PET/CT and exome sequencing in late onset multiple acyl-CoA dehydrogenase deficiency: a case series and literature review

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare autosomal recessive disorder. Riboflavin-responsive MADD (RR-MADD) represents a treatable subtype, though its molecular mechanisms are incompletely characterized. Two patients presented to department of Rheumatology, the 3rd Affiliated Hospital of Sun Yet-sen University with progressive proximal muscle weakness. A 2-fluorine-18-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan revealed marked metabolic hyperactivity in cervical and paraspinal muscles. Histopathology confirmed lipid storage myopathy, and exome sequencing (ES) identified electron transfer flavoprotein dehydrogenase gene (ETFDH) mutations. Both patients harbored the common variant NM_004453.4:c.250G > A (p.Ala84Thr). Case 1 exhibited homozygosity for this variant and potential XYY syndrome, while Case 2 carried a compound heterozygous mutation including a novel frameshift variant, NM_004453.4: c.265_266del (p. Gln89Valfs*6), and concurrent SLC25A13 mutation linked to adult-onset citrullinemia type II. Riboflavin supplementation achieved complete biochemical remission in both cases. Retrospective analysis for previous reports of homozygous single-locus missense ETFDH gene mutations revealed that patients with mutations in the flavin adenine dinucleotide binding domain (FAD) or the iron-sulfur cluster domain (Fe-S) exhibited a better response to riboflavin and better prognosis. 18F-FDG PET/CT is a promising tool for evaluating myopathic involvement in MADD. ES enables rapid and comprehensive diagnosis of MADD and detection of coexisting genetic disorders. The prognosis is related to mutation forms, mutation pathogenicity, and the located structural domain.