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浙江大学学报(医学版)  2021, Vol. 50 Issue (4): 454-462    DOI: 10.3724/zdxbyxb-2021-0261
专题报道     
浙江省新生儿多酰基辅酶A脱氢酶缺乏症筛查及随访分析
周朵1(),叶梅玲2,胡真真1,张玉3,朱琳3,杨茹莱1,黄新文1,*()
1.浙江大学医学院附属儿童医院遗传与代谢科 国家儿童健康与疾病临床医学研究中心 国家儿童区域医疗中心,浙江 杭州 310052
2.浙江省台州医院 台州恩泽医疗中心(集团),浙江 台州 317000
3.浙江博圣生物技术股份有限公司,浙江 杭州 310012
Screening of multiple acyl-CoA dehydrogenase deficiency in newborns and follow-up of patients
ZHOU Duo1(),YE Meiling2,HU Zhenzhen1,ZHANG Yu3,ZHU Lin3,YANG Rulai1,HUANG Xinwen1,*()
1. Department of Genetics and Metabolism, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou 310052, China;
2. Taizhou Hospital of Zhejiang Province, Taizhou Enze Medical Center (Group), Taizhou 317000, Zhejiang Province, China;
3. Zhejiang Biosan Biochemical Technology Co., Ltd., Hangzhou 310012, China
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摘要:

目的:了解浙江省新生儿多酰基辅酶A脱氢酶缺乏症(MADD)的发病率、临床特征及基因突变特点。方法:采用串联质谱法对2009年1月至2020年12月浙江省新生儿疾病筛查中心3?896?789名新生儿进行遗传代谢病筛查,结合尿有机酸分析及电子转移黄素蛋白(ETF)或电子转移黄素蛋白脱氢酶(ETFDH)基因检测确诊。确诊患儿进行饮食和生活管理,补充左卡尼汀、核黄素、辅酶Q10治疗,长期随访并评估患儿的生长和智力发育情况。结果:确诊MADD患儿13例,除1例为Ⅱ型,其余均为Ⅲ型(迟发型),发病率为1/299?753。13例患儿中,1例死亡,4例因感染诱发以低血糖为主要表现的急性代谢失调,1例出现肌张力降低,其余患儿随访发育良好(随访时间3~45个月)。患儿初筛血C4~C18:1不同程度升高。13例患儿进行基因检测,其中ETFA基因复合杂合突变1例,ETFA基因纯合突变1例,ETFB基因复合杂合突变1例,ETFDH基因复合杂合突变8例,ETFDH基因纯合突变1例,仅检测出一个ETFDH基因突变位点1例。c.250G>A为热点突变。结论:MADD临床表现高度异质,新生儿期发病较为严重,迟发型常无明显临床症状,初筛血C4~C18:1不同程度升高,最常见基因突变为c.250G>A。

关键词: 新生儿筛查多酰基辅酶A脱氢酶缺乏症电子转移黄素蛋白电子转移黄素蛋白脱氢酶串联质谱法    
Abstract:

Objective:To investigate the incidence rate, clinical and gene mutation characteristics of multiple acyl-CoA dehydrogenase deficiency (MADD) in newborns in Zhejiang province. Methods:A total of 3 896 789 newborns were screened for MADD using tandem mass spectrometry in Zhejiang Neonatal Screening Center during January 2009 and December 2020. Patients of MADD were confirmed by urine organic acid and electron transferring flavoprotein (ETF)or electron transferring flavoprotein dehydrogenase (ETFDH) gene detection. MADD patients were given diet and life management, supplemented with L-carnitine, riboflavin and coenzyme Q 10 treatment, and their growth and intellectual development were evaluated during the followed up.Results:Thirteen patients with MADD were diagnosed, with an incidence of 1/299 753. One patient was type Ⅱ, and the rest were type Ⅲ. Patients were followed up for 3–45?months, 1 case died, 4 cases had acute metabolic disorders with hypoglycemia as the main manifestation due to infection, 1 case had hypotonia, and the rest 7 cases developed well. Patients had raised levels of C4–C18:1 acylcarnitines in the initial screening. Thirteen children were genetically tested, 1 case with compound heterozygous mutation in the ETFA gene, 1 case with homozygous mutation in theETFA gene, 1 case with compound heterozygous mutation in the ETFB gene, 8 cases with compound heterozygous mutation and 1 case with homozygous mutation in the ETFDH gene, 1 case that only 1 locus of ETFDH gene was detected. The c.250G>A was the hotspot mutation in this study.Conclusion:The clinical manifestations of MADD are highly heterogeneous. The neonatal-onset form is serious, and late onset form usually has no obvious clinical symptoms. C4–C18:1 acylcarnitines usually increased in the initial screening, and the hotspot gene mutation is c.250G>A.

Key words: Neonatal screening    Multiple acyl-CoA dehydrogenase deficiency    Electron transferring flavoprotein    Electron transferring flavoprotein dehydrogenase    Tandem mass spectrometry
收稿日期: 2021-04-10 出版日期: 2021-11-01
CLC:  R722.11  
基金资助: 国家重点研发计划(2018YFC1002204);国家自然科学基金(82073560);浙江省公益技术研究计划(LGC19B050013)
通讯作者: 黄新文     E-mail: 11318120@zju.edu.cn;6305022@zju.edu.cn
作者简介: 周 朵,主治医师,主要从事儿童遗传代谢病筛查和诊治工作;E-mail:11318120@zju.edu.cn;https://orcid.org/0000-0002-6545-5351
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引用本文:

周朵,叶梅玲,胡真真,张玉,朱琳,杨茹莱,黄新文. 浙江省新生儿多酰基辅酶A脱氢酶缺乏症筛查及随访分析[J]. 浙江大学学报(医学版), 2021, 50(4): 454-462.

ZHOU Duo,YE Meiling,HU Zhenzhen,ZHANG Yu,ZHU Lin,YANG Rulai,HUANG Xinwen. Screening of multiple acyl-CoA dehydrogenase deficiency in newborns and follow-up of patients. J Zhejiang Univ (Med Sci), 2021, 50(4): 454-462.

链接本文:

http://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2021-0261        http://www.zjujournals.com/med/CN/Y2021/V50/I4/454

例序

性别

肌酸激酶(U/L)

CK-MB(U/L)

乳酸脱氢酶(U/L)

血氨(μmol/L)

乳酸(mmol/L)

ALT(U/L)

高脂血症

高胆固醇血症

凝血功能

肝脏超声

肾脏超声

心脏超声

心电图

脑核磁共振

1

1235

175

1085

149

5.1

79

异常

肝脐下1.4?cm

双肾回声增强

正常

正常

脑发育落后

2

58

27

473

正常

正常

78

未查

正常

正常

正常

正常

双侧侧脑室颞脚丰满

3

6755

185

1505

正常

2.9

92

正常

肝肋下3?cm

正常

正常

正常

未查

4

376

正常

正常

正常

4.1

正常

未查

未查

未查

正常

正常

未查

5

正常

正常

正常

73

正常

正常

未查

未查

未查

未查

未查

未查

6

正常

正常

正常

正常

正常

正常

未查

未查

未查

正常

正常

未查

7

正常

正常

正常

正常

正常

79

未查

未查

未查

正常

正常

未查

8

2653

54

762

正常

4.7

正常

未查

正常

双肾小结晶

正常

正常

未查

9

正常

正常

正常

正常

正常

正常

未查

未查

未查

正常

正常

未查

10

正常

正常

正常

正常

正常

56

未查

未查

未查

正常

正常

未查

11

142

45

正常

正常

3.2

正常

未查

未查

未查

正常

正常

未查

12

正常

正常

正常

正常

正常

正常

正常

正常

正常

正常

正常

未查

13

253

42

正常

56

3.5

78

未查

未查

未查

左室假腱索

T波轻度改变

正常

表 1  13例多酰基辅酶A脱氢酶缺乏症确诊患儿实验室和影像学检查结果

例序

C0

C4

C5

C6

C8

C10

C12

C12:1

C14

C14:1

C14:2

C16

C16:1

C18

C18:1

1

正常

1.13

0.49

1.22

1.58

1.72

2.56

0.48

2.54

1.83

0.14

6.42

1.61

正常

3.06

2

正常

1.61

2.00

0.42

0.59

0.64

1.03

0.38

2.45

0.81

0.08

11.71

1.63

3.80

5.11

3

正常

正常

正常

正常

0.30

0.48

0.81

正常

0.76

0.59

0.11

正常

正常

正常

正常

4

正常

0.91

0.57

1.46

2.34

2.06

1.89

0.32

1.99

1.06

0.10

6.24

1.13

正常

正常

5

正常

0.63

1.10

0.23

0.41

0.48

0.94

正常

1.96

0.65

0.07

6.37

1.37

2.46

3.61

6

正常

0.62

正常

0.78

1.61

2.46

3.04

0.66

1.76

1.57

0.15

6.21

0.85

正常

正常

7

正常

正常

正常

0.26

0.74

1.29

1.02

0.46

0.59

0.55

0.07

6.58

正常

正常

正常

8

4.74

1.93

0.89

0.20

0.42

0.40

0.75

正常

1.94

0.44

正常

9.68

1.06

3.93

4.61

9

正常

正常

正常

0.28

0.75

1.12

1.96

0.43

1.14

1.09

0.22

正常

正常

正常

正常

10

正常

正常

正常

正常

0.38

0.66

0.70

正常

0.49

0.37

正常

正常

正常

正常

正常

11

正常

2.75

0.63

0.68

0.81

0.88

1.01

正常

0.56

0.71

0.12

正常

正常

正常

正常

12

正常

正常

正常

0.38

0.77

1.40

2.35

0.34

1.43

1.21

0.11

正常

0.77

正常

正常

13

正常

0.75

正常

1.15

1.99

2.79

3.60

1.09

2.90

2.27

0.12

10.27

1.50

2.26

3.42

表 2  13例多酰基辅酶A脱氢酶缺乏症确诊患儿血酰基肉碱水平

例序

基因突变

突变1

突变2

编码区

互补DNA改变

氨基酸改变

编码区

互补DNA改变

氨基酸改变

1

ETFDH

2(外显子)

c.242T>C

p.L81P

未检出

未检出

未检出

2

ETFA

5(外显子)

c.520C>T

p.R174X

2(外显子)

c.218G>A

p.R73K

3

ETFDH

3(外显子)

c.250G>A

p.A84T

11(外显子)

c.1450C>T

p.A84T

4

ETFDH

3(外显子)

c.229G>A

p.G77S

5(外显子)

c.524G>A

p.R175L

5

ETFA

3(外显子)

c.365G>A

p.A122L

3(外显子)

c.365G>A

p.A122L

6

ETFDH

11(外显子)

c.1395T>G

P.Y465X

3(外显子)

c.250G>A

p.A84T

7

ETFDH

7(外显子)

c.770A>G

P.Y257C

11(外显子)

c.1450C>T

p.A484R

8

ETFDH

11(外显子)

c.1395T>G

P.Y465X

11(外显子)

c.1450C>T

p.A484R

9

ETFDH

3(外显子)

c.353G>T

p.A117P

3(外显子)

c.250G>A

p.A84T

10

ETFDH

3(外显子)

c.250G>A

p.A84T

3(外显子)

c.250G>A

p.A84T

11

ETFB

5(外显子)

c.574T>G

p.Y192D

6(外显子)

c.614_616del

p.K250del

12

ETFDH

6(外显子)

c.643G>A

p.A215T

11(外显子)

c.1395T>G

P.Y465X

13

ETFDH

6(内含子)

c.684+1G>T

非编码区

8(外显子)

c.982G>C

p.D328H

表 3  13例多种酰基辅酶A脱氢酶缺乏症确诊患儿基因突变检测结果
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13 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
14 TAMAOKIY, KIMURAM, HASEGAWAY, et al.A survey of Japanese patients with mitochondrial fatty acid β-oxidation and related disorders as detected from 1985 to 2000[J]Brain Dev, 2002, 24( 7): 675-680.
doi: 10.1016/s0387-7604(02)00074-8
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 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
17 WANGC, CUIY, QUX. Optimization of electrotransformation (ETF) conditions in lactic acid bacteria (LAB)[J]J MicroBiol Methods, 2020, 105944.
doi: 10.1016/j.mimet.2020.105944
18 胡晓明, 李 莉, 米 荣, 等. ETFDH基因复合杂合突变致新生儿多种酰基辅酶A脱氢酶缺乏症家系一例并文献复习[J]. 中华新生儿科杂志, 2018, 33(3): 205-209
HU Xiaoming, LI Li, MI Rong, et al. A family affected by multiple acyl-CoA dehydrogenase deficiency due to compound heterozygous mutations on ETFDH and literature review[J]. Chinese Journal of Neonato-logy, 2018, 33(3): 205-209. (in Chinese)
19 FANX, XIEB, ZOUJ, et al.Novel ETFDH mutations in four cases of riboflavin responsive multiple acyl-CoA dehydrogenase deficiency[J]Mol Genet Metab Rep, 2018, 15-19.
doi: 10.1016/j.ymgmr.2018.05.007
20 王伟青, 宋东坡, 于春冬, 等. 多种酰基辅酶A脱氢酶缺乏症1例病例报告[J]. 中国循证儿科杂志, 2019, 14(4): 313-316
WANG Weiqing, SONG Dongpo, YU Chundong, et al. A case report of multiple acyl-CoA dehydrogenase deficiency[J].Chinese Journal of Evidence Based Pediatrics, 2019, 14(4): 313-316. (in Chinese)
21 DINGM, LIUR, QIUBOL, et al.Neonatal-onset multiple acyl-CoA dehydrogenase deficiency (MADD) in the ETFDH gene: a case report and a literature review[J/OL]Medicine, 2020, 99( 37): e21944.
doi: 10.1097/MD.0000000000021944
22 VAN DER WESTHUIZENF H, SMUTSI, HONEYE, et al.A novel mutation in ETFDH manifesting as severe neonatal-onset multiple acyl-CoA dehydrogenase deficiency[J]J Neurol Sci, 2018, 121-125.
doi: 10.1016/j.jns.2017.11.012
23 VAN RIJTW J, FERDINANDUSSES, GIANNOPOULOSP, et al.Prediction of disease severity in multiple acyl‐CoA dehydrogenase deficiency: a retrospective and laboratory cohort study[J]J Inherit Metab Dis, 2019, 42( 5): 878-889.
doi: 10.1002/jimd.12147
24 ZHUM, ZHUX, QIX, et al.Riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency in 13 cases, and a literature review in mainland Chinese patients[J]J Hum Genet, 2014, 59( 5): 256-261.
doi: 10.1038/jhg.2014.10
25 OLSENR K J, ANDRESENB S, CHRISTENSENE, et al.Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency[J]Hum Mutat, 2003, 22( 1): 12-23.
doi: 10.1002/humu.10226
26 XIJ, WENB, LINJ, et al.Clinical features and ETFDH mutation spectrum in a cohort of 90 Chinese patients with late-onset multiple acyl-CoA dehydrogenase deficiency[J]J Inherit Metab Dis, 2014, 37( 3): 399-404.
doi: 10.1007/s10545-013-9671-6
27 WANGZ Q, CHENX J, MURONGS X, et al.Molecular analysis of 51 unrelated pedigrees with late-onset multiple acyl-CoA dehydrogenation deficiency (MADD) in southern China confirmed the most common ETFDH mutation and high carrier frequency of c.250G>A[J]J Mol Med, 2011, 89( 6): 569-576.
doi: 10.1007/s00109-011-0725-7
28 LANM Y, FUM H, LIUY F, et al.High frequency of ETFDH c.250G>A mutation in Taiwanese patients with late-onset lipid storage myopathy[J]Clin Genet, 2010, 78( 6): 565-569.
doi: 10.1111/j.1399-0004.2010.01421.x
29 GRüNERTS C. Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency[J]Orphanet J Rare Dis, 2014, 9( 1): 117.
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30 ERSOYE O, RAMAD, üNAL?, et al.Glutaric aciduria type 2 presenting with acute respiratory failure in an adult[J]Respir Med Case Rep, 2015, 92-94.
doi: 10.1016/j.rmcr.2015.02.009
31 FUH X, LIUX Y, WANGZ Q, et al.Significant clinical heterogeneity with similar ETFDH genotype in three Chinese patients with late-onset multiple acyl-CoA dehydrogenase deficiency[J]Neurol Sci, 2016, 37( 7): 1099-1105.
doi: 10.1007/s10072-016-2549-2
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