新生儿尿素循环障碍5例临床分析

doi:10.12372/jcp.2023.22e1656

Abstract

Abstract:

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

CHU Xiaoyun, SUN Yifan, YAN Chongbing, HONG Wenchao, GONG Xiaohui, CAI Cheng. Clinical analysis of urea cycle disorders in 5 neonates[J].Journal of Clinical Pediatrics, 2023, 41(4): 266-271.

Figures/Tables 4

References 26

[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. doi: 10.1016/j.pcl.2017.11.004
[2]	Nettesheim S, Kölker 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. doi: 10.1186/s13023-017-0661-x pmid: 28619060
[3]	Häberle 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. doi: 10.1002/jimd.12100 pmid: 30982989
[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. doi: 10.1038/s41581-020-0267-8 pmid: 32269302
[5]	Matsumoto S, Häberle J, Kido J, et al. Urea cycle disorders-update[J]. J Hum Genet, 2019, 64(9): 833-847. doi: 10.1038/s10038-019-0614-4 pmid: 31110235
[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. doi: S1096-7192(18)30083-0 pmid: 29703588
[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]	Kölker 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. doi: 10.1007/s10545-015-9839-3 pmid: 25875215
[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. doi: 10.1148/radiol.2018161834 pmid: 29558304
[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. doi: 10.1016/j.jgg.2015.04.003 pmid: 26059767
[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. doi: 10.1007/BF00216144 pmid: 8365726
[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. doi: 10.1002/lt.26186
[16]	Braissant O, McLin VA, Cudalbu C. Ammonia toxicity to the brain[J]. J Inherit Metab Dis, 2013, 36(4): 595-612. doi: 10.1007/s10545-012-9546-2 pmid: 23109059
[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. doi: 10.1007/s10545-011-9427-0 pmid: 22167275
[18]	Saritaş Nakip Ö, Yıldız Y, Tokatlı 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. doi: 10.1515/jpem-2019-0413 pmid: 32447331
[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. doi: 10.1002/ana.25492 pmid: 31018246
[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. doi: 10.1007/s11011-018-0259-6 pmid: 29948653
[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. doi: 10.1038/s41598-020-67496-3 pmid: 32686765
[22]	Burgard P, Kölker 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. doi: 10.1007/s10545-015-9901-1 pmid: 26634836
[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. doi: S1096-7192(20)30062-7 pmid: 32273051
[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. doi: 10.1002/jimd.2019.42.issue-1
[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. doi: 10.1007/s10545-018-0157-4 pmid: 29520739
[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. doi: 10.1016/j.jpeds.2022.03.043

病例	性别	胎龄/周	出生体重/g	入院日期	发病日龄/d	起病特征	危重症评分	预后
1	男	38⁺¹	3 750	2018.12	8	呕吐、嗜睡	88	存活
2	男	39⁺¹	3 460	2017.12	1	气促、纳差	80	死亡
3	男	38	2 850	2022.07	1	纳差	80	死亡
4	男	41	4 080	2019.02	2	低体温、纳差	86	死亡
5	女	38⁺⁵	4 070	2021.02	2	气促、低体温	80	死亡

病例	初始血氨/ μmol·L^-1	乳酸/ mmol·L^-1	谷氨酰胺/ μmol·L^-1	瓜氨酸/ μmol·L^-1	精氨酸/ μmol·L^-1	尿嘧啶/mmol·molCr^-1	尿乳清酸/ mmol·molCr^-1	治疗后血氨/ μmol·L^-1
1	700	3.0	1 577.3	2.7	6.1	32.0	352.1	218
2	1 574	13.7	2 776.5	4.9	26.7	-	110.8	131
3	1 700	14	3 841.2	4.6	9.7	-	106.4	1 700
4	1 560	3.9	1 204.4	1.6	5.3	-	0.4	1 560
5	1 400	6.8	1 281.1	4.3	6.5	-	1.0	143
参考值	16~60	0.5~2.2	5~1 150	6~50	0.8~60	0~19.7	0~2.5	16~60

病例	突变基因	核苷酸变化	氨基酸变化	遗传方式	原发病	变异来源
1	OTC	c.803T>C	p. Met268Thr	XL	OTCD	母亲
2	OTC	c.177delA	p.S60QfsTer4	XL	OTCD	母亲
3	OTC	c.387-1G>T	-	XL	OTCD	母亲
4	CPS1	c.3784C>T c.3734T>A	p.Arg1262 p.Leu1245His	AR	CPS1D	母亲父亲
5	CPS1	c.548T>C c.3G>C	-	AR	CPS1D	父母未检测

病例	糖速/ mg·kg^－1·min^－1	脂肪/ g·kg^－1·d^－1	热卡/ kcal·kg^－1·d^－1	静脉营养时间/d	腹膜透析循环次数/次·d^－1	腹膜透析时间/d	CRRT模式	CRRT时间/d	住院时间/d
1	8	1~2	95~100	6	8~12	3	-	-	6.5
2	8	0.5	80~100	8	-	-	CVVHDF	4.5	7.5
3	8	0.5	80	0.5	24	0.5	-	-	0.5
4	8	1	90	2.5	-	-	CVVHDF	1	2.5
5	8.5~10	0.5~1.5	100~110	8	-	-	CVVHDF	4.5	8.5

Clinical analysis of urea cycle disorders in 5 neonates

RichHTML

PDF (PC)

Like

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 4

References 26

Related Articles 15

Metrics

Comments

Recommended 0

[1]	XIANG Chao, ZHANG Rong, KANG Lan, LEI Xiaoping, LIU Xingqing, DONG Wenbin. Association of coefficient of glycemic variation and SNAPPE-Ⅱ with prognosis in critically ill neonates [J]. Journal of Clinical Pediatrics, 2023, 41(6): 430-435.
[2]	XU Jinglin, YANG Hansong, CHEN Xinhua, CHEN Jiangbin, LI Xiaoqing, ZHANG Weifeng, CHEN Dongmei. Clinical analysis of continuous blood purification in the treatment of neonatal septic shock with acute kidney injury [J]. Journal of Clinical Pediatrics, 2023, 41(6): 436-441.
[3]	ZHANG Yongjun, ZHU Tianwen. Early diagnosis and precise intervention of neonatal hyperammonemia [J]. Journal of Clinical Pediatrics, 2023, 41(4): 241-246.
[4]	CHEN Yan, WANG Lin. Attention should be paid to neonatal hyperammonemia [J]. Journal of Clinical Pediatrics, 2023, 41(4): 247-251.
[5]	Shenzhen Neonatal Data Network. A multicenter survey and clinical analysis of neonatal hyperammonemia [J]. Journal of Clinical Pediatrics, 2023, 41(4): 252-258.
[6]	ZHANG Yinchun, MO Wenhui, BAI Bo, CHEN Jinmian, SHI Congcong, GU Xia, XIAO Xin, HAO Hu. Genetic screening and early intervention in neonatal hyperammonemia caused by urea cycle disorder [J]. Journal of Clinical Pediatrics, 2023, 41(4): 259-265.
[7]	LIU Ling, JIANG Yuhui, NIE Panrong, ZENG Limei, DUAN Gaiyuan, LI Yuchen. Investigation of the relationship between gene polymorphisms and neonatal hyperbilirubinemia in southwest China [J]. Journal of Clinical Pediatrics, 2022, 40(9): 672-678.
[8]	YANG Yang, CHI Xia, TONG Meiling, ZHOU Xiaoyu, CHENG Rui, PAN Jingjing, CHEN Xiaoqing. Predictive value of different neonatal illness severity scores for predischarge outcomes in very and extremely low birth weight infants [J]. Journal of Clinical Pediatrics, 2022, 40(8): 608-615.
[9]	ZHANG Kun, FAN Sainan, ZHENG Fang, ZHANG Jiahui, WU Zhimin, LYU Anping, MA Yanan, FANG Xiaohui, ZHANG Jinping. The effect of phototherapy on intestinal flora and drug-resistant genes in jaundiced neonates [J]. Journal of Clinical Pediatrics, 2022, 40(6): 436-441.
[10]	WANG Yingcan, TAN Jintong, CHEN Yan, HUANG Qi, XIA Hongping. Neonatal severe hyperparathyroidism caused by novel variation in CASR gene: a case report [J]. Journal of Clinical Pediatrics, 2022, 40(6): 442-445.
[11]	CHEN Biao, ZHAO Ruiqiu. Clinical research progress on neonatal sepsis induced by Streptococcus agalactiae [J]. Journal of Clinical Pediatrics, 2022, 40(11): 875-880.
[12]	DING Jing, XIAO Yihan, XUE Yujuan, FU Jie, LIU Jie, QIN Jiong, ZENG Chaomei. Clinical analysis of neonates affected by maternal chronic myeloid leukemia [J]. Journal of Clinical Pediatrics, 2022, 40(10): 760-764.
[13]	ZHANG Ting, LI Xiaowen. Analysis of risk factors for the prognosis of neonatal acute kidney injury [J]. Journal of Clinical Pediatrics, 2021, 39(9): 646-.
[14]	GAO Chuchu, WANG Sannan, FU Kai, et al. The value of receptor interacting protein 3 in the diagnosis of neonatal sepsis [J]. Journal of Clinical Pediatrics, 2021, 39(3): 167-.
[15]	XIN Chun, MEI Hua, ZHANG Yanbo, et al. Cleft palate associated with COL2A1 gene mutation: a case report and literature review [J]. Journal of Clinical Pediatrics, 2021, 39(3): 187-.