Variants in the Ethylmalonyl-CoA Decarboxylase (ECHDC1) Gene; a Novel Player in Ethylmalonic Aciduria?

TY - JOUR

T1 - Variants in the Ethylmalonyl-CoA Decarboxylase (ECHDC1) Gene; a Novel Player in Ethylmalonic Aciduria?

AU - Fogh, Sarah

AU - Dipace, Graziana

AU - Bie, Anne

AU - Veiga-da-Cunha, Maria

AU - Hansen, Jakob

AU - Kjeldsen, Margrethe

AU - Mosegaard, Signe

AU - Ribes, Antonia

AU - Gregersen, Niels

AU - Aagaard, Lars

AU - Schaftingen, Emile Van

AU - Olsen, Rikke K J

N1 - This article is protected by copyright. All rights reserved.

PY - 2021/9

Y1 - 2021/9

N2 - 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.

AB - 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.

KW - digenic inheritance

KW - ethylmalonic aciduria (EMA)

KW - ethylmalonyl-CoA decarboxylase (ECHDC1)

KW - short-chain acyl-CoA dehydrogenase (SCAD)

KW - synergistic heterozygosity

KW - GENOTYPE

KW - PHENOTYPE

KW - CREATINE-KINASE ACTIVITY

KW - DEHYDROGENASE

KW - CHAIN

KW - SEQUENCE

KW - MOLECULAR PATHOGENESIS

KW - MUTATIONS

KW - INHERITANCE

U2 - 10.1002/jimd.12394

DO - 10.1002/jimd.12394

M3 - Journal article

C2 - 33973257

SN - 0141-8955

VL - 44

SP - 1215

EP - 1225

JO - Journal of Inherited Metabolic Disease

JF - Journal of Inherited Metabolic Disease

IS - 5

ER -