Miyazaki Teruo, Nagasaka Hironori, Komatsu Haruki, Inui Ayano, Morioka Ichiro, Tsukahara Hirokazu, Kaji Shunsaku, Hirayama Satoshi, Miida Takashi, Kondou Hiroki, Ihara Kenji, Yagi Mariko, Kizaki Zenro, Bessho Kazuhiko, Kodama Takahiro, Iijima Kazumoto, Yorifuji Tohru, Matsuzaki Yasushi, Honda Akira
Division of Gastroenterology, Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan.
Department of Pediatrics, Takarazuka City Hospital, Takarazuka, Hyogo, Japan.
JIMD Rep. 2019;43:53-61. doi: 10.1007/8904_2018_99. Epub 2018 Apr 14.
Citrin (mitochondrial aspartate-glutamate transporter) deficiency causes the failures in both carbohydrate-energy metabolism and the urea cycle, and the alterations in the serum levels of several amino acids in the stages of newborn (NICCD) and adult (CTLN2). However, the clinical manifestations are resolved between the NICCD and CTLN2, but the reasons are still unclear. This study evaluated the serum amino acid profile in citrin-deficient children during the healthy stage.
Using HPLC-MS/MS analysis, serum amino acids were evaluated among 20 citrin-deficient children aged 5-13 years exhibiting normal liver function and 35 age-matched healthy controls.
The alterations in serum amino acids characterized in the NICCD and CTLN2 stages were not observed in the citrin-deficient children. Amino acids involved in the urea cycle, including arginine, ornithine, citrulline, and aspartate, were comparable in the citrin-deficient children to the respective control levels, but serum urea was twofold higher, suggestive of a functional urea cycle. The blood sugar level was normal, but glucogenic amino acids and glutamine were significantly decreased in the citrin-deficient children compared to those in the controls. In addition, significant increases of ketogenic amino acids, branched-chain amino acids (BCAAs), a valine intermediate 3-hydroxyisobutyrate, and β-alanine were also found in the citrin-deficient children.
The profile of serum amino acids in the citrin-deficient children during the healthy stage showed different characteristics from the NICCD and CTLN2 stages, suggesting that the failures in both urea cycle function and energy metabolism might be compensated by amino acid metabolism.
In the citrin-deficient children during the healthy stage, the characteristics of serum amino acids, including decrease of glucogenic amino acids, and increase of ketogenic amino acids, BCAAs, valine intermediate, and β-alanine, were found by comparison to the age-matched healthy control children, and it suggested that the characteristic alteration of serum amino acids may be resulted from compensation for energy metabolism and ammonia detoxification.
柠素（线粒体天冬氨酸-谷氨酸转运体）缺乏会导致碳水化合物-能量代谢和尿素循环功能障碍，以及新生儿期（NICCD）和成人期（CTLN2）血清中多种氨基酸水平的改变。然而，NICCD和CTLN2阶段的临床表现有所不同，但其原因仍不清楚。本研究评估了柠素缺乏儿童在健康阶段的血清氨基酸谱。
采用高效液相色谱-串联质谱分析法（HPLC-MS/MS），对20名5至13岁肝功能正常的柠素缺乏儿童和35名年龄匹配的健康对照者的血清氨基酸进行了评估。
在柠素缺乏儿童中未观察到NICCD和CTLN2阶段所特有的血清氨基酸改变。参与尿素循环的氨基酸，包括精氨酸、鸟氨酸、瓜氨酸和天冬氨酸，在柠素缺乏儿童中的水平与各自的对照水平相当，但血清尿素高出两倍，提示尿素循环功能正常。血糖水平正常，但与对照组相比，柠素缺乏儿童的生糖氨基酸和谷氨酰胺显著降低。此外，柠素缺乏儿童中还发现生酮氨基酸、支链氨基酸（BCAAs）、缬氨酸中间体3-羟基异丁酸和β-丙氨酸显著增加。
柠素缺乏儿童在健康阶段的血清氨基酸谱显示出与NICCD和CTLN2阶段不同的特征，提示尿素循环功能和能量代谢的障碍可能通过氨基酸代谢得到代偿。
在健康阶段的柠素缺乏儿童中，通过与年龄匹配的健康对照儿童比较，发现血清氨基酸的特征，包括生糖氨基酸减少，生酮氨基酸、BCAAs、缬氨酸中间体和β-丙氨酸增加，提示血清氨基酸的特征性改变可能是能量代谢和氨解毒代偿的结果。
