Hydrocephalus presented as the prominent symptom of severe 5,10‑methylenetetrahydrofolate reductase deficiency in an infant: A case report

Ding,Yuan; Wang,Qiao; Gong,Chun-Xiu

doi:10.3892/mi.2022.37

Hydrocephalus presented as the prominent symptom of severe 5,10‑methylenetetrahydrofolate reductase deficiency in an infant: A case report

Authors:
- Yuan Ding
- Qiao Wang
- Chun-Xiu Gong
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Affiliations: Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University, National Centre for Children's Health, Beijing 100045, P.R. China
Published online on: April 5, 2022 https://doi.org/10.3892/mi.2022.37
Article Number: 12
Copyright: © Ding et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Hyperhomocysteinemia is a common medical condition observed in patients with aminoaciduria. Deficiency in cystathionine beta‑synthase, metabolism of cobalamin associated C, peroxiredoxin 1, 5‑methyltetrahydrofolate‑homocysteine methyltransferase reductase, LMBR1 domain containing 1, 5‑methyltetrahydrofolate‑homocysteine methyltransferase or 5,10‑methylenetetrahydrofolate reductase (MTHFR) all can result in an elevation in plasma homocysteine, which has been reported to be a risk factor of vascular events, such as atherosis, acute myocardial infarction and cerebral stroke. Hyperhomocysteinemia due to the deficiency of 5,10‑methylenetetrahydrofolate reductase (MTHFR; also known as 5,10‑methyl THR reductase) is an autosomal recessive rare disease caused by defects in the MTHFR gene. The clinical manifestations of this disorder are heterogeneous, ranging from asymptomatic to severe neurological disorders. However, hydrocephalus has seldomly been reported in patients with MTHFR deficiency. The present study thus describes a case of severe MTHFR deficiency in an infant, whose main manifestation was hydrocephalus. The clinical course and genotype of the patient were also examined. Specifically, a 4‑month‑old boy with hydrocephalus was admitted to hospital. Clinical examinations and genetic sequencing of the patient were performed to determine the probable causative factors. A physical examination revealed that the patient had developmental delay and progressive hydrocephalus. Amino acid analysis of the blood revealed an enhancement in serum homocysteine levels and a decrease in blood methionine and free carnitine levels. The organic acid levels in urine were normal. Therefore, he was diagnosed with hyperhomocysteinemia. Targeted next‑generation sequencing was performed to determine the pathogenetic gene in this case. A paternal mutation c.1530G>A (p.K510K) and a maternal mutation c.233C>A (p.S78X) were identified. Previous experimental evidence indicated that these two mutations were all pathogenic; therefore, this patient was ultimately diagnosed with MTHFR deficiency. The patient in described herein study presented with severe progressive hydrocephalus in association with a delayed developmental milestone. According to the clinical and genetic tests, the patient was diagnosed with severe MTHFR deficiency. It thus is recommended that screening for metabolites and performing gene sequencing in infants presenting with undisclosed hydrocephalus.

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1	McCully KS: Vascular pathology of homocysteinemia: Implications for the pathogenesis of arteriosclerosis. Am J Pathol. 56:111–128. 1969.PubMed/NCBI
2	Brustolin S, Giugliani R and Félix TM: Genetics of homocysteine metabolism and associated disorders. Braz J Med Biol Res. 43:1–7. 2010.PubMed/NCBI View Article : Google Scholar
3	Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, Andria G, Boers GH, Bromberg IL and Cerone R: The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet. 37:1–31. 1985.PubMed/NCBI
4	Kuo HK, Sorond FA, Chen JH, Hashmi A, Milberg WP and Lipsitz LA: The role of homocysteine in multisystem age-related problems: A systematic review. J Gerontol A Biol Sci Med Sci. 60:1190–1201. 2005.PubMed/NCBI View Article : Google Scholar
5	Geng B, Chang L, Du JB and Tang CS: A new strategy to treat hyperhomocysteinemia. Beijing Da Xue Xue Bao Yi Xue Ban. 37:215–219. 2005.PubMed/NCBI(In Chinese).
6	Carson NA and Neill DW: Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland. Arch Dis Child. 37:505–513. 1962.PubMed/NCBI View Article : Google Scholar
7	Gerritsen T, Vaughn JG and Waisman HA: The identification of homocystine in the urine. Biochem Biophys Res Commun. 9:493–496. 1962.PubMed/NCBI View Article : Google Scholar
8	Mudd SH, Finkelstein JD, Irreverre F and Laster L: Homocystinuria: An enzymatic defect. Science. 143:1443–1445. 1964.PubMed/NCBI View Article : Google Scholar
9	Mudd SH, Levy HL, Abeles RH and Jennedy JP Jr: A derangement in B 12 metabolism leading to homocystinemia, cystathioninemia and methylmalonic aciduria. Biochem Biophys Res Commun. 35:121–126. 1969.PubMed/NCBI View Article : Google Scholar
10	Baethmann M, Wendel U, Hoffmann GF, Göhlich-Ratmann G, Kleinlein B, Seiffert B, Blom H and Voit T: Hydrocephalus internus in two patients with 5,10-methylenetetrahydrofolate reductase deficiency. Neuropediatrics. 31:314–317. 2000.PubMed/NCBI View Article : Google Scholar
11	Guenther BD, Sheppard CA, Tran P, Rozen R, Matthews RG and Ludwig ML: The structure and properties of methylenetetrahydrofolate reductase from escherichia coli suggest how folate ameliorates human hyperhomocysteinemia. Nat Struct Biol. 6:359–365. 1999.PubMed/NCBI View Article : Google Scholar
12	Shahzad K, Hai A, Ahmed A, Kizilbash N and Alruwaili J: A structured-based model for the decreased activity of Ala222Val and Glu429Ala methylenetetrahydrofolate reductase (MTHFR) mutants. Bioinformation. 9:929–936. 2013.PubMed/NCBI View Article : Google Scholar
13	Leclerc D, Sibani S and Rozen R: Molecular biology of methylenetetrahydrofolate reductase (MTHFR) and overview of mutations/polymorphisms. MTHFR polymorphisms and disease: CRC Press; 2005. p.15-3.
14	Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR and Vorechovsky I: Aberrant 5' splice sites in human disease genes: Mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. Nucleic Acids Res. 35:4250–4263. 2007.PubMed/NCBI View Article : Google Scholar
15	Burda P, Schäfer A, Suormala T, Rummel T, Bürer C, Heuberger D, Frapolli M, Giunta C, Sokolova J, Vlášková H, et al: Insights into severe 5,10-methylenetetrahydrofolate reductase deficiency: Molecular genetic and enzymatic characterization of 76 patients. Hum Mutat. 36:611–621. 2015.PubMed/NCBI View Article : Google Scholar
16	Broomfield A, Abulhoul L, Pitt W, Jameson E and Cleary M: Reversal of respiratory failure in both neonatal and late onset isolated remethylation disorders. JIMD Rep. 16:51–56. 2014.PubMed/NCBI View Article : Google Scholar
17	Richard E, Desviat LR, Ugarte M and Pérez B: Oxidative stress and apoptosis in homocystinuria patients with genetic remethylation defects. J Cell Biochem. 114:183–191. 2013.PubMed/NCBI View Article : Google Scholar
18	Knowles L, Morris AA and Walter JH: Treatment with mefolinate (5-Methyltetrahydrofolate), but not folic acid or folinic acid, leads to measurable 5-Methyltetrahydrofolate in cerebrospinal fluid in methylenetetrahydrofolate reductase deficiency. JIMD Rep. 29:103–107. 2016.PubMed/NCBI View Article : Google Scholar
19	Froese DS, Huemer M, Suormala T, Burda P, Coelho D, Gueant JL, Landolt MA, Kozich V, Fowler B and Baumgartner MR: Mutation update and review of severe methylenetetrahydrofolate reductase deficiency. Hum Mutat. 37:427–438. 2016.PubMed/NCBI View Article : Google Scholar
20	Tonetti C, Saudubray JM, Echenne B, Landrieu P, Giraudier S and Zittoun J: Relations between molecular and biological abnormalities in 11 families from siblings affected with methylenetetrahydrofolate reductase deficiency. Eur J Pediatr. 162:466–475. 2003.PubMed/NCBI View Article : Google Scholar
21	Kristin E, Bearden D, Watkins D, Hyland K, Rosenblatt DS and Ficicioglu C: Severe 5, 10-methylenetetrahydrofolate reductase deficiency and two MTHFR variants in an adolescent with progressive myoclonic epilepsy. Pediatr Neurol. 51:266–270. 2014.PubMed/NCBI View Article : Google Scholar
22	Prasad AN, Rupar CA and Prasad C: Methylenetetrahydrofolate reductase (MTHFR) deficiency and infantile epilepsy. Brain Dev. 33:758–769. 2011.PubMed/NCBI View Article : Google Scholar
23	Algassim N, Alfadhel M, Nashabat M and Eyaid W: Clinical presentation of seven patients with Methylenetetrahydrofolate reductase deficiency. Mol Genet Metab Rep. 25(100644)2020.PubMed/NCBI View Article : Google Scholar
24	Tsuji M, Takagi A, Sameshima K, Iai M, Yamashita S, Shinbo H, Furuya N, Kurosawa K and Osaka H: 5,10-Methylenetetrahydrofolate reductase deficiency with progressive polyneuropathy in an infant. Brain Dev. 33:521–524. 2011.PubMed/NCBI View Article : Google Scholar
25	Greitz D: Radiological assessment of hydrocephalus: New theories and implications for therapy. Neuroradiol J. 19:475–495. 2006.PubMed/NCBI View Article : Google Scholar
26	Zittoun J: Congenital errors of folate metabolism. Baillieres Clin Haematol. 8:603–616. 1995.PubMed/NCBI View Article : Google Scholar
27	Lossos A, Teltsh O, Milman T, Meiner V, Rozen R, Leclerc D, Schwahn BC, Karp N, Rosenblatt DS, Watkins D, et al: Severe methylenetetrahydrofolate reductase deficiency: Clinical clues to a potentially treatable cause of adult-onset hereditary spastic paraplegia. JAMA Neurol. 71:901–904. 2014.PubMed/NCBI View Article : Google Scholar
28	Kim YI: 5,10-methylenetetrahydrofolate reductase polymorphisms and pharmacogenetics: A new role of single nucleotide polymorphisms in the folate metabolic pathway in human health and disease. Nut Rev. 63:398–407. 2005.PubMed/NCBI View Article : Google Scholar