Occurrence and Gene Analysis of Primary Carnitine Deficiency in Li Nationality Newborns in Hainan Province

doi:10.12114/j.issn.1007-9572.2020.00.293

Abstract

Abstract: Background　Primary carnitine deficiency（PCD） is considered as a potentially lethal disease.The loss of carnitine transporter function will lead to the obstruction of fatty acid β oxidation metabolism.Without timely carnitine supplementation，patients with PCD will suffer from acute metabolic decompensation early in life，and bone disease and cardiomyopathy or even sudden death of arrhythmias will occur in the later stages of life.Therefore，PCD screening in neonatal period can prevent sudden death due to acute energy metabolism disorder or acute heart failure and ensure the quality of life and safety of life.Objective　To investigate the incidence of PCD in neonates of Li nationality in Hainan Province，and explore the types of gene mutations in Li nationality population.Methods　Through the Hainan Provincial Newborn Screening Network Platform，22 950 neonates（3 to 28 days after birth） of Li nationality born in Hainan Province from August 1 in 2016 to July 31 in 2019 were collected.The C0 and acylcarnitine（C2，C3，C16，and C18） were screened by tandem mass spectrometry.The suspected neonates（C0<10.0 μmol/L） and mothers were recalled for tandem mass spectrometry.Blood samples of those with low C0 were sent for SLC22A5 gene sequencing.The diagnosis of PCD was based on the detection of SLC22A5 gene mutation.Results　Among the initial screening of 22 950 neonates of Li nationality，the C0 of 14 cases was low，and the abnormal rate was1/1 639（14/22 950） with 7（1/1 710） males and 7（1/1 569） females.There was no significant difference in the abnormal rate of initial screening among Li neonates of different genders（χ2=0.026，P=0.872）.After SLC22A5 gene sequencing，10 neonates were diagnosed with PCD.The incidence of PCD in Li neonates was 1/2 295（10/22 950），of which seven cases had heterozygous mutations and three had homozygous mutations，and 5（1/2 394） cases were males and 5（1/2 196） were females.There was no significant difference in the incidence of PCD among Li neonates of different genders（χ2=0.019，P=0.892）.A total of eight types of gene mutations were detected，c.51C>G，c.760C>T，c.338G>A，c.428C>T，c.1340A>T，c.825G>A，c.4442C>T，and c.1400C>G.Conclusion　The incidence of PCD in Li neonates in Hainan Province is high（1/2 295）.PCD genes have abundant mutations，and c.51C>G and c.760C>T mutations are more common.

Key words: Deficiency diseases, Primary carnitine deficiency, Li nationality, Newborn screening, Tandem mass spectrometry, Genes

摘要： 背景　原发性肉碱缺乏症（PCD）被认为是一种潜在致死性疾病，肉碱转运蛋白功能缺陷会导致脂肪酸β氧化代谢受阻，如果没有及时补充肉碱，PCD患者在生命早期就会出现急性代谢失代偿，或晚期出现骨骼和心肌病或心律失常突然死亡。因此在新生儿期开展PCD筛查，对患儿早期治疗能防范急性能量代谢障碍危象或急性心力衰竭而猝死情况的发生，保证生活质量和生命安全。目的　调查海南省黎族新生儿PCD的发病情况，并探究黎族人群PCD基因突变类型。方法　借助海南省新生儿筛查网络平台，收集2016-08-01至2019-07-31在海南省出生的黎族新生儿22 950例（出生3~28 d）。通过串联质谱技术筛查黎族新生儿游离肉碱（C0）及酰基肉碱（C2、C3、C16、C18等指标）。可疑患儿（C0<10.0 μmol/L）需母婴同时召回，复查串联质谱检测，C0仍低者外送血标本进行SLC22A5基因测序。PCD基因确诊依据：检测到SLC22A5基因突变。结果　22 950例黎族新生儿初筛C0减低14例，初筛异常发生率为1/1 639（14/22 950），其中男7例（1/1 710），女7例（1/1 569）；不同性别黎族新生儿PCD初筛异常发生率比较，差异无统计学意义（χ2=0.026，P=0.872）。经SLC22A5基因测序，10例黎族新生儿确诊为PCD，黎族新生儿PCD发生率为1/2 295（10/22 950），其中7例为杂合突变，3例为纯合突变；男5例（1/2 394），女5例（1/2 196）；不同性别黎族新生儿PCD发生率比较，差异无统计学意义（χ2=0.019，P=0.892）。共检出8种基因突变类型：c.51C>G、c.760C>T、c.338G>A、c.428C>T、c.1340A>T、c.825G>A、c.4442C>T、c.1400C>G。结论　海南省黎族新生儿PCD发生率较高（1/2 295），基因突变类型较为丰富，以c.51C>G和c.760C>T基因突变较为常见。

关键词: 缺乏症, 原发性肉碱缺乏症, 黎族, 新生儿筛查, 串联质谱法, 基因

WEN Yingmei,ZHAO Zhendong,WANG Jie. Occurrence and Gene Analysis of Primary Carnitine Deficiency in Li Nationality Newborns in Hainan Province　[J]. Chinese General Practice, 2020, 23(18): 2299-2303. DOI: 10.12114/j.issn.1007-9572.2020.00.293.
温英梅,赵振东,王洁. 海南省黎族新生儿原发性肉碱缺乏症筛查及基因情况分析[J]. 中国全科医学, 2020, 23(18): 2299-2303. DOI: 10.12114/j.issn.1007-9572.2020.00.293.

References

［1］王维鹏，邹琳，王治国.新生儿疾病筛查与产前诊断实验室管理［M］．北京：人民卫生出版社，2018.
［2］杨茹莱，童凡，郑静.原发性肉碱缺乏症筛查诊断及治疗［J］．中国实用儿科杂志，2019，34（1）：14-18．DOI：10.19538/j.ek2019010606.
YANG R L，TONG F，ZHENG J.Screening，diagnosis and treatment of primary carnitine deficiency［J］．Chinese Journal of Practical Pediatrics，2019，34（1）：14-18．DOI：10.19538/j.ek2019010606.
［3］HASSAN F A，EL-MOUGY F，SHARAF S A，et al．Inborn errors of metabolism detectable by tandem mass spectrometry in Egypt：the first newborn screening pilot study［J］．J Med Screen，2016，23（3）：124-129．DOI：10.1177/0969141315618229.
［4］THERRELL B L Jr，LLOYD-PURYEAR M A，CAMP K M，et al．Inborn errors of metabolism identified via newborn screening：ten-year incidence data and costs of nutritional interventions for research agenda planning［J］．Mol Genet Metab，2014，113（1/2）：14-26．DOI：10.1016/j.ymgme.2014.07.009.
［5］陈大宇，谭建强，杨金玲，等．桂中地区原发性肉碱缺乏症基因测序精准检测及研究［J］．中国优生与遗传杂志，2018，26（6）：13-14．DOI：10.13404/j.cnki.cjbhh.2018.06.004.
CHEN D Y，TAN J Q，YANG J L，et al．Precision testing and research of primary carnitine deficiency in Central Guangxi［J］．Chinese Journal of Birth Health & Heredity，2018，26（6）：13-14．DOI：10.13404/j.cnki.cjbhh.2018.06.004.
［6］LONGO N，FRIGENI M，PASQUALI M.Carnitine transport and fatty acid oxidation［J］．Biochim Et Biophys Acta BBA-Mol Cell Res，2016，1863（10）：2422-2435．DOI：10.1016/j.bbamcr.2016.01.023.
［7］ROSE E C，DI SAN FILIPPO C A，NDUKWE ERLINGSSON U C，et al．Genotype-phenotype correlation in primary carnitine deficiency［J］．Hum Mutat，2012，33（1）：118-123．DOI：10.1002/humu.21607.
［8］LI F Y，EL-HATTAB A W，BAWLE E V，et al．Molecular spectrum of SLC22A5 （OCTN2） gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency［J］．Hum Mutat，2010，31（8）：E1632-1651．DOI：10.1002/humu.21311.
［9］中华人民共和国卫生行业标准（WS 376.3—2013）［EB/OL］．（2013-12-27）［2019-05-02］．http://www.doc88.com/p-4999198359185.html.
［10］GUEVARA-CAMPOS J，GONZáLEZ-GUEVARA L，GUEVARA-GONZáLEZ J，et al．First case report of primary carnitine deficiency manifested as intellectual disability and autism spectrum disorder［J］．Brain Sci，2019，9（6）：E137．DOI：10.3390/brainsci9060137.
［11］LONGO N，FRIGENI M，PASQUALI M.Carnitine transport and fatty acid oxidation［J］．Biochim Biophys Acta，2016，1863（10）：2422-2435．DOI：10.1016/j.bbamcr.2016.01.023.
［12］顾学范.临床遗传代谢病［M］．北京：人民卫生出版社，2015.
［13］崔冬，胡宇慧，唐根，等．原发性肉碱缺乏症临床和基因突变特点及1例产前诊断研究［J］．临床儿科杂志，2019，37（6）：449-453．DOI：10.3969/j.issn.1000-3606.2019.06.012.
CUI D，HU Y H，TANG G，et al．Clinical and gene mutation characteristics of primary carnitine deficiency and prenatal diagnosis in one case［J］．Journal of Clinical Pediatrics，2019，37（6）：449-453．DOI：10.3969/j.issn.1000-3606.2019.06.012．
［14］孙英梅，宋东坡，王伟青，等．新生儿原发性肉碱缺乏症诊治与基因突变分析［J/OL］．中国儿童保健杂志，2019．［2019-03-26］．http：//kns.cnki.net/kcms/detail/61.1346.R.20190325.1449.018.html.
［15］ZHOU W，LI H Z，HUANG T，et al．Biochemical，molecular，and clinical characterization of patients with primary carnitine deficiency via large-scale newborn screening in Xuzhou area［J］．Front Pediatr，2019，7：50．DOI：10.3389/fped.2019.00050.
［16］FRIGENI M，BALAKRISHNAN B，YIN X，et al．Functional and molecular studies in primary carnitine deficiency［J］．Hum Mutat，2017，38（12）：1684-1699．DOI：10.1002/humu.23315.
［17］陈大宇，谭建强，黄际卫，等．串联质谱联合Sanger基因检测肉碱缺乏症的应用研究［J］．中国妇幼保健，2018，33（19）：4451-4454．DOI：10.7620/zgfybj.j.issn.1001-4411.2018.19.44.
［18］ZHANG Y H，LI H X，LIU J，et al．Molecular investigation in Chinese patients with primary carnitine deficiency［J］．Mol Genet Genomic Med，2019，7（9）：e901．DOI：10.1002/mgg3.901.
［19］赵振东，王洁，谢曼芳，等．海南省少数民族自治市县原发性肉碱缺乏症筛查分析［J］．中华检验医学杂志，2019，42（4）：293-296．DOI：10.3760/cma.j.issn.1009-8158.2019.04.012.
ZHAO Z D，WANG J，XIE M F，et al．The screening and genetic analysis of primary carnitine deficiency in the minority municipalities in Hainan Province［J］．Chinese Journal of Laboratory Medicine，2019，42（4）：293-296．DOI：10.3760/cma.j.issn.1009-8158.2019.04.012．
［20］谭建强，陈大宇，李哲涛，等．10例原发性肉碱缺乏症新生儿的基因诊断［J］．中国当代儿科杂志，2017，19（11）：1150-1154．DOI：10.7499/j.issn.1008-8830.2017.11.005.
TAN J Q，CHEN D Y，LI Z T，et al．Genetic diagnosis of 10 neonates with primary carnitine deficiency［J］．Chin J Contemp Pediatr，2017，19（11）：1150-1154．DOI：10.7499/j.issn.1008-8830.2017.11.005.
［21］赵振东，王洁，杨春，等．海南省新生儿苯丙酮尿症筛查现状分析［J］．中国妇幼保健，2013，28（32）：5313-5314．DOI：10.7620/zgfybj.j.issn.1001-4411.2013.28.20.
［22］黄慈丹，王洁，赵振东，等．海南省新生儿先天性甲状腺功能减低症流行病学特征及促甲状腺激素筛查截断值的设定［J］．山东医药，2019，59（14）：60-62.

[1]	FANG Binbin, SHAN Chunfang, LIU Fen, TIAN Ting, XIE Qian, JI Wei, LI Yanhong, YANG Yining, LI Xiaomei. Screening of Hub Genes and Immune Infiltration Analysis in Stanford Type A Aortic Dissection [J]. Chinese General Practice, 2026, 29(18): 2523-2531.
[2]	CHEN Huiyu, XU Ziyan, LI Yuhong. Correlation between Dietary Inflammatory Index and Delayed Onset of Lactogenesis in Women of the Third Trimester [J]. Chinese General Practice, 2025, 28(35): 4442-4448.
[3]	WANG Tingting, TANG Yong, ZHANG Wenke, LI Zhigang. Research Progress on Exercise Intervention of Hyperuricemia [J]. Chinese General Practice, 2025, 28(30): 3841-3846.
[4]	ZHOU Sheng, DENG Changsheng, ZOU Guanyang, SONG Jianping. Research Progress on the Pathogenesis of Complications of Malaria in Cardiovascular Diseases [J]. Chinese General Practice, 2025, 28(27): 3466-3472.
[5]	YANG Jun, MAIBUBAIMU· Aisikaer, YANG Qianqian, LI Kai, YIN Gaojun, CAI Huizhen. Effects of Frequent Diets on Glucolipid Metabolism and Biorhythmic Expression in Humans [J]. Chinese General Practice, 2025, 28(27): 3432-3440.
[6]	CHEN Beibei, LI Jia, TAN Wenbin. Progress in the Research of Endocrine and Metabolic System Diseases and Secondary Osteoporosis [J]. Chinese General Practice, 2025, 28(17): 2082-2091.
[7]	WANG Yuxin, PENG Wenwan, ZHOU Zheng, HUANG Haiyang, LU Xiaomin, DONG Mingguo. Research Progress on Cancer Risk and Its Pathogenesis of Gastric Precancerous Conditions [J]. Chinese General Practice, 2025, 28(11): 1411-1416.
[8]	ZHANG Shan, ZHANG Meng, XU Xin, LIAO Lixin, SUN Mingjun, MA Haiyan, ZHANG Haibin, GUO Yuzhen. Advances in Pathogenesis, Diagnosis and Treatment of Ovarian Teratoma Associated Anti-N-methyl-D-aspartate Receptor Encephalitis [J]. Chinese General Practice, 2024, 27(24): 3038-3043.
[9]	HE Xianshun, WEI Yurou, HE Mincong, LIN Kun, TIAN Jiaqing, ZHAN Zhiwei, LIN Tianye, HE Xiaoming, HE wei, WEI Qiushi. Regulation of Activating Blood and Dredging Collate Method on Serum Bone Resorption/Angiogenesis/Osteogenic Protein in Patients with Steriod-induced Osteonecrosis of Femoral Head Cystic Degeneration [J]. Chinese General Practice, 2024, 27(12): 1504-1510.
[10]	PENG Yilun, LI Yang, WANG Xiaotao. Study on the Mechanisms of Multiple Myeloma Cells Promoting M2 Macrophage Polarization through PI3K/AKT Signaling Pathway [J]. Chinese General Practice, 2024, 27(08): 978-984.
[11]	LIU Yu, YUE Ting, YANG Dongyu, ZHAO Zhongting, YANG Jibo, ZHU Tiantian. Research Progress on Mechanism of Autophagy in the Pathogenesis of Rheumatoid Arthritis [J]. Chinese General Practice, 2023, 26(29): 3710-3714.
[12]	YU Jie, LI Hongling, ZHAO Gang, LI Jingui. Effect of Circling Moxibustion on the Ultrastructure of Wound Tissue in Rats with Pressure Injury [J]. Chinese General Practice, 2023, 26(11): 1375-1381.
[13]	HUANG Xiangping, WU Ling, TAN Chaochao. Serum Metabolomic Study on the Difference between Mild and Severe Acute Pancreatitis Based on Liquid Chromatography-tandem Mass Spectrometry [J]. Chinese General Practice, 2023, 26(09): 1118-1124.
[14]	CHAI Yan, ZHAO Yuqing, GUO Xunan, WANG Dongying, BIAN Yunfei. Bioinformatics Analysis of the Role of Epicardial Adipose Tissue in Coronary Artery Disease [J]. Chinese General Practice, 2023, 26(08): 939-950.
[15]	HE Xiaoli, LIANG Shuheng, LI Miaoxia, KONG Jinliang, SHAN Qingwen. Hereditary Pancreatitis in Children: Report of One Case with Pedigree Analysis and Literature Review [J]. Chinese General Practice, 2023, 26(05): 641-646.