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J Zhejiang Univ (Med Sci)  2021, Vol. 50 Issue (4): 472-480    DOI: 10.3724/zdxbyxb-2021-0259
    
Screening and follow-up results of fatty acid oxidative metabolism disorders in 608 818 newborns in Jining, Shandong province
YANG Chiju1(),SHI Caihong2,ZHOU Cheng1,WAN Qiuhua1,ZHOU Yanbin1,CHEN Xigui1,JIN Xianlian1,HUANG Chenggang3,XU Peng1,*()
1. Neonatal Disease Screening Center, Jining Maternal and Child Health and Family Planning Service Center, Jining 272000, Shandong Province, China;
2. Clinical Laboratory, Jining Second People’s Hospital, Jining 272000, Shandong Province, China;
3. Zhejiang Bosheng Biotechnology Co., Ltd., Hangzhou 310012, China
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Abstract  

Objective:To investigate the incidence and gene mutation characteristics of fatty acid oxidative metabolism disorders in Jining area of Shandong province , and to evaluate the therapeutic effect.Methods: Blood samples of newborns were collected in Jining of Shandong province between July 14, 2014 and December 31, 2019. Tandem mass spectrometry was used to determine the levels of carnitine and acylcarnitine in the blood to screen for fatty acid oxidative metabolism disorder. For newborns with positive screening result, blood DNA was analyzed by MassARRAY and high-throughput sequencing, then verified by Sanger sequencing. The diagnosed children were given early intervention and treatment, and followed up. Results:Forty-two children with fatty acid oxidative metabolism disorders were screened out of 608 818 newborns, with an incidence rate of 1/14 496. Primary carnitine deficiency (16 cases, 38.10%) and short-chain acyl-CoA dehydrogenase deficiency (16 cases, 38.10%) were the most common, followed by very long-chain acyl-CoA dehydrogenase deficiency (6 cases, 14.29%), medium-chain acyl-CoA dehydrogenase deficiency (4 cases, 9.53%). In children with primary carnitine deficiency, c.1400C>G (p.S467C) and c.51C>G (p.F17L) were the most common inSLC22A5 mutations; and c.278C>T (p.S93L), c.1049T >C (p.L350P), c.572A>G (p.K191R), c.431T>C (p.L144P) were newly discovered mutations. Ten children with carnitine replacement therapy showed normal development during the follow-up. In 6 children without carnitine replacement treatment, hypoglycemia developed during the neonatal period in 1 case, in whom the creatine kinase was increased, and the intellectual and language development delayed in the later period; the other 5 children developed normally during the follow-up period. TheACADS gene mutations c.1031A>G (p.E344G) and c.164C>T (p.P55L) were common in children with short-chain acyl-CoA dehydrogenase deficiency, and the children developed normally during the follow-up. In children with very long-chain acyl-CoA dehydrogenase deficiency, the c.1349G>A (p.R450H) was common inACADVL gene mutations; and c.488T>A (p.L163*), c.1228G>T (p.D410Y), c.1276G>A (p.A426T), c.1522C>T (p.Q508*), c.1226C>T (p.T409M) were newly discovered mutations. Three children treated with milk powder rich in medium-chain fatty acids had normal development during the follow-up. The other 3 cases with combined carnitine reduction were treated with levocarnitine and milk powder enriched of medium-chain fatty acids, 1 case developed normally during the follow-up, 1 case died of acute illness at the age of 3?months, and 1 case had acute illness and recovered after treatment, and developed normally during the follow-up. c.449_452del (p.T150Rfs*4) was the most commonACADM gene mutation in children with medium-chain acyl-CoA dehydrogenase deficiency, and c. 718A>G (p.M240V) was a newly discovered mutation. All children received low-fat diet, and hunger and fatigue were avoided; 1 child was supplemented with L-carnitine, and the other 3 children were not treated with drugs, and all of them developed normal during the follow-up.Conclusions:Primary carnitine deficiency and short-chain acyl-CoA dehydrogenase deficiency are the most common fatty acid oxidative metabolism disorders in Jining area. There are gene hotspot mutations and new discovered gene mutations in patients. Patients with early diagnosis and treatment through neonatal screening have a good prognosis.



Key wordsLipid metabolism, inborn errors      Gene mutation      Tandem mass spectrometry      Neonatal screening      Follow-up studies     
Received: 26 April 2021      Published: 01 November 2021
CLC:  R596  
  R722.11  
  R446  
Corresponding Authors: XU Peng     E-mail: zyzza2@126.com;1365216874@qq.com
Cite this article:

YANG Chiju,SHI Caihong,ZHOU Cheng,WAN Qiuhua,ZHOU Yanbin,CHEN Xigui,JIN Xianlian,HUANG Chenggang,XU Peng. Screening and follow-up results of fatty acid oxidative metabolism disorders in 608 818 newborns in Jining, Shandong province. J Zhejiang Univ (Med Sci), 2021, 50(4): 472-480.

URL:

http://www.zjujournals.com/med/10.3724/zdxbyxb-2021-0259     OR     http://www.zjujournals.com/med/Y2021/V50/I4/472


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

目的:了解山东省济宁地区脂肪酸氧化代谢病的发病率、基因突变特征,并评估治疗效果。方法:采集2014年7月14日—2019年12月31日出生的新生儿血样,用串联质谱法测定血肉碱和酰基肉碱水平,筛查脂肪酸氧化代谢病。提取筛查阳性新生儿外周血DNA,用MassARRAY和高通量测序进行基因突变分析,用桑格–库森法验证。对确诊患儿早期干预治疗并随访。结果:从608?818名新生儿中筛查出脂肪酸氧化代谢病患儿42例,总发病率为1/14?496。以原发性肉碱缺乏症(16例,38.10%)和短链酰基辅酶A脱氢酶缺乏症(16例,38.10%)多见,其次为极长链酰基辅酶A脱氢酶缺乏症(6例,14.29%)和中链酰基辅酶A脱氢酶缺乏症(4例,9.53%)。原发性肉碱缺乏症患儿SLC22A5突变以c.1400C>G(p.S467C)和c.51C>G(p.F17L)常见,新发现c.278C>T(p.S93L)、c.1049T>C(p.L350P)、c.572A>G(p.K191R)、c.431T>C(p.L144P)突变。随访期内,肉碱替代治疗10例患儿发育正常;未用肉碱替代治疗6例患儿中5例发育正常,另1例新生儿期出现低血糖,肌酸激酶增高,后期出现智力和语言发育落后。短链酰基辅酶A脱氢酶缺乏症患儿ACADS基因突变以c.1031A>G(p.E344G)和c.164C>T(p.P55L)常见,随访期内发育正常。极长链酰基辅酶A脱氢酶缺乏症患儿ACADVL基因突变以c.1349G>A(p.R450H)常见,新发现c.488T>A(p.L163*)、c.1228G>T(p.D410Y)、c.1276G>A(p.A426T)、c.1522C>T(p.Q508*)、c.1226C>T(p.T409M)突变。3例使用中链脂肪酸奶粉患儿随访期内发育正常;3例合并肉碱降低患儿使用左卡尼汀和中链脂肪酸奶粉治疗,其中1例患儿随访期内发育正常,1例患儿3月龄时急性发病死亡,1例患儿8月龄时曾急性发病,治疗后症状消失,随访期内发育正常。中链酰基辅酶A脱氢酶缺乏症患儿ACADM基因突变以c.449_452del(p.T150Rfs*4)常见,新发现c.718A>G(p.M240V)突变。所有患儿确诊后进行低脂肪饮食并避免饥饿和疲劳,1例患儿补充左卡尼汀,其余3例患儿未使用药物治疗,随访期内发育均正常。结论:济宁地区脂肪酸氧化代谢病以原发性肉碱缺乏症和短链酰基辅酶A脱氢酶缺乏症常见,存在基因热点突变或新发现的基因突变,通过新生儿筛查早期诊治,患儿预后良好。


关键词: 脂质代谢缺陷, 先天性,  基因突变,  串联质谱法,  新生儿筛查,  随访研究 
[1]   MCHUGHD M S, CAMERONC A, ABDENURJ E, et al.Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project[J]Genet Med, 2011, 13( 3): 230-254.
doi: 10.1097/GIM.0b013e31820d5e67
[2]   马志军, 韩连书, 李水军, 等. MS/MS技术在新生儿氨基酸、有机酸及脂肪酸氧化代谢障碍性疾病筛查中的应用共识[J]. 检验医学,2019, 34(6): 479-485
MA Zhijun, HAN Lianshu, LI Shuijun, et al. Expert consensus on neonatal disease screening of amino acid, organic acid and fatty acid oxidative metabolic disorders using MS/MS technology[J]. Laboratory Medicine, 2019, 34(6): 479-485. (in Chinese)
[3]   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
[4]   FRAZIERD M, MILLINGTOND S, MCCANDLESSS E, et al.The tandem mass spectrometry newborn screening experience in North Carolina: 1997–2005[J]J Inherit Metab Dis, 2006, 29( 1): 76-85.
doi: 10.1007/s10545-006-0228-9
[5]   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
[6]   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
[7]   LINDNERM, GRAMERG, HAEGEG, et al.Efficacy and outcome of expanded newborn screening for metabolic diseases - report of 10 years from South-West Germany[J]Orphanet J Rare Dis, 2011, 6( 1): 44.
doi: 10.1186/1750-1172-6-44
[8]   LA MARCAG, MALVAGIAS, CASETTAB, et al.Progress in expanded newborn screening for metabolic conditions by LC-MS/MS in Tuscany: update on methods to reduce false tests[J]J Inherit Metab Dis, 2008, 31( S2): 395-404.
doi: 10.1007/s10545-008-0965-z
[9]   LIMJ S, TANE S, JOHNC M, et al.Inborn error of metabolism (IEM) screening in Singapore by electrospray ionization-tandem mass spectrometry (ESI/MS/MS): an 8 year journey from pilot to current program[J]Mol Genet Metab, 2014, 113( 1-2): 53-61.
doi: 10.1016/j.ymgme.2014.07.018
[10]   VILARINHOL, ROCHAH, SOUSAC, et al.Four years of expanded newborn screening in Portugal with tandem mass spectrometry[J]J Inherit Metab Dis, 2010, 33( S3): 133-138.
doi: 10.1007/s10545-010-9048-z
[11]   NAGARAJAD, MAMATHAS N, DET, et al.Screening for inborn errors of metabolism using automated electrospray tandem mass spectrometry: Study in high-risk Indian population[J]Clin Biochem, 2010, 43( 6): 581-588.
doi: 10.1016/j.clinbiochem.2009.12.009
[12]   CHACED H, DIPERNAJ C, NAYLORE W. Laboratory integration and utilization of tandem mass spectrometry in neonatal screening: a model for clinical mass spectrometry in the next millennium[J]Acta Paediatrica, 1999, 88( 432): 45-47.
doi: 10.1111/j.1651-2227.1999.tb01156.x
[13]   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
[14]   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
[15]   HANL, HANF, YEJ, et al.Spectrum analysis of common inherited metabolic diseases in Chinese patients screened and diagnosed by tandem mass spectrometry[J]J Clin Lab Anal, 2015, 29( 2): 162-168..
doi: 10.1002/jcla.21745
[16]   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)
[17]   MAGOULASP L, EL-HATTABA W. Systemic primary carnitine deficiency: an overview of clinical manifestations, diagnosis, and management[J]Orphanet J Rare Dis, 2012, 7( 1): 68.
doi: 10.1186/1750-1172-7-68
[18]   LEEN C, TANGN L S, CHIENY H, et al.Diagnoses of newborns and mothers with carnitine uptake defects through newborn screening[J]Mol Genet Metab, 2010, 100( 1): 46-50.
doi: 10.1016/j.ymgme.2009.12.015
[19]   LIF Y, EL-HATTABA W, BAWLEE V, et al.Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency[J/OL]Hum Mutat, 2010, 31( 8): E1632-E1651.
doi: 10.1002/humu.21311
[20]   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
[21]   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]. 临床儿科学杂志, 2019, 37(6): 449-453
CUI Dong, HU Yuhui, TANG Gen, 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. (in Chinese)
[22]   王舒婷. 脂肪酸氧化障碍筛查与致病基因突变探讨[D]. 天津: 天津医科大学, 2020
WANG Shuting. Screening and pathogenic genes analysis of fatty acid oxidation deficiencies[D]. Tianjin: Tianjin Medical University, 2020. (in Chinese)
[23]   ADAM M P, ARDINGER H H, PAGON R A, et al. GeneReviews?[M/OL]//EL-HATTAB A W. Systemic primary carnitine deficiency. Seattle (WA): University of Washington, 1993-2019[2020-08-01]. https://www.ncbi.nlm.nih.gov/books/NBK84551/
[24]   CHIEN Y H, LEE N C, CHAO M C, et al. Fatty acid oxidation disorders in a Chinese population in taiwan [J]. JIMD Rep, 2013, 11: 165-172
[25]   ANS J, KIMS Z, KIMG H, et al.Compound heterozygous mutations of ACADS gene in newborn with short chain acyl-CoA dehydrogenase deficiency: case report and literatures review[J]Korean J Pediatr, 2016, 59( Suppl 1): S45-S48.
doi: 10.3345/kjp.2016.59.11.S45
[26]   MINKLERP E, STOLLM S K, INGALLSS T, et al.Quantitative acylcarnitine determination by UHPLC-MS/MS — going beyond tandem MS acylcarnitine “profiles”[J]Mol Genet Metab, 2015, 116( 4): 231-241.
doi: 10.1016/j.ymgme.2015.10.002
[27]   KOIZUMIA, NOZAKIJ, OHURAT, et al.Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency[J]Hum Mol Genet, 1999, 8( 12): 2247-2254.
doi: 10.1093/hmg/8.12.2247
[28]   VAN MALDEGEMB T, WANDERSR J A, WIJBURGF A. Clinical aspects of short-chain acyl-CoA dehydrogenase deficiency[J]J Inherit Metab Dis, 2010, 33( 5): 507-511.
doi: 10.1007/s10545-010-9080-z
[29]   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
[30]   PEDERSENC B, ZOLKIPLIZ, VANGS, et al.Antioxidant dysfunction: potential risk for neurotoxicity in ethylmalonic aciduria[J]J Inherit Metab Dis, 2010, 33( 3): 211-222.
doi: 10.1007/s10545-010-9086-6
[31]   王伟青, 李文杰, 宋东坡, 等. 短链酰基辅酶A脱氢酶缺乏症患儿临床特点及基因变异分析[J]. 临床儿科杂志, 2020, 38(9): 687-690
WANG Weiqing, LI Wenjie, SONG Dongpo, et al. Clinical characteristics and gene variation of short-chain acyl-CoA dehydrogenase deficiency[J]. Journal of Clinical Pediatrics, 2020, 38(9): 687-690. (in Chinese)
[32]   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
[33]   OBAID A, NASHABAT M, ALFADHEL M, et al. Clinical, iochemical, and molecular features in 37 Saudi patients with very long chain acyl CoA dehydrogenase deficiency [J]. JIMD Rep, 2018, 40: 47-53
[34]   SYKUT-CEGIELSKAJ, GRADOWSKAW, PIEKUTOWSKA-ABRAMCZUKD, et al.Urgent metabolic service improves survival in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency detected by symptomatic identification and pilot newborn screening[J]J Inherit Metab Dis, 2011, 34( 1): 185-195.
doi: 10.1007/s10545-010-9244-x
[35]   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
[36]   SPIEKERKOETTERU, LINDNERM, SANTERR, et al.Management and outcome in 75 individuals with long-chain fatty acid oxidation defects: results from aworkshop[J]J Inherit Metab Dis, 2009, 32( 4): 488-497.
doi: 10.1007/s10545-009-1125-9
[37]   BOUTRONA, ACQUAVIVAC, VIANEY-SABANC, et al.Comprehensive cDNA study and quantitative analysis of mutant HADHA and HADHB transcripts in a French cohort of 52 patients with mitochondrial trifunctional protein deficiency[J]Mol Genet Metab, 2011, 103( 4): 341-348.
doi: 10.1016/j.ymgme.2011.04.006
[38]   ROCHA H, CAST?IRAS D, DELGADO C, et al. Birth prevalence of fatty acid beta-oxidation disorders in Iberia [J].JIMD Rep, 2014, 16: 89-94
[39]   LOUKASY L, SOUMELASG S, DOTSIKASY, et al.Expanded newborn screening in Greece: 30 months of experience[J]J Inherit Metab Dis, 2010, 33( S3): 341-348.
doi: 10.1007/s10545-010-9181-8
[40]   OERTONJ, KHALIDJ M, BESLEYG, et al.Newborn screening for medium chain acyl-CoA dehydrogenase deficiency in England: prevalence, predictive value and test validity based on 1.5 million screened babies[J]J Med Screen, 2011, 18( 4): 173-181.
doi: 10.1258/jms.2011.011086
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