Hepatocerebral mitochondrial DNA depletion syndrome: Clinical and morphologic features of a nuclear gene mutation
Hepatocerebral mitochondrial DNA depletion syndrome: Clinical and morphologic features of a nuclear gene mutation
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DOI：
10.1097/00005176-200402000-00022
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发表时间：
2004-02-01
影响因子：
2.9
通讯作者：
DiMauro, S
中科院分区：
文献类型：
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作者：
Rabinowitz, SS;Gelfond, D;DiMauro, S
母系遗传的线粒体 DNA (mtDNA) 需要细胞器内的脱氧核糖核苷酸 (dNTP) 才能复制。 mtDNA 编码细胞器的核糖体蛋白、tRNA 及其 13 种呼吸链蛋白 (1)。核 DNA 编码剩余的线粒体氧化磷酸化酶以及挽救核苷酸和维持细胞器 dNTP 池所需的两种脱氧核糖核苷激酶。因此，核基因组或线粒体基因组的突变会损害线粒体功能并导致多种临床表型 (1, 2)。 1991 年，Moraes 等人(3) 首次描述了线粒体 DNA 耗竭综合征 (MDS)，这是一种与线粒体 DNA 水平低相关的氧化磷酸化缺陷所定义的病症。随后，许多研究人员描述了肝脏 MDS 的临床、生化和形态学特征 (4-8)。婴儿出现口腔摄入不良且发育迟缓。除了肝功能障碍的标准生化指标外，还会出现严重的乳酸酸中毒和酮症低血糖。有些婴儿会出现肌张力低下、神经肌肉无力和眼球震颤。 MDS 儿童的肝脏病理包括微泡脂肪变性、小管胆汁淤积伴胆管血栓、导管增生、糖原耗竭，偶尔还有肝细胞性胆汁淤积。某些肝细胞中出现的嗜酸细胞外观是异常线粒体积累的结果 (8)。超微结构的发现已被详细描述 (9)，包括肝细胞含有数量增加的肿胀线粒体和异常嵴。然而，在具有线粒体呼吸链缺陷和 mtDNA 水平正常的家族中也描述了一种难以区分的临床、生化和形态学形式的肝衰竭 (10)。MDS 表型可以在单个器官中表达，例如肝脏或肌肉，也可以更广泛地表达 (1, 2)。单个分子缺陷如何导致在不同器官中具有表型表达的多种综合征尚未阐明。 mtDNA 复制和维持 mtDNA 水平需要两种线粒体激酶 (11, 12)。两者都受到核基因的控制。肌病型 MDS 与胸苷激酶 2 (TK2) 基因有关(11)。一些肝脑 MDS 患者的脱氧鸟苷激酶基因 (dGK) 发生突变，导致肝衰竭，伴有 (12, 13) 或不伴有中枢神经系统受累 (13)。然而，在 3 个家族的肝脏中未发现 dGK 突变 (12)，并且在 21 个患有肝脑 MDS 的婴儿的肝脏中，只有 3 个肝脏中未发现 dGK 突变 (13)。
Maternally inherited mitochondrial DNA (mtDNA) requires deoxyribonucleotides (dNTP) within the organelle to replicate. mtDNA codes for the organelle’s ribosomal proteins, tRNAs, and 13 of its respiratory chain proteins (1). Nuclear DNA codes for the remainder of the mitochondrial oxidative phosphorylation enzymes and for the two deoxyribonucleoside kinases needed to salvage nucleotides and maintain the organelle’s dNTP pools. Therefore, mutations in either the nuclear or mitochondrial genomes can impair mitochondrial function and cause a wide spectrum of clinical phenotypes (1, 2). In 1991, Moraes et al.(3) first described mitochondrial DNA depletion syndrome (MDS), a condition defined by defective oxidative phosphorylation associated with low levels of mtDNA. Subsequently, a number of investigators have described the clinical, biochemical, and morphologic features of MDS in liver (4–8). Infants present with poor oral intake and failure to thrive. In addition to the standard biochemical indicators of liver dysfunction, severe lactic acidosis and ketotic hypoglycemia occur. Some infants experience hypotonia, neuromuscular weakness, and nystagmus. Hepatic pathology in children with MDS includes microvesicular steatosis, canalicular cholestasis with bile duct thrombi, ductular proliferation, glycogen depletion, and occasionally hepatocellular cholestasis. An oncocytic appearance seen in certain hepatocytes results from the accumulation of abnormal mitochondria (8). Ultrastructural findings have been described in detail (9) and include hepatocytes containing an increased number of swollen mitochondria with abnormal cristae. However, an indistinguishable clinical, biochemical, and morphologic form of liver failure has also been described in a family with a mitochondrial respiratory chain defect and normal levels of mtDNA (10).The MDS phenotype can be expressed in a single organ, such as liver or muscle, or be more generalized (1, 2). How a single molecular defect can lead to multiple syndromes with phenotypic expression in different organs has yet to be elucidated. There are two mitochondrial kinases that are required for mtDNA replication and maintenance of mtDNA levels (11, 12). Both are under the control of nuclear genes. A myopathic form of MDS has been linked to the gene for thymidine kinase-2 (TK2)(11). Some patients with hepatocerebral MDS have mutations in the deoxyguanosine kinase gene (dGK) that yields liver failure with (12, 13) or without central nervous system involvement (13). However, dGK mutations were not found in livers from three families (12), and in only three of 21 livers from infants with hepatocerebral MDS (13).