Ethylmalonic acid (EMA) is a major and potentially cytotoxic metabolite associated with short-chain acyl-CoA dehydrogenase (SCAD) deficiency, a condition whose status as a disease is uncertain. Unexplained high EMA is observed in some individuals with complex neurological symptoms, who carry the SCAD gene (ACADS) variants, c.625G>A and c.511C>T. The variants have a high allele frequency in the general population, but are significantly overrepresented in individuals with elevated EMA. This has led to the idea that these variants need to be associated with variants in other genes to cause hyperexcretion of ethylmalonic acid and possibly a diseased state. Ethylmalonyl-CoA decarboxylase (ECHDC1) has been described and characterized as an EMA metabolite repair enzyme, however, its clinical relevance has never been investigated. In this study, we sequenced the ECHDC1 gene (ECHDC1) in 82 individuals, who were reported with unexplained high EMA levels due to the presence of the common ACADS variants only. Three individuals with ACADS c.625G>A variants were found to be heterozygous for ECHDC1 loss-of-function variants. Knockdown experiments of ECHDC1, in healthy human cells with different ACADS c.625G>A genotypes, showed that ECHDC1 haploinsufficiency and homozygosity for the ACADS c.625G>A variant had a synergistic effect on cellular EMA excretion. This study reports the first cases of ECHDC1 gene defects in humans and suggests that ECHDC1 may be involved in elevated EMA excretion in only a small group of individuals with the common ACADS variants. However, a direct link between ECHDC1/ACADS deficiency, EMA and disease could not be proven.

中文翻译：

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乙基丙二酰辅酶A脱羧酶（ECHDC1）基因的变异体：乙基丙二酸尿症的新参与者？

乙基丙二酸 (EMA) 是一种与短链酰基辅酶 A 脱氢酶 (SCAD) 缺乏相关的主要且具有潜在细胞毒性的代谢物，这种疾病的疾病状态尚不确定。在一些携带 SCAD 基因（ACADS) 变体，c.625G>A 和 c.511C>T。这些变体在一般人群中具有较高的等位基因频率，但在 EMA 升高的个体中明显过多。这导致了这样一种想法，即这些变异需要与其他基因中的变异相关联，以导致乙基丙二酸的过度排泄，并可能导致疾病状态。乙基丙二酰辅酶 A 脱羧酶 (ECHDC1) 已被描述为一种 EMA 代谢物修复酶，但从未对其临床相关性进行过研究。在这项研究中，我们对 82 名个体的 ECHDC1 基因 ( ECHDC1 ) 进行了测序，据报道，由于仅存在常见的ACADS变体，这些人的 EMA 水平无法解释的高。三个患有ACADS的人c.625G>A 变体被发现是ECHDC1功能丧失变体的杂合子。ECHDC1在具有不同ACADS c.625G>A 基因型的健康人类细胞中的敲低实验表明，ACADS c.625G>A 变体的ECHDC1单倍体不足和纯合性对细胞 EMA 排泄具有协同作用。该研究报告了人类 ECHDC1 基因缺陷的第一例病例，并表明ECHDC1可能仅在一小部分具有常见ACAD变体的个体中与 EMA 排泄升高有关。然而，ECHDC1 / ACAD之间的直接联系 缺乏，EMA和疾病不能被证明。