Leigh syndrome caused by the mitochondrial m.8993T&gt;G mutation with hypocitrullinemia: a report of four cases and literature review

LI Ying-Xue; WANG Dong-Juan; ZHOU Mao-Bin; SUN Hao-Xuan; HONG Si-Qi; JIANG Li; GUO Yi

doi:10.7499/j.issn.1008-8830.2404036

PDF(769 KB)

Chinese Journal of Contemporary Pediatrics ›› 2024, Vol. 26 ›› Issue (9) : 940-945. DOI: 10.7499/j.issn.1008-8830.2404036

CLINICAL RESEARCH

Leigh syndrome caused by the mitochondrial m.8993T>G mutation with hypocitrullinemia: a report of four cases and literature review

LI Ying-Xue, WANG Dong-Juan, ZHOU Mao-Bin, SUN Hao-Xuan, HONG Si-Qi, JIANG Li, GUO Yi

Author information +

History +

Abstract

Objective To explore early diagnostic biological markers for Leigh syndrome caused by the m.8993T>G mutation. Methods A retrospective analysis was performed on the clinical data of four children diagnosed with m.8993T>G mutation-related mitochondrial disease at the Children's Hospital of Chongqing Medical University from January 2014 to January 2024. Additionally, a literature review was conducted. Results All four children had plasma amino acid and acylcarnitine analyses that revealed decreased citrulline levels, and one child was initially identified through neonatal genetic metabolic disease screening. According to the literature review, there were 26 children with mitochondrial disease and hypocitrullinemia caused by the m.8993T>G mutation (including the four children in this study). Among these, 12 children exhibited clinical phenotypes of Leigh syndrome or Leigh-like syndrome, while 18 children were identified with hypocitrullinemia and/or elevated levels of 3-hydroxyisovalerylcarnitine (C5-OH) during neonatal genetic metabolic disease screening. Conclusions Hypocitrullinemia may serve as a potential biomarker for the early diagnosis of m.8993T>G mutation-associated Leigh syndrome, detectable as early as during neonatal genetic metabolic disease screening.

Key words

Leigh syndrome / m.8993T>G / MT-ATP6 gene / Hypocitrullinemia / Child

Cite this article

EndNote

Ris (Procite)

Bibtex

Download Citations

LI Ying-Xue, WANG Dong-Juan, ZHOU Mao-Bin, SUN Hao-Xuan, HONG Si-Qi, JIANG Li, GUO Yi. Leigh syndrome caused by the mitochondrial m.8993T>G mutation with hypocitrullinemia: a report of four cases and literature review[J]. Chinese Journal of Contemporary Pediatrics. 2024, 26(9): 940-945 https://doi.org/10.7499/j.issn.1008-8830.2404036

References

1 Leigh D. Subacute necrotizing encephalomyelopathy in an infant[J]. J Neurol Neurosurg Psychiatry, 1951, 14(3): 216-221. PMID: 14874135. PMCID: PMC499520. DOI: 10.1136/jnnp.14.3.216.
2 中华医学会儿科学分会神经学组, 福棠儿童医学发展研究中心神经内科专业委员会, 中华儿科杂志编辑委员会. Leigh综合征诊断与治疗中国专家共识（2023）[J]. 中华儿科杂志, 2023, 61(12): 1077-1085. PMID: 38018044. DOI: 10.3760/cma.j.cn112140-20230904-00153.
3 Stendel C, Neuhofer C, Floride E, et al. Delineating MT-ATP6-associated disease: from isolated neuropathy to early onset neurodegeneration[J]. Neurol Genet, 2020, 6(1): e393. PMID: 32042921. PMCID: PMC6975175. DOI: 10.1212/NXG.0000000000000393.
4 Baertling F, Rodenburg RJ, Schaper J, et al. A guide to diagnosis and treatment of Leigh syndrome[J]. J Neurol Neurosurg Psychiatry, 2014, 85(3): 257-265. PMID: 23772060. DOI: 10.1136/jnnp-2012-304426.
5 Wongkittichote P, Ganetzky RD, Demczko MM, et al. Low plasma citrulline guiding the diagnosis of a mitochondrial disorder[J]. Clin Chem, 2023, 69(6): 661-664. PMID: 37258485. DOI: 10.1093/clinchem/hvad039.
6 Tise CG, Verscaj CP, Mendelsohn BA, et al. MT-ATP6 mitochondrial disease identified by newborn screening reveals a distinct biochemical phenotype[J]. Am J Med Genet A, 2023, 191(6): 1492-1501. PMID: 36883293. DOI: 10.1002/ajmg.a.63159.
7 Peretz RH, Ah Mew N, Vernon HJ, et al. Prospective diagnosis of MT-ATP6-related mitochondrial disease by newborn screening[J]. Mol Genet Metab, 2021, 134(1-2): 37-42. PMID: 34176718. PMCID: PMC8578202. DOI: 10.1016/j.ymgme.2021.06.007.
8 Balasubramaniam S, Lewis B, Mock DM, et al. Leigh-like syndrome due to homoplasmic m.8993T>G variant with hypocitrullinemia and unusual biochemical features suggestive of multiple carboxylase deficiency (MCD)[J]. JIMD Rep, 2017, 33: 99-107. PMID: 27450367. PMCID: PMC5413447. DOI: 10.1007/8904_2016_559.
9 Mori M, Mytinger JR, Martin LC, et al. m.8993T>G-associated Leigh syndrome with hypocitrullinemia on newborn screening[J]. JIMD Rep, 2014, 17: 47-51. PMID: 25240982. PMCID: PMC4241199. DOI: 10.1007/8904_2014_332.
10 Henriques M, Diogo L, Garcia P, et al. Mitochondrial DNA 8993T>G mutation in a child with ornithine transcarbamylase deficiency and Leigh syndrome: an unexpected association[J]. J Child Neurol, 2012, 27(8): 1059-1061. PMID: 22241703. DOI: 10.1177/0883073811431015.
11 Debray FG, Lambert M, Allard P, et al. Low citrulline in Leigh disease: still a biomarker of maternally inherited Leigh syndrome[J]. J Child Neurol, 2010, 25(8): 1000-1002. PMID: 20472868. DOI: 10.1177/0883073809351983.
12 Enns GM, Bai RK, Beck AE, et al. Molecular-clinical correlations in a family with variable tissue mitochondrial DNA T8993G mutant load[J]. Mol Genet Metab, 2006, 88(4): 364-371. PMID: 16546428. DOI: 10.1016/j.ymgme.2006.02.001.
13 Carrozzo R, Verrigni D, Rasmussen M, et al. Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients[J]. J Inherit Metab Dis, 2016, 39(2): 243-252. PMID: 26475597. DOI: 10.1007/s10545-015-9894-9.
14 Saunders C, Smith L, Wibrand F, et al. CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria[J]. Am J Hum Genet, 2015, 96(2): 258-265. PMID: 25597511. PMCID: PMC4320254. DOI: 10.1016/j.ajhg.2014.12.020.
15 Maas RR, Iwanicka-Pronicka K, Kalkan Ucar S, et al. Progressive deafness-dystonia due to SERAC1 mutations: a study of 67 cases[J]. Ann Neurol, 2017, 82(6): 1004-1015. PMID: 29205472. PMCID: PMC5847115. DOI: 10.1002/ana.25110.
16 Yang H, Yu D. Clinical, biochemical and metabolic characterization of patients with short-chain enoyl-CoA hydratase(ECHS1) deficiency: two case reports and the review of the literature[J]. BMC Pediatr, 2020, 20(1): 50. PMID: 32013919. PMCID: PMC6996175. DOI: 10.1186/s12887-020-1947-z.
17 Wang J, Liu Z, Xu M, et al. Cinical, metabolic, and genetic analysis and follow-up of eight patients with HIBCH mutations presenting with leigh/leigh-like syndrome[J]. Front Pharmacol, 2021, 12: 605803. PMID: 33762937. PMCID: PMC7982470. DOI: 10.3389/fphar.2021.605803.
18 Boyer M, Sowa M, Di Meo I, et al. Response to medical and a novel dietary treatment in newborn screen identified patients with ethylmalonic encephalopathy[J]. Mol Genet Metab, 2018, 124(1): 57-63. PMID: 29526615. DOI: 10.1016/j.ymgme.2018.02.008.
19 Rabier D, Kamoun P. Metabolism of citrulline in man[J]. Amino Acids, 1995, 9(4): 299-316. PMID: 24178879. DOI: 10.1007/BF00807268.
20 庞韦, 田锐, 王瑞兰. 血浆瓜氨酸在肠功能损伤中的临床应用进展[J]. 临床急诊杂志, 2018, 19(4): 274-278. DOI: 10.13201/j.issn.1009-5918.2018.04.017.
21 Elliott KR, Tipton KF. Product inhibition studies on bovine liver carbamoyl phosphate synthetase[J]. Biochem J, 1974, 141(3): 817-824. PMID: 4377108. PMCID: PMC1168187. DOI: 10.1042/bj1410817.