DNM1L-related mitochondrial fission defect presenting as refractory epilepsy
DNM1L-related mitochondrial fission defect presenting as refractory epilepsy
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DOI：
10.1038/ejhg.2015.243
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发表时间：
2016-07-01
影响因子：
5.2
通讯作者：
Lines, Matthew A.
中科院分区：
文献类型：
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作者：
Vanstone, Jason R.;Smith, Amanda M.;Lines, Matthew A.
线粒体分裂和融合是对线粒体质量控制和细胞呼吸维持至关重要的动态过程。在分裂线粒体时，膜断裂是由动力蛋白相关的GTP酶DNM 1 L完成的，DNM 1 L在分裂位点寡聚并以GTP依赖性方式收缩。先前仅有一例DNM 1 L相关临床疾病的报告：一例患有由线粒体和过氧化物酶体分裂缺陷引起的脑病（EMPF; OMIM #614388）的女性新生儿，这是一种致命性疾病，其特征为脑发育不全、癫痫发作、乳酸酸中毒、极长链脂肪酸升高以及线粒体和过氧化物酶体异常伸长。在这里，我们描述了第二个人，诊断通过全外显子组测序，谁提出了发育迟缓，难治性癫痫，生存期延长，并没有证据表明线粒体或过氧化物酶体功能障碍的标准筛选调查的血液和尿液。脑电图是非特异性的，显示背景放缓与频繁的癫痫样活动在额叶和中央头部区域。骨骼肌的电子显微镜显示细微的，非特异性的嵴组织异常，和患者成纤维细胞的共聚焦显微镜显示惊人的过度融合的线粒体网络。在患者成纤维细胞中进行的一组进一步生物能量研究显示与对照组相比无显著差异。先证者的从头DNM 1 L变异，NM_012062.4：c.1085G>A; NP_036192.2：p.（Gly 362 Asp），福尔斯位于DNM 1 L的中间（寡聚化）结构域，暗示可能的显性-负性机制。这种疾病，提出非特异性和提供很少的诊断线索，可以通过DNM 1 L测序和/或共聚焦显微镜诊断。
Mitochondrial fission and fusion are dynamic processes vital to mitochondrial quality control and the maintenance of cellular respiration. In dividing mitochondria, membrane scission is accomplished by a dynamin-related GTPase, DNM1L, that oligomerizes at the site of fission and constricts in a GTP-dependent manner. There is only a single previous report of DNM1L-related clinical disease: a female neonate with encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF; OMIM #614388), a lethal disorder characterized by cerebral dysgenesis, seizures, lactic acidosis, elevated very long chain fatty acids, and abnormally elongated mitochondria and peroxisomes. Here, we describe a second individual, diagnosed via whole-exome sequencing, who presented with developmental delay, refractory epilepsy, prolonged survival, and no evidence of mitochondrial or peroxisomal dysfunction on standard screening investigations in blood and urine. EEG was nonspecific, showing background slowing with frequent epileptiform activity at the frontal and central head regions. Electron microscopy of skeletal muscle showed subtle, nonspecific abnormalities of cristal organization, and confocal microscopy of patient fibroblasts showed striking hyperfusion of the mitochondrial network. A panel of further bioenergetic studies in patient fibroblasts showed no significant differences versus controls. The proband's de novo DNM1L variant, NM_012062.4:c.1085G>A; NP_036192.2:p. (Gly362Asp), falls within the middle ( oligomerization) domain of DNM1L, implying a likely dominant-negative mechanism. This disorder, which presents nonspecifically and affords few diagnostic clues, can be diagnosed by means of DNM1L sequencing and/or confocal microscopy.