Biochemical-clinical correlation in patients with different loads of the mitochondrial DNA T8993G mutation
Biochemical-clinical correlation in patients with different loads of the mitochondrial DNA T8993G mutation
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DOI：
10.1001/archneur.59.2.264
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发表时间：
2002-02-01
影响因子：
--
通讯作者：
Solaini, G
中科院分区：
文献类型：
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作者：
Carelli, V;Baracca, A;Solaini, G
目的：探讨T8993G突变异质性与神经病、共济失调和视网膜色素变性-Leigh综合征相关的3个无关家系的6例患者的生化和临床表型的相关性。方法：我们研究了血小板衍生的亚线粒体颗粒中的三磷酸腺苷合成酶活性(合成和水解)，并评估了用于生化分析的血小板和其他可用组织中的突变载量。生化和分子结果与临床特征相关，结果：线粒体DNA突变34%~90%的患者，ATP水解率正常，但ATP合成严重受损(剩余p活性的30%~4%)，没有任何证据表明这种缺陷的表达阈值。来自每个患者的组织之间的异质性几乎没有变化，但在两个母亲中检测到了更大的差异。异质性与临床和生化特征的相关性表明，当表型为神经病、共济失调和视网膜色素变性-Leigh综合征时，突变负荷低至34%时，ATP合成缺陷，当突变负荷超过80%时，ATP合成极度减少。结论：组织异质性、血小板生化缺陷的表达与临床参与密切相关。生化缺陷比之前报道的更严重，我们没有发现生化阈值的证据。高突变负荷在患者组织中的均匀分布表明，不同组织对线粒体ATP合成的依赖程度不同。
Objective: To investigate the correlation between biochemical and clinical phenotype in 6 patients from 3 unrelated families with different mutation loads (heteroplasmy) of the T8993G mitochondrial DNA mutation associated with neuropathy, ataxia, and retinitis pigmentosa-Leigh syndrome.Methods: We studied adenosine triphosphate (ATP) synthase activity (synthesis and hydrolysis) in platelet-derived submitochondrial particles and assessed mutant loads both in platelets used for biochemical analysis and in other available tissues. Biochemical and molecular results were correlated with clinical features,Results: The rate of ATP hydrolysis was normal, but ATP synthesis was severely impaired (30% to 4% of residual p activity) in patients harboring 34% to 90% mutant mitochondrial DNA, without any evidence of a threshold for the expression of this defect. There was little variation in heteroplasmy among tissues from each patient, but wider variability was detected in 2 mothers. Correlation of heteroplasmy and clinical and biochemical features suggested that ATP synthesis is defective at mutant loads as low as 34% and is extremely reduced at mutant loads above 80% when the phenotype is neuropathy, ataxia, and retinitis pigmentosa-Leigh syndrome.Conclusions: This study indicates a close relationship between tissue heteroplasmy, expression of the biochemical defect in platelets, and clinical involvement. The biochemical defect was greater than previously reported, and we found no evidence of a biochemical threshold. The uniform distribution of high mutant loads among our patients' tissues suggests a differential tissue-specific reliance on mitochondrial ATP synthesis.