We hypothesize that a possible underlying mechanism is gene-environment interactions, that is the residual ETFDH enzyme activity caused by the single heterozygous variations in ETFDH with stronger pathogenicity would be further reduced below the threshold under the influence of environmental factors, ultimately leading to the manifestation of the MADD phenotype. The gene discussed is ETFDH; the disease is multiple acyl-CoA dehydrogenase deficiency.