海南省少数民族地区脂肪酸氧化代谢病新生儿筛查结果分析

doi:10.12372/jcp.2024.22e1193

摘要/Abstract

摘要：

目的探讨海南省少数民族地区新生儿人群脂肪酸氧化代谢障碍（FAOD）的发病率，分析确诊患儿的临床特点，为海南省出生缺陷预防提供依据。方法收集海南省少数民族地区2016年10月至2021年12月新生儿遗传代谢疾病串联质谱筛查数据。采用串联质谱技术检测新生儿干血斑中游离肉碱以及30种酰基肉碱水平。初筛阳性新生儿进行召回复查血串联质谱，气相质谱测尿有机酸，采集新生儿及其父母外周血进行基因测序。结果研究期间共出生66 578名新生儿，参与筛查46 285名（69.5%），初筛阳性513例（初筛阳性率为1/90），召回501例，确诊FAOD 11例，发病率1/4208，其中原发性肉碱缺乏症6例，短链、中链、极长酰基辅酶A脱氢酶缺乏症各1例，肉碱棕榈酰转移酶Ⅰ和Ⅱ缺乏症各1例。结论海南省少数民族地区新生儿人群FAOD发病率较高，以原发性肉碱缺乏症较为多见。建议将新生儿遗传代谢病串联质谱筛查纳入新生儿常规筛查项目。

关键词: 脂肪酸氧化代谢障碍, 串联质谱法, 酰基肉碱, 新生儿筛查

Abstract:

Objective To investigate the incidence of fatty acid oxidative metabolism disorders (FAOD) in the neonatal population in ethnic minority areas of Hainan Province, and to analyse the clinical characteristics of the diagnosed children, so as to provide the basis for the prevention of birth defects in Hainan Province. Methods Tandem mass spectrometry screening data of newborns with inherited metabolic disorders from October 2016 to December 2021 were collected from ethnic minority areas in Hainan Province. Tandem mass spectrometry was used to detect the levels of free carnitine as well as 30 acylcarnitines in dried blood spots of newborns. Initial screen-positive neonates were recalled for review of blood tandem mass spectrometry, urinary organic acids were measured by gas-phase mass spectrometry, and peripheral blood was collected from neonates and their parents for gene sequencing. Results A total of 46285 newborn samples were screened, of which 513 were positive in the first screening, the positive rate of the first screening was 1/90, 501 cases were recalled, and 11 cases of fatty acid β -oxidation metabolic disease were diagnosed, the incidence rate was 1/4208, including 6 cases of primary carnitine deficiency, 1 case of short chain, medium chain and very long acyl-CoA dehydrogenase deficiency, and 1 case of carnitine palmitoyl transferase I and II deficiency. Conclusion The incidence of fatty acid β-oxidative metabolic disease is high among newborns in minority areas of Hainan province, and primary carnitine deficiency is more common. It is suggested that the screening of neonatal genetic metabolic diseases by tandem mass spectrometry should be included in the routine of newborn screening program.

Key words: fatty acid oxidative metabolic disease, tandem mass spectrometry, acyl carnitine, newborn screening

黄慈丹, 许海珠, 温英梅, 刘秀莲. 海南省少数民族地区脂肪酸氧化代谢病新生儿筛查结果分析[J]. 临床儿科杂志, 2024, 42(2): 133-138.

HUANG Cidan, XU Haizhu, WEN Yingmei, LIU Xiulian. Analysis of the results of newborn screening for fatty acid oxidative metabolic diseases in ethnic minority areas of Hainan Province[J]. Journal of Clinical Pediatrics, 2024, 42(2): 133-138.

图/表 3

表1

表2

表3

11例FAOD患儿治疗随访情况"

病例	性别	确诊年龄	末次随访年龄	治疗情况	随访情况
PCD	男	1月7天	4岁3月	左卡尼汀100~200 mg·kg^-1·d^-1保持C0在正常或接近正常水平	体格检查、智力发育、肝功能、心肌酶谱、心电图、彩色多普勒超声心动图未见异常
PCD	男	6月13天	4岁2月	左卡尼汀100~200 mg·kg^-1·d^-1保持C0在正常水平	体格检查、智力发育、肝功能、心肌酶谱、心电图、彩色多普勒超声心动图未见异常
PCD	男	1月18天	4岁	左卡尼汀100~200 mg·kg^-1·d^-1保持C0在正常水平	体格检查、智力发育、肝功能、心肌酶谱、心电图、彩色多普勒超声心动图未见异常
PCD	男	3月2天	3岁3月	左卡尼汀100~200 mg·kg^-1·d^-1保持C0在正常水平	体格检查、智力发育、肝功能、心肌酶谱、心电图、彩色多普勒超声心动图未见异常
PCD	男	3月15天	4岁4月	左卡尼汀100~200 mg·kg^-1·d^-1保持C0在正常水平	体格检查、智力发育、肝功能、心肌酶谱、心电图、彩色多普勒超声心动图未见异常
PCD	女	1岁1月	3岁11月	左卡尼汀100~200 mg·kg^-1·d^-1保持C0在正常或接近正常水平	1岁确诊，心肌受损、致密化不全，射血分数低，肝功能、心电图异常。经规律用药后，上述检测指标逐渐恢复正常
SCADD	女	3月9天	2岁7月	低脂肪饮食，避免饥饿、限制运动时间和强度，补充肉碱、维生素B₂	体格检查、智力发育、肝功能、心肌酶谱、心电图、彩色多普勒超声心动图未见异常
MCADD	男	3月6天	3岁6月	采用低脂肪饮食，避免饥饿、限制运动时间和强度，未用药物治疗	体格检查、智力发育、肝功能、心肌酶谱、心电图、彩色多普勒超声心动图未见异常
VLCADD	女	5月6天	5岁1月	高碳水化合物和低脂肪饮食，补充中链三酰甘油，避免饥饿、限制运动时间和强度	因“感冒、纳差、幼儿园运动时间长”出现昏迷，当地诊所输注葡萄糖后缓解。平素随访依从性差，体格检查、智力发育、肝功能、心肌酶谱、心电图、彩色多普勒超声心动图未见异常
CPTⅠ	女	6月3天	-	家长拒绝随访	失访
CPTⅡ	男	8月7天	4岁1月	高碳水化合物和低脂肪饮食，避免饥饿、限制运动时间和强度	体格检查、智力发育、肝功能、心肌酶谱、心电图、彩色多普勒超声心动图未见明显异常

表3

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病例	民族	C0	C2	C3	C3DC+ C4OH	C4	C4DC+ C5OH	C5	C6	C8	C10	C12	C14	C16	C18	其他异常指标
1	汉	2.39↓	2.26↓	0.27↓	0.01↓	0.03↓	0.03↓	0.01↓	0.01	0.01↓	0.01↓	0.01↓	0.04↓	0.56	0.15↓
2	汉	4.83↓	3.22↓	0.27↓	0.03	0.05↓	0.10	0.02↓	0.03	0.03	0.03	0.02	0.04↓	0.86	0.26↓
3	黎	2.17↓	0.59↓	0.1↓	0.01↓	0.02↓	0.04↓	0.01↓	0↓	0.01↓	0.01↓	0.01↓	0.01↓	0.12↓	0.1↓
4	汉	4.47↓	2.16↓	0.28↓	0.01↓	0.03↓	0.06↓	0.02↓	0.01	0.01↓	0.01↓	0.02	0.03↓	0.48	0.18↓
5	黎	3.14↓	1.98↓	0.29↓	0.02↓	0.03↓	0.06↓	0.03↓	0.01	0.01↓	0.02	0.02	0.04↓	0.80	0.23↓
6	汉	1.07↓	0.35↓	0.03↓	0.01↓	0.02↓	0.02↓	0.01↓	0↓	0.01↓	0.01↓	0.01↓	0.01↓	0.09↓	0.07↓
7	汉	32.83	12.61	1.54	0.04	1.17↑	0.19	0.16	0.05	0.04	0.05	0.05	0.10	0.79	0.26↓
8	汉	39.10	15.33	3.12	0.04	0.13	0.21	0.25	1.26↑	12.85	0.39	0.25	0.16	2.96	1.35
9	汉	28.98	9.94	1.72	0.03	0.09	0.28	0.08	0.02	0.02	0.04	0.14	1.01↑	2.38	1.64	C14:1 (1.59↑)
10	黎	65.34	11.58	1.69	0.11	0.22	0.37	0.06	0.03	0.02	0.02	0.02	0.05↓	0.16↓	0.12↓
11	黎	24.11	12.38	1.03	0.16	0.19	0.44↑	0.08	0.02	0.02	0.02	0.29↑	0.86↑	6.68↑	1.91↑	(C16+ C18:1)/ C2(0.42↑)

病种	基因	变异1		变异2		纯合/ 复合杂合
病种	基因	核苷酸改变	氨基酸改变	核苷酸改变	氨基酸改变	纯合/ 复合杂合
PCD	SLC22A5	c.760C>T	p.Arg254*	c.51C>G	p.Phe17Leu	复合杂合
PCD	SLC22A5	c.760C>T	p.Arg254*	c.1400C>G	p.Ser467Cys	复合杂合
PCD	SLC22A5	c.760C>T	p.Arg254*	c.51C>G	p.Phe17Leu	复合杂合
PCD	SLC22A5	c.760C>T	p.Arg254*	c.760C>T	p.Arg254*	纯合
PCD	SLC22A5	c.51C>G	p.Phe17Leu	c.51C>G	p.Phe17Leu	纯合
PCD	SLC22A5	c.51C>G	p.Phe17Leu	c.51C>G	p.Phe17Leu	纯合
SCADD	ACADS	c.889C>T	p.Arg297Cys	c.256G>A	p.Glu86Lys	复合杂合
MCADD	ACADM	c.1097G>A	p.Gly366Glu	c.1097G>A	p.Gly366Glu	纯合
VLCADD	ACADVL	c.664G>A	p.Gly222Arg	c.1819T>G	p.Cys607Gly	复合杂合
CPTⅠ	CPT1A	c.1163+4C>T	-	c.1163+4C>T	-	纯合
CPTⅡ	CPT2	c.1408G>T	p.Ala470Ser	c.1102G>A	p.Val368Ile	复合杂合