Table_3_Hepatic Presentation of Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD): Case Report and Systematic Review.DOCX

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.

儿童脂肪性肝炎的诊断因众多已知及新发致病因素而极具挑战性。本文报告1例以易被忽视的肌无力、运动耐量减低及非典型性重度肝脏脂肪变受累为表现的多种酰基辅酶A脱氢酶缺乏症（Multiple Acyl-CoA Dehydrogenase Deficiency，MADD）患儿，同时针对MADD的肝脏受累情况开展了系统性文献回顾。

本例患者为11岁男性，平素体健、无肥胖病史，因乏力、呕吐及反复发作的重度高转氨酶血症（天冬氨酸转氨酶与丙氨酸转氨酶最高达正常值上限的20倍）入院。肝脏超声提示亮肝表现；磁共振成像（Magnetic Resonance Imaging，MRI）显示大腿肌肉存在轻度脂质沉积；肝活检结果提示为微囊泡性与大囊泡性混合的脂肪性肝炎，伴轻度纤维化。已排除高转氨酶血症的常见致病因素。

血清氨基酸检测显示脯氨酸升高，酰基肉碱检测显示C4-C18酰基肉碱升高，尿液中戊二酸、乙基丙二酸、丁酸、异丁酸、2-甲基丁酸及异戊酸大量排泄，上述检测结果支持MADD的诊断。在疾病发作/分解代谢应激期间，血清酰基肉碱与尿液有机酸水平随时间波动，且与血清转氨酶水平同步变化，证实了该病情的反复发作特性。基因检测最终确诊：ETFDH基因第12号外显子存在纯合突变c.1658A>G（p.Tyr553Cys）。

予以低脂饮食联合核黄素治疗后，患者症状、肝脏超声表现、转氨酶水平及代谢谱均快速得到改善。本次文献回顾共纳入37项符合纳入标准的研究、283例患者，结果显示：肝脏作为肌肉外器官，在迟发性MADD患者中极少受累（共70例迟发性MADD患者）；在45例合并脂肪肝的患者中，仅9例表现为重度肝脏受累。

结论：MADD是一种临床表型异质性极强的疾病。本研究提示，在排查与肥胖无关的重度脂肪性肝炎时，应将MADD纳入鉴别诊断范围。