中国北方3-羟基异戊酰肉碱异常患儿代谢及遗传分析

doi:10.12372/jcp.2023.22e0556

临床儿科杂志 ›› 2023, Vol. 41 ›› Issue (10): 692-696.doi: 10.12372/jcp.2023.22e0556

中国北方3-羟基异戊酰肉碱异常患儿代谢及遗传分析

张万巧¹^,³^,⁴, 闫磊¹^,³^,⁴, 朱丽娜²^,³^,⁴, 马秀伟²^,³^,⁴()

1.中国人民解放军总医院第七医学中心儿科医学部儿科研究所（北京 100700）
2.中国人民解放军总医院第七医学中心儿科医学部儿内科（北京 100700）
3.中国人民解放军总医院第七医学中心儿科医学部出生缺陷防控关键技术国家工程实验室（北京 100700）
4.中国人民解放军总医院第七医学中心儿科医学部儿童器官功能衰竭北京市重点实验室（北京 100700）

收稿日期:2022-04-26 出版日期:2023-10-15 发布日期:2023-10-08
通讯作者: 马秀伟, 电子信箱：pony007@vip.sina.com
基金资助:
吴阶平医学基金会临床科研专项资助基金(320.6750.2020-06-74);国家重点研发计划课题(2018YFC1002701)

Metabolic and genetic analysis of abnormal 3-hydroxyisovalerylcarnitine in children from northern China

ZHANG Wanqiao¹^,³^,⁴, YAN Lei¹^,³^,⁴, ZHU Lina²^,³^,⁴, MA Xiuwei²^,³^,⁴()

1. Pediatric Research Institute, Senior Department of Pediatrics, The Seventh Medical Center of PLA General Hospital, Beijing 100700, China
2. Pediatric Internal Medicine, Senior Department of Pediatrics, The Seventh Medical Center of PLA General Hospital, Beijing 100700, China
3. National Engineering Laboratory for Birth defects Prevention and Control of Key Technology, Senior Department of Pediatrics, The Seventh Medical Center of PLA General Hospital, Beijing 100700, China
4. Beijing Key Laboratory of Pediatric Organ Failure, Senior Department of Pediatrics, The Seventh Medical Center of PLA General Hospital, Beijing 100700, China

Received:2022-04-26 Published:2023-10-15 Online:2023-10-08

摘要/Abstract

摘要：

目的研究血3-羟基异戊酰肉碱（C5OH）增高对诊断相关遗传代谢病（IMD）的意义，并探讨北方人群中该指标异常患儿的疾病谱及遗传学特点。方法回顾性分析2012年11月至2021年10月住院患儿的IMD筛查诊断资料，包括干血斑串联质谱（MS/MS）、尿液气相质谱（GC-MS）检测以及基因变异的高通量测序结果。分析C5OH指标异常患儿的血、尿代谢谱及基因变异谱。结果 53 119例0~7岁住院患儿检出C5OH增高48例（0.090%），结合尿GC-MS分析生化诊断相关IMD 9例（0.017%），且均基因验证。提示多种羧化酶缺乏（MCD）的4例患儿中，2例检出HLCS变异，确诊为全羧化酶合成酶缺乏；2例检出BTD变异，确诊为生物素酶缺乏。提示β-酮硫解酶缺乏症的2例均检出ACAT1变异；提示3羟基3甲基戊二酸尿症的1例检出HMGCL变异。生化诊断未分型疑似MCD或3-甲基巴豆酰辅酶A羧化酶缺乏的2例，1例检出HLCS变异，另1例检出BTD变异，最终确诊MCD。C5OH单一指标假阳性率0.073%，阳性预测值18.75%；合并多指标（C4OH、C3、C5:1）假阳性率0.009%，阳性预测值58.33%；合并尿GC-MS分析无一假阳性，阳性预测值达100%。结论 MCD 是血C5OH增高患儿中的主要疾病类型。对于C5OH相关IMD，MS/MS联合GC-MS的代谢分析具有较高的诊断效率及提前指导干预的临床价值。

关键词: 羟基异戊酰肉碱, 串联质谱, 代谢谱, 基因变异谱

Abstract:

Objective To investigate the significance of elevated blood 3-hydroxyisovalerylcarnitine (C5OH) in the diagnosis of inherited metabolic diseases (IMD) and to explore the disease spectrum and genetic characteristics of children with abnormal C5OH in the population of northern China. Methods The data of IMD screening and diagnosis in hospitalized children from November 2012 to October 2021 were retrospectively analyzed, including tandem mass spectrometry (MS/MS) screening of blood metabolites, gas chromatography-mass spectrometry (GC-MS) analysis of urine metabolites and high-throughput sequencing analysis of gene variations. The blood and urine metabolic spectrum and gene variation spectrum of children with abnormal C5OH were analyzed. Results Among 53119 hospitalized children aged 0 to 7 years who underwent MS/MS screening for IMD, 48 (0.090%) children with increased C5OH were detected. Combined with urine GC-MS analysis, 9 (0.017%) children obtained biochemical diagnosis of IMD which verified by gene analysis. Of the 4 children with multiple carboxylase deficiency (MCD), 2 had HLCS gene variation and were confirmed as holocarboxylase synthetase deficiency, while the other 2 had BTD gene variation and were confirmed as biotinidase deficiency. ACAT1 variation was detected in 2 children with β-ketothiolase deficiency, and HMGCL variation was detected in 1 child with 3-hydroxy-3-methyl-glutaricacidemia. In 2 children with suspected MCD or 3-methylcrotonyl coenzyme A carboxylase deficiency that were not classified by biochemical diagnosis, HLCS variation was detected in 1 child, and BTD variation was detected in the other child, and MCD was finally diagnosed. The false positive rate of C5OH detection was 0.073% and the positive predictive value was 18.75%. The false positive rate of C5OH combined with other indicators (C4OH, C3 and C5:1) was 0.009%, and the positive predictive value was 58.33%. There was no false positive in the analysis of C5OH combined with urinary GC-MS, and the positive predictive value was 100%. Conclusions MCD is the main disease type in children with increased C5OH. For C5OH-related IMD, MS/MS combined with GC-MS metabolic analysis has high diagnostic efficiency and clinical value of guiding intervention in advance.

Key words: hydroxyisovalerylcarnitine, tandem mass spectrometry, metabolic spectrum, gene variation spectrum

张万巧, 闫磊, 朱丽娜, 马秀伟. 中国北方3-羟基异戊酰肉碱异常患儿代谢及遗传分析[J]. 临床儿科杂志, 2023, 41(10): 692-696.

ZHANG Wanqiao, YAN Lei, ZHU Lina, MA Xiuwei. Metabolic and genetic analysis of abnormal 3-hydroxyisovalerylcarnitine in children from northern China[J]. Journal of Clinical Pediatrics, 2023, 41(10): 692-696.

图/表 2

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参考文献 17

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指标	HLCS			BTD			HMGCL	ACAT1		参考范围
指标	1	2	3	4	5	6	7	8	9	参考范围
C0	41.85	44.77	24.24	41.37	126.19	70.08	32.57	22.38	36.55	8.00~60.00
C3	2.63	7.47	8.20	4.04	10.51	5.56	1.36	0.43	0.72	0.20~4.50
C5:1	0.01	0.01	0.03	0.02	0.02	0.01	0.03	0.15	0.13	0~0.05
C3DC+C4OH	0.48	0.24	0.30	0.25	0.21	0.13	0.24	0.97	0.97	0~0.30
C4DC+C5OH	4.93	3.11	7.82	3.89	2.69	0.74	2.46	0.60	0.60	0~0.40
C3/C0	0.09	0.25	0.34	0.15	0.12	0.08	0.06	0.03	0.02	0~0.22
C3/C2	0.13	0.28	0.27	0.13	0.14	0.07	0.05	0.03	0.02	0~0.24

病例	性别	生化诊断	变异基因	转录本	基因型	碱基改变	氨基酸改变	来源	ACMG分类	编号
1	女	MCD/3MCCD	HLCS	NM_000411.8	Het	c.1544G>A c.1648G>A	p.Ser515Asn p.Val550Met	父亲母亲	可能致病致病	428585²⁾ 11735028¹⁾
2	男	MCD	HLCS	NM_000411.8	Het	c.1522C>T c.1313delC	p.Arg508Trp p.Pro438Leufs*3	父亲母亲	致病可能致病	11735028¹⁾ 未报道
3	男	MCD	HLCS	NM_000411.8	Het	c.1544G>A c.1648G>A	p.Ser515Asn p.Val550Met	父亲母亲	可能致病致病	428585²⁾ 11735028¹⁾
4	男	MCD/3MCCD	BTD	NM_000060.4	Het	c.172T>C c.1413T>C	p.Tyr58His p.Cys471Cys	父亲母亲	可能致病良性	未报道 11668630¹⁾
5	男	MCD	BTD	NM_000060.4	Het	c.491dupG c.637delC	p.Arg164fs p.His213fs	父亲母亲	可能致病可能致病	未报道 590811²⁾
6	女	MCD	BTD	NM_000060.4	Hom	c.1491dupT	p.Pro497fs	父/母	致病	17382128²⁾

中国北方3-羟基异戊酰肉碱异常患儿代谢及遗传分析

Metabolic and genetic analysis of abnormal 3-hydroxyisovalerylcarnitine in children from northern China

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