Hepatic Presentation of Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD): Case Report and Systematic Review

Abstract

Diagnosis of pediatric steatohepatitis is a challenging issue due to a vast number of established and novel causes. Here, we report a child with Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) presenting with an underrated muscle weakness, exercise intolerance and an atypically severe steatotic liver involvement. A systematic literature review of liver involvement in MADD was performed as well. Our patient is a 11-year-old otherwise healthy, non-obese, male child admitted for some weakness/asthenia, vomiting and recurrent severe hypertransaminasemia (aspartate and alanine aminotransferases up to ×20 times upper limit of normal). Hepatic ultrasound showed a bright liver. MRI detected mild lipid storage of thighs muscles. A liver biopsy showed a micro-macrovacuolar steatohepatitis with minimal fibrosis. Main causes of hypertransaminasemia were ruled out. Serum aminoacids (increased proline), acylcarnitines (increased C4-C18) and a large excretion of urinary glutaric acid, ethylmalonic, butyric, isobutyric, 2-methyl-butyric and isovaleric acids suggested a diagnosis of MADD. Serum acylcarnitines and urinary organic acids fluctuated overtime paralleling serum transaminases during periods of illness/catabolic stress, confirming their recurrent nature. Genetic testing confirmed the diagnosis [homozygous c.1658A > G (p.Tyr553Cys) in exon 12 of the ETFDH gene]. Lipid-restricted diet and riboflavin treatment rapidly ameliorated symptoms, hepatic ultrasonography/enzymes, and metabolic profiles. Literature review (37 retrieved eligible studies, 283 patients) showed that liver is an extramuscular organ rarely involved in late-onset MADD (70 patients), and that amongst 45 patients who had fatty liver only nine had severe presentation.Conclusion: MADD is a disorder with a clinically heterogeneous phenotype. Our study suggests that MADD warrants consideration in the work-up of obesity-unrelated severe steatohepatitis.

Stealthy progression of type 2 diabetes mellitus due to impaired ketone production in an adult patient with multiple acyl-CoA dehydrogenase deficiency

“…Second, the presence of non-alcoholic fatty liver disease (NAFLD) is also a known risk factor for T2DM [ 20 , 21 ]. NAFLD is observed in a smaller proportion of patients with MADD [ 22 ], while our patient had this finding, as confirmed by both ultrasound and CT scan. Finally, excessive consumption of sugar-containing soft drinks is a recognized risk factor for the onset of diabetic ketosis which may present as an initial manifestation of non-insulin dependent diabetes mellitus [ 12 ].…”

Differential requirements for mitochondrial electron transport chain components in the adult murine liver

“…In humans, mutations in proteins of the ETF complex are causative for glutaric acidemia type II disease (also known as multiply acyl-CoA dehydrogenase deficiency), which has similar biochemical abnormalities as our Cox10 -/- animal model ( Frerman and Goodman, 1985 ; Grünert, 2014 ). The clinical progression of these patients can be variable; however, patients with hepatic involvement exhibit hepatic steatosis, elevated ALT/AST levels and periodic hypoglycemia ( Siano et al, 2021 ). In addition, mice carrying a knock-in ETFDH mutation displayed diet-dependent phenotypes, including hepatic steatosis and elevated levels of acyl-carnitine species ( Xu et al, 2018 ).…”

Differential requirements for mitochondrial electron transport chain components in the adult murine liver

“…In humans, mutations in proteins of the ETF complex are causative for glutaric acidemia type II disease (also known as multiply acyl-CoA dehydrogenase deficiency), which has similar biochemical abnormalities ( 48, 49 ). The clinical progression of these patients can be variable; however, patients with hepatic involvement exhibit hepatic steatosis, elevated ALT/AST levels and periodic hypoglycemia ( 50 ). In addition, mice carrying a knock-in ETFDH mutation displayed diet-dependent phenotypes, including hepatic steatosis and elevated levels of acyl-carnitine species ( 51 ).…”