Can endogenous ethylene glycol production occur in humans? A detailed investigation of adult monozygotic twin sisters

To the best of our knowledge, clinically significant endogenous ethylene glycol production has never been reported in humans, very seldom reported in other animals or microorganisms, and then only under rare and specific conditions. We describe the detailed investigations we undertook in two adult monozygotic twin sisters to ascertain whether they were producing endogenous ethylene glycol. Two previously healthy monozygotic adult twin sisters presented with recurrent episodes of apparent ethylene glycol poisoning beginning at age 35, requiring chronic hemodialysis to remove ethylene glycol and its metabolites as well as to restore metabolic homeostasis. The sisters denied ingestion or exposure to ethylene glycol. At their request, they were admitted to hospital under strict supervision to exclude surreptitious ingestion of ethylene glycol and to evaluate the need for treatment. Hemodialysis was withheld during this prospective study. Twin A was admitted for 14 days and twin B for 11 days. Serial biochemical analyses were performed in blood and urine. Clinical exome sequencing and mitochondrial deoxyribonucleic acid sequencing were also completed. In both twins, ethylene glycol was detected in urine, along with intermittent increases in concentrations of lactate, glycolate, and glycine in blood and/or urine. Blood ethylene glycol concentrations, however, remained <62 mg/L (<1 mmol/L) but became positive soon after discharge. The oxalate concentration remained normal in blood and urine. Plasma and urine amino acid profiles showed intermittent small increases in glycine, serine, taurine, proline, and/or alanine concentrations. Exome sequencing and mitochondrial deoxyribonucleic acid sequencing were non-diagnostic. Neither twin has been admitted with metabolic acidosis nor ethylene glycol poisoning since chronic hemodialysis was started. Twin A developed a calcium oxalate dihydrate lithiasis. Mitochondrial disease, methylmalonic/propionic/isovaleric aciduria, primary hyperoxaluria, and analyte error were all excluded in these twins, as were obvious common environmental exposures. Detailed investigations were performed in adult monozygotic twin sisters to ascertain whether they were producing endogenous ethylene glycol. Alternative explanations were excluded to the very best of our efforts and knowledge. Global metabolomics, gut microbiome analyses, and whole genome sequencing are pending.

据我们所知，临床意义上的内源性乙二醇（ethylene glycol）生成在人类中从未有过报道，在其他动物或微生物中亦鲜有报道，且仅在极罕见且特定的条件下才会出现。本文报道了我们对两名成年同卵双胞胎姐妹开展的详细研究，以确认她们是否会产生内源性乙二醇。两名此前身体健康的成年同卵双胞胎姐妹在35岁时开始出现反复发作的疑似乙二醇中毒症状，需长期接受血液透析以清除乙二醇及其代谢产物，并恢复代谢稳态。两名姐妹均否认摄入或接触过乙二醇。应她们的要求，两人入院接受严格监管，以排除偷偷摄入乙二醇的可能，并评估治疗需求。本前瞻性研究期间未进行血液透析。双胞胎A入院14天，双胞胎B入院11天。我们对其血液和尿液开展了系列生化分析，同时完成了临床外显子组测序与线粒体脱氧核糖核酸（mitochondrial deoxyribonucleic acid）测序。在两名双胞胎的尿液中均检测到乙二醇，同时血液和/或尿液中的乳酸、乙醇酸与甘氨酸浓度出现间歇性升高。不过，血液中的乙二醇浓度始终低于62mg/L（<1mmol/L），但在出院后很快转为阳性。血液和尿液中的草酸浓度均保持正常。血浆与尿液氨基酸谱显示，甘氨酸、丝氨酸、牛磺酸、脯氨酸和/或丙氨酸浓度出现间歇性小幅升高。外显子组测序与线粒体脱氧核糖核酸测序均未获得诊断性结果。自启动长期血液透析治疗以来，两名双胞胎均未再因代谢性酸中毒或乙二醇中毒入院。双胞胎A罹患二水草酸钙结石症。我们已排除这对双胞胎罹患线粒体疾病、甲基丙二酸/丙酸/异戊酸血症、原发性高草酸尿症以及分析物检测误差的可能，同时也排除了常见的明确环境暴露因素。我们针对这两名成年同卵双胞胎姐妹开展了详细研究，以确认她们是否会产生内源性乙二醇。我们已尽己所能并结合现有认知，排除了所有其他可能的解释。全局代谢组学（global metabolomics）、肠道微生物组分析（gut microbiome analyses）及全基因组测序（whole genome sequencing）仍在开展中。