Das Anibh M, Illsinger Sabine, Lücke Thomas, Hartmann Hans, Ruiter Jos P N, Steuerwald Ulrike, Waterham Hans R, Duran Marinus, Wanders Ronald J A
Department of Paediatrics, Hannover Medical School, Hannover, Germany.
Clin Chem. 2006 Mar;52(3):530-4. doi: 10.1373/clinchem.2005.062000. Epub 2006 Jan 19.
The human mitochondrial trifunctional protein (MTP) complex is composed of 4 hydroacyl-CoA dehydrogenase-alpha (HADHA) and 4 hydroacyl-CoA dehydrogenase-beta (HADHB) subunits, which catalyze the last 3 steps in the fatty acid beta-oxidation spiral of long-chain fatty acids. The HADHB gene encodes long-chain ketoacyl-CoA thiolase (LCTH) activity, whereas the HADHA gene contains the information for the long-chain enoyl-CoA hydratase and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) functions. At present, 2 different biochemical phenotypes of defects in the mitochondrial trifunctional protein complex are known: isolated LCHAD deficiency and generalized MTP deficiency, with decreased activities of all 3 enzymes. Isolated LCTH deficiency with mutations in the HADHB gene has not been reported.
We report a male newborn who presented with lactic acidosis, pulmonary edema, and cardiomyopathy leading to acute heart failure and death at the age of 6 weeks. Routine newborn screening by tandem mass spectrometry showed increased concentrations of the acylcarnitines tetradecenoylcarnitine, hexadecenoylcarnitine, hydroxypalmitoylcarnitine, and hydroxyoctadecenoylcarnitine, suggesting LCHAD deficiency or complete MTP deficiency. Enzyme investigations revealed very low LCTH (4% of normal) and normal LCHAD activities, whereas molecular analysis showed compound heterozygosity for 185G > A (R62H) and 1292T > C (F431S) mutations in the HADHB gene.
We describe the first case of isolated LCTH deficiency based on a mutation in the HADHB gene.
人线粒体三功能蛋白（MTP）复合物由4个α-羟酰基辅酶A脱氢酶（HADHA）亚基和4个β-羟酰基辅酶A脱氢酶（HADHB）亚基组成，它们催化长链脂肪酸β-氧化螺旋中的最后3步反应。HADHB基因编码长链酮酰基辅酶A硫解酶（LCTH）活性，而HADHA基因包含长链烯酰基辅酶A水合酶和长链3-羟酰基辅酶A脱氢酶（LCHAD）功能的信息。目前，已知线粒体三功能蛋白复合物缺陷有2种不同的生化表型：孤立性LCHAD缺乏症和全身性MTP缺乏症，所有3种酶的活性均降低。尚未有关于HADHB基因突变导致孤立性LCTH缺乏症的报道。
我们报告了一名男性新生儿，其出现乳酸酸中毒、肺水肿和心肌病，导致6周龄时急性心力衰竭并死亡。串联质谱法进行的常规新生儿筛查显示酰基肉碱十四碳烯酰肉碱、十六碳烯酰肉碱、羟基棕榈酰肉碱和羟基十八碳烯酰肉碱浓度升高，提示LCHAD缺乏症或完全性MTP缺乏症。酶学研究显示LCTH活性极低（为正常的4%）而LCHAD活性正常，而分子分析显示HADHB基因存在185G>A（R62H）和1292T>C（F431S）突变的复合杂合性。
我们描述了首例基于HADHB基因突变的孤立性LCTH缺乏症病例。
