Reversible infantile respiratory chain deficiency is a unique, genetically heterogenous mitochondrial disease.
Reversible infantile respiratory chain deficiency is a unique, genetically heterogenous mitochondrial disease.
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DOI：
10.1136/jmg.2011.089995
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发表时间：
2011-10
影响因子：
4
通讯作者：
Poulton J
中科院分区：
文献类型：
--
作者：
Uusimaa J;Jungbluth H;Fratter C;Crisponi G;Feng L;Zeviani M;Hughes I;Treacy EP;Birks J;Brown GK;Sewry CA;McDermott M;Muntoni F;Poulton J
母系同源遗传，m.14674T>；C或m.14674T>；G mt-tRNAGlu突变最近在可逆性婴儿细胞色素C氧化酶缺乏症(或“良性环氧合酶缺乏症”)中被发现。我们寻找了其他可能导致类似表现的基因缺陷。我们调查了来自7个家系的8例婴儿可逆性细胞色素C氧化酶缺乏症的临床病理特征。我们回顾了线粒体DNA和核编码候选基因的诊断特征并进行了分子遗传学分析。患者在出生后的头几个月内出现严重低眼压、喂养困难和乳酸中毒的亚急性发作。虽然恢复很显著，但轻微的肌病一直持续到成年。肌肉的组织病理学表现包括脂肪和/或糖原含量增加，粗糙的红色和COX阴性纤维。生化研究表明，比单纯的COX缺乏症更普遍的异常。乳酸酸中毒和组织病理学异常的正常化反映了临床的改善。在4个家系中发现m.14674T>；C mt-tRNAGlu突变，但未发现m.14674T>；G突变。此外，在2个家系中，我们还发现了核TRMU基因的致病突变，这是以前没有与这种表型相关的。在一个家庭中，遗传病因仍不清楚。良性COX缺乏症更好地描述为“可逆性婴幼儿呼吸链缺乏症”。它在遗传上是异质性的，没有携带m.14674T>；C或T>；G mt-tRNAGlu突变的患者可能有TRMU基因突变。在分子水平上诊断这种疾病对于儿科神经科医生和重症监护儿科医生来说是一个重大的进步，使他们能够从那些在婴儿期出现严重线粒体的儿童中选择预后良好的儿童进行持续的呼吸支持。
Homoplasmic maternally inherited, m.14674T>C or m. 14674T>G mt-tRNAGlu mutations have recently been identified in Reversible infantile cytochrome c oxidase deficiency (or “Benign COX deficiency”). We sought other genetic defects that may give rise to similar presentations. We investigated 8 patients from 7 families with clinico-pathological features of infantile reversible cytochrome c oxidase deficiency. We reviewed the diagnostic features and performed molecular genetic analyses of mitochondrial DNA and nuclear-encoded candidate genes. Patients presented with subacute onset of profound hypotonia, feeding difficulties and lactic acidosis within the first months of life. Although recovery was remarkable, a mild myopathy persisted into adulthood. Histopathological findings in muscle included increased lipid and/or glycogen content, ragged-red and COX negative fibres. Biochemical studies suggested more generalized abnormalities than pure COX deficiency. Clinical improvement was reflected by normalization of lactic acidosis and histopathological abnormalities. The m.14674T>C mt-tRNAGlu mutation was identified in 4 families, but none had the m.14674T>G mutation. Furthermore, in 2 families we also found pathogenic mutations in nuclear TRMU gene which has not previously been associated with this phenotype. In one family, the genetic etiology still remains unknown. Benign COX deficiency is better described as “Reversible Infantile Respiratory Chain Deficiency”. It is genetically heterogeneous, and patients not carrying the m.14674T>C or T>G mt-tRNAGlu mutations may have mutations in TRMU gene. Diagnosing this disorder at the molecular level is a significant advance for paediatric neurologists and intensive care paediatricians, enabling them to select children with an excellent prognosis for continuing respiratory support from those with severe mitochondrial presentation in infancy.