Endocrinologic, Genetic, and Metabolic Disease

Two cases of hydrocephalus due to methylenetetrahydrofolate reductase deficiency and MTHFR gene variants

  • Hui DONG ,
  • Zhehui CHEN ,
  • Xue MA ,
  • Yao ZHANG ,
  • Jinqing SONG ,
  • Ying JIN ,
  • Mengqiu LI ,
  • Hongwu ZHANG ,
  • Hongxin YAO ,
  • Yanling YANG
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  • 1. Department of Pediatrics, Peking University First Hospital, Beijing 100034, China
    2. Department of Pediatric Surgery, Peking University First Hospital, Beijing 100034, China

Received date: 2022-11-29

  Online published: 2023-02-16

Abstract

Objective To investigate the clinical characteristics, treatment, and prognosis of hydrocephalus due to methylenetetrahydrofolate reductase (MTHFR) deficiency caused by MTHFR gene variations. Methods Two boys admitted to the Department of Pediatrics of Peking University First Hospital with hydrocephalus were diagnosed by serum total homocysteine, blood amino acid and acylcarnitine profile, urinary organic acid, and genetic analysis. The clinical manifestations, biochemical features, MTHFR gene variants, diagnosis, therapy, and prognosis were retrospectively analyzed. Results Two children presented with hydrocephalus and seizures at 2 and 4 months of age, respectively, with significantly increased serum total homocysteine, reduced or low normal blood methionine, normal urinary organic acids, and severe hydrocephalus on cranial imaging. Serum total homocysteine decreased after treatment with betaine, calcium folinic acid, and cobalamin in both children, and intracranial pressure improved after lateral ventriculoperitoneal shunt surgery, but intellectual and motor development was delayed and seizures were still present. The diagnosis of homocysteinemia type 2 due to MTHFR deficiency was confirmed by the presence of compound heterozygous variants in the MTHFR gene in both children. One of the 4 variants was a known pathogenic variant and 3 were unreported novel variants. Conclusion Children with MTHFR deficiency may develop severe neurological symptoms such as hydrocephalus and epilepsy in early infancy, and serum total homocysteine and gene analysis are keys for the diagnosis.

Cite this article

Hui DONG , Zhehui CHEN , Xue MA , Yao ZHANG , Jinqing SONG , Ying JIN , Mengqiu LI , Hongwu ZHANG , Hongxin YAO , Yanling YANG . Two cases of hydrocephalus due to methylenetetrahydrofolate reductase deficiency and MTHFR gene variants[J]. Journal of Clinical Pediatrics, 2023 , 41(2) : 108 -112 . DOI: 10.12372/jcp.2023.22e1574

References

[1] Aljassim N, Alfadhel M, Nashabat M, et al. Clinical presentation of seven patients with methy-lenetetrahydrofolate reductase deficiency[J]. Mol Genet Metab Rep, 2020, 25: 100644.
[2] Tortorelli S, Turgeon CT, Lim JS, et al. Two-tier approach to the newborn screening of methylenetetrahydrofolate reductase deficiency and other remethylation disorders with tandem mass spectrometry[J]. J Pediatr, 2010, 157(2):271-275.
[3] 李东晓, 张尧, 张宏武, 等. 高同型半胱氨酸血症的诊断、治疗与预防专家共识[J]. 罕少疾病杂志, 2022, 29(6): 1-4.
[4] 顾学范, 韩连书, 余永国. 中国新生儿遗传代谢病筛查现状及展望[J]. 罕见病研究, 2022, 1(1): 13-19.
[5] Li DX, Li XY, Dong H, et al. Eight novel mutations of CBS gene in nine Chinese patients with classical homocystinuria[J]. World J Pediatr, 2018, 14(2): 197-203.
[6] 中国妇幼保健协会出生缺陷防治与分子遗传分会. 甲基丙二酸血症合并同型半胱氨酸血症cblC型所致脑积水诊疗与预防专家共识[J]. 中华新生儿科杂志, 2022, 37 (6): 481-487
[7] Garcia-Bonilla M, McAllister JP, Limbrick DD. Genetics and Molecular Pathogenesis of Human Hydrocephalus[J]. Neurol India, 2021, 69(Supplement): S268-S274.
[8] Bauer DF, Baird LC, Klimo P, et al. Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Treatment of Pediatric Hydrocephalus: update of the 2014 guidelines[J]. Neurosurgery, 2020, 87(6): 1071-1075.
[9] 谢艺, 袁义, 陈瑜, 等. 早发型亚甲基四氢叶酸还原酶缺陷症1例临床及基因分析[J]. 临床儿科杂志, 2018, 36(9): 658-661.
[10] Richard E, Desviat LR, Ugarte M, et al. Oxidative stress and apoptosis in homocystinuria patients with genetic remethylation defects[J]. J Cell Biochem, 2013, 114(1): 183-191.
[11] 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[J]. Genet Med, 2015, 17: 405-424.
[12] 王峤, 刘靖, 刘玉鹏, 等. 亚甲基四氢叶酸还原酶缺陷导致学童精神分裂症[J]. 中国当代儿科杂志, 2014, 16(1): 62-66.
[13] Al Mutairi F. Hyperhomocysteinemia: clinical insights[J]. J Cent Nerv Syst Dis, 2020, 12: 1179573520962230.
[14] Mudd SH, Uhlendorf BW, Freeman JM, et al. Homocystinuria associated with decreased methylenetetrahydrofolate reductase activity[J]. Biochem Biophys Res Commun, 1972, 46(2): 905-912.
[15] Huemer M, Mulder-Bleile R, Burda P, et al. Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency[J]. J Inherit Metab Dis, 2016, 39(1): 115-124.
[16] Huemer M, Diodato D, Schwahn B, et al. Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency[J]. J Inherit Metab Dis, 2017. 40(1): 21-48.
[17] 北京医学会罕见病分会, 中国妇幼保健协会儿童疾病和保健分会遗传代谢学组, 中国医师协会青春期医学专业委员会临床遗传学组及生化学组, 等. 遗传代谢病所致贫血的诊疗专家共识[J]. 标记免疫分析与临床, 2021, 28(10): 1626-1634.
[18] Goyette P, Rosenblatt D, Rozen R. Homocystinuria (methylenetetra hydrofolate reductase deficiency) and mutation of factor gene[J]. Inherit Metab Dis, 1998, 21(6): 690-691.
[19] Froese DS, Huemer M, Suormala T, et al. Mutation update and review of severe methylenetetrahydrofolate reductase Deficiency[J]. Hum Mutat, 2016, 37(5): 427-438.
[20] Burda P, Schafer A, Suormala T, et al. Insights into severe 5, 10-methylenetetrahydrofolate reductase deficiency: molecular genetic and enzymatic characterization of 76 patients[J]. Hum Mutat, 2015, 36(6): 611-621.
[21] Tonetti C, Saudubray JM, Echenne B, et al. Relations between molecular and biological abnormalities in 11 families from siblings affected with methylenetetrahydrofolate reductase deficiency[J]. Eur J Pediatr, 2003, 162(7-8):466-475.
[22] Tsang BL, Devine OJ, Cordero AM, et al. Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies[J]. Am J Clin Nutr, 2015, 101(6): 1286-1294.
[23] Diekman EF, de Koning TJ, Verhoeven-Duif NM, et al. Survival and psychomotor development with early betaine treatment in patients with severe methylenetetrahydrofolate reductase deficiency[J]. JAMA Neurol, 2014, 71(2):188-194.
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