SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness
SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness
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DOI：
10.1093/brain/awl389
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发表时间：
2007-03-01
期刊：
影响因子：
14.5
通讯作者：
Wevers, Ron A.
中科院分区：
文献类型：
--
作者：
Carrozzo, Rosalba;Dionisi-Vici, Carlo;Wevers, Ron A.
最近报道了一个有4名患者的家系，其线粒体DNA缺失和SUCLA 2基因突变导致琥珀酰辅酶A合酶缺乏症。患者有Leigh样脑肌病和耳聋，但除了存在乳酸酸中毒外，未报告尿有机酸的特征。我们研究了14例轻度'未标记'甲基丙二酸尿症（MMA）从11个家庭。其中八个家庭来自法罗群岛，有一个共同的祖先，三个来自意大利南部。由于琥珀酰辅酶A合酶在三羧酸（TCA）循环中催化的反应代表了甲基丙二酸途径的远端步骤，我们研究了SUCLA 2基因作为我们患者的候选基因。对14名患者的基因进行遗传分析证实了所有患者的缺陷，并鉴定出三种新的突变（p.Gly118Arg; p.Arg284Cys; c.534 + 1G -> A）。该缺陷可以令人信服地显示在蛋白质水平上，我们的数据也证实了先前描述的线粒体DNA缺失。SUCLA 2缺陷可在代谢物水平发现，定义为与可变乳酸酸中毒相关的体液中甲基丙二酸和C4-二羧酸肉毒碱浓度轻度升高。临床上，诊断应考虑在早期/新生儿发病脑肌病，肌张力障碍，耳聋和Leigh样MRI异常，主要影响壳核和尾状核的患者。法罗群岛人群中突变等位基因的频率为2%，估计纯合子频率为1：2500。我们的数据扩展了关于导致MMA的遗传缺陷的知识。我们的病人表现为早期婴儿型Leigh样脑肌病伴耳聋，后来出现进行性肌张力障碍。轻度MMA、乳酸酸中毒和肉毒碱酯谱的特定异常是该疾病的生化标志。鉴于法罗群岛上突变等位基因的频率，采取措施预防该疾病在岛上的发生是可行的。我们确认并扩展了TCA循环中这种先天性代谢错误的研究结果，必须通过准确的代谢物分析进行仔细研究。
One pedigree with four patients has been recently described with mitochondrial DNA depletion and mutation in SUCLA2 gene leading to succinyl-CoA synthase deficiency. Patients had a Leigh-like encephalomyopathy and deafness but besides the presence of lactic acidosis, the profile of urine organic acid was not reported. We have studied 14 patients with mild 'unlabelled' methylmalonic aciduria (MMA) from 11 families. Eight of the families are from the Faroe Islands, having a common ancestor, and three are from southern Italy. Since the reaction catalysed by succinyl-CoA synthase in the tricarboxylic acid (TCA) cycle represents a distal step of the methylmalonic acid pathway, we investigated the SUCLA2 gene as a candidate gene in our patients. Genetic analysis of the gene in the 14 patients confirmed the defect in all patients and led to the identification of three novel mutations (p.Gly118Arg; p.Arg284Cys; c.534 + 1G -> A). The defect could be convincingly shown at the protein level and our data also confirm the previously described mitochondrial DNA depletion. Defects in SUCLA2 can be found at the metabolite level and are defined by mildly elevated methylmalonic acid and C4-dicarboxylic carnitine concentrations in body fluids in association with variable lactic acidosis. Clinically the diagnosis should be considered in patients with early/neonatal onset encephalomyopathy, dystonia, deafness and Leigh-like MRI abnormalities mainly affecting the putamen and the caudate nuclei. The frequency of the mutated allele in the Faroese population amounted to 2%, corresponding with an estimated homozygote frequency of 1 : 2500. Our data extend knowledge on the genetic defects causing MMA. Our patients present with an early infantile Leigh-like encephalomyopathy with deafness, and later on a progressive dystonia. Mild MMA, lactic acidosis and specific abnormalities in the carnitine ester profile are the biochemical hallmarks of the disease. In view of the frequency of the mutated allele on the Faroe Islands, measures become feasible to prevent the occurrence of the disease on the islands. We confirm and extend the findings on this inborn error of metabolism in the TCA cycle that must be carefully investigated by accurate metabolite analyses.