Zhang Ting, Zhu Shasha, Miao Haixia, Yang Jianbin, Shi Yezhen, Yue Yuwei, Zhang Yu, Yang Rulai, Wu Benqing, Huang Xinwen
Department of Genetics and Metabolism, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
Department of Technical Support, Zhejiang Biosan Biochemical Technologies Co. Ltd., Hangzhou, China.
Front Mol Biosci. 2022 Aug 24;9:939837. doi: 10.3389/fmolb.2022.939837. eCollection 2022.
Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a pan-ethnic complicated inborn error of metabolism but the specific mechanism is not fully understood. A total of 169 patients with NICCD who have biallelic pathogenic variants detected by targeted next-generation sequencing were collected. They were divided into the "Newborn-screen Group" and "Clinical diagnosed Group" depending on the newborn screening results. Amino acid and acylcarnitine profiles were measured by MS/MS. The total bile acids, blood amino acids and acylcarnitines, general biochemistry, blood count, and coagulation parameters were monitored every 2-3 months. We compared the differences in metabolic indices and their dynamic changes between these two groups. The Mann-Whitney test and orthogonal partial least squares discrimination analysis (OPLS-DA) were used for statistical analysis. At the onset of NICCD, we found that the "Clinical diagnosed Group" had higher levels of intermediate products of the urea cycle, free carnitine, and short-chain and long-chain acylcarnitines than those in the "Newborn-screen Group," but the levels of ketogenic/glucogenic amino acids and several medium-chain acylcarnitines were lower. Furthermore, concentrations of direct bilirubin, total bile acid, lactate, prothrombin time, and several liver enzymes were significantly higher while total protein, amylase, and hemoglobin were lower in the "Clinical diagnosed Group" than in the "Newborn-screen Group." Dynamic change analysis showed that direct bilirubin, albumin, arginine, and citrulline were the earliest metabolic derangements to reach peak levels in NICCD groups, followed by acylcarnitine profiles, and finally with the elevation of liver enzymes. All abnormal characteristic metabolic indicators in the "Newborn-screen Group" came back to normal levels at earlier ages than the "Clinical diagnosed Group." c.852_855del (41.2%), IVS16ins3kb (17.6%), c.615 + 5G>A (9.6%), 1638_1660dup (4.4%), and c.1177 + 1G>A (3.7%) accounted for 76.5% of all the mutated alleles in our population. Argininosuccinate synthesis, gluconeogenesis, ketogenesis, fatty acid oxidation, liver function, and cholestasis were more severely affected in the "Clinical diagnosed Group." The "Newborn-screen Group" had a better prognosis which highlighted the importance of newborn screening of NICCD.
由瓜氨酸缺乏引起的新生儿肝内胆汁淤积症（NICCD）是一种全民族性的复杂先天性代谢缺陷病，但其具体机制尚未完全明确。收集了169例通过靶向二代测序检测到双等位基因致病性变异的NICCD患者。根据新生儿筛查结果，将他们分为“新生儿筛查组”和“临床诊断组”。采用串联质谱法检测氨基酸和酰基肉碱谱。每2 - 3个月监测一次总胆汁酸、血液氨基酸和酰基肉碱、常规生化指标、血常规及凝血参数。我们比较了两组之间代谢指标的差异及其动态变化。采用曼 - 惠特尼检验和正交偏最小二乘法判别分析（OPLS - DA）进行统计分析。在NICCD发病时，我们发现“临床诊断组”的尿素循环中间产物、游离肉碱、短链和长链酰基肉碱水平高于“新生儿筛查组”，但生酮/生糖氨基酸和几种中链酰基肉碱水平较低。此外，“临床诊断组”的直接胆红素、总胆汁酸、乳酸、凝血酶原时间和几种肝酶浓度显著高于“新生儿筛查组”，而总蛋白、淀粉酶和血红蛋白则较低。动态变化分析表明，直接胆红素、白蛋白、精氨酸和瓜氨酸是NICCD组最早达到峰值水平的代谢紊乱指标，其次是酰基肉碱谱，最后是肝酶升高。“新生儿筛查组”所有异常的特征性代谢指标恢复正常水平的年龄比“临床诊断组”更早。c.852_855del（41.2%）、IVS16ins3kb（17.6%）、c.615 + 5G>A（9.6%）、1638_1660dup（4.4%）和c.1177 + 1G>A（3.7%）占我们研究人群中所有突变等位基因的76.5%。“临床诊断组”的精氨酸琥珀酸合成、糖异生、酮体生成、脂肪酸氧化、肝功能和胆汁淤积受到的影响更严重。“新生儿筛查组”预后较好，这突出了NICCD新生儿筛查的重要性。
