GFM1基因突变致儿童线粒体病一例并文献复习

doi:10.12280/gjszjk.20210554

摘要/Abstract

摘要：

线粒体病（mitochondrial disease,MD）是由于线粒体基因或核基因突变引起线粒体代谢酶功能缺陷,致使ATP合成障碍、能量产生不足而导致的一组全身多系统性病变,临床表现多样、复杂且预后差,目前尚无特效治疗。回顾性分析1例因GFM1基因突变导致的儿童MD的临床特征及基因突变位点,女性患儿1岁,主要表现为反复代谢性酸中毒,高乳酸血症,生长发育落后,GFM1基因存在c.688G>A的纯合突变,氨基酸改变为p.Gly230Ser（甘氨酸>丝氨酸）,并复习相关文献中病例情况,旨在提高临床医师对MD的认识,并为产前诊断提供一定的指导。

关键词: 突变, 线粒体疾病, 儿童, 病例报告, GFM1基因

Abstract:

Mitochondrial disease (MD) is a group of multi-systemic lesions caused by the mutations of mitochondrial genes or nuclear genes, which causes the dysfunction of mitochondrial metabolic enzyme, the disorder of ATP synthesis and the deficiency of energy production. The clinical manifestations are diverse and complex, and the prognoses are poor. There is no specific treatment at present. We reported a case of mitochondrial disease caused by GFM1 gene mutation. She was a female child of 1 year, presenting with repeated metabolic acidosis, hyperlactemia, growth and development lag. A homozygous mutation of GFM1 gene, C.688G>A was found. The amino acid was changed to p.Gly230ser (glycine>serine). Combined with literature review, this case of mitochondrial disease was analyzed so as to improve the clinical physicians′ understanding, and to provide some guidance for prenatal diagnosis.

Key words: Mutation, Mitochondrial diseases, Child, Case reports, GFM1 gene

戴小娟, 郑丽玲, 陈柔, 杨小云. GFM1基因突变致儿童线粒体病一例并文献复习[J]. 国际生殖健康/计划生育, 2022, 41(3): 199-203.

DAI Xiao-juan, ZHENG Li-ling, CHEN Rou, YANG Xiao-yun. Mitochondrial Disease Caused by GFM1 Gene Mutation：A Case Report and Literature Review[J]. Journal of International Reproductive Health/Family Planning, 2022, 41(3): 199-203.

图/表 2

参考文献 30

[1]	Kisler JE, Whittaker RG, McFarland R. Mitochondrial diseases in childhood: a clinical approach to investigation and management[J]. Dev Med Child Neurol, 2010, 52(5):422-433. doi: 10.1111/j.1469-8749.2009.03605.x. doi: 10.1111/j.1469-8749.2009.03605.x pmid: 20163433
[2]	Gorman GS, Schaefer AM, Ng Y, et al. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease[J]. Ann Neurol, 2015, 77(5):753-759. doi: 10.1002/ana.24362. doi: 10.1002/ana.24362 URL
[3]	Graham BH. Diagnostic challenges of mitochondrial disorders: complexities of two genomes[J]. Methods Mol Biol, 2012, 837:35-46. doi: 10.1007/978-1-61779-504-6_3. doi: 10.1007/978-1-61779-504-6_3 pmid: 22215539
[4]	Thorburn DR. Mitochondrial disorders: prevalence, myths and advances[J]. J Inherit Metab Dis, 2004, 27(3):349-362. doi: 10.1023/B:BOLI.0000031098.41409.55. doi: 10.1023/B:BOLI.0000031098.41409.55 pmid: 15190193
[5]	刘志梅, 方方. 核基因突变导致儿童线粒体病的分子遗传学进展[J]. 中国循证儿科杂志, 2015, 10(6):470-474. doi: 10.3969/j.issn.1673-5501.2015.06.000. doi: 10.3969/j.issn.1673-5501.2015.06.000
[6]	Coenen MJ, Antonicka H, Ugalde C, et al. Mutant mitochondrial elongation factor G1 and combined oxidative phosphorylation deficiency[J]. N Engl J Med, 2004, 351(20):2080-2086. doi: 10.1056/NEJMoa041878. doi: 10.1056/NEJMoa041878 URL
[7]	Antonicka H, Sasarman F, Kennaway NG, et al. The molecular basis for tissue specificity of the oxidative phosphorylation deficiencies in patients with mutations in the mitochondrial translation factor EFG1[J]. Hum Mol Genet, 2006, 15(11):1835-1846. doi: 10.1093/hmg/ddl106. doi: 10.1093/hmg/ddl106 pmid: 16632485
[8]	Valente L, Tiranti V, Marsano RM, et al. Infantile encephalopathy and defective mitochondrial DNA translation in patients with mutations of mitochondrial elongation factors EFG1 and EFTu[J]. Am J Hum Genet, 2007, 80(1):44-58. doi: 10.1086/510559. doi: 10.1086/510559 pmid: 17160893
[9]	Smits P, Antonicka H, van Hasselt PM, et al. Mutation in subdomain G′ of mitochondrial elongation factor G1 is associated with combined OXPHOS deficiency in fibroblasts but not in muscle[J]. Eur J Hum Genet, 2011, 19(3):275-279. doi: 10.1038/ejhg.2010. 208. doi: 10.1038/ejhg.2010. 208 URL
[10]	Balasubramaniam S, Choy YS, Talib A, et al. Infantile Progressive Hepatoencephalomyopathy with Combined OXPHOS Deficiency due to Mutations in the Mitochondrial Translation Elongation Factor Gene GFM1[J]. JIMD Rep, 2012, 5:113-122. doi: 10.1007/8904_2011_107. doi: 10.1007/8904_2011_107 pmid: 23430926
[11]	Galmiche L, Serre V, Beinat M, et al. Toward genotype phenotype correlations in GFM1 mutations[J]. Mitochondrion, 2012, 12(2):242-247. doi: 10.1016/j.mito.2011.09.007. doi: 10.1016/j.mito.2011.09.007 pmid: 21986555
[12]	Brito S, Thompson K, Campistol J, et al. Corrigendum: Long-term survival in a child with severe encephalopathy, multiple respiratory chain deficiency and GFM1 mutations[J]. Front Genet, 2015, 6:254. doi: 10.3389/fgene.2015.00254. doi: 10.3389/fgene.2015.00254 pmid: 26284110
[13]	Ravn K, Schönewolf-Greulich B, Hansen RM, et al. Neonatal mitochondrial hepatoencephalopathy caused by novel GFM1 mutations[J]. Mol Genet Metab Rep, 2015, 3:5-10. doi: 10.1016/j.ymgmr.2015.01.004. doi: 10.1016/j.ymgmr.2015.01.004
[14]	尤艺杰, AgnèsRotig, 王建设. GFM1突变所致儿童急性肝衰竭1例:质疑GFM1错义突变位置决定临床表型[J]. 中国循证儿科杂志, 2016, 11(5):369-372. doi: 10.3969/j.issn.1673-5501.2016.05.011. doi: 10.3969/j.issn.1673-5501.2016.05.011
[15]	Simon MT, Ng BG, Friederich MW, et al. Activation of a cryptic splice site in the mitochondrial elongation factor GFM1 causes combined OXPHOS deficiency[J]. Mitochondrion, 2017, 34:84-90. doi: 10.1016/j.mito.2017.02.004. doi: 10.1016/j.mito.2017.02.004 URL
[16]	Barcia G, Rio M, Assouline Z, et al. Clinical, neuroimaging and biochemical findings in patients and patient fibroblasts expressing ten novel GFM1 mutations[J]. Hum Mutat, 2020, 41(2):397-402. doi: 10.1002/humu.23937. doi: 10.1002/humu.23937 URL
[17]	沈亚平, 严恺, 董旻岳, 等. 联合氧化磷酸化缺陷症1型一家系临床表型及GFM1基因突变分析[J]. 浙江大学学报(医学版), 2020, 49(5):574-580. doi: 10.3785/j.issn.1008-9292.2020.10.04. doi: 10.3785/j.issn.1008-9292.2020.10.04
[18]	You C, Xu N, Qiu S, et al. A novel composition of two heterozygous GFM1 mutations in a Chinese child with epilepsy and mental retardation[J]. Brain Behav, 2020, 10(10):e01791. doi: 10.1002/brb3.1791. doi: 10.1002/brb3.1791
[19]	张梅娟, 黄君, 沈天阳, 等. 新生儿期起病的线粒体病二例[J]. 中华新生儿科杂志, 2020, 35(5):380-381. doi: 10.3760/cma.j.issn.2096-2932.2020.05.015. doi: 10.3760/cma.j.issn.2096-2932.2020.05.015
[20]	Gao J, Yu L, Zhang P, et al. Cloning and characterization of human and mouse mitochondrial elongation factor G, GFM and Gfm, and mapping of GFM to human chromosome 3q25.1-q26.2[J]. Genomics, 2001, 74(1):109-114. doi: 10.1006/geno.2001.6536. doi: 10.1006/geno.2001.6536 pmid: 11374907
[21]	Smits P, Smeitink J van den Heuvel L, Mitochondrial translation and beyond: processes implicated in combined oxidative phosphorylation deficiencies[J]. J Biomed Biotechnol, 2010, 2010:737385. doi: 10.1155/2010/737385. doi: 10.1155/2010/737385
[22]	Koscielny G, Yaikhom G, Iyer V, et al. The International Mouse Phenotyping Consortium Web Portal, a unified point of access for knockout mice and related phenotyping data[J]. Nucleic Acids Res, 2014,42(Database issue):D802-D809. doi: 10.1093/nar/gkt977. doi: 10.1093/nar/gkt977
[23]	van Waveren C, Moraes CT. Transcriptional co-expression and co-regulation of genes coding for components of the oxidative phosphorylation system[J]. BMC Genomics, 2008, 9:18. doi: 10.1186/1471-2164-9-18. doi: 10.1186/1471-2164-9-18 pmid: 18194548
[24]	Saada A. Mitochondria: mitochondrial OXPHOS (dys) function ex vivo--the use of primary fibroblasts[J]. Int J Biochem Cell Biol, 2014, 48:60-65. doi: 10.1016/j.biocel.2013.12.010. doi: 10.1016/j.biocel.2013.12.010 pmid: 24412346
[25]	Debray FG, Lambert M, Chevalier I, et al. Long-term outcome and clinical spectrum of 73 pediatric patients with mitochondrial diseases[J]. Pediatrics, 2007, 119(4):722-733. doi: 10.1542/peds.2006-1866. doi: 10.1542/peds.2006-1866 URL
[26]	Khurana D, Salganicoff L, Melvin J, et al. Epilepsy and respiratory chain defects in children with mitochondrial encephalopathies[J]. Epilepsia, 2008, 49(11):1972. doi: 10.1111/j.1528-1167.2008.01783.x. doi: 10.1111/j.1528-1167.2008.01783.x.
[27]	Lee HF, Chi CS, Tsai CR, et al. Epileptic seizures in infants and children with mitochondrial diseases[J]. Pediatr Neurol, 2011, 45(3):169-174. doi: 10.1016/j.pediatrneurol.2011.04.008. doi: 10.1016/j.pediatrneurol.2011.04.008 URL
[28]	韩萧迪, 方方, 李华, 等. 儿童线粒体疾病相关癫痫62例的临床和遗传特征[J]. 中华儿科杂志, 2019, 57(11):844-851. doi: 10.3760/cma.j.issn.0578?1310.2019.11.006. doi: 10.3760/cma.j.issn.0578?1310.2019.11.006
[29]	Calvo SE, Compton AG, Hershman SG, et al. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing[J]. Sci Transl Med, 2012, 4(118):118ra10. doi: 10.1126/scitranslmed.3003310. doi: 10.1126/scitranslmed.3003310
[30]	纪冬梅, 曹云霞. 生殖遗传技术预防线粒体遗传病的研究进展[J]. 国际生殖健康/计划生育杂志, 2020, 39(2):153-157,162. doi: 10.3969/j.issn.1674-1889.2020.02.016. doi: 10.3969/j.issn.1674-1889.2020.02.016

文献	发表时间（年）	例数	基因突变位点、发病年龄、性别	突变类型	结局
Coenen等^[6]	2004	2	c.521A>G、10 d、女 c.521A>G、出生时、男两者为姐弟,父母近亲结婚	均为纯合	均死亡
Antonicka等^[7]	2006	2	c.1068T>C、1872-2_1872-2delAG、均为出生时发病、女两者为姐妹	复合杂合	均死亡
Valente等^[8]	2007	2	C.139c>T, c.1487T>G、7 d、女 C.1016G>A、2个月、女	复合杂合纯合	均死亡
Smits等^[9]	2011	1	c.748C>T、2 d、女父母近亲结婚	纯合	死亡
Balasubramaniam等^[10]	2012	1	C.539delG;C.688G>A、2 d、女	复合杂合	死亡
Galmiche等^[11]	2012	2	c.2011C>T、出生时、男 c.1193c>T、出生时、男父母近亲结婚	均为纯合	均死亡
Brito等^[12]	2015	1	c.1404delA, c.2011C>T、2个月、女	复合杂合	存活
Ravn等^[13]	2015	3	c.130_137delinsAAAAAAAAA（前2例）,出生时,女、男, 两者为姐弟,父母近亲结婚 c.964G>A and c.1655T>G、出生时、女	均为复合杂合	均死亡
尤艺杰等^[14]	2016	1	c.688G>A, c.168delG、出生时、女	复合杂合	死亡
Simon等^[15]	2017	2	c.689+908 G>A、3个月、男 c.748C>T、出生时、男	复合杂合纯合	存活死亡
Barcia等^[16]	2020	9	c.2011C>T/c.1297_1300del、1个月、女 c.2011C>T/c.1404delA、1个月、女 c.958C>G/c.1922C>A、1个月、女 c.248A>T/c.1149_1160del、8个月、男 c.2011C>T/ c.1546T>C、1个月、男 c.2011C>T/c.100C>T、1个月、女 c.1571C>T、出生时、男 c.2011C>T、1个月、女,父母近亲结婚 c.2011C>T/c.1822C>T、1个月、女	复合杂合复合杂合复合杂合复合杂合复合杂合复合杂合纯合纯合复合杂合	存活存活死亡存活存活存活死亡存活存活
沈亚平等^[17]	2020	2	c.688G>A, c.1576C>T、出生时、女 c.688G>A, c.1576C>T、出生时、男两者为姐弟	均为复合杂合	均死亡
You等^[18]	2020	1	c.679G>A, c.1765-1_1765-2del、出生时、男	复合杂合	存活
张梅娟等^[19]	2020	2	c.688G>A, c.1576C>T、出生时、女 c.688G>A, c.1576C>T、出生时、男两者为姐弟	均为复合杂合	均死亡

文献	发表时间（年）	例数	基因突变位点、发病年龄、性别	突变类型	结局
Coenen等^[6]	2004	2	c.521A>G、10 d、女 c.521A>G、出生时、男两者为姐弟,父母近亲结婚	均为纯合	均死亡
Antonicka等^[7]	2006	2	c.1068T>C、1872-2_1872-2delAG、均为出生时发病、女两者为姐妹	复合杂合	均死亡
Valente等^[8]	2007	2	C.139c>T, c.1487T>G、7 d、女 C.1016G>A、2个月、女	复合杂合纯合	均死亡
Smits等^[9]	2011	1	c.748C>T、2 d、女父母近亲结婚	纯合	死亡
Balasubramaniam等^[10]	2012	1	C.539delG;C.688G>A、2 d、女	复合杂合	死亡
Galmiche等^[11]	2012	2	c.2011C>T、出生时、男 c.1193c>T、出生时、男父母近亲结婚	均为纯合	均死亡
Brito等^[12]	2015	1	c.1404delA, c.2011C>T、2个月、女	复合杂合	存活
Ravn等^[13]	2015	3	c.130_137delinsAAAAAAAAA（前2例）,出生时,女、男, 两者为姐弟,父母近亲结婚 c.964G>A and c.1655T>G、出生时、女	均为复合杂合	均死亡
尤艺杰等^[14]	2016	1	c.688G>A, c.168delG、出生时、女	复合杂合	死亡
Simon等^[15]	2017	2	c.689+908 G>A、3个月、男 c.748C>T、出生时、男	复合杂合纯合	存活死亡
Barcia等^[16]	2020	9	c.2011C>T/c.1297_1300del、1个月、女 c.2011C>T/c.1404delA、1个月、女 c.958C>G/c.1922C>A、1个月、女 c.248A>T/c.1149_1160del、8个月、男 c.2011C>T/ c.1546T>C、1个月、男 c.2011C>T/c.100C>T、1个月、女 c.1571C>T、出生时、男 c.2011C>T、1个月、女,父母近亲结婚 c.2011C>T/c.1822C>T、1个月、女	复合杂合复合杂合复合杂合复合杂合复合杂合复合杂合纯合纯合复合杂合	存活存活死亡存活存活存活死亡存活存活
沈亚平等^[17]	2020	2	c.688G>A, c.1576C>T、出生时、女 c.688G>A, c.1576C>T、出生时、男两者为姐弟	均为复合杂合	均死亡
You等^[18]	2020	1	c.679G>A, c.1765-1_1765-2del、出生时、男	复合杂合	存活
张梅娟等^[19]	2020	2	c.688G>A, c.1576C>T、出生时、女 c.688G>A, c.1576C>T、出生时、男两者为姐弟	均为复合杂合	均死亡