Habarou Florence, Hamel Yamina, Haack Tobias B, Feichtinger René G, Lebigot Elise, Marquardt Iris, Busiah Kanetee, Laroche Cécile, Madrange Marine, Grisel Coraline, Pontoizeau Clément, Eisermann Monika, Boutron Audrey, Chrétien Dominique, Chadefaux-Vekemans Bernadette, Barouki Robert, Bole-Feysot Christine, Nitschke Patrick, Goudin Nicolas, Boddaert Nathalie, Nemazanyy Ivan, Delahodde Agnès, Kölker Stefan, Rodenburg Richard J, Korenke G Christoph, Meitinger Thomas, Strom Tim M, Prokisch Holger, Rotig Agnes, Ottolenghi Chris, Mayr Johannes A, de Lonlay Pascale
Reference Center of Inherited Metabolic Diseases, University Paris Descartes, Hospital Necker Enfants Malades, APHP, 75015 Paris, France; Metabolic Biochemistry, University Paris Descartes, Hospital Necker Enfants Malades, 75015 Paris, France.
Reference Center of Inherited Metabolic Diseases, University Paris Descartes, Hospital Necker Enfants Malades, APHP, 75015 Paris, France; UMR1163, University Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015 Paris, France.
Am J Hum Genet. 2017 Aug 3;101(2):283-290. doi: 10.1016/j.ajhg.2017.07.001. Epub 2017 Jul 27.
Lipoate serves as a cofactor for the glycine cleavage system (GCS) and four 2-oxoacid dehydrogenases functioning in energy metabolism (α-oxoglutarate dehydrogenase [α-KGDHc] and pyruvate dehydrogenase [PDHc]), or amino acid metabolism (branched-chain oxoacid dehydrogenase, 2-oxoadipate dehydrogenase). Mitochondrial lipoate synthesis involves three enzymatic steps catalyzed sequentially by lipoyl(octanoyl) transferase 2 (LIPT2), lipoic acid synthetase (LIAS), and lipoyltransferase 1 (LIPT1). Mutations in LIAS have been associated with nonketotic hyperglycinemia-like early-onset convulsions and encephalopathy combined with a defect in mitochondrial energy metabolism. LIPT1 deficiency spares GCS deficiency and has been associated with a biochemical signature of combined 2-oxoacid dehydrogenase deficiency leading to early death or Leigh-like encephalopathy. We report on the identification of biallelic LIPT2 mutations in three affected individuals from two families with severe neonatal encephalopathy. Brain MRI showed major cortical atrophy with white matter abnormalities and cysts. Plasma glycine was mildly increased. Affected individuals' fibroblasts showed reduced oxygen consumption rates, PDHc, α-KGDHc activities, leucine catabolic flux, and decreased protein lipoylation. A normalization of lipoylation was observed after expression of wild-type LIPT2, arguing for LIPT2 requirement in intramitochondrial lipoate synthesis. Lipoic acid supplementation did not improve clinical condition nor activities of PDHc, α-KGDHc, or leucine metabolism in fibroblasts and was ineffective in yeast deleted for the orthologous LIP2.
硫辛酸作为甘氨酸裂解系统（GCS）和四种在能量代谢中起作用的2-氧代酸脱氢酶（α-酮戊二酸脱氢酶[α-KGDHc]和丙酮酸脱氢酶[PDHc]）或氨基酸代谢（支链氧代酸脱氢酶、2-氧代己二酸脱氢酶）的辅助因子。线粒体硫辛酸合成涉及三个酶促步骤，依次由硫辛酰（辛酰）转移酶2（LIPT2）、硫辛酸合成酶（LIAS）和硫辛酰转移酶1（LIPT1）催化。LIAS突变与非酮症高甘氨酸血症样早发性惊厥和脑病相关，并伴有线粒体能量代谢缺陷。LIPT1缺乏症不累及GCS缺乏症，与2-氧代酸脱氢酶联合缺乏导致早期死亡或Leigh样脑病的生化特征有关。我们报告了在来自两个患有严重新生儿脑病家庭的三名受影响个体中鉴定出双等位基因LIPT2突变。脑部MRI显示主要皮质萎缩伴白质异常和囊肿。血浆甘氨酸轻度升高。受影响个体的成纤维细胞显示氧消耗率、PDHc、α-KGDHc活性、亮氨酸分解代谢通量降低，蛋白质硫辛酰化减少。在表达野生型LIPT2后观察到硫辛酰化正常化，这表明线粒体内硫辛酸合成需要LIPT2。补充硫辛酸并没有改善临床状况，也没有改善成纤维细胞中PDHc、α-KGDHc或亮氨酸代谢的活性，并且对缺失直系同源LIP2的酵母无效。
