Department of Neurology, Miller School of Medicine, University of Miami, 1717 N Bayshore Drive, Apt 3134, Miami, FL, 33132, USA.
Forbes Norris MDA/ALS Research and Treatment Center, California Pacific Medical Center, San Francisco, CA, USA.
Neurotox Res. 2018 Jan;33(1):192-198. doi: 10.1007/s12640-017-9741-x. Epub 2017 May 19.
β-N-Methylamino-L-alanine (BMAA) has been linked to Guam ALS/PDC and shown to produce neurodegeneration in vitro and in vivo (Drosophila, mice, rats, primates). BMAA misincorporation into neuroproteins produces protein misfolding and is inhibited by L-serine. Case-control studies in Northern New England indicate that living near to water-bodies with cyanobacterial blooms increases the risk of developing amyotrophic lateral sclerosis (ALS). The distribution of addresses of ALS cases in New Hampshire, Vermont, and Florida was compared to that of controls. Areas of statistically significantly increased numbers of ALS cases were examined for sources of environmental toxins. A phase I trial of oral L-serine was performed in 20 ALS patients (0.5 to 15 g twice daily). Safety and tolerability were assessed by comparing the rate of deterioration with 430 matched placebo controls. The distribution of residential addresses of ALS cases in New England and Florida revealed many areas where the age- and gender-adjusted frequency of ALS was greater than expected (P < 0.01). GIS studies of these "hot spots" in relation to sources of environmental pollutants, like cyanobacterial blooms, Superfund and Brownfield sites, and landfills, are ongoing. In the phase I trial of L-serine, two patients withdrew from because of gastrointestinal side effects. Three patients died during the study, which was about the expected number. The ALSFRS-R in the L-serine-treated patients showed a dose-related decrease in the rate of progression (34% reduction in slope, P = 0.044). The non-random distribution of addresses of ALS patients suggests that residential exposure to environmental pollutants may play an important role in the etiology of ALS. L-Serine in doses up to 15 g twice daily appears to be safe in patients with ALS. Exploratory studies of efficacy suggested that L-serine might slow disease progression. A phase II trial is planned.
β-N-甲基氨基-L-丙氨酸（BMAA）与关岛肌萎缩侧索硬化症/额颞叶痴呆（ALS/PDC）有关，并已被证明可在体外和体内（果蝇、小鼠、大鼠、灵长类动物）引起神经退行性变。BMAA 错误掺入神经蛋白会导致蛋白质错误折叠，并被 L-丝氨酸抑制。新英格兰北部的病例对照研究表明，生活在蓝藻水华的水体附近会增加患肌萎缩侧索硬化症（ALS）的风险。新罕布什尔州、佛蒙特州和佛罗里达州 ALS 病例的地址分布与对照组进行了比较。对统计学上显著增加的 ALS 病例数量的区域进行了环境毒素来源的检查。在 20 名 ALS 患者中进行了口服 L-丝氨酸的 I 期试验（0.5 至 15g 每日两次）。通过比较 430 名匹配的安慰剂对照的恶化率来评估安全性和耐受性。新英格兰和佛罗里达州 ALS 病例的居住地址分布显示，许多地区的 ALS 年龄和性别调整频率高于预期（P<0.01）。正在进行与环境污染物（如蓝藻水华、超级基金和棕地场地以及垃圾填埋场）来源有关的这些“热点”的 GIS 研究。在 L-丝氨酸的 I 期试验中，有两名患者因胃肠道副作用而退出。三名患者在研究期间死亡，这与预期数量相符。在接受 L-丝氨酸治疗的患者中，ALSFRS-R 显示出与剂量相关的进展速度降低（斜率降低 34%，P=0.044）。ALS 患者地址的非随机分布表明，居住环境暴露于环境污染物可能在 ALS 的病因学中起重要作用。高达 15g 每日两次的 L-丝氨酸剂量在 ALS 患者中似乎是安全的。探索性疗效研究表明，L-丝氨酸可能会减缓疾病进展。计划进行 II 期试验。
