Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients
Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients
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DOI：
10.1007/s10545-015-9894-9
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发表时间：
2016-03-01
影响因子：
4.2
通讯作者：
Ostergaard, Elsebet
中科院分区：
文献类型：
--
作者：
Carrozzo, Rosalba;Verrigni, Daniela;Ostergaard, Elsebet
背景脑肌病mtDNA耗竭综合征合并甲基丙二酸尿症与琥珀酸辅酶A连接酶缺陷有关，这种缺陷是由SUCLA2或SUCLG1突变引起的。我们报告了25例新的琥珀酸辅酶A连接酶缺乏症患者，回顾了这些患者和46例先前报道的患者的临床和分子表现。在71名患者中，50名患者有SUCLA2突变，21名患者有SUCLG1突变。在新报道的20例SUCLA2患者中，我们发现了16种不同的突变，其中9种是新发现的：两个大的基因缺失，一个1bp的重复，两个1bp的缺失，一个3bp的插入，一个无义突变和两个错义突变。在新报告的SUCLG1患者中，发现了五个错义突变，其中两个是新的。SUCLA2突变患者的中位症状出现时间为两个月，SUCLG1患者出生时的中位症状出现时间为两个月。SUCLA2和SUCLG1的中位生存期分别为20年和20个月。两组之间显著的临床差异是肝病，在SUCLG1患者中发现38%，但在SUCLA2患者中未发现；肥厚性心肌病，在SUCLG1突变患者中未见报道，但有14%。据报道，12%的SUCLA2患者和10%的SUCLG1患者可以长期存活到20岁或20岁以上。最常见的神经影像异常是基底节受累，在SUCLA2和SUCLG1患者中分别有69%和80%。对肌肉呼吸链酶活性的分析通常显示为复合体I和IV的联合缺陷，但肌肉中正常的组织学和生化结果并不排除琥珀酸辅酶A连接酶缺陷的诊断。在5名患者中，尿甲基丙二酸排泄量仅轻微升高，而血浆甲基丙二酸持续升高。结论据我们所知，这是对SUCLA2和SUCLG1缺乏症患者进行的最大规模的研究。最重要的发现是，与SUCLG1突变相比，SUCLA2突变患者的生存期显著延长，与功能丧失突变相比，错义突变患者的生存期有延长的趋势。肥厚性心肌病和肝脏受累仅见于SUCLG1突变的患者，而癫痫在SUCLA2突变的患者中比SUCLG1突变的患者更常见。突变分析揭示了一些新的突变，包括整个SUCLA2基因的纯合缺失，我们在斯堪的纳维亚人群中发现了两个创始人突变的证据，除了法罗群岛已知的SUCLA2创始人突变。
Background The encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria is associated with deficiency of succinate-CoA ligase, caused by mutations in SUCLA2 or SUCLG1. We report here 25 new patients with succinate-CoA ligase deficiency, and review the clinical and molecular findings in these and 46 previously reported patients.Patients and results Of the 71 patients, 50 had SUCLA2 mutations and 21 had SUCLG1 mutations. In the newly-reported 20 SUCLA2 patients we found 16 different mutations, of which nine were novel: two large gene deletions, a 1 bp duplication, two 1 bp deletions, a 3 bp insertion, a nonsense mutation and two missense mutations. In the newly-reported SUCLG1 patients, five missense mutations were identified, of which two were novel. The median onset of symptoms was two months for patients with SUCLA2 mutations and at birth for SUCLG1 patients. Median survival was 20 years for SUCLA2 and 20 months for SUCLG1. Notable clinical differences between the two groups were hepatopathy, found in 38 % of SUCLG1 cases but not in SUCLA2 cases, and hypertrophic cardiomyopathy which was not reported in SUCLA2 patients, but documented in 14 % of cases with SUCLG1 mutations. Long survival, to age 20 years or older, was reported in 12 % of SUCLA2 and in 10 % of SUCLG1 patients. The most frequent abnormality on neuroimaging was basal ganglia involvement, found in 69 % of SUCLA2 and 80 % of SUCLG1 patients. Analysis of respiratory chain enzyme activities in muscle generally showed a combined deficiency of complexes I and IV, but normal histological and biochemical findings in muscle did not preclude a diagnosis of succinate-CoA ligase deficiency. In five patients, the urinary excretion of methylmalonic acid was only marginally elevated, whereas elevated plasma methylmalonic acid was consistently found.Conclusions To our knowledge, this is the largest study of patients with SUCLA2 and SUCLG1 deficiency. The most important findings were a significantly longer survival in patients with SUCLA2 mutations compared to SUCLG1 mutations and a trend towards longer survival in patients with missense mutations compared to loss-of-function mutations. Hypertrophic cardiomyopathy and liver involvement was exclusively found in patients with SUCLG1 mutations, whereas epilepsy was much more frequent in patients with SUCLA2 mutations compared to patients with SUCLG1 mutations. The mutation analysis revealed a number of novel mutations, including a homozygous deletion of the entire SUCLA2 gene, and we found evidence of two founder mutations in the Scandinavian population, in addition to the known SUCLA2 founder mutation in the Faroe Islands.