重庆市新生儿脂肪酸氧化代谢病筛查及确诊患儿随访分析

doi:10.3724/zdxbyxb-2022-0218

浙江大学学报（医学版）

2022, Vol. 51

Issue (3): 290-297 DOI: 10.3724/zdxbyxb-2022-0218

专题报道

重庆市新生儿脂肪酸氧化代谢病筛查及确诊患儿随访分析

陈敏,尹一帆,刘浩,彭勇,叶亮,罗茜,苗静琨(

)

重庆医科大学附属妇女儿童医院儿科新生儿疾病筛查中心，重庆 401147

Screening for newborn fatty acid oxidation disorders in Chongqing and the follow-up of confirmed children

CHEN Min,YIN Yifan,LIU Hao,PENG Yong,YE Liang,LUO Qian,MIAO Jingkun(

)

Neonatal Screening Center, Department of Pediatrics, Women and Children’s Hospital of Chongqing Medical University, Chongqing 401147, China

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摘要：

目的：了解重庆市脂肪酸氧化代谢病（FAOD）的发病率、临床特征、基因突变特点及预后。方法：采集2020年7月至2022年2月重庆医科大学附属妇女儿童医院新生儿疾病筛查中心招募的35 374名新生儿的血液标本，采用串联质谱法检测干血斑中酰基肉碱谱，初筛阳性的患儿于2周内召回，进一步通过尿有机酸、血生化及基因检测等方法确诊，并对确诊患儿进行治疗和随访。结果：35?374名新生儿初筛阳性267例，初筛阳性率为0.75%，基因确诊5例（FAOD发病率为1/7075），其中原发性肉碱缺乏症（PCD）3例（发病率为1/11 791），短链酰基辅酶A脱氢酶缺乏症（SCADD）和极长链酰基辅酶A脱氢酶缺乏症（VLCADD）各1例（发病率均为1/35?374）。3例PCD患儿SLC22A5基因突变以c.1400C>G和c.338G>A常见，c.621G>T为新突变，其中2例患儿予口服补充左卡尼汀，随访期间无临床表现；1例患儿拒绝治疗，于6月龄急性发作，补充左卡尼汀后症状好转，现生长发育正常。1例SCADD患儿检出ACADS基因复合杂合突变（c.417G>C和c.1054G>A），无临床表现。1例VLCADD患儿检出ACADVL基因复合杂合突变（c.1349G>A和c.1843C>T），新生儿期急性发作，治疗好转后予富含中链脂肪酸的奶粉喂养至今，随访期间发育正常。结论：重庆市FAOD发病率较高，其中PCD比例最高，VLCADD患儿临床表型严重。通过新生儿筛查，早诊断、早治疗有助于改善患儿预后。

关键词： 脂肪酸氧化代谢病; 新生儿筛查; 串联质谱法; 基因突变; 随访研究

Abstract:

Objective: To investigate the incidence, clinical characteristics, gene mutations and prognosis of fatty acid oxidation disorders (FAOD) in newborns in Chongqing. Methods: Blood samples were collected from 35 374 newborns for screening of FAOD in the Neonatal Screening Center of Women and Children’s Hospital of Chongqing Medical University from July 2020 to February 2022. The acylcarnitine spectrum was detected by tandem mass spectrometry, the positive children in primary screening were recalled within 2 weeks, and the diagnosis of FAOD was confirmed by urine organic acid measurement, blood biochemistry testing and genetic analysis. The confirmed children were given early intervention, treatment and followed-up. Results: Among 35 374 newborns, there were 267 positive children in primary screening, with a positive rate of 0.75%. Five children with FAOD were diagnosed by gene detection, with an incidence rate of 1/7075. Among them, there were 3 cases of primary carnitine deficiency (PCD, 1/11 791), 1 case of short-chain acyl-CoA dehydrogenase deficiency (SCADD, 1/35 374) and 1 case of very long-chain acyl-CoA dehydrogenase deficiency (VLCADD, 1/35 374). The c.1400C>G and c.338G>A were the common mutations ofSLC22A5 gene in 3 children with PCD, while c.621G>T was a novel mutation. There were no clinical manifestations during the follow-up period in 2 children with supplementation of L-carnitine. Another child with PCD did not follow the doctor’s advice of L-carnitine treatment, and had acute attack at the age of 6?months. The child recovered after treatment, and developed normally during the follow-up. The detectedACADS gene mutations were c.417G>C and c.1054G>A in child with SCADD, who showed normal intelligence and physical development without any clinical symptoms. The mutations ofACADVL gene were c.1349G>A and c.1843C>T in child with VLCADD, who showed acute attack in the neonatal period and recovered after treatment; the child was fed with milk powder rich in medium-chain fatty acids and had normal development during the follow-up.Conclusions: The incidence of FAOD in Chongqing area is relatively high. PCD is the most common type, and the clinical phenotype of VLCADD is serious. After early diagnosis through neonatal screening, standardized treatment and management is followed, most of FAOD children can have good prognosis.

Key words: Fatty acid oxidation disorders Neonatal screening Tandem mass spectrometry Gene mutation Follow-up studies

收稿日期: 2022-05-01 出版日期: 2022-09-21

CLC:

R722.11

基金资助: 重庆市妇幼保健院院级科研课题（2019YJMS08）；重庆市留学人员回国创业创新支持计划（cx2019111）；重庆市中青年医学高端人才项目；重庆市社会事业与民生保障科技创新专项（cstc2016shmszx130026）

通讯作者: 苗静琨 E-mail: ingkun

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引用本文:

陈敏,尹一帆,刘浩,彭勇,叶亮,罗茜,苗静琨. 重庆市新生儿脂肪酸氧化代谢病筛查及确诊患儿随访分析[J]. 浙江大学学报（医学版）, 2022, 51(3): 290-297.

CHEN Min,YIN Yifan,LIU Hao,PENG Yong,YE Liang,LUO Qian,MIAO Jingkun. Screening for newborn fatty acid oxidation disorders in Chongqing and the follow-up of confirmed children. J Zhejiang Univ (Med Sci), 2022, 51(3): 290-297.

链接本文:

https://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2022-0218 或 https://www.zjujournals.com/med/CN/Y2022/V51/I3/290

表 1 五例脂肪酸氧化代谢病患儿的基因突变检测结果

1	HOUTENS M, WANDERSR J A. A general introduction to the biochemistry of mitochondrial fatty acid β-oxidation[J]J Inherit Metab Dis, 2010, 33( 5): 469-477. doi: 10.1007/s10545-010-9061-2
2	MOCZULSKI D, MAJAK I, MAMCZUR D. An overview of beta-oxidation disorders[J]. Postepy Hig Med Dosw (Online), 2009, 63: 266-277
3	GASTONG, GANGOITIJ A, WINNS, et al.Cardiac tissue citric acid cycle intermediates in exercised very long‐chainacyl‐CoA dehydrogenase‐deficient mice fed triheptanoin or medium‐chain triglyceride[J]Jrnl Inher Metab Disea, 2020, 43( 6): 1232-1242. doi: 10.1002/jimd.12284
4	FUL, HUANGM, CHENS. Primary carnitine deficiency and cardiomyopathy[J]Korean Circ J, 2013, 43( 12): 785. doi: 10.4070/kcj.2013.43.12.785
5	CHAMPIONM P. An approach to the diagnosis of inherited metabolic disease[J]Arch Dis Childhood - Education Pract, 2010, 95( 2): 40-46. doi: 10.1136/adc.2008.151183
6	SCHATZU A, ENSENAUERR. The clinical manifestation of MCAD deficiency: challenges towards adulthood in the screened population[J]J Inherit Metab Dis, 2010, 33( 5): 513-520. doi: 10.1007/s10545-010-9115-5
7	WILCKENB, WILEYV, HAMMONDJ, et al.Screening newborns for inborn errors of metabolism by tandem mass spectrometry[J]N Engl J Med, 2003, 348( 23): 2304-2312. doi: 10.1056/NEJMoa025225
8	韩连书. 新生儿遗传病基因筛查技术及相关疾病[J]. 浙江大学学报(医学版), 2021, 50(4): 429-435 HANLianshu. Genetic screening techniques and diseases for neonatal genetic diseases[J]Journal of Zhejiang University (Medical Sciences), 2021, 50( 4): 429-435. (in Chinese). doi: 10.3724/zdxbyxb-2021-0288
9	中华人民共和国卫生部.新生儿疾病筛查技术规范 (2010年版) [A/OL]. (2010-11-10) [2022-04-11]. http://www.nhc.gov.cn/cmsresources/mohfybjysqwss/cmsrsdocument/doc10798.doc Ministry of Health of the People’s Republic of China. Technical guide of newborn screening in China (2010) [A/OL]. (2010-11-10) [2022-04-11]. http://www.nhc.gov.cn/cmsresources/mohfybjysqwss/cmsrsdocument/doc10798. doc. (in Chinese)
10	RICHARDSS, AZIZN, BALES, et al.Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]Genet Med, 2015, 17( 5): 405-424. doi: 10.1038/gim.2015.30
11	GARGU, DASOUKIM. Expanded newborn screening of inherited metabolic disorders by tandem mass spectrometry: clinical and laboratory aspects[J]Clin Biochem, 2006, 39( 4): 315-332. doi: 10.1016/j.clinbiochem.2005.12.009
12	SCHULZEA, LINDNERM, KOHLMÜLLERD, et al.Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications[J]Pediatrics, 2003, 111( 6): 1399-1406. doi: 10.1542/peds.111.6.1399
13	中华预防医学会出生缺陷预防与控制专业委员会新生儿遗传代谢病筛查学组, 中华医学会儿科分会出生缺陷预防与控制专业委员会, 中国医师协会医学遗传医师分会临床生化遗传专业委员会,等. 原发性肉碱缺乏症筛查与诊治共识[J]. 中华医学杂志, 2019, 99(2): 88-92 The Subspecialty Group of Newborn Screening, Society of Birth Defects Prevention and Control, Chinese Preventive Medicine Association; The Subspecialty Committee of Birth Defects Prevention and Control, the Society of Chinese Pediatric, Chinese Medical Association; the Subspecialty Committee of Clinical Biochemistry and Genetics, the Society of Medical Genetics, Chinese Medical Doctor Association, et al. Consensus on the screening, diagnosis and treatment of primary carnitine deficiency[J]. National Medical Journal of China, 2019, 99(2): 88-92. (in Chinese)
14	韩连书, 叶军, 邱文娟, 等. 原发性肉碱缺乏症17例诊治与随访[J]. 中华儿科杂志, 2012, 50(6): 405-409 HAN Lianshu, YE Jun, QIU Wenjuan, et al. Primary carnitine deficiency in 17 patients: diagnosis, treatment and follow up[J]. Chinese Journal of Pediatrics, 2012, 50(6): 405-409. (in Chinese)
15	SHIBATAN, HASEGAWAY, YAMADAK, et al.Diversity in the incidence and spectrum of organic acidemias, fatty acid oxidation disorders, and amino acid disorders in Asian countries: selective screening vs. expanded newborn screening[J]Mol Genet Metab Rep, 2018, 5-10. doi: 10.1016/j.ymgmr.2018.05.003
16	LINDNERM, HOFFMANNG F, MATERND. Newborn screening for disorders of fatty-acid oxidation: experience and recommendations from an expert meeting[J]J Inherit Metab Dis, 2010, 33( 5): 521-526. doi: 10.1007/s10545-010-9076-8
17	杨池菊, 史彩虹, 周成, 等. 山东省济宁地区新生儿脂肪酸氧化代谢病筛查及随访分析[J]. 浙江大学学报(医学版), 2021, 50(4): 472-480 YANG Chiju, SHI Caihong, ZHOU Cheng, et al. Screening and follow-up results of fatty acid oxidative metabolism disorders in 608 818 newborns in Jining, Shandong province[J]., 2021, 50(4): 472-480. (in Chinese)
18	郑静, 张玉, 洪芳, 等. 浙江省新生儿脂肪酸氧化代谢疾病筛查及随访分析[J]. 浙江大学学报(医学版), 2017, 46(3): 248-255 ZHENG Jing, ZHANG Yu, HONG Fang, et al. Screening for fatty acid oxidation disorders of newborns in Zhejiang province: prevalence, outcome and follow-up[J]. Journal of Zhejiang University (Medical Sciences), 2017, 46(3): 248-255. (in Chinese)
19	WANGS, LENGJ, DIAOC, et al.Genetic characteristics and follow-up of patients with fatty acid β-oxidation disorders through expanded newborn screening in a northern Chinese population[J]J Pediatr Endocrinol Metab, 2020, 33( 6): 683-690. doi: 10.1515/jpem-2019-0551
20	FEUCHTBAUML, CARTERJ, DOWRAYS, et al.Birth prevalence of disorders detectable through newborn screening by race/ethnicity[J]Genet Med, 2012, 14( 11): 937-945. doi: 10.1038/gim.2012.76
21	WILCKENB, WILEYV, SIMK G, et al.Carnitine transporter defect diagnosed by newborn screening with electrospray tandem mass spectrometry[J]J Pediatr, 2001, 138( 4): 581-584. doi: 10.1067/mpd.2001.111813
22	LINW, WANGK, ZHENGZ, et al.Newborn screening for primary carnitine deficiency in Quanzhou, China[J]Clinica Chim Acta, 2021, 166-171. doi: 10.1016/j.cca.2020.11.005
23	TANGN L S, HWUW L, CHANR T, et al.A founder mutation (R254X) of SLC22A5 (OCTN2) in Chinese primary carnitine deficiency patients[J]Hum Mutat, 2002, 20( 3): 232. doi: 10.1002/humu.9053
24	OHASHIR, TAMAII, INANOA, et al.Studies on functional sites of organic cation/carnitine transporter OCTN2 (SLC22A5) using a Ser467Cys mutant protein[J]J Pharmacol Exp Ther, 2002, 302( 3): 1286-1294. doi: 10.1124/jpet.102.036004
25	CHENY C, CHIENY H, CHENP W, et al.Carnitine uptake defect (primary carnitine deficiency): risk in genotype-phenotype correlation[J]Hum Mutat, 2013, 34( 4): 655. doi: 10.1002/humu.22286
26	WANGS, RAOJ, LIY, et al.Primary carnitine deficiency cardiomyopathy[J]Int J Cardiol, 2014, 174( 1): 171-173. doi: 10.1016/j.ijcard.2014.03.190
27	CANOA, OVAERTC, VIANEY-SABANC, et al.Carnitine membrane transporter deficiency: a rare treatable cause of cardiomyopathy and anemia[J]Pediatr Cardiol, 2008, 29( 1): 163-165. doi: 10.1007/s00246-007-9051-9
28	ZYTKOVICZT H, FITZGERALDE F, MARSDEND, et al.Tandem mass spectrometric analysis for amino, organic, and fatty acid disorders in newborn dried blood spots[J]Clin Chem, 2001, 47( 11): 1945-1955. doi: 10.1093/clinchem/47.11.1945
29	GALLANTN M, LEYDIKERK, TANGH, et al.Biochemical, molecular, and clinical characteristics of children with short chain acyl-CoA dehydrogenase deficiency detected by newborn screening in California[J]Mol Genet Metab, 2012, 106( 1): 55-61. doi: 10.1016/j.ymgme.2012.02.007
30	SHIRAOK, OKADAS, TAJIMAG, et al.Molecular pathogenesis of a novel mutation, G108D, in short-chain acyl-CoA dehydrogenase identified in subjects with short-chain acyl-CoA dehydrogenase deficiency[J]Hum Genet, 2010, 127( 6): 619-628. doi: 10.1007/s00439-010-0822-7
31	LINY, ZHANGW, CHEND, et al.Newborn screening and genetic characteristics of patients with short- and very long-chain acyl-CoA dehydrogenase deficiencies[J]Clinica Chim Acta, 2020, 285-290. doi: 10.1016/j.cca.2020.07.038
32	TONINR, CACIOTTIA, FUNGHINIS, et al.Clinical relevance of short-chain acyl-CoA dehydrogenase (SCAD) deficiency: exploring the role of new variants including the first SCAD-disease-causing allele carrying a synonymous mutation[J]BBA Clin, 2016, 114-119. doi: 10.1016/j.bbacli.2016.03.004
33	PENAL, ANGLEB, BURTONB, et al.Follow-up of patients with short-chain acyl-CoA dehydrogenase and isobutyryl-CoA dehydrogenase deficiencies identified through newborn screening: one center’s experience[J]Genet Med, 2012, 14( 3): 342-347. doi: 10.1038/gim.2011.9
34	PENAL D M, VAN CALCARS C, HANSENJ, et al.Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database[J]Mol Genet Metab, 2016, 118( 4): 272-281. doi: 10.1016/j.ymgme.2016.05.007
35	MERRITT 2NDJ L, MACLEODE, JURECKAA, et al.Clinical manifestations and management of fatty acid oxidation disorders[J]Rev Endocr Metab Disord, 2020, 21( 4): 479-493. doi: 10.1007/s11154-020-09568-3
36	SMONA, REPIC LAMPRETB, GROSELJU, et al.Next generation sequencing as a follow-up test in an expanded newborn screening programme[J]Clin Biochem, 2018, 48-55. doi: 10.1016/j.clinbiochem.2017.10.016
37	BUQ, PANZ, SAINIS S, et al.Correspondence[J]Ind Pediatr, 2016, 53( 3): 262-264. doi: 10.1007/s13312-016-0833-0

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