Rare mtDNA variants in Leber hereditary optic neuropathy families with recurrence of myoclonus
Rare mtDNA variants in Leber hereditary optic neuropathy families with recurrence of myoclonus
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DOI：
10.1212/01.wnl.0000295505.74234.d0
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发表时间：
2008-03-04
期刊：
影响因子：
9.9
通讯作者：
Carelli, V.
中科院分区：
文献类型：
--
作者：
La Morgia, C.;Achilli, A.;Carelli, V.
目的：探讨Leber遗传性视神经病变中肌阵挛的发病机制。方法：对来自两个携带11778/ND4和3460/ND1基因突变的意大利家系的5名患者和1名未受影响的携带者进行统一的检查，包括神经生理学检查、肌肉活检、运动后血清乳酸、肌肉(P-31)和脑(H-1)磁共振波谱(MRS)。对两个家系的成纤维细胞和线粒体DNA(MtDNA)全序列进行了生化研究。结果：6个个体均有肌阵挛。尽管脑电背景正常，没有巨大的SEP和C反射，但EEG-EMG反向平均显示出先前的痉挛锁定的EEG电位，与肌阵挛的皮质生成器一致。11778/nd4家族中的特殊合并症包括肌肉痉挛和精神障碍，而两个家族的共同特征是偏头痛和心脏异常。在肌肉活组织检查中可以看到线粒体增殖的迹象，在6名患者中有4名患者观察到乳酸升高。6例患者中5例P-31-MRS异常，3例H-1-MRS显示脑室乳酸蓄积。在LHON/肌阵挛患者中，与半乳糖孵育48小时后，成纤维细胞ATP明显耗竭。序列分析显示单倍组T2(11778/ND4家族)和U4a(3460/ND1家族)mtDNA。氨基酸保守性分析支持非同义4136A>；G/ND1、9139G>；A/ATPase6和15773G>；A/cyt b变异的功能作用。结论：肌阵挛和其他共病是Leber遗传性视神经病变(LHON)家系的特征。功能调查显示，所有个体都存在生物能量损伤。我们的序列分析表明，我们病例中的LHON+表型可能与mtDNA变体的协同作用有关。
Objective: To investigate the mechanisms underlying myoclonus in Leber hereditary optic neuropathy (LHON).Methods: Five patients and one unaffected carrier from two Italian families bearing the homoplasmic 11778/ND4 and 3460/ND1 mutations underwent a uniform investigation including neurophysiologic studies, muscle biopsy, serum lactic acid after exercise, and muscle (P-31) and cerebral (H-1) magnetic resonance spectroscopy (MRS). Biochemical investigations on fibroblasts and complete mitochondrial DNA (mtDNA) sequences of both families were also performed.Results: All six individuals had myoclonus. In spite of a normal EEG background and the absence of giant SEPs and C reflex, EEG-EMG back-averaging showed a preceding jerk-locked EEG potential, consistent with a cortical generator of the myoclonus. Specific comorbidities in the 11778/ND4 family included muscular cramps and psychiatric disorders, whereas features common to both families were migraine and cardiologic abnormalities. Signs of mitochondrial proliferation were seen in muscle biopsies and lactic acid elevation was observed in four of six patients. P-31-MRS was abnormal in five of six patients and H-1-MRS showed ventricular accumulation of lactic acid in three of six patients. Fibroblast ATP depletion was evident at 48 hours incubation with galactose in LHON/myoclonus patients. Sequence analysis revealed haplogroup T2 (11778/ND4 family) and U4a (3460/ND1 family) mtDNAs. A functional role for the non-synonymous 4136A>G/ND1, 9139G>A/ATPase6, and 15773G>A/cyt b variants was supported by amino acid conservation analysis.Conclusions: Myoclonus and other comorbidities characterized our Leber hereditary optic neuropathy (LHON) families. Functional investigations disclosed a bioenergetic impairment in all individuals. Our sequence analysis suggests that the LHON plus phenotype in our cases may relate to the synergic role of mtDNA variants.