Please wait a minute...
浙江大学学报（医学版）
浙江大学学报（医学版）  2019, Vol. 48 Issue (4): 459-464    DOI: 10.3785/j.issn.1008-9292.2019.08.18
专题报道     
新生儿酪氨酸血症筛查及基因谱分析
童凡(),杨茹莱,刘畅,吴鼎文,张婷,黄新文,洪芳,钱古柃,黄晓磊,周雪莲,舒强,赵正言*()
浙江大学医学院附属儿童医院遗传代谢科 浙江省新生儿疾病筛查中心, 浙江 杭州 310052
Screening for hereditary tyrosinemia and genotype analysis in newborns
TONG Fan(),YANG Rulai,LIU Chang,WU Dingwen,ZHANG Ting,HUANG Xinwen,HONG Fang,QIAN Guling,HUANG Xiaolei,ZHOU Xuelian,SHU Qiang,ZHAO Zhengyan*()
Zhejiang Neonatal Screening Center, Department of Genetic and Metabolic Disease, the Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
 全文: PDF(977 KB)   HTML( 11 )
摘要：

目的: 探讨酪氨酸血症（HT）在中国南方人群中的流行、分布、基因谱特征和预后。方法: 回顾性分析2013年11月至2018年11月以酪氨酸/琥珀酰丙酮增高为关键指标，经串联质谱筛查检出并结合基因检测诊断为HT的新生儿的资料。结果: 共2 188 784名新生儿接受筛查，酪氨酸、琥珀酰丙酮正常范围（0.5%~95.5%）分别为34.5~280.0 μmol/L、0.16~2.58 μmol/L。诊断HT 3例，患病率为1:729 595。其中HTⅠ型（FAH基因c.455G>A纯合变异）、Ⅱ型（TAT基因c.890G>T及c.408+1G>A复合杂合变异）、Ⅲ型（HPD基因c.257T>C纯合变异）各1例，后两者为新发突变。HT筛查阳性预测值为3.4%。Ⅰ型患儿初筛酪氨酸666.9 μmol/L，琥珀酰丙酮3.87 μmol/L，伴胆汁淤积，肝酶、乳酸轻度增高，虽经特殊奶粉（去除酪氨酸、苯丙氨酸）治疗，2月龄时仍死于家中；Ⅱ型患儿初筛酪氨酸625.6 μmol/L，琥珀酰丙酮正常，经特殊奶粉治疗，酪氨酸控制在正常范围，随访至7个月，体格、行为发育正常，未见眼、皮肤病变；Ⅲ型患儿初筛酪氨酸1035.3 μmol/L，琥珀酰丙酮正常，不规则应用特殊奶粉治疗，随访至29个月，酪氨酸在532.1~1060.3 μmol/L波动，体格发育、智力发育正常。结论: HT在中国南方人群中罕见，三型在人群中均有分布，基因谱分散。Ⅰ型患儿建议早期联合尼替西农治疗，否则预后可能不良；Ⅱ型患儿如早期采取特殊饮食治疗，一般预后良好；Ⅲ型患儿的预后有待进一步积累资料后确定。
关键词： 酪氨酸血症;  患病率;  基因型;  表型;  串联质谱法;  新生儿筛查;  预后;  回顾性研究    
Abstract:

Objective: To analyze the results of screening for hereditary tyrosinemia (HT) in newborns and its clinical features and genotype. Methods: The HT screening was conducted among 2 188 784 newborns from November 2013 to November 2018. The tyrosine (TYR)/ succinylacetone (SA) levels were detected by tandem mass spectrometry (MS-MS). The clinical characteristics, genetic results and following up data of identified patients were analyzed. Results: The normal ranges (0.5%-95.5%) of TYR and SA were 34.5-280.0 μmol/L and 0.16-2.58 μmol/L, respectively. Three HT cases were confirmed with a detection rate of 1:729 595. There was 1 case of tyrosinemia type Ⅰ (HTⅠ) (homozygous variations of c.455G>A in FAH gene), 1 case of tyrosinemia type Ⅱ(HTⅡ) (heterozygous variations of c.890G>T and c.408+1G>A in TAT gene), and 1 case of tyrosinemia type Ⅲ (HT Ⅲ) (homozygous variations of c.257T>C in HPD gene). The variations of c.890G>T, c.4081G>A of TAT and c.257T>C of HPD were novel. The positive predictive value of the screening was 3.4%. Case 1 (HTⅠ) with TYR and SA values of 666.9 μmol/L and 3.87 μmol/L respectively, presented cholestasis, mild elevated of liver enzyme and lactic acid, who were although fed with TYR and phenylalanine free milk, but died at 2 months of age. Case 2 (HTⅡ) with higher TYR (625.6 μmol/L) and normal SA at screening, received medical milk treatment; during the 7 months of follow-up the baby showed normal score of Bayley assessment and normal TYR without eye and skin symptoms. Case 3 (HT Ⅲ) with TYR of 1035.3 μmol/L and normal SA at screening; during the 29 months of follow-up the value of TYR fluctuated from 532.1 μmol/L to 1060.3 μmol/L due to irregular medical milk treatment, while the score of Bayley assessment was normal. Conclusions: HT is rare in the southern Chinese population, and the gene spectrum is scattered. Early treatment with nitisinone is recommended in children with HTⅠ, otherwise the prognosis is poor; the prognosis of children with HTⅡ is good when early treated with special diet; the prognosis of children with HTⅢ needs to be determined with more data.
Key words: Tyrosinemias    Prevalence    Genotype    Phenotype    Tandem mass spectrometry    Neonatal screening    Prognosis    Retrospective studies
收稿日期: 2019-03-01 出版日期: 2019-10-30
:  R722.11  
基金资助: 国家重点研发计划(2017YFC1001700);国家自然科学基金(81741090)
通讯作者: 赵正言     E-mail: 6194008@zju.edu.cn;zhaozy@zju.edu.cn
作者简介: 童凡(1970—), 女, 硕士, 主任医师, 主要从事遗传代谢病研究; E-mail: 6194008@zju.edu.cn; https://orcid.org/0000-0002-1692-2769
服务　　
把本文推荐给朋友
加入引用管理器
E-mail Alert
RSS
作者相关文章　　
童凡
杨茹莱
刘畅
吴鼎文
张婷
黄新文
洪芳
钱古柃
黄晓磊
周雪莲
舒强
赵正言

引用本文:

童凡,杨茹莱,刘畅,吴鼎文,张婷,黄新文,洪芳,钱古柃,黄晓磊,周雪莲,舒强,赵正言. 新生儿酪氨酸血症筛查及基因谱分析[J]. 浙江大学学报（医学版）, 2019, 48(4): 459-464.

TONG Fan,YANG Rulai,LIU Chang,WU Dingwen,ZHANG Ting,HUANG Xinwen,HONG Fang,QIAN Guling,HUANG Xiaolei,ZHOU Xuelian,SHU Qiang,ZHAO Zhengyan. Screening for hereditary tyrosinemia and genotype analysis in newborns. J Zhejiang Univ (Med Sci), 2019, 48(4): 459-464.

链接本文:

http://www.zjujournals.com/med/CN/10.3785/j.issn.1008-9292.2019.08.18    或    http://www.zjujournals.com/med/CN/Y2019/V48/I4/459

图 1  三例酪氨酸血症患儿基因测序结果
1 KING L S, TRAHMS C, SCOTT C R. Tyrosinemia type Ⅰ[M]//GeneReviews: genetic disease online reviews at GeneTests-GeneClinics. Seattle: University of Washington, 2014.
2 窦丽敏, 方玲娟, 王晓红 et al. 酪氨酸血症Ⅰ型的临床及基因突变分析[J]. 中华儿科杂志, 2013, 51 (4): 302- 307
DOU Limin , FANG Lingjuan , WANG Xiaohong et al. Mutation analysis of FAH gene in patients with tyrosinemia type 1[J]. Chinese Journal of Pediatrics, 2013, 51 (4): 302- 307
doi: 10.3760/cma.j.issn.0578-1310.2013.04.013
3 苏婷, 王宏伟, 孙蔚凌 et al. 酪氨酸血症Ⅱ型一家系调查及致病基因分析[J]. 中华皮肤科杂志, 2018, 51 (3): 169- 172
SU Ting , WANG Hongwei , SUN Weiling et al. Analysis of causative genes of tyrosinemia type Ⅱ in a pedigree[J]. Chinese Journal of Dermatology, 2018, 51 (3): 169- 172
doi: 10.3760/cma.j.issn.0412-4030.2018.03.001
4 RICHARDS S , AZIZ N , BALE S 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
5 VAN SPRONSEN F J , VAN RIJN M , MEYER U et al. Dietary considerations in tyrosinemia type Ⅰ[J]. Adv Exp Med Biol, 2017, 959:197- 204
6 CHINSKY J M , SINGH R , FICICIOGLU C et al. Diagnosis and treatment of tyrosinemia type Ⅰ:a US and Canadian consensus group review and recommendations[J]. Genet Med, 2017, 19 (12):
7 Québec NTBC Study Group , ALVAREZ F , ATKINSON S et al. The Québec NTBC study[J]. Adv Exp Med Biol, 2017, 959:187- 195
8 Newborn screening: toward a uniform screening panel and system[J]. Genet Med, 2006, 8 Suppl 1: 1S-252S.
9 Tyrosinemia, type Ⅱ[EB/OL].[2019-02-25]. http://www.babysfirsttest.org/newborn-screening/conditions/tyrosinemia-typeⅱ.
10 PE?A-QUINTANA L , SCHERER G , CURBELO-ESTéVEZM L et al. Tyrosinemia type Ⅱ:Mutation update, 11 novel mutations and description of 5 independent subjects with a novel founder mutation[J]. Clin Genet, 2017, 92 (3): 306- 317
doi: 10.1111/cge.13003
11 AL-ESSA M A , RASHED M S , OZAND P T . Tyrosinaemia type Ⅱ:an easily diagnosed metabolic disorder with a rewarding therapeutic response[J]. East Mediterr Health J, 1999, 5 (6): 1204- 1207
12 RVETSCHI U , CERONE R , PéREZ-CERDA C et al. Mutations in the 4-hydroxyphenylpyruvate dioxygenase gene (HPD) in patients with tyrosinemia type Ⅲ[J]. Hum Genet, 2000, 106 (6): 654- 662
13 D'EUFEMIA P , FINOCCHIARO R , CELLI M et al. Increased nitric oxide release by neutrophils of a patient with tyrosinemia type Ⅲ[J]. Biomed Pharmacother, 2009, 63 (5): 359- 361
doi: 10.1016/j.biopha.2008.06.030
[1] 张丹丹,王军梅. 胎儿肝血管瘤的产前影像学诊断和管理[J]. 浙江大学学报（医学版）, 2019, 48(4): 439-445.
[2] 黄淑敏,赵正言. 重症联合免疫缺陷病新生儿筛查及免疫系统重建研究进展[J]. 浙江大学学报（医学版）, 2019, 48(4): 351-357.
[3] 叶青,张莹莹,王晶晶,毛建华. Ⅳ型胶原α5链基因突变致奥尔波特综合征两家系遗传学分析[J]. 浙江大学学报（医学版）, 2019, 48(4): 384-389.
[4] 吴鼎文,芦斌,杨建滨,杨茹莱,黄新文,童凡,郑静,赵正言. 3-羟基异戊酰基肉碱代谢异常新生儿遗传学分析[J]. 浙江大学学报（医学版）, 2019, 48(4): 390-396.
[5] 王雅芸,陈原,杨蒙蒙,习芳芳,占琪涛,蒋颖,赵柏惠,罗琼. 淋巴水囊瘤或颈部组织增厚胎儿预后分析[J]. 浙江大学学报（医学版）, 2019, 48(4): 434-438.
[6] 钟晚思, 陈智才, 陈红芳, 徐冬娟, 王志敏, 胡海芳, 吴承龙, 张晓玲, 马小董, 王亚仙, 胡海涛, 楼敏, 浙江省缺血性脑卒中静脉溶栓的临床行为干预研究协作组 . 院前急救医疗服务对缺血性脑卒中患者静脉溶栓预后的影响[J]. 浙江大学学报（医学版）, 2019, 48(3): 241-246.
[7] 张聪聪, 楼敏, 陈智才, 陈红芳, 徐冬娟, 王志敏, 胡海芳, 吴承龙, 张晓玲, 马小董, 王亚仙, 胡海涛, 浙江省缺血性脑卒中静脉溶栓的临床行为干预研究协作组 . 医院内缺血性脑卒中患者静脉溶栓时间及预后分析[J]. 浙江大学学报（医学版）, 2019, 48(3): 260-266.
[8] 陶安阳, 王志敏, 陈红芳, 徐冬娟, 胡海芳, 吴承龙, 张晓玲, 马小董, 王亚仙, 胡海涛, 楼敏, 浙江省缺血性脑卒中静脉溶栓的临床行为干预研究协作组 . 合并心房颤动对缺血性脑卒中患者静脉溶栓后颅内出血转化的影响[J]. 浙江大学学报（医学版）, 2019, 48(3): 254-259.
[9] 陈红芳, 龚筱弦, 徐冬娟, 王志敏, 胡海芳, 吴承龙, 张晓玲, 马小董, 王亚仙, 胡海涛, 楼敏, 陈智才, 浙江省缺血性脑卒中静脉溶栓的临床行为干预研究协作组 . 治疗时间提前可改善缺血性脑卒中患者再灌注治疗的预后[J]. 浙江大学学报（医学版）, 2019, 48(3): 247-253.
[10] 泮飞虎, 楼敏, 陈智才, 陈红芳, 徐冬娟, 王志敏, 胡海芳, 吴承龙, 张晓玲, 马小董, 王亚仙, 胡海涛, 浙江省缺血性脑卒中静脉溶栓的临床行为干预研究协作组 . 不同工作时间段就诊对缺血性脑卒中患者静脉溶栓预后的影响[J]. 浙江大学学报（医学版）, 2019, 48(3): 267-274.
[11] 付涧兰,宋法寰,程爱萍. 脂肪肉瘤的18F-氟代脱氧葡萄糖PET-CT显像特征[J]. 浙江大学学报（医学版）, 2019, 48(2): 193-199.
[12] 虞雅,魏凯,姚秋萍,田申,梁昆,周黎明,王丽萍,金敏. 子宫内膜异位症合并不孕患者的体外受精促排卵治疗:拮抗剂可代替激动剂吗?[J]. 浙江大学学报（医学版）, 2019, 48(2): 165-173.
[13] 吕朵,谢锡绍,张晓辉,陈江华. 腹膜透析患者平均动脉压水平与死亡的关系[J]. 浙江大学学报（医学版）, 2019, 48(2): 180-185.
[14] 孙婷,徐明娟. 妊娠期正常高值血压产妇体质量及妊娠结局的回顾性分析[J]. 浙江大学学报（医学版）, 2019, 48(2): 174-179.
[15] 杜东芬,朱丽霞,王云贵,叶琇锦. 肾母细胞瘤1基因表达及其对急性髓系白血病患者预后的预测价值[J]. 浙江大学学报（医学版）, 2019, 48(1): 50-57.