von Renesse Anja, Morales-Gonzalez Susanne, Gill Esther, Salomons Gajja S, Stenzel Werner, Schuelke Markus
NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany.
Department of Neuropediatrics, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany.
JIMD Rep. 2019;43:27-35. doi: 10.1007/8904_2018_93. Epub 2018 Apr 14.
Mutations in SLC25A4 (syn. ANT1, Adenine nucleotide translocase, type 1) are known to cause either autosomal dominant progressive external ophthalmoplegia (adPEO) or recessive mitochondrial myopathy, hypertrophic cardiomyopathy, and lactic acidosis.
Whole exome sequencing in a young man with myopathy, subsarcolemmal mitochondrial aggregations, cardiomyopathy, lactic acidosis, and L-2-hydroxyglutaric aciduria (L-2-HGA) revealed a new homozygous mutation in SLC25A4 [c.653A>C, NM_001151], leading to the replacement of a highly conserved glutamine by proline [p.(Q218P); NP_001142] that most likely affects the folding of the ANT1 protein. No pathogenic mutation was found in L2HGDH, which is associated with "classic" L-2-HGA. Furthermore, L-2-HGDH enzymatic activity in the patient fibroblasts was normal. Long-range PCR and Southern blot confirmed absence of mtDNA-deletions in blood and muscle.
The disturbed ADP/ATP transport across the inner mitochondrial membrane may lead to an accumulation of different TCA-cycle intermediates such as 2-ketoglutarate (2-KG) in our patient. As L-2-HG is generated from 2-KG we hypothesize that the L-2-HG increase is a secondary effect of 2-KG accumulation. Hence, our report expands the spectrum of laboratory findings in ANT1-related diseases and hints towards a connection with organic acidurias.
已知SLC25A4（同义词：ANT1，腺嘌呤核苷酸转运体1型）突变可导致常染色体显性进行性眼外肌麻痹（adPEO）或隐性线粒体肌病、肥厚性心肌病和乳酸性酸中毒。
对一名患有肌病、肌膜下线粒体聚集、心肌病、乳酸性酸中毒和L-2-羟基戊二酸尿症（L-2-HGA）的年轻男性进行全外显子组测序，发现SLC25A4有一个新的纯合突变[c.653A>C，NM_001151]，导致一个高度保守的谷氨酰胺被脯氨酸取代[p.(Q218P); NP_001142]，这很可能影响ANT1蛋白的折叠。在与“经典”L-2-HGA相关的L2HGDH中未发现致病突变。此外，患者成纤维细胞中的L-2-HGDH酶活性正常。长距离PCR和Southern印迹证实血液和肌肉中不存在线粒体DNA缺失。
线粒体内膜上ADP/ATP转运紊乱可能导致我们的患者体内不同三羧酸循环中间产物如2-酮戊二酸（2-KG）的积累。由于L-2-HG由2-KG生成，我们推测L-2-HG增加是2-KG积累的继发效应。因此，我们的报告扩展了ANT1相关疾病的实验室检查结果范围，并提示与有机酸尿症有关。
