1)基因中三核苷酸(CGG)重复序列的微小扩张引起。这种扩展被称为“前突变”，与完全突变不同，在全突变中，该基因中CGG重复的大量扩展会导致脆性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特定蛋白产物(FMRP)缺陷引起的，但从前突变到神经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有关。分子研究表明，信使RNA(信使RNA)水平升高，这表明FMR1基因过度表达。我们自己的研究显示，与年龄匹配的正常人群相比，50岁的男性前突变携带者神经受累的患病率显著增加(41.7%)。此外，对与震颤相关的两种神经系统疾病患者的筛查显示，前突变携带者显著增加(5%-22%)。这项研究的目的是通过筛查男性中是否存在脆性X前突变，来测试有关原因不明的迟发性神经疾病与震颤和失衡的相关性的假说；然后对已确定的前突变携带者进行全面评估，包括详细的神经学、神经心理学和核磁共振测试，以建立神经受累的谱系。这种参与将与分子(DNA、mRNA、FMRP)发现相关。这一结果将有助于理解这种前突变引起的神经参与的机制。此外，对这种前突变在相关神经疾病中的流行率的估计将影响神经病学临床的标准诊断，并可能影响未来的治疗方法。

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.