钠牛磺胆酸共转运多肽缺陷病临床特征及SLC10A1基因突变分析

杨峰霞; 曾凡森; 谭丽梅; 龚余; 刘玲丽; 徐翼

doi:10.3969/j.issn.1001-5256.2022.03.022

钠牛磺胆酸共转运多肽缺陷病临床特征及SLC10A1基因突变分析

DOI: 10.3969/j.issn.1001-5256.2022.03.022

广州市妇女儿童医疗中心感染性疾病科，广州 510120

基金项目:

广州市卫生健康科技项目 (20201A011036)

伦理学声明：本研究方案于2019年8月22日经由广州市妇女儿童医疗中心伦理委员会批准，批号：穗妇儿2019-32400，所有检查均取得患儿家属知情同意。

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：杨峰霞负责课题设计，资料分析，撰写论文；曾凡森、谭丽梅、龚余、刘玲丽参与收集数据，修改论文；徐翼负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
徐翼，E-mail: xuyi70@163.com

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出版历程
- 收稿日期: 2021-08-17
- 录用日期: 2021-09-20
- 出版日期: 2022-03-20

Clinical features of sodium taurocholate cotransporting polypeptide deficiency and an analysis of SLC10A1 gene mutation

Department of Infectious Diseases, Guangzhou Women and Children's Medical Center, Guangzhou 510120, China

Research funding:

Guangzhou Health Science and Technology Project (20201A011036)

More Information

Corresponding author: XU Yi, xuyi70@163.com(ORCID: 0000-0001-8971-9334)

摘要

摘要: 目的总结钠牛磺胆酸共转运多肽(NTCP)缺陷病的临床和基因突变特征。方法选取2020年6月—2021年6月于广州市妇女儿童医疗中心经基因检测确诊的10例NTCP缺陷病患儿(年龄 < 18岁)，分析一般资料(性别、年龄、身高、体质量、家族史和既往病史)、临床表现、病情转归、实验室检查(血常规、肝功能、嗜肝病毒、自身免疫性肝炎筛查)及基因突变检测结果。结果 10例患儿生长发育均正常，其中男8例，女2例；确诊年龄3~37个月。首次就诊病因包括新生儿黄疸延长(5/10，50%)、转氨酶升高(2/10，20%)、体检(2/10，20%)和肺炎(1/10，10%)。所有患儿确诊时血清TBA水平均明显升高；ALT、AST水平升高2例；TBil水平升高1例，且以DBil水平升高为主(DBil/TBil＞50%)。经第二代基因测序，10例患儿均为SLC10A1基因纯合突变：c.800C＞T(p.Ser267Phe，chr14∶70245193)。结论尽管NTCP缺乏症往往无明显症状，但部分患儿早期可表现为婴儿胆汁淤积症，对于显著而持续的高胆汁酸血症，且血清总TBA水平与其他肝功能指标的变化趋势不一致时，应考虑NTCP缺陷病可能。
- 代谢疾病 /
- 钠牛磺胆酸共转运多肽 /
- SLC10A1基因 /
- 胆汁淤积
Abstract: Objective To investigate the clinical and gene mutation features of sodium taurocholate cotransporting polypeptide (NTCP) deficiency. Methods A total of 10 children, aged < 18 years, who were diagnosed with NTCP deficiency in Guangzhou Women and Children's Medical Center from June 2020 to June 2021 were enrolled, and related data were analyzed, including general information (sex, age, body height, body weight, family history, and past history), clinical manifestation, disease outcome, laboratory examination (routine blood test, liver function, hepatotropic virus, and autoimmune hepatitis screening), and gene mutation. Results All 10 children had normal growth and development, among whom there were 8 boys and 2 girls, with an age of 3-37 months at the time of diagnosis. The etiology of children attending the hospital for the first time was prolonged jaundice (5/10, 50%), elevation of aminotransferases (2/10, 20%), abnormal physical examination results (2/10, 20%), and pneumonia (1/10, 10%). At the time of diagnosis, all children had a significant increase in serum total bile acid (TBA), 2 children had increases in alanine aminotransferase and aspartate aminotransferase, and 1 child had an increase in total bilirubin (TBil), mainly direct bilirubin (DBil) (DBil/TBil ratio > 50%). Second-generation gene sequencing showed that all 10 children had a homozygous mutation of the SLC10A1 gene, i.e., c.800C > T(p.Ser267Phe, chr14∶70245193). Conclusion Although NTCP deficiency often has no symptoms, some of the children may manifest as infant cholestasis in the early stage. The possibility of NTCP deficiency should be considered when there is persistent hypercholanemia and the changing trend of serum TBA is not consistent with that of other liver function parameters.
- Metabolic Diseases /
- Sodium-Taurocholate Cotransporting Polypeptide /
- SLC10A1 Gene /
- Cholestasis

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表 1 确诊时患儿主要临床表现、实验室检查结果

病例	性别	发病/确诊年龄(月)	首次就诊原因	ALT (U/L)	AST (U/L)	TBil (μmol/L)	DBil (μmol/L)	IBil (μmol/L)	TBA (μmol/L)	Alb (g/L)	GGT (U/L)
P1	男	-/10	体检	26	36	6.6	1.0	5.6	108.3	41.1	9
P2	男	2/37	转氨酶高	15	36	5.7	1.8	3.9	107.8	45.4	11
P3	男	1/4	黄疸	38	42	13.7	6.5	7.2	230.0	43.1	42
P4	女	2/13	肺炎	32	43	4.4	1.0	3.4	69.3	48.4	11
P5	男	1/23	黄疸	24	36	8.5	1.5	7.0	44.4	45.2	8
P6	男	1/3	黄疸	441	355	112.5	82.3	30.2	221.6	45.6	103
P7	男	1/4	黄疸	34	34	3.8	0.7	3.1	97.1	46.7	34
P8	女	1/5	黄疸	40	67	9.9	3.6	6.3	316.4	43.3	22
P9	男	3/13	转氨酶升高	53	58	6.0	1.5	4.5	245.6	45.2	12
P10	男	-/13	体检	27	34	11.4	3.2	8.2	107.2	44.3	35
注：ALT正常值范围7~40 U/L，AST正常值范围5~60 U/L，TBil正常值范围2~17 μmol/L，DBil正常值范围0~7 μmol/L，IBil正常值范围2~13.7 μmol/L，TBA正常值范围0.5~10 μmol/L，Alb正常值范围40~55 g/L，GGT正常值范围7~45 U/L。“-”表示发病时间不明确。

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表 2 10例患儿及其父母第二代基因检测结果

病例	患儿碱基改变	父亲碱基改变	母亲碱基改变	氨基酸改变	HGMD报道	ACMG分级	备注
P1	c.800C＞T(纯合)	c.800C＞T(杂合)	c.800C＞T(纯合)	p.Ser267phe	DFP	致病	母亲无症状，血清TBA 18.4 μmol/L
P2	c.800C＞T(纯合)	c.800C＞T(杂合)	c.800C＞T(杂合)	p.Ser267phe	DFP	致病	35周早产
P3	c.800C＞T(纯合)	c.800C＞T(杂合)	c.800C＞T(杂合)	p.Ser267phe	DFP	致病	无
P4	c.800C＞T(纯合)	c.800C＞T(杂合)	c.800C＞T(纯合)	p.Ser267phe	DFP	致病	母亲孕期高TBA水平
P5	c.800C＞T(纯合)	c.800C＞T(杂合)	c.800C＞T(杂合)	p.Ser267phe	DFP	致病	无
P6	c.800C＞T(纯合)	c.800C＞T(杂合)	c.800C＞T(杂合)	p.Ser267phe	DFP	致病	足月小样儿
P7	c.800C＞T(纯合)	c.800C＞T(杂合)	c.800C＞T(杂合)	p.Ser267phe	DFP	致病	无
P8	c.800C＞T(纯合)	c.800C＞T(杂合)	c.800C＞T(杂合)	p.Ser267phe	DFP	致病	父亲确诊为肝豆状核变性
P9	c.800C＞T(纯合)	c.800C＞T(杂合)	c.800C＞T(杂合)	p.Ser267phe	DFP	致病	无
P10	c.800C＞T(纯合)	c.800C＞T(杂合)	c.800C＞T(纯合)	p.Ser267phe	DFP	致病	母亲无症状，血清TBA 21.6 μmol/L
注：DFP，有功能证据的与疾病相关的多态性。

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