新生儿尿素循环障碍5例临床分析
收稿日期: 2022-12-13
网络出版日期: 2023-04-07
基金资助
上海市2020年度“科技创新行动计划”医学创新研究专项项(20Y11907000)
Clinical analysis of urea cycle disorders in 5 neonates
Received date: 2022-12-13
Online published: 2023-04-07
目的 总结新生儿尿素循环障碍（UCDs）的临床特征、诊治过程、转归及预后，以提高对该病的认识。方法 回顾性分析2017年7月至2022年7月收治的经基因测序证实为阳性变异的5例新生儿UCDs的临床特点、治疗及预后等资料。结果 5例新生儿中男4例、女1例，胎龄（39.0±1.2）周，出生体重（3 642.0±511.6）g，中位发病日龄2（1~5）d，初始血氨水平（1 386.8±398.4）μmol/L。起病特征分别为纳差3例、低体温2例、气促2例、呕吐1例，均有肌张力减退、意识障碍及惊厥。原发病为鸟氨酸氨甲酰转移酶缺乏症(OTCD)3例，氨甲酰磷酸合成酶1缺乏症（CPS1D）2例。OTCD患儿瓜氨酸降低，尿乳清酸增高，存在3种基因致病变异，其中c.177delA和c.387-1G>T为新发变异。CPS1D患儿瓜氨酸降低，尿乳清酸浓度正常或降低，基因测序存在4个变异位点，其中c.548T>C和c.3G>C为新发变异。5例UCDs新生儿均在饮食控制及药物治疗的基础上叠加透析疗法以快速清除血氨，其中3例患儿血氨水平降至（164.0±47.1）μmol/L，但因神经系统不良预后，最终4例放弃治疗后死亡，1例存活。存活患儿在1岁时接受了肝移植手术，随访至2022年12月存在语言及运动发育落后。结论 新生儿UCDs病死率高且预后差，临床起病特征常缺乏特异性，尽早的血氨检测是发现该病的关键，基因分析可明确诊断。尽早给予有效干预可挽救患儿生命及改善其神经系统预后。
楚晓云 , 孙祎璠 , 颜崇兵 , 洪文超 , 龚小慧 , 蔡成 . 新生儿尿素循环障碍5例临床分析[J]. 临床儿科杂志, 2023 , 41(4) : 266 -271 . DOI: 10.12372/jcp.2023.22e1656
Objective To summarize the clinical features, diagnosis and treatment, regression and prognosis of 5 neonatal urea cycle disorders (UCDs) in order to improve the understanding of the disease. Methods The clinical characteristics, treatment and prognosis of 5 neonatal UCDs confirmed by gene sequencing admitted from July 2017 to July 2022 were retrospectively analyzed. Results The gestational age of the five neonates (4 boys and 1 girl) was (39.0±1.2) weeks, the birth weight was (3642.0±511.6) g, the age of onset was 2(1-5) days, and the initial blood ammonia level was (1386.8±398.4) μmol/L. The onset characteristics of the children were poor appetite (3 cases), hypothermia (2 cases), shortness of breath (2 cases) and vomiting (1 case). All the children had hypotonia, disturbance of consciousness and convulsion. The primary disease was ornithine transcarbamylase deficiency (OTCD) in 3 cases and carbamoyl phosphate synthase 1 deficiency (CPS1D) in 2 cases. Decreased citrulline and increased urinary orotate was found in children with OTCD, and there were three gene pathogenic variants, among which c.177delA and c.387-1G>T were new variants. In CPS1D children, citrulline was decreased, urinary orotate concentration was normal or decreased, and four variation loci were found by gene sequencing, among which c.548T>C and c.3G>C were new variants. All 5 neonates with UCDs were treated with diet control and medication followed by dialysis for rapid clearance of ammonia, and the blood ammonia level in 3 of them decreased to (164.0±47.1) μmol/L. However, due to the poor prognosis of the nervous system, 4 patients died and 1 patient survived. The surviving neonate underwent liver transplantation at the age of 1 year and was followed up until December 2022. The child had delayed language and motor development. Conclusions UCDs in newborns have a high mortality rate and a poor prognosis, and the clinical features are often unspecific. Early blood ammonia detection is the key to detect the disease, and genetic analysis can confirm the diagnosis. Early and effective intervention can save the children’s life and improve their neurological prognosis.
Key words： hyperammonemia; urea cycle disorder; clinical analysis; neonate
| [1] | Summar ML, Mew NA. Inborn errors of metabolism with hyperammonemia: urea cycle defects and related disorders[J]. Pediatr Clin North Am, 2018, 65(2): 231-246. |
| [2] | Nettesheim S, K?lker S, Karall D, et al. Incidence, disease onset and short-term outcome in urea cycle disorders-cross-border surveillance in Germany, Austria and Switzerland[J]. Orphanet J Rare Dis, 2017, 12(1): 111. |
| [3] | H?berle J, Burlina A, Chakrapani A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: first revision[J]. J Inherit Metab Dis, 2019, 42(6): 1192-1230. |
| [4] | Raina R, Bedoyan JK, Lichter-Konecki U, et al. Consensus guidelines for management of hyperammonaemia in paediatric patients receiving continuous kidney replacement therapy[J]. Nat Rev Nephrol, 2020, 16(8): 471-482. |
| [5] | Matsumoto S, H?berle J, Kido J, et al. Urea cycle disorders-update[J]. J Hum Genet, 2019, 64(9): 833-847. |
| [6] | Alfadhel M, Mutairi FA, Makhseed N, et al. Guidelines for acute management of hyperammonemia in the Middle East region[J]. Ther Clin Risk Manag, 2016, 12: 479-487. |
| [7] | Merritt JL 2nd, Brody LL, Pino G, et al. Newborn screening for proximal urea cycle disorders: current evidence supporting recommendations for newborn screening[J]. Mol Genet Metab, 2018, 124(2): 109-113. |
| [8] | Savy N, Brossier D, Brunel-Guitton C, et al. Acute pediatric hyperammonemia: current diagnosis and management strategies[J]. Hepat Med, 2018, 10: 105-115. |
| [9] | K?lker S, Garcia-Cazorla A, Valayannopoulos V, et al. The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation[J]. J Inherit Metab Dis, 2015, 38(6): 1041-1057. |
| [10] | Hershman M, Carmody R, Udayasankar UK. Case 252: acute hyperammonemic encephalopathy resulting from late-onset ornithine transcarbamylase deficiency[J]. Radiology, 2018, 287(1): 353-359. |
| [11] | Caldovic L, Abdikarim I, Narain S, et al. Genotype-phenotype correlations in ornithine transcarbamylase deficiency: a mutation update[J]. J Genet Genomics, 2015, 42(5): 181-194. |
| [12] | 中国妇幼保健协会儿童疾病和保健分会遗传代谢学组. 鸟氨酸氨甲酰转移酶缺乏症诊治专家共识[J]. 浙江大学学报(医学版), 2020, 49(5): 539-547. |
| [13] | Matsuura T, Hoshide R, Setoyama C, et al. Four novel gene mutations in five Japanese male patients with neonatal or late onset OTC deficiency: application of PCR-single-strand conformation polymorphisms for all exons and adjacent introns[J]. Hum Genet, 1993, 92(1): 49-56. |
| [14] | Zhou Q, Huang H, Ma L, et al. The application of next-generation sequencing (NGS) in neonatal-onset urea cycle disorders (UCDs): clinical course, metabolomic profiling, and genetic findings in nine Chinese hyperammonemia patients[J]. Biomed Res Int, 2020: 5690915. |
| [15] | Ziogas IA, Wu WK, Matsuoka LK, et al. Liver trans-plantation in children with urea cycle disorders: the importance of minimizing waiting time[J]. Liver Transpl, 2021, 27(12): 1799-1810. |
| [16] | Braissant O, McLin VA, Cudalbu C. Ammonia toxicity to the brain[J]. J Inherit Metab Dis, 2013, 36(4): 595-612. |
| [17] | Kido J, Nakamura K, Mitsubuchi H, et al. Long-term outcome and intervention of urea cycle disorders in Japan[J]. J Inherit Metab Dis, 2012, 35(5): 777-785. |
| [18] | Sarita? Nakip ?, Y?ld?z Y, Tokatl? A. Retrospective evaluation of 85 patients with urea cycle disorders: one center experience, three new mutations[J]. J Pediatr Endocrinol Metab, 2020, 33(6): 721-728. |
| [19] | Posset R, Gropman AL, Nagamani SCS, et al. Impact of diagnosis and therapy on cognitive function in urea cycle disorders[J]. Ann Neurol, 2019, 86(1): 116-128. |
| [20] | Kido J, Matsumoto S, Mitsubuchi H, et al. Early liver transplantation in neonatal-onset and moderate urea cycle disorders may lead to normal neurodevelopment[J]. Metab Brain Dis, 2018, 33(5): 1517-1523. |
| [21] | Posset R, Garbade SF, Gleich F, et al. Long-term effects of medical management on growth and weight in individuals with urea cycle disorders[J]. Sci Rep, 2020, 10(1): 11948. |
| [22] | Burgard P, K?lker S, Haege G, et al. Neonatal mortality and outcome at the end of the first year of life in early onset urea cycle disorders--review and meta-analysis of observational studies published over more than 35 years[J]. J Inherit Metab Dis, 2016, 39(2): 219-229. |
| [23] | Pontoizeau C, Roda C, Arnoux JB, et al. Neonatal factors related to survival and intellectual and developmental outcome of patients with early-onset urea cycle disorders[J]. Mol Genet Metab, 2020, 130(2): 110-117. |
| [24] | Posset R, Garbade SF, Boy N, et al. Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders - a successful strategy for clinical research of rare diseases[J]. J Inherit Metab Dis, 2019, 42(1): 93-106. |
| [25] | Hediger N, Landolt MA, Diez-Fernandez C, et al. The impact of ammonia levels and dialysis on outcome in 202 patients with neonatal onset urea cycle disorders[J]. J Inherit Metab Dis, 2018, 41(4): 689-698. |
| [26] | Ames EG, Powell C, Engen RM, et al. Multisite retro-spective review of outcomes in renal replacement therapy for neonates with inborn errors of metabolism[J]. J Pediatr, 2022, 246: 116-122. |
/
| 〈 |
|
〉 |
沪公网安备 31011002000392号
