Oey Nadia A, den Boer Margarethe E J, Wijburg Frits A, Vekemans Michel, Augé Joëlle, Steiner Céline, Wanders Ronald J A, Waterham Hans R, Ruiter Jos P N, Attié-Bitach Tania
Department of Pediatrics, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Pediatr Res. 2005 Jun;57(6):755-9. doi: 10.1203/01.PDR.0000161413.42874.74. Epub 2005 Apr 21.
Patients with very long-chain acyl-CoA dehydrogenase (VLCAD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)/mitochondrial trifunctional protein (MTP) deficiency, disorders of the mitochondrial long-chain fatty acid oxidation, can present with hypoketotic hypoglycemia, rhabdomyolysis, and cardiomyopathy. In addition, patients with LCHAD/MTP deficiency may suffer from retinopathy and peripheral neuropathy. Until recently, there was no indication of intrauterine morbidity in these disorders. This observation was in line with the widely accepted view that fatty acid oxidation (FAO) does not play a significant role during fetal life. However, the high incidence of the gestational complications acute fatty liver of pregnancy and hemolysis, elevated liver enzymes, and low platelets syndrome observed in mothers carrying a LCHAD/MTP-deficient child and the recent reports of fetal hydrops due to cardiomyopathy in MTP deficiency, as well as the high incidence of intrauterine growth retardation in children with LCHAD/MTP deficiency, suggest that FAO may play an important role during fetal development. In this study, using in situ hybridization of the VLCAD and the LCHAD mRNA, we report on the expression of genes involved in the mitochondrial oxidation of long-chain fatty acids during early human development. Furthermore, we measured the enzymatic activity of the VLCAD, LCHAD, and carnitine palmitoyl-CoA transferase 2 (CPT2) enzymes in different human fetal tissues. Human embryos (at d 35 and 49 of development) and separate tissues (5-20 wk of development) were used. The results show a strong expression of VLCAD and LCHAD mRNA and a high enzymatic activity of VLCAD, LCHAD, and CPT2 in a number of tissues, such as liver and heart. In addition, high expression of LCHAD mRNA was observed in the neural retina and CNS. The observed pattern of expression during early human development is well in line with the spectrum of clinical signs and symptoms reported in patients with VLCAD or LCHAD/MTP deficiency.
患有极长链酰基辅酶A脱氢酶（VLCAD）和长链3-羟酰基辅酶A脱氢酶（LCHAD）/线粒体三功能蛋白（MTP）缺乏症（线粒体长链脂肪酸氧化障碍）的患者，可能会出现低酮性低血糖、横纹肌溶解和心肌病。此外，LCHAD/MTP缺乏症患者可能患有视网膜病变和周围神经病变。直到最近，这些疾病尚无宫内发病的迹象。这一观察结果与脂肪酸氧化（FAO）在胎儿期不发挥重要作用这一广泛接受的观点一致。然而，在携带LCHAD/MTP缺陷患儿的母亲中观察到的妊娠并发症——妊娠急性脂肪肝和溶血、肝酶升高及血小板减少综合征的高发病率，以及近期关于MTP缺乏导致胎儿水肿性心肌病的报道，还有LCHAD/MTP缺乏症患儿宫内生长迟缓的高发病率，都表明FAO可能在胎儿发育过程中发挥重要作用。在本研究中，我们通过对VLCAD和LCHAD mRNA进行原位杂交，报告了人类早期发育过程中参与线粒体长链脂肪酸氧化的基因表达情况。此外，我们还测量了不同人类胎儿组织中VLCAD、LCHAD和肉碱棕榈酰辅酶A转移酶2（CPT2）的酶活性。使用了人类胚胎（发育第35天和49天）及不同组织（发育5 - 20周）。结果显示，VLCAD和LCHAD mRNA在许多组织（如肝脏和心脏）中有强烈表达，VLCAD、LCHAD和CPT2具有高酶活性。此外，在神经视网膜和中枢神经系统中观察到LCHAD mRNA的高表达。在人类早期发育过程中观察到的表达模式与VLCAD或LCHAD/MTP缺乏症患者报告的临床体征和症状谱非常一致。
