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.
Highlights
CASE REPORTMultiple acyl-CoA dehydrogenase deficiency (MADD, MIM #231680), known as Glutaric aciduria type II, is a rare autosomal recessive inherited disorder of fatty acid, amino acid, and choline metabolism
Our study suggests that Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) warrants consideration in the work-up of obesity-unrelated severe steatohepatitis
It is caused by deficiency of either an electron-transfer flavoprotein (ETF, encoded by ETFA and ETFB genes) or an electrontransfer flavoprotein dehydrogenase (ETFDH, encoded by ETFDH gene)
Summary
Multiple acyl-CoA dehydrogenase deficiency (MADD, MIM #231680), known as Glutaric aciduria type II, is a rare autosomal recessive inherited disorder of fatty acid, amino acid, and choline metabolism. The proband was a 12-year-old otherwise healthy child admitted for some weakness/asthenia along with episodes of vomiting, and recently discovered severe hypertransaminasemia [alanine aminotransferase (ALT) and aspartate aminotransferase (AST) × 20 times upper limit of normal (uln)]. Laboratory showed hypertransaminasemia and increased serum values of creatine phosphokinase (CK) and lactic dehydrogenase (LDH) (ALT × 30 uln, AST × 20 uln, CK × 13 uln, and LDH × 6 uln), neutropenia (values at the entrance: WBC 3310/μL, N 650/μL) and positive serology of Parvovirus B19 infection [IgG 52,7 (positive if >11,5); IgM 98,5 (positive if >11,5)] He was discharged after 10 days, following a sharp reduction of the values of serum enzymes and neutrophils normalization. Repeat 6 min walking test showed no/minimal fatigue after 2 months (oxygen saturation 100%, heart frequency 150 beats per FIGURE 2 | (A) Fluctuating trend of Aspartate (AST) and Alanine (ALT) aminotransferases from the onset of the symptoms to the present moment. Control Magnetic Resonance Imaging, after 10 months of therapy, showed absent/sharp decrease of lipid storage of thighs muscles (Figure 1D)
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