Hyperhomocysteinemia in patients with riboflavin‐responsive multiple acyl‐CoA dehydrogenase deficiency

Abstract Introduction/Aims Riboflavin‐responsive multiple acyl‐CoA dehydrogenase deficiency (RR‐MADD) is an autosomal recessive disease chiefly caused by variants of ETFDH affecting fatty acid metabolism. In our cohort, hyperhomocysteinemia (HHcy) was common. In this study we aimed to identify the association between RR‐MADD and HHcy. Methods We performed a retrospective review of 13 patients with RR‐MADD. Thirty‐three healthy controls were recruited, and logistic regression was used to investigate the association between RR‐MADD and HHcy. Muscle tissues from six patients and six controls without myopathies were collected to measure the levels of flavin adenine dinucleotide (FAD), an active form of riboflavin. Whole‐exome sequencing was performed to identify the disease‐associated variants. Results The RR‐MADD patients had a higher prevalence of HHcy (9 of 12) than controls (6 of 33, P < .001). In the multivariate analysis, RR‐MADD was positively related to HHcy ( P = .014). Muscular FAD levels were decreased in RR‐MADD patients ( P = .006). Thirteen variants (8 reported and 5 novel) were identified in ETFDH. Of these, c.250G > A was the most common pathogenic variant with an allelic frequency of 4 of 20. Discussion HHcy was associated with RR‐MADD and may aid in the diagnosis of the disease. Our findings expand the mutational spectrum of RR‐MADD.