Huang Xiaoping, Bedoyan Jirair K, Demirbas Didem, Harris David J, Miron Alexander, Edelheit Simone, Grahame George, DeBrosse Suzanne D, Wong Lee-Jun, Hoppel Charles L, Kerr Douglas S, Anselm Irina, Berry Gerard T
Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA.
Center for Human Genetics, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA; Center for Inherited Disorders of Energy Metabolism (CIDEM), University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA.
Mol Genet Metab. 2017 Mar;120(3):213-222. doi: 10.1016/j.ymgme.2016.11.005. Epub 2016 Nov 12.
Mutations in SUCLA2 result in succinyl-CoA ligase (ATP-forming) or succinyl-CoA synthetase (ADP-forming) (A-SCS) deficiency, a mitochondrial tricarboxylic acid cycle disorder. The phenotype associated with this gene defect is largely encephalomyopathy. We describe two siblings compound heterozygous for SUCLA2 mutations, c.985A>G (p.M329V) and c.920C>T (p.A307V), with parents confirmed as carriers of each mutation. We developed a new LC-MS/MS based enzyme assay to demonstrate the decreased SCS activity in the siblings with this unique genotype. Both siblings shared bilateral progressive hearing loss, encephalopathy, global developmental delay, generalized myopathy, and dystonia with choreoathetosis. Prior to diagnosis and because of lactic acidosis and low activity of muscle pyruvate dehydrogenase complex (PDC), sibling 1 (S1) was placed on dichloroacetate, while sibling 2 (S2) was on a ketogenic diet. S1 developed severe cyclic vomiting refractory to therapy, while S2 developed Leigh syndrome, severe GI dysmotility, intermittent anemia, hypogammaglobulinemia and eventually succumbed to his disorder. The mitochondrial DNA contents in skeletal muscle (SM) were normal in both siblings. Pyruvate dehydrogenase complex, ketoglutarate dehydrogenase complex, and several mitochondrial electron transport chain (ETC) activities were low or at the low end of the reference range in frozen SM from S1 and/or S2. In contrast, activities of PDC, other mitochondrial enzymes of pyruvate metabolism, ETC and, integrated oxidative phosphorylation, in skin fibroblasts were not significantly impaired. Although we show that propionyl-CoA inhibits PDC, it does not appear to account for decreased PDC activity in SM. A better understanding of the mechanisms of phenotypic variability and the etiology for tissue-specific secondary deficiencies of mitochondrial enzymes of oxidative metabolism, and independently mitochondrial DNA depletion (common in other cases of A-SCS deficiency), is needed given the implications for control of lactic acidosis and possible clinical management.
SUCLA2基因突变会导致琥珀酰辅酶A连接酶（生成ATP）或琥珀酰辅酶A合成酶（生成ADP）（A-SCS）缺乏，这是一种线粒体三羧酸循环障碍。与该基因缺陷相关的表型主要是脑肌病。我们描述了两名携带SUCLA2基因突变c.985A>G（p.M329V）和c.920C>T（p.A307V）的复合杂合子同胞，其父母被确认为每个突变的携带者。我们开发了一种基于液相色谱-串联质谱的新酶检测方法，以证明具有这种独特基因型的同胞中SCS活性降低。两名同胞均患有双侧进行性听力丧失、脑病、全面发育迟缓、全身性肌病以及伴有舞蹈手足徐动症的肌张力障碍。在诊断之前，由于乳酸酸中毒和肌肉丙酮酸脱氢酶复合体（PDC）活性低下，同胞1（S1）接受了二氯乙酸治疗，而同胞2（S2）采用了生酮饮食。S1出现了对治疗无效的严重周期性呕吐，而S2则患上了 Leigh 综合征、严重的胃肠动力障碍、间歇性贫血、低丙种球蛋白血症，最终死于该疾病。两名同胞的骨骼肌（SM）中线粒体DNA含量均正常。在S1和/或S2的冷冻SM中，丙酮酸脱氢酶复合体、酮戊二酸脱氢酶复合体以及几种线粒体电子传递链（ETC）的活性较低或处于参考范围的下限。相比之下，皮肤成纤维细胞中PDC、丙酮酸代谢的其他线粒体酶、ETC以及整合的氧化磷酸化活性并未受到明显损害。尽管我们表明丙酰辅酶A会抑制PDC，但这似乎并不能解释SM中PDC活性降低的原因。鉴于对乳酸酸中毒控制和可能的临床管理的影响，需要更好地了解表型变异性的机制以及氧化代谢线粒体酶组织特异性继发性缺乏的病因，以及独立的线粒体DNA耗竭（在其他A-SCS缺乏病例中常见）。
