Berry-Kravis Elizabeth, Sumis Allison, Hervey Crystal, Nelson Michael, Porges Stephen W, Weng Ning, Weiler Ivan Jeanne, Greenough William T
Department of Pediatrics, Rush University Medical Center, University of Illinois at Chicago, IL 60612, USA.
J Dev Behav Pediatr. 2008 Aug;29(4):293-302. doi: 10.1097/DBP.0b013e31817dc447.
In fragile X syndrome (FXS), it is hypothesized that absence of the fragile X mental retardation protein (FMRP) disrupts regulation of group 1 metabotropic glutamate receptor (mGluR and mGluR5)-dependent translation in dendrites. Lithium reduces mGluR-activated translation and reverses phenotypes in the dfxr mutant fly and fmr1 knockout mouse. This pilot add-on trial was conducted to evaluate safety and efficacy of lithium in humans with FXS.
Fifteen individuals with FXS, ages 6-23, received lithium titrated to levels of 0.8-1.2 mEq/L. The primary outcome measure, the Aberrant Behavior Checklist --Community Edition (ABC-C) Irritability Subscale, secondary outcome measures (other ABC-C subscales, clinical global improvement scale (CGI), visual analog scale for behavior (VAS), Vineland Adaptive Behavior Scale (VABS)), exploratory cognitive and psychophysiological measures and an extracellular signal-regulated kinase (ERK) activation assay were administered at baseline and 2 months of treatment. Side effects were quantified with a standardized checklist and lithium level, complete blood count (CBC), thyroid stimulating hormone (TSH), and chemistry screen were done at baseline, 2 weeks, 4 weeks and 2 months.
The only significant treatment-related side effects were polyuria/polydipsia (n = 7) and elevated TSH (n = 4). Although the ABC-C Irritability Subscale showed only a trend toward improvement, there was significant improvement in the Total ABC-C score (p = 0.005), VAS (p = 0.003), CGI (p = 0.002), VABS Maladaptive Behavior Subscale (p = 0.007), and RBANS List Learning (p = 0.03) and an enhanced ERK activation rate (p = 0.007). Several exploratory tasks proved too difficult for lower-functioning FXS subjects.
Results from this study are consistent with results in mouse and fly models of FXS, and suggest that lithium is well-tolerated and provides functional benefits in FXS, possibly by modifying the underlying neural defect. A placebo-controlled trial of lithium in FXS is warranted.
在脆性X综合征（FXS）中，据推测脆性X智力低下蛋白（FMRP）的缺失会破坏依赖于1型代谢型谷氨酸受体（mGluR1和mGluR5）的树突翻译调控。锂可减少mGluR激活的翻译，并逆转dfxr突变果蝇和fmr1基因敲除小鼠的表型。本初步附加试验旨在评估锂对FXS患者的安全性和有效性。
15名年龄在6至23岁之间的FXS患者接受锂治疗，滴定至0.8 - 1.2 mEq/L的水平。主要结局指标为异常行为检查表——社区版（ABC - C）易激惹分量表，次要结局指标（ABC - C的其他分量表、临床总体改善量表（CGI）、行为视觉模拟量表（VAS）、文兰适应行为量表（VABS））、探索性认知和心理生理指标以及细胞外信号调节激酶（ERK）激活试验在基线和治疗2个月时进行。使用标准化检查表对副作用进行量化，并在基线、2周、4周和2个月时检测锂水平、全血细胞计数（CBC）、促甲状腺激素（TSH）和化学筛查。
唯一与治疗相关的显著副作用是多尿/烦渴（n = 7）和TSH升高（n = 4）。虽然ABC - C易激惹分量表仅显示出改善趋势，但ABC - C总分（p = 0.005）、VAS（p = 0.003）、CGI（p = 0.002）、VABS适应不良行为分量表（p = 0.007）、RBANS列表学习（p = 0.03）有显著改善，且ERK激活率提高（p = 0.007）。一些探索性任务对功能较低的FXS受试者来说难度太大。
本研究结果与FXS小鼠和果蝇模型的结果一致，表明锂耐受性良好，并可能通过改善潜在的神经缺陷为FXS患者带来功能益处。有必要对FXS患者进行锂的安慰剂对照试验。
