Reversible Infantile Respiratory Chain Deficiency: A Clinical and Molecular Study
Reversible Infantile Respiratory Chain Deficiency: A Clinical and Molecular Study
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DOI：
10.1002/ana.22111
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发表时间：
2010-12-01
影响因子：
11.2
通讯作者：
Goto, Yu-ichi
中科院分区：
文献类型：
--
作者：
Mimaki, Masakazu;Hatakeyama, Hideyuki;Goto, Yu-ichi
目的：探讨良性细胞色素C氧化酶缺乏性肌病的临床特点及致病机制。6名患者接受了肌肉活组织检查，8名患者全部接受了线粒体DNA分析。为了证实检测到的线粒体DNA突变的致病性，我们利用肌肉标本进行了Northern杂交分析，并对传递线粒体细胞系(囊虫)进行了蓝色天然聚丙烯酰胺凝胶电泳法和呼吸链酶活性测定。结果：所有病例的临床症状都局限于骨骼肌，并自发改善，但2例兄弟姐妹有基底节损害。在所有患者中，我们发现了一种同质m.14674T>；C或m.14674T>；G线粒体转移RNA-谷氨酸突变。Northern印迹分析显示线粒体转移RNA-谷氨酸分子水平降低。来自患者的肌肉标本和杂交体显示呼吸复合体IV和/或I，III活性降低；然而，这在幼稚的成肌细胞中是正常的。解释：除了m.14674T和GT；C之外，鉴定出一个新的m.14674T和GT；G突变，表明该位点对疾病病因的重要性。对线虫的分析揭示了m.14674T和Gt；C突变的致病性，该突变导致细胞色素C氧化酶和多个呼吸链酶的缺陷。此外，基底节病变的患者为这种疾病提供了新的见解，在这种疾病中，只有骨骼肌被认为受到影响。幼稚成肌细胞呼吸链酶活性正常提示核因子的代偿作用，这可能为了解携带该突变的家系自发恢复和低外显性的机制提供线索。Ann Neurol 2010；68：845-854
Objective: To character ze the clinical features and clarify the pathogenicity of "benign cytochrome c oxidase deficiency myopathy."Methods: The study included 8 patients with the phenotype of this disease. Six patients underwent muscle biopsies and all the 8 underwent mitochondrial DNA analyses. To confirm the pathogenicity of the detected mitochondrial DNA mutation, we performed northern blot analysis, using muscle specimens, and blue native polyacrylamide gel electrophoresis and respiratory chain enzyme activity assay of transmitochondrial cell lines (cybrids).Results: Clinical symptoms were limited to skeletal muscle and improved spontaneously in all cases; however, 2 siblings had basal ganglia lesions. In all patients, we identified a homoplasmic m.14674T>C or m.14674T>G mitochondrial transfer RNA-glutamate mutation. Northern blot analysis revealed decreased levels of mitochondrial transfer RNA-glutamate molecules. Muscle specimens and cybrids derived from patients showed decreased activity of respiratory complexes IV, and/or I, III; however, this was normal in naive myoblasts.Interpretation: Identification of a novel m.14674T>G mutation in addition to m.14674T>C indicated the importance of this site for disease causation. Analyses of cybrids revealed the pathogenicity of m.14674T>C mutation, which resulted in defects of cytochrome c oxidase and multiple respiratory chain enzymes. Furthermore, patients with basal ganglia lesions provided new insights into this disease, in which only skeletal muscle was thought to be affected. Normal respiratory chain enzyme activities in naive myoblasts suggested the compensatory influence of nuclear factors, which may be clue to understanding the mechanisms of spontaneous recovery and low penetrance in families carrying the mutation. ANN NEUROL 2010;68:845-854