尿素循环障碍所致新生儿高氨血症基因筛查和早期干预

doi:10.12372/jcp.2023.22e1714

Abstract

Abstract:

Objective To explore the prevalence of neonatal urea circulation disorder (UCD) by genetic screening and achieve the early identification and intervention of neonatal hyperammonemia (NHA) caused by UCD in Guangdong province. Methods The gene screening data of 38159 neonates from multiple centers in Guangdong region from 2019 to 2022 were collected, and the gene positive rate of UCD neonates was calculated. Meanwhile, the clinical intervention and efficacy of 9 children with UCD related NHA were further analyzed. Results The gene positive rate of UCD in newborns in Guangdong was 0.472%, and citrin deficiency was the commonest (0.314%). All three cases of citrin deficiency had homozygous variation of c.852_855delTATG in SLC25A13 gene. Due to the different diagnosis time and clinical intervention period, the prognosis of children is also different. Six children with UCD related NHA had early onset and advanced progression. After active early symptomatic treatment, two patients with citrullinemia typeⅠimproved, four patients died and one was lost to follow-up. Conclusions The etiology of NHA is complex and diverse, and UCD is the commonest. Its clinical manifestations lack specificity, and it is easy to be missed and misdiagnosed. Early blood and urine metabolism screening combined with UCD-related gene screening can achieve early identification, diagnosis and treatment of UCD-related NHA, and can guide genetic counseling and prenatal diagnosis of another pregnancy.

Key words: hyperammonemia, genetic metabolic disease, urea circulation disorder, early diagnosis and treatment, neonatal

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.

Figures/Tables 4

References 26

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基因	对应疾病	病例
SLC25A13	Citrin缺陷病	120（0.314）
OTC	鸟氨酸氨甲酰基转移酶缺乏症	40（0.105）
CPS1	氨甲酰磷酸合成酶I缺乏症	14（0.037）
ASS1	瓜氨酸血症I型	3（0.008）
NAGS	N-乙酰谷氨酸合成酶缺乏症	2（0.005）
ASL	精氨酰琥珀酸尿症	1（0.003）
SLC25A15	高鸟氨酸血症-高氨血症-同型瓜氨酸尿症	0
ARG1	精氨酸酶缺乏症	0
合计		180（0.472）

患儿	临床特点	异常检查情况	疾病进展和干预措施	确诊时间	诊疗和预后特点	基因结果
例1	出生第8天血检查：瓜氨酸增高3.31倍，提示Citrin缺陷病	凝血、甲胎蛋白检测结果异常	11天尿检查：4-羟基苯乳酸和4-羟基苯丙酮酸明显升高，分别达1 331倍和641倍，高度提示Citrin缺陷病。第15天时换用特殊奶粉喂养	16天时基因确诊Citrin缺陷病	超早期饮食管理，患儿无明显临床症状	SLC25A13基因c.852_ 855delTATG纯合，来自父母双方
例2	出生第10天血检查：瓜氨酸增高4.8倍，提示Citrin缺陷病	肝功能、凝血、血氨、甲胎蛋白检测异常	1个月6天时尿液气相色谱质谱结果：4-羟基苯丙酮酸大量检出，高度提示Citrin缺陷病。建议换用特殊奶粉喂养	1个月20天基因确诊Citrin缺陷病	超早期提示疾病风险，未积极干预，出现临床症状后开始饮食管理，恢复慢	SLC25A13基因c.852_ 855delTATG纯合，来自父母双方
例3	生后反复表现为黄疸、胆汁淤积	多次肝功能、血氨、甲胎蛋白异常	7月龄发展为肝硬化、肝衰竭（血清Ⅳ型胶原 601.04 ng·mL^-1、血清透明质酸1 934.74 ng·mL^-1、III型前胶原71.12 ng·mL^-1和血清层黏连蛋白 804.56 ng·mL^-1，瞬时弹性成像检查肝脏硬度值明显升高>17.5 kPa）	7月20天基因确诊为Citrin缺陷病	一直未明确诊断，仅临床对症治疗，效果差，死亡	SLC25A13基因c.852_ 855delTATG纯合，来自父母双方

患儿	年龄	性别	主要临床特点	干预措施	血氨/ μmol·L^-1	基因特点				疾病	结局
患儿	年龄	性别	主要临床特点	干预措施	血氨/ μmol·L^-1	变异基因	变异位点	致病性	来源	疾病	结局
例1	5天	女	高血氨，心跳呼吸骤停，休克，昏迷状态，代谢异常（瓜氨酸 936 μmol·L^-1，鸟氨酸、精氨酸正常；尿乳清酸增高10.5 μmol·L^-1，高5~10倍）	抗休克治疗+限制蛋白摄入+精氨酸+左卡尼汀+苯丁酸钠+呼吸机通气	655	ASS1	c.1128_1134delinsG（p.Ser376_Asn378del）	致病	母源	瓜氨酸血症I型	好转
例1	5天	女		抗休克治疗+限制蛋白摄入+精氨酸+左卡尼汀+苯丁酸钠+呼吸机通气	655	ASS1	Chr9q34.11（133364710-133376418）缺失	致病	父源	瓜氨酸血症I型	好转
例2	3天	女	高血氨、气促、呻吟、抽搐、昏迷状态，代谢异常（瓜氨酸852.59 μmol·L^-1，鸟氨酸、精氨酸正常）	氧疗+止痉+限制蛋白摄入+特殊配方奶粉喂养+精氨酸+左卡尼汀+护肝	2 077	ASS1	c.981_1018del38 （p.H327 Qfs*33）	可能致病	母源	瓜氨酸血症I型	好转
例2	3天	女	高血氨、气促、呻吟、抽搐、昏迷状态，代谢异常（瓜氨酸852.59 μmol·L^-1，鸟氨酸、精氨酸正常）	氧疗+止痉+限制蛋白摄入+特殊配方奶粉喂养+精氨酸+左卡尼汀+护肝	2 077	ASS1	c.421-2A>G	可能致病	父源	瓜氨酸血症I型	好转
例3	3天	男	病情进展快，浅昏迷和多器官功能障碍，家属放弃	呼吸机通气+限制蛋白摄入+精氨酸	1 485	OTC	c.421C>T（p.Arg141*）	致病	母源	OTCD	死亡
例4	7天	男	血氨升高、代谢异常、电解质紊乱和多器官功能障碍，家属放弃	呼吸机通气+限制蛋白摄入+精氨酸+左卡尼汀	1 250	OTC	c.512A>G（p.Q171R）	可能致病	母源	OTCD	死亡
例5	10天	男	代谢异常（血多种氨基酸增高，尿嘧啶和乳清酸排泄增高）	限制蛋白摄入+精氨酸+左卡尼汀	287	OTC	c.782T>C（p. I 261 T）	致病	母源	OTCD	失访
例6	11天	男	血氨升高，代谢异常，多器官功能障碍，有家族史，家属放弃	呼吸机通气+限制蛋白摄入+精氨酸	90	OTC	c.119G>A（p.Arg40His）	致病	母源	OTCD	死亡

Genetic screening and early intervention in neonatal hyperammonemia caused by urea cycle disorder

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