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

该研究涉及一种新的进行性神经系统疾病，与老年男性发生的震颤和身体失衡有关，由脆性X （FMR1）基因中三核苷酸（CGG）重复的小扩展引起。与完全突变相反，这种扩展被称为“预突变”，在完全突变中，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。虽然全突变中的脑异常是由FMR1特异性蛋白产物（FMRP）的缺陷引起的，但从突变前兆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有关。分子研究显示信使RNA （mRNA）水平升高，这表明FMR1基因过度表达。我们自己的研究显示，与年龄匹配的正常值相比，50岁男性突变前携带者的神经系统受累率显著增加（41.7%）。此外，对两种与震颤相关的神经系统疾病患者的筛查显示，突变前携带者显著增加（5%- 22%）。本研究的目的是通过筛查男性脆性X基因突变的存在，来检验关于未知原因的迟发性神经系统疾病表现为震颤和失衡与脆性X基因突变之间关系的假设；然后对已确定的突变前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检查，以确定神经系统的发病范围。这种参与将与分子（DNA, mRNA， FMRP）发现相关。该结果将有助于理解由这种预突变引起的神经系统受累机制。此外，对相关神经疾病中这种前兆的患病率的估计将影响标准诊断，并可能影响神经病学诊所未来的治疗方法。

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.