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J Zhejiang Univ (Med Sci)  2021, Vol. 50 Issue (4): 454-462    DOI: 10.3724/zdxbyxb-2021-0261
    
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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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 wordsNeonatal screening      Multiple acyl-CoA dehydrogenase deficiency      Electron transferring flavoprotein      Electron transferring flavoprotein dehydrogenase      Tandem mass spectrometry     
Received: 10 April 2021      Published: 01 November 2021
CLC:  R722.11  
  R596  
Corresponding Authors: HUANG Xinwen     E-mail: 11318120@zju.edu.cn;6305022@zju.edu.cn
Cite this article:

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.

URL:

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


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

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 

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

Table 1 Results of laboratory and imaging examination of 13 patients with multiple acyl-CoA dehydrogenase deficiency

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

Table 2 Carnitine concentrations in 13 patients with multiple acyl-CoA dehydrogenase deficiency

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

Table 3 ETF/ETFDH mutations in 13 patients with multiple acyl-CoA dehydrogenase deficiency
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