Combined isobutyryl‐CoA and multiple acyl‐CoA dehydrogenase deficiency in a boy with altered riboflavin homeostasis

Abstract

In this report, we describe the case of an 11-year-old boy, who came to our attention for myalgia and muscle weakness, associated with inappetence and vomiting. Hypertransaminasemia was also noted, with ultrasound evidence of hepatomegaly. Biochemical investigations revealed acylcarnitine and organic acid profiles resembling those seen in MADD, that is, multiple acyl-CoA dehydrogenase deficiencies (OMIM #231680) a rare inherited disorder of fatty acids, amino acids, and choline metabolism. The patient carried a single pathogenetic variant in the ETFDH gene (c.524G>A, p.Arg175His) and no pathogenetic variant in the riboflavin (Rf) homeostasis related genes (SLC52A1, SLC52A2, SLC52A3, SLC25A32, FLAD1). Instead, compound heterozygosity was found in the ACAD8 gene (c.512C>G, p.Ser171Cys; c.822C>A, p.Asn274Lys), coding for isobutyryl-CoA dehydrogenase (IBD), whose pathogenic variants are associated to IBD deficiency (OMIM #611283), a rare autosomal recessive disorder of valine catabolism. The c.822C>A was never previously described in a patient. Subsequent further analyses of Rf homeostasis showed reduced

New insights into the nutritional genomics of adult-onset riboflavin-responsive diseases

“…The precise molecular mechanisms underpinning the flavo-enzyme variants described herein that lead to the range of late-onset riboflavin-responsive pathologies remains unclear. Very few individuals who exhibit riboflavin-responsiveness demonstrate riboflavin deficiency [ 86 , 87 ]. However, at least in part, FAD appears to function as a chemical chaperone that is important for correct flavo-enzyme folding and stability.…”