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10例原发性肉碱缺乏症新生儿的基因诊断
谭建强, 陈大宇, 李哲涛, 严提珍, 黄际卫, 蔡稔
中国当代儿科杂志 ›› 2017, Vol. 19 ›› Issue (11) : 1150-1154.
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10例原发性肉碱缺乏症新生儿的基因诊断
Genetic diagnosis of 10 neonates with primary carnitine deficiency
目的 对新生儿原发性肉碱缺乏症（PCD）基因突变谱进行分析，为PCD早期诊断和治疗以及遗传咨询和产前诊断提供理论依据。方法 对进行新生儿串联质谱筛查的34 167份滤纸干血片进行血酰基肉碱谱分析，对其中游离肉碱（C0）低于10 μmol/L的新生儿及父母行SLC22A5基因测序。结果 酰基肉碱谱筛查C0低于10 μmol/L的新生儿10例，患儿母亲游离肉碱均未见降低，10例患儿的SLC22A5基因测序检测到10种20个突变位点，其中c.976C > T、c.919delG、c.517delC、c.338G > A未见报道，生物信息学分析提示高致病风险。结论 串联质谱技术结合SLC22A5基因测序有助于PCD早期诊断，新突变的发现丰富了SLC22A5基因突变谱。
Objective To study the gene mutation profile of primary carnitine deficiency (PCD) in neonates, and to provide a theoretical basis for early diagnosis and treatment, genetic counseling, and prenatal diagnosis of PCD. Methods Acylcarnitine profile analysis was performed by tandem mass spectrometry using 34 167 dry blood spots on filter paper. The SLC22A5 gene was sequenced and analyzed in neonates with free carnitine (C0) levels lower than 10 μmol/L as well as their parents. Results In the acylcarnitine profile analysis, a C0 level lower than 10 μmol/L was found in 10 neonates, but C0 level was not reduced in their mothers. The 10 neonates had 10 types of mutations at 20 different sites in the SLC22A5 gene, which included 4 previously unreported mutations:c.976C > T, c.919delG, c.517delC, and c.338G > A. Bioinformatics analysis showed that the four new mutations were associated with a risk of high pathogenicity. Conclusions Tandem mass spectrometry combined with SLC22A5 gene sequencing may be useful for the early diagnosis of PCD. Identification of new mutations enriches the SLC22A5 gene mutation profile.
原发性肉碱缺乏症 / 串联质谱 / SLC22A5基因 / 基因突变 / 新生儿
Primary carnitine deficiency / Tandem mass spectrometry / SLC22A5 gene / Gene mutation / Neonate
[1] 王洪允, 江骥, 胡蓓. 串联质谱在新生儿遗传代谢性疾病筛查中的应用[J]. 质谱学报, 2011, 32(1):24-30.
[2] 林壹明, 林卫华, 余科, 等. 八例原发性肉碱缺乏症SLC22A5基因突变分析[J]. 中华医学遗传学杂志, 2017, 34(1):35-39.
[3] 苏艳华, 刘洋, 谢建生, 等. 原发性肉碱缺乏症一家系的SLC22A5基因突变检测与产前诊断[J]. 中华医学遗传学杂志, 2015, 32(4):490-494.
[4] 饶姣, 曾国洪, 王树水, 等. 原发性肉碱缺乏症性心肌病患儿基因突变及家系分析[J].中华儿科杂志, 2014, 52(7):544-547.
[5] Han L, Wang F, Wang Y, et al. Analysis of genetic mutations in Chinese patients with systemic primary carnitine deficiency[J]. Eur J Med Genet, 2014, 57(10):571-575.
[6] 顾学范, 韩连书, 高晓岚, 等. 串联质谱技术在遗传性代谢病高危儿童筛查中的初步应用[J]. 中华儿科杂志, 2004, 42(6):401-404.
[7] Magoulas PL, El-Hattab AW. Systemic primary carnitine deficiency:an overview of clinical manifestations, diagnosis, and management[J]. Orphanet J Rare Dis, 2012, 7:68.
[8] 韩连书.原发性肉碱缺乏症[M]//顾学范临床遗传代谢病. 北京:人民卫生出版社, 2015:135-139.
[9] 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.
[10] Li FY, EI-Hattab AW, Bawle EV, 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-E1651.
[11] Amat di San Filippo C, Wang Y, Longo N. Functional domains in the carnitine transporter OCTN2, defective in primary carnitine deficiency[J]. J Biol Chem, 2003, 278(48):47776-47784.
[12] Amat di San Filippo C, Longo N. Tyrosine residues affecting sodium stimulation of carnitine transport in the OCTN2 carnitine/organic cationtransporter[J]. J Biol Chem, 2004, 279(8):7247-7253.
[13] Burwinkel B, Kreuder J, Schweitzer S, et al. Carnitine transporter OCTN2 mutations in systemic primary carnitine deficiency:a novel Arg169Gln mutation and a recurrent Arg282ter mutation associated with an unconventional splicing abnormality[J]. Biochem Biophys Res Commun, 1999, 261(2):484-487.
[14] Vaz FM, Scholte HR, Ruiter J, et al. Identification of two novel mutations in OCTN2 of three patients with systemic carnitine deficiency[J]. Hum Genet, 1999, 105(1-2):157-161.
[15] Wang Y, Ye J, Ganapathy V, et al. Mutations in the organic cation/carnitine transporter OCTN2 in primary carnitine deficiency[J]. Proc Natl Acad Sci U S A, 1999, 96(5):2356-2360.
[16] Koizumi A, Nozaki J, Ohura T, 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.
[17] Nezu J, Tamai I, Oku A, et al. Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter[J]. Nat Genet, 1999, 21(1):91-94.
[18] Tang NL, Ganapathy V, Wu X, et al. Mutations of OCTN2, an organic cation/carnitine transporter, lead to deficient cellular carnitine uptake in primary carnitine deficiency[J]. Hum Mol Genet, 1999, 8(4):655-660.
[19] Lee NC, Tang NL, Chien YH, et al. Diagnoses of newborns and mothers with carnitine uptake defects through newborn screening[J]. Mol Genet Metab, 2010, 100(1):46-50.
[20] Tang NL, Hwu WL, Chan RT, et al. A founder mutation (R254X) of SLC22A5(OCTN2) in Chinese primary carnitine deficiency patients[J]. Hum Mutat, 2002, 20(3):232.
[21] Yang LL, Huang XW, Yang JB, et al. Screening and diagnosis of children with primary carnitine deficiency in Zhejiang Province, China[J]. HK J Paediatr, 2013, 18(3):167-173.
[22] Jun JS, Lee EJ, Park HD, et al. Systemic primary carnitine deficiency with hypoglycemic encephalopathy[J]. Ann Pediatr Endocrinol Metab, 2016, 21(4):226-229.
[23] Mahale RR, Mehta A, Timmappaya A, et al. Primary carnitine deficiency as a cause of metabolic leukoencephalopathy:Report of one case[J]. Neurol India, 2016, 64(1):166-168.
[24] Lahrouchi N, Lodder EM, Mansouri M, et al. Exome sequencing identifies primary carnitine deficiency in a family with cardiomyopathy and sudden death[J]. Eur J Hum Genet, 2017, 25(6):783-787.
[25] 黄倬, 韩连书. 原发性肉碱缺乏症发病机制及基因突变研究进展[J]. 中国实用儿科杂志, 2012, 27(5):393-396.
[26] Spiekerkoetter U, Huener G, Baykal T, et al. Silent and symptomatic primary carnitine deficiency within the same family due to identical mutations in the organic cation-carnitine transporter OCTN2[J]. J Inherit Metab Dis, 2003, 26(6):613-615.
[27] Shibbani K, Fahed AC, Al-Shaar L, et al. Primary carnitine deficiency:novel mutations and insights into the cardiac phenotype[J]. Clin Genet, 2014, 85(2):127-137.
广西卫生厅项目（Z2016547）（Z20170530），柳州市科学研究与技术开发计划项目研究成果资助（2014G020404）。
