目的 探讨C12orf65基因变异相关联合氧化磷酸化缺陷症7型（combined oxidative phosphorylation deficiency type 7, COXPD7）的临床特征及基因变异特点，提高对该病的认识。 方法 以郑州大学附属儿童医院神经内科2021年诊断的1例COXPD7患儿及文献报道的10例患者为研究对象，对其基因型和临床表型进行分析。 结果 共纳入11例COXPD7患者，均为C12orf65基因变异，9例为纯合变异，2例为复合杂合变异。起病年龄为生后1 d至2岁，临床均表现为视神经萎缩、智力运动发育落后，8例存在眼外肌麻痹，5例存在痉挛性瘫痪。头颅磁共振成像检查示11例均存在视神经萎缩，10例有脑干异常信号，3例脑干磁共振波谱分析成像可见乳酸峰。 结论 C12orf65基因相关的COXPD7为纯合或复合杂合变异所致，其主要临床表现为视神经萎缩和智力运动发育落后，部分患者存在痉挛性瘫痪、眼外肌麻痹，头颅影像学可见双侧基底节、脑干对称性异常信号，脑干磁共振波谱分析成像可见乳酸峰。
Abstract
Objective To investigate the clinical features and gene mutation characteristics of combined oxidative phosphorylation deficiency type 7 (COXPD7) caused by mutations in the C12orf65 gene, and to enhance the awareness of this disease. Methods A child diagnosed with COXPD7 in the Department of Neurology, Children's Hospital Affiliated to Zhengzhou University in 2021 was included, along with 10 patients reported in the literature. All subjects were analyzed for their genotypes and clinical phenotypes. Results A total of 11 patients with COXPD7 were included, comprising 1 reported in this study and 10 from the literature. Among the 11 patients, 9 had homozygous mutations in the C12orf65 gene, while 2 had compound heterozygous mutations, which were identified as frameshift or nonsense mutations. The age of onset ranged from 1 day to 2 years, and clinical manifestations included optic nerve atrophy and delays in intellectual and motor development. Eight patients exhibited external ophthalmoplegia, and five patients displayed spastic paralysis. Cranial magnetic resonance imaging revealed optic nerve atrophy in all 11 patients, abnormal brainstem signals in 10 patients, and a lactate peak on brainstem magnetic resonance spectroscopy scans in 3 patients. Conclusions COXPD7 associated with the C12orf65 gene results from homozygous or compound heterozygous mutations, with primary clinical manifestations of optic nerve atrophy and delays in intellectual and motor development. Some patients may also present with spastic paralysis or external ophthalmoplegia. Cranial imaging reveals symmetrical abnormal signals in bilateral basal ganglia and brainstem, and a lactate peak is observed on brainstem magnetic resonance spectroscopy scans.
关键词
联合氧化磷酸化缺陷症7型 /
Leigh综合征 /
C12orf65基因 /
线粒体病 /
儿童
Key words
Combined oxidative phosphorylation deficiency type 7 /
Leigh syndrome /
C12orf65 gene /
Mitochondrial disease /
Child
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参考文献
1 Davis RL, Liang C, Sue CM. Mitochondrial diseases[J]. Handb Clin Neurol, 2018, 147: 125-141. PMID: 29325608. DOI: 10.1016/B978-0-444-63233-3.00010-5.
2 Antonicka H, Ostergaard E, Sasarman F, et al. Mutations in C12orf65 in patients with encephalomyopathy and a mitochondrial translation defect[J]. Am J Hum Genet, 2010, 87(1): 115-122. PMID: 20598281. PMCID: PMC2896764. DOI: 10.1016/j.ajhg.2010.06.004.
3 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. Genet Med,2015,17(5):405-424. PMID: 25741868.PMCID: PMC4544753. DOI: 10.1038/gim. 2015.30.
4 Heidary G, Calderwood L, Cox GF, et al. Optic atrophy and a Leigh-like syndrome due to mutations in the C12orf65 gene:report of a novel mutation and review of the literature[J]. J Neuroophthalmol, 2014, 34(1): 39-43. PMID: 24284555. DOI: 10.1097/WNO.0000000000000076.
5 Imagawa E, Fattal-Valevski A, Eyal O, et al. Homozygous p.V116* mutation in C12orf65 results in Leigh syndrome[J]. J Neurol Neurosurg Psychiatry, 2016, 87(2): 212-216. PMID: 25995486. DOI: 10.1136/jnnp-2014-310084.
6 Perrone E, Cavole TR, Oliveira MG, et al. Leigh syndrome in a patient with a novel C12orf65 pathogenic variant: case report and literature review[J]. Genet Mol Biol, 2020, 43(2): e20180271. PMID: 32478789. PMCID: PMC7263430. DOI: 10.1590/1678-4685-GMB-2018-0271.
7 Nishihara H, Omoto M, Takao M, et al. Autopsy case of the C12orf65 mutation in a patient with signs of mitochondrial dysfunction[J]. Neurol Genet, 2017, 3(4): e171. PMID: 28804760. PMCID: PMC5532748. DOI: 10.1212/NXG.0000000000000171.
8 Pyle A, Ramesh V, Bartsakoulia M, et al. Behr's syndrome is typically associated with disturbed mitochondrial translation and mutations in the C12orf65 gene[J]. J Neuromuscul Dis, 2014, 1(1): 55-63. PMID: 26380172. PMCID: PMC4568311. DOI: 10.3233/JND-140003.
9 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. PMID: 25652200. PMCID: PMC4737121. DOI: 10.1002/ana.24362.
10 Shimazaki H, Takiyama Y, Ishiura H, et al. A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55)[J]. J Med Genet, 2012, 49(12): 777-784. PMID: 23188110. DOI: 10.1136/jmedgenet-2012-101212.
11 Buchert R, Uebe S, Radwan F, et al. Mutations in the mitochondrial gene C12ORF65 lead to syndromic autosomal recessive intellectual disability and show genotype phenotype correlation[J]. Eur J Med Genet, 2013, 56(11): 599-602. PMID: 24080142. DOI: 10.1016/j.ejmg.2013.09.010.
12 Spiegel R, Mandel H, Saada A, et al. Delineation of C12orf65-related phenotypes: a genotype-phenotype relationship[J]. Eur J Hum Genet, 2014, 22(8): 1019-1025. PMID: 24424123. PMCID: PMC4350599. DOI: 10.1038/ejhg.2013.284.
13 Tucci A, Liu YT, Preza E, et al. Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy[J]. J Neurol Neurosurg Psychiatry, 2014, 85(5): 486-492. PMID: 24198383. PMCID: PMC3995331. DOI: 10.1136/jnnp-2013-306387.
14 Fang XJ, Zhang W, Lyu H, et al. Compound heterozygote mutation of C12orf65 causes distal motor neuropathy and optic atrophy[J]. Chin Med J (Engl), 2017, 130(2): 242-244. PMID: 28091420. PMCID: PMC5282685. DOI: 10.4103/0366-6999.198019.
15 Tinker RJ, Lim AZ, Stefanetti RJ, et al. Current and emerging clinical treatment in mitochondrial disease[J]. Mol Diagn Ther, 2021, 25(2): 181-206. PMID: 33646563. PMCID: PMC7919238. DOI: 10.1007/s40291-020-00510-6.
基金
河南省儿科疾病临床医学研究中心开放课题（YJZX202202）；河南省医学科技攻关计划联合共建项目（LHGJ20230584）。
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