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J Zhejiang Univ (Med Sci)  2021, Vol. 50 Issue (4): 436-443    DOI: 10.3724/zdxbyxb-2021-0276
    
Clinical features and outcomes of patients with cblC type methylmalonic acidemia carrying MMACHC gene c.609G>A mutation
YU Yue(),LING Shiying,SHUAI Ruixue,QIU Wenjuan,ZHANG Huiwen,LIANG Lili,JI Wenjun,LIU Yuchao,GU Xuefan,HAN Lianshu()
Department of Pediatric Endocrino-logy and Genetic Metabolism, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai 200092, China
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Abstract  

Objective:To explore the clinical features and long-term outcomes of patients with cblC type methylmalonic acidemia (MMA) carrying c.609G>A (p.W203X) mutation ofMMACHC gene. Methods: The clinical and laboratory findings of 720 patients with MMA carrying the c.609G>A mutation were retrospectively analyzed. There were 172 cases carrying homozygous mutations of c.609G>A (group A), 169 cases carrying compound heterozygous mutations of c.609G>A with c.482G>A (p.R161Q), c.80A>G (p.Q27R) or c.394C>T (p.R132X) (group B), and 379 cases carrying compound heterozygous mutations of c.609G>A with c.658_660delAAG(p.K220del), c.315A>T(p.Y105X) or c.567dupT(p.I190fs*13)(group C).The clinical manifestations, the level of blood acylcarnitine, homocysteine and urinary organic acid, and the therapeutic efficacy were compared among groups. Logistic regression was used to analyze the factors influencing the prognosis of patients. Results:There were 306 patients (42.5%) detected from newborn screening, including 156 cases with disease onset; and 414 patients were not detected from the screening, among whom 10 cases were diagnosed by testing after the sibling confirmed, and the remaining 404 were clinical cases. In 560 patients with disease onset, the median onset age is 1.2?months (3 days to 20?years). The onset age of patients in group B was later than that in group A and group C (P<0.01). Patients aged <1?year mostly manifested as vomiting, diarrhea, feeding difficulties and convulsions, while those aged >1?year mostly manifested as movement disorders and mental retardation. Patients with renal disease all carried mutations of c.80A>G or c.482G>A, and patients with pulmonary hypertension all carried c.80A>G mutations. A total of 621 cases had long-term follow-up, 156 cases (25.1%) developed well, 433 cases (69.7%) had development delay and 32 cases (5.2%) died. The available data of 559 cases were analyzed by logistic regression, and the results showed that the neonatal screening, disease onset, age of onset and gene mutation site were significantly associated with the prognosis of patients (P<0.05 orP<0.01).Conclusions:The c.609G>A mutation inMMACHC gene is associated with early-onset MMA, and most patients, clinical onset occurred within 1?month after birth. The neonatal screening and early treatment can improve the prognosis of patients,whereas clinical onset is unfavorable for prognosis. Patients with c.609G>A homozygous mutation have a worse prognosis than those with the compound heterozygous mutation of c.609G>A with other mutations.



Key wordsNeonatal screening      Methylmalonic acidemia      MMACHC gene      Cobalamin C deficiency      Prognosis      Influencing factors     
Received: 11 May 2021      Published: 01 November 2021
CLC:  R725.8  
Corresponding Authors: HAN Lianshu     E-mail: yuyue0524@sjtu.edu.cn;hanlianshu@xinhuamed.com.cn
Cite this article:

YU Yue,LING Shiying,SHUAI Ruixue,QIU Wenjuan,ZHANG Huiwen,LIANG Lili,JI Wenjun,LIU Yuchao,GU Xuefan,HAN Lianshu. Clinical features and outcomes of patients with cblC type methylmalonic acidemia carrying MMACHC gene c.609G>A mutation. J Zhejiang Univ (Med Sci), 2021, 50(4): 436-443.

URL:

http://www.zjujournals.com/med/10.3724/zdxbyxb-2021-0276     OR     http://www.zjujournals.com/med/Y2021/V50/I4/436


720例甲基丙二酸血症MMACHC基因c.609G>A突变患者临床特征及随访分析

目的:分析携带MMACHC基因c.609G>A(p.W203X)突变的cblC型甲基丙二酸血症(MMA)患者的临床表现、治疗效果、预后及影响因素。方法:回顾性分析2007至2020年在上海交通大学医学院附属新华医院就诊的720例携带c.609G>A突变的cblC型MMA患者的临床及实验室检查资料。根据基因突变位点不同将患者分为三组,携带c.609G>A纯合突变的患者为A组(172例);携带c.609G>A与c.482G>A(p.R161Q)、c.80A>G(p.Q27R)及c.394C>T(p.R132X)中任一突变形成的复合杂合突变患者为B组(169例);携带c.609G>A与上述突变位点以外突变[如c.658_660delAAG(p.K220del)、c.315A>T(p.Y105X)、c.567dupT(p.I190fs*13)]的复合杂合突变患者为C组(379例)。对不同基因突变位点患者的临床表现,血酰基肉碱、血同型半胱氨酸、尿有机酸水平以及治疗效果进行比较,根据随访结果采用logistic回归分析患者预后的影响因素。结果:720例患者中306例(42.5%)来自新生儿筛查,其中156例发病;414例未进行新生儿筛查的患者中10例因同胞确诊后诊断(临床未发病),其余404例均为临床发病病例。560例发病患者中,发病年龄中位数为1.2个月(3?d~20岁)。B组发病年龄晚于A组和C组,三组间发病年龄差异有统计学意义(P<0.01)。患者临床症状各异,1岁以内发病患者多表现为呕吐、腹泻、喂养困难及抽搐,1岁以后发病患者多以运动障碍及智力落后为主要表现。肾脏疾病起病的患者均携带c.80A>G或c.482G>A突变,伴有肺动脉高压的患者均携带c.80A>G突变。长期随访患者621例,其中预后正常156例(25.1%),落后433例(69.7%),死亡32例(5.2%)。剔除失访、死亡及资料缺失的患者,对559例患者的预后影响因素进行logistic回归分析,结果显示新生儿筛查与否、发病与否、发病年龄及基因突变位点对预后的影响有统计学意义(P<0.05或P<0.01)。结论:MMACHC基因c.609G>A突变与早发型MMA相关,患者多于出生后1个月内起病。维生素B12肌内注射对携带不同突变的患者均有效。新生儿筛查对患者预后有益,而临床发病则不利于患者预后,携带c.609G>A纯合突变患者较携带c.609G>A与其他突变位点形成的复合杂合突变患者预后差。


关键词: 新生儿筛查,  甲基丙二酸血症,  MMACHC基因,  钴胺素C缺乏,  预后,  影响因素 

组别

n

新生儿筛查

临床发病

发病年龄

确诊

治疗后发病#

A组

172

77(44.8)

41(53.2)

136(79.1)*

0.24个月(3?d~3.6岁)*

B组

169

82(48.5)

29(35.4)

113(66.9)

5.00个月(3?d~20.0岁)

C组

379

147(38.8)

86(58.5)*

311(82.1)*

0.96个月(3?d~8.0岁)*

χ2/Z

4.537

10.952

15.450

61.061

P

<0.05

<0.01

<0.01

<0.01

Table 1 Time of onset in three groups of patients with cblC-type methylmalonic acidemia

组别

n

C3

(μmol/L )

C3/C2

甲基丙二酸

(mmol/mol肌酐)

甲基枸橼酸

(mmol/mol肌酐)

血同型半胱氨酸

(μmol/L)

A组

?

治疗前

157

7.16(0.28~46.32)*

0.72(0.26~2.79)*

135.60(4.84~1010.80)

4.29(0.80~57.00)

124.00(21.30~463.00)*

治疗后

157

3.03(0.04~11.35)*#

0.12(0.02~0.32)#

6.45(0.00~49.76)*#

0.77(0.00~14.08)*#

35.00(6.47~58.80)*#

差值

157

4.90(0.40~42.00)*

0.59(0.04~2.69)

123.35(1.18~1010.80)

3.40(0.00~53.80)

101.90(1.00~420.70)

B组

?

治疗前

132

5.30(0.41~35.44)

0.43(0.25~15.44)

78.90(6.84~2988.42)

3.02(0.50~137.70)

94.40(25.60~750.00)

治疗后

132

2.57(0.04~19.33)#

0.11(0.02~0.32)#

3.21(0.00~37.40)#

0.49(0.00~4.99)#

30.40(1.37~57.54)#

差值

132

2.90(0.10~34.19)

0.31(0.07~15.40)

67.11(1.50~2982.99)

2.79(0.50~135.90)

66.70(7.80~741.50)

C组

?

治疗前

317

8.28(0.69~41.66)*

0.72(0.25~3.55)*

126.00(3.04~1660.20)*

4.80(0.20~451.60)*

117.40(22.00~765.10)*

治疗后

317

3.65(0.06~17.83)*#

0.13(0.01~0.39)*#

7.66(0.00~50.00)*#

0.70(0.00~4.95)*#

37.10(4.17~59.70)*#

差值

317

5.15(0.10~36.00)*

0.56(0.01~3.42)

123.56(1.66~1445.25)

4.41(0.00~248.88)

80.24(0.00~739.30)

Z治疗前

60.458

68.613

11.418

10.785

9.257

P治疗前

<0.01

<0.01

<0.01

<0.01

<0.05

Z治疗后

24.102

15.589

29.217

11.841

18.266

P治疗后

<0.01

<0.01

<0.01

>0.05

<0.01

Z差值

7.432

2.447

0.896

1.211

0.540

P差值

<0.01

>0.05

>0.05

>0.05

>0.05

Table 2 Biochemical test results of 606 patients with cblC type methylmalonic acidemia before and after treatment

影响因素

n

正常

落后*

OR

95%CI

P

性别

?

298

78(26.2)

220(73.8)

1.00

261

74(28.4)

187(71.6)

1.26

0.674~2.368

>0.05

新生儿筛查确诊

?

246

125(50.8)

121(49.2)

1.00

313

27(8.6)

286(91.4)

0.18

0.088~0.355

<0.01

临床发病

?

434

61(14.1)

373(85.9)

1.00

125

125(100.0)

0(0.0)

7.38

4.335~12.562

<0.01

发病年龄

0.99

0.979~0.996

<0.01

基因突变位点

?

A组

145

40(27.6)

105(72.4)

1.00

B组

123

58(47.2)

65(52.8)

0.45

0.218~0.921

<0.05

C组

291

54(18.6)

237(81.4)

0.37

0.159~0.863

<0.05

Table 3 Results of logistic regression analysis of factors influencing prognosis of patients with cblC type methylmalonic acidemia
[1]   ZHOUX, CUIY, HANJ. Methylmalonic acidemia: current status and research priorities[J]Intractable Rare Dis Res, 2018, 7( 2): 73-78.
doi: 10.5582/irdr.2018.01026
[2]   WANGF, HANL, YANGY, et al.Clinical, biochemical, and molecular analysis of combined methylmalonic acidemia and hyperhomocysteinemia (cblC type) in China[J]J Inherit Metab Dis, 2010, 33( S3): 435-442.
doi: 10.1007/s10545-010-9217-0
[3]   WANGC, LID, CAIF, et al.Mutation spectrum of MMACHC in Chinese pediatric patients with cobalamin c disease: a case series and literature review[J]Eur J Med Genet, 2019, 62( 10): 103713..
doi: 10.1016/j.ejmg.2019.103713
[4]   LERNER-ELLISJ P, TIRONEJ C, PAWELEKP D, et al.Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type[J]Nat Genet, 2006, 38( 1): 93-100.
doi: 10.1038/ng1683
[5]   ALMANNAIM, MAROMR, DIVINK, et al.Milder clinical and biochemical phenotypes associated with the c.482G>A (p.Arg161Gln) pathogenic variant in cobalamin C disease: implications for management and screening[J]Mol Genet Metab, 2017, 122( 1-2): 60-66.
doi: 10.1016/j.ymgme.2017.06.011
[6]   鄂慧姝, 韩连书, 叶 军, 等. 甲基丙二酸血症MMACHC基因c.482G>A突变患者临床资料及随访分析[J].中华内分泌代谢杂志, 2019, 35(7): 581-585
ER Huishu, HAN Lianshu, YE Jun, et al. Clinical analysis and outcome of patients with c.482G>A variant ofMMACHC gene in cblc type methylmalonic acidemia[J]. Chinese Journal Endocrinology and Metabolism, 2019, 35(7): 581-585. (in Chinese)
[7]   韩连书, 叶 军, 邱文娟, 等. 串联质谱联合气相色谱-质谱检测遗传性代谢病[J]. 中华医学杂志, 2008, 88(30): 2122-2126
HAN Lianshu, YE Jun, QIU Wenjuan, et al. Diagnosis of inborn errors of metabolism using tandem mass spectrometry and gas chromatography mass spectrometry[J]. National Medical Journal of China, 2008, 88(30): 2122-2126. (in Chinese)
[8]   YOUJ, SHAMSIB H, HAOM C, et al.A study on the neurodevelopment outcomes of late preterm infants[J]BMC Neurol, 2019, 19( 1): 108.
doi: 10.1186/s12883-019-1336-0
[9]   LERNER-ELLISJ P, ANASTASION, LIUJ, et al.Spectrum of mutations in MMACHC , allelic expression, and evidence for genotypea ?phenotype correlations[J]Hum Mutat, 2009, 30( 7): 1072-1081.
doi: 10.1002/humu.21001
[10]   CARRILLO-CARRASCON, CHANDLERR J, VENDITTIC P. Combined methylmalonic acidemia and homocystinuria, cblC type. Ⅰ. Clinical presentations, diagnosis and management[J]J Inherit Metab Dis, 2012, 35( 1): 91-102.
doi: 10.1007/s10545-011-9364-y
[11]   LIQ L, SONGW Q, PENGX X, et al.Clinical characteristics of hemolytic uremic syndrome secondary to cobalamin C disorder in Chinese children[J]World J Pediatr, 2015, 11( 3): 276-280..
doi: 10.1007/s12519-015-0032-4
[12]   LIUJ, TANGX, ZHOUC, et al.Cobalamin C deficiency presenting with diffuse alveolar hemorrhage and pulmonary microangiopathy[J]Pediatr Pulmonol, 2020, 55( 6): 1481-1486.
doi: 10.1002/ppul.24781
[13]   LIUJ, PENGY, ZHOUN, et al.Combined methylmalonic acidemia and homocysteinemia presenting predominantly with late-onset diffuse lung disease: a case series of four patients[J]Orphanet J Rare Dis, 2017, 12( 1): 58.
doi: 10.1186/s13023-017-0610-8
[14]   WEISFELD-ADAMSJ D, BENDERH A, MILEY-?KERSTEDTA, et al.Neurologic and neurodevelopmental phenotypes in young children with early-treated combined methylmalonic acidemia and homocystinuria, cobalamin C type[J]Mol Genet Metab, 2013, 110( 3): 241-247.
doi: 10.1016/j.ymgme.2013.07.018
[15]   KARAVAV, KONDOUA, DOTISJ, et al.Hemolytic uremic syndrome due to methylmalonic acidemia and homocystinuria in an infant: a case report and literature review[J]Children, 2021, 8( 2): 112.
doi: 10.3390/children8020112
[16]   K?MHOFFM, ROOFTHOOFTM T, WESTRAD, et al.Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency[J/OL]Pediatrics, 2013, 132( 2): e540-e544.
doi: 10.1542/peds.2012-2581
[17]   IODICEF G, DI CHIARAL, BOENZIS, et al.Cobalamin C defect presenting with isolated pulmonary hypertension[J/OL]Pediatrics, 2013, 132( 1): e248-e251.
doi: 10.1542/peds.2012-1945
[18]   GüNDüZM, EKICIF, ?ZAYD?NE, et al.Reversible pulmonary arterial hypertension in cobalamin-dependent cobalamin C disease due to a novel mutation in the MMACHC gene[J]Eur J Pediatr, 2014, 173( 12): 1707-1710.
doi: 10.1007/s00431-014-2330-6
[19]   FISCHERS, HUEMERM, BAUMGARTNERM, et al.Clinical presentation and outcome in a series of 88 patients with the cblC defect[J]J Inherit Metab Dis, 2014, 37( 5): 831-840.
doi: 10.1007/s10545-014-9687-6
[20]   李文杰, 魏超平, 吕金峰, 等. cblC型甲基丙二酸血症23例患儿临床及基因特点分析[J]. 中国优生与遗传杂志, 2018, 26(6): 10-12, 21
LI Wenjie, WEI Chaoping, LYU Jinfeng, et al. Clinical and genetic analysis of 23 MMA-cblC cases[J]. Chinese Journal of Birth Health&Heredity, 2018, 26(6): 10-12, 21. (in Chinese)
[21]   陆相朋, 郑 宏, 梁瑞星, 等. 甲基丙二酸血症86例患儿的神经发育特征[J]. 中华实用儿科临床杂志, 2020, 35(3): 221-226
LU Xiangpeng, ZHENG Hong, LIANG Ruixing, et al. Study on neurodevelopment of 86 children with methylmalonic acidemia[J]. Chinese Journal of Applied Clinical Pediatrics, 2020, 35(3): 221-226.(in Chinese)
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