Clinical and Molecular Characteristics of Mitochondrial DNA Depletion Syndrome Associated with Neonatal Cholestasis and Liver Failure
Clinical and Molecular Characteristics of Mitochondrial DNA Depletion Syndrome Associated with Neonatal Cholestasis and Liver Failure
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DOI：
10.1016/j.jpeds.2013.10.082
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发表时间：
2014-03-01
影响因子：
5.1
通讯作者：
Taylor, Robert W.
中科院分区：
文献类型：
--
作者：
Al-Hussaini, Abdulrahman;Faqeih, Eissa;Taylor, Robert W.
目的了解胆汁淤积和肝功能衰竭患儿线粒体DNA缺失综合征（MDS）发生的频率，进一步阐明脱氧鸟苷激酶（DGUOK）和MPV17基因突变与MDS相关的临床、生化、影像学、组织病理学和分子特征。研究设计我们研究了2007年至2013年间到我们三级保健中心就诊的20名疑似肝脑MDS婴儿。通过标准方法从血液白细胞、肝脏和/或骨骼肌样本中分离基因组DNA。使用实时定量聚合酶链反应测定肌肉和/或肝脏DNA中相对于核DNA水平的线粒体DNA拷贝数，并与年龄匹配的对照组进行比较。核候选基因，包括聚合酶γ， MPV17和DGUOK使用标准分析测序。结果我们在11名婴儿（6名女性）中发现致病性MPV17和DGUOK突变，占我们中心在研究期间提交的450例婴儿胆汁淤滞症的2.5%和50例婴儿肝衰竭的22%。所有11例患者均表现为胆汁淤积，随后迅速进展性肝功能衰竭，并在2岁前死亡。在11例可用组织中，有8例在肝脏或肌肉中发现线粒体DNA缺失。MPV17基因突变7例（新突变3例），DGUOK基因突变4例（新突变2例）。结论MPV17和DGUOK基因突变存在于很大比例的肝衰竭婴儿中，并与不良预后相关。
Objective To determine the frequency of mitochondrial DNA depletion syndrome (MDS) in infants with cholestasis and liver failure and to further clarify the clinical, biochemical, radiologic, histopathologic, and molecular features associated with MDS due to deoxyguanosine kinase (DGUOK) and MPV17 gene mutations.Study design We studied 20 infants with suspected hepatocerebral MDS referred to our tertiary care center between 2007 and 2013. Genomic DNA was isolated from blood leukocytes, liver, and/or skeletal muscle samples by standard methods. Mitochondrial DNA copy number relative to nuclear DNA levels was determined in muscle and/or liver DNA using real-time quantitative polymerase chain reaction and compared with age-matched controls. Nuclear candidate genes, including polymerase gamma, MPV17, and DGUOK were sequenced using standard analyses.Results We identified pathogenic MPV17 and DGUOK mutations in 11 infants (6 females) representing 2.5% of the 450 cases of infantile cholestasis and 22% of the 50 cases of infantile liver failure referred to our center during the study period. All of the 11 patients manifested cholestasis that was followed by a rapidly progressive liver failure and death before 2 years of life. Mitochondrial DNA depletion was demonstrated in liver or muscle for 8 out of the 11 cases where tissue was available. Seven patients had mutations in the MPV17 gene (3 novel mutations), 4 patients had DGUOK mutations (of which 2 were novel mutations).Conclusion Mutations in the MPV17 and DGUOK genes are present in a significant percentage of infants with liver failure and are associated with poor prognosis.