孤独症谱系障碍患儿睡眠问题及其与6-羟基硫酸褪黑素水平的关联性

Sleep problems and the association with the levels of 6-sulfatoxymelatonin in children with autism spectrum disorder

目的了解孤独症谱系障碍（ASD）患儿的睡眠问题发生情况，并探讨其与褪黑激素代谢指标6-羟基硫酸褪黑素（6-SM）的关联性。方法前瞻性病例对照研究。2015年10月至2017年4月在哈尔滨医科大学儿童发育行为研究中心进行康复训练及哈尔滨市特殊教育学校就读的ASD患儿作为ASD组。采用分层整群随机抽样的方法，在哈尔滨市5所幼儿园及1所小学抽取健康儿童作为对照组。采用儿童睡眠习惯问卷（CSHQ）对两组儿童进行睡眠问题调查，并采集按年龄、性别1∶1匹配的病例-对照儿童的晨尿，应用酶联免疫吸附试验（ELISA）方法检测晨尿中的6-SM水平。采用t检验进行组间比较，Pearson相关分析进行相关性检验。结果共纳入212例ASD患儿，平均年龄（6.0±2.7）岁，男181例（85.4%）；334名对照儿童，平均年龄（5.9±2.6）岁，男272例（81.4%）；其中101对病例-对照儿童采集晨尿。经统计分析发现，ASD患儿CSHQ总分及睡眠抵触、入睡潜伏期、睡眠持续时间、夜醒、异态睡眠、睡眠呼吸障碍及日间困倦共7个维度的得分均明显高于对照组儿童（分：48.2±6.2比46.6±5.4、11.4±2.5比10.7±2.8、1.7±0.8比1.5±0.7、4.1±1.4比3.7±1.1、4.2±1.5比3.8±1.1、8.5±1.5比8.3±1.4、3.7±1.0比3.4±0.8、11.7±2.5比12.4±2.7, t=3.16、3.00、3.23、2.76、3.19、1.99、3.45、-2.72, P=0.002、0.003、0.001、0.006、0.002、0.048、0.001、0.007）；ASD患儿6-SM的水平明显低于对照组[（1.24±0.50）比（1.68±0.63）μg/h, t=-5.50, P〈0.01]，且与CSHQ总分呈负相关（r=-0.50, P〈0.01）。结论ASD患儿是发生睡眠问题的高发群体，且褪黑激素代谢水平异于对照儿童；ASD患儿睡眠问题的严重程度与褪黑激素代谢产物6-SM水平存在关联；褪黑激素代谢异常可能是ASD患儿易发生睡眠问题的原因之一。

ObjectiveTo identify the prevalence of sleep problems in children with autism spectrum disorder （ASD） and to explore the association with the main melatonin metabolite, 6-sulfatoxymelatonin （6-SM）.MethodThis was a prospective case-control study. Children with ASD were recruited from Child Development and Behavioral Research Center （CDBRC） of the Harbin Medical University and Harbin Special Education School from October 2015 to April 2017 （ASD group） . Healthy controls were selected from five kindergartens and one primary school in Harbin by the stratified cluster random sampling （control group） . The Children＇s Sleep Habits Questionnaire （CSHQ） was used to investigate the sleep problems of the two groups. The patients were matched in a 1∶1 ratio for the age and sex, and the urine samples of case-control pairs were collected in the morning. The level of 6-SM was measured by the enzyme linked immunosorbent assay （ELISA）. The student＇s t test was used for comparison between the ASD group and control group, and the Pearson correlation analysis was used to determine the correlation difference.ResultA total of 212 ASD children （mean （±SD） age was （6.0±2.7） years, and 181 patients （85.4%） were male）, and a total of 334 healthy children（mean （±SD） age was （5.9±2.6） years, and 272 patients （81.4%） were male） were recruited. Among them, 101 matched case-control pairs completed the collection of urine samples. According to the statistical analysis, the scores of total CSHQ, bedtime resistance, sleep onset delay, sleep duration, night waking, parasomnia, sleep disordered breathing and daytime sleepiness in children with ASD were significantly higher than those in the control group （48.2±6.2 vs. 46.6±5.4, 11.4±2.5 vs. 10.7±2.8, 1.7±0.8 vs. 1.5±0.7, 4.1±1.4 vs. 3.7±1.1, 4.2±1.5 vs. 3.8±1.1, 8.5±1.5 vs. 8.3±1.4, 3.7±1.0 vs. 3.4±0.8, 11.7±2.5 vs. 12.4±2.7, t=3.16, 3.00, 3.23, 2.76, 3.19, 1.99, 3.45,-2.72, P=0.002, 0.003, 0.001, 0.006, 0.002, 0.048, 0.001, 0.007）, the level of 6-SM was significantly lower in children with ASD than that of healthy controls （（1.24±0.50） vs. （1.68±0.63）μg/h, t=-5.50, P〈0.01）, and the total CSHQ score was negatively correlated with the level of 6-SM （r=-0.50, P〈0.01）.ConclusionThe children with ASD were at high risk for sleep problems, and the melatonin metabolite of ASD group was abnormal compared with that of the control group. Moreover, there was a negative correlation between the severity of sleep problems and the level of 6-SM in ASD children. The results of our study indicate that the abnormal melatonin metabolism may be one of the causes of sleep problems in children with ASD.