Open-label treatment trial of lithium to target the underlying defect in fragile X syndrome
Open-label treatment trial of lithium to target the underlying defect in fragile X syndrome
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DOI：
10.1097/dbp.0b013e31817dc447
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发表时间：
2008-08-01
影响因子：
2.4
通讯作者：
Greenough, William T.
中科院分区：
文献类型：
--
作者：
Berry-Kravis, Elizabeth;Sumis, Allison;Greenough, William T.
目的：在脆性X综合征（FXS）中，假设脆性X智力低下蛋白（FMRP）的缺失破坏了树突中第1组代谢型谷氨酸受体（mGluR和mGluR 5）依赖性翻译的调节。锂减少mGluR激活的翻译和逆转dfxr突变果蝇和fmr 1基因敲除小鼠的表型。进行该试验性添加试验以评估锂在患有FXS的人类中的安全性和有效性。方法：15名6-23岁的FXS患者接受锂滴定至0.8-1.2 mEq/L。主要结局指标，异常行为检查表社区版（ABC-C）易怒子量表，次要结局指标（其他ABC-C子量表、临床总体改善量表（CGI）、行为视觉模拟量表（VAS）、Vineland适应行为量表（VABS）），探索性认知和心理生理学测量以及细胞外信号调节激酶（ERK）在基线和治疗2个月时进行活化测定。采用标准化检查表量化副作用，并在基线、2周、4周和2个月时进行锂水平、全血细胞计数（CBC）、促甲状腺激素（TSH）和化学筛查。结果：唯一显著的治疗相关副作用是多尿/多夹（n = 7）和TSH升高（n = 4）。尽管ABC-C易怒子量表仅显示改善趋势，但总ABC-C评分（p = 0.005）、VAS（p = 0.003）、CGI（p = 0.002）、VABS适应不良行为子量表（p = 0.007）和RBANS列表学习（p = 0.03）均显著改善，ERK激活率也有所提高（p = 0.007）。几个探索性的任务被证明是太困难的低功能FXS科目。结论：这项研究的结果与FXS小鼠和苍蝇模型的结果一致，表明锂耐受性良好，并可能通过改变潜在的神经缺陷在FXS中提供功能益处。一个安慰剂对照试验锂在FXS是必要的。
Objective: 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. Methods: 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. Results: The only significant treatment-related side effects were polyuria/polyclipsia (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. Conclusions: 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.