Abstract：Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. It is known that MTHFR deficiency may result in hyperhomocysteinemia, but MTHFR deficiency-induced schizophrenia has been rarely reported. Here we present the clinical course, biochemical and genetic characteristics of schizophrenia resulted from MTHFR deficiency in a school-age boy. He was 13 years old. He was admitted with a two-year history of fear, auditory hallucination, learning difficulty, sleeping problems, irascibility, drowsing and giggling. At admission, he had significantly elevated plasma and urine levels of total homocysteine, significantly decreased levels of folate in serum and cerebrospinal fluid, and a normal blood concentration of methionine. Further DNA sequencing analysis showed 665C>T homozygous mutations in the MTHFR gene. The patient was diagnosed with MTHFR deficiency-associated schizophrenia and treatment with calcium folinate, vitamin B12, vitamin B6, and betaine was initiated. After the treatment for 1 week, his plasma and urine levels of homocysteine were decreased to a normal range and the clinical symptoms were significantly improved. After 3 months of treatment, the patient returned to school. He is now living with normal school life. In summary, children with late-onset MTHFR deficiency and secondary cerebral folate deficiency may lead to schizophrenia. This rare condition can be early diagnosed through analyses of blood and urine total homocysteine, amino acids in blood and folate in blood and cerebral fluid and successfully treated with folinic acid, vitamin B6, vitamin B12 and betaine.
WANG Qiao,LIU Jing,LIU Yu-Peng et al. Methylenetetrahydrofolate reductase deficiency-induced schizophrenia in a school-age boy[J]. CJCP, 2014, 16(1): 62-66.
Rosenblatt DS. Disorders of cobalamin and folate transport and metabolism[M]//Fernandes J, Saudubray JM, Van den Berghe G, eds. Inborn Metabolic Diseases Diagnosis and Treatment. 3rd ed. New York: Springer, 2000: 284-296.
Haworth JC, Dilling LA, Surtees RA, et al. Symptomatic and asymptomatic methylenetetrahydrofolate reductase deficiency in two adult brothers[J]. Am J Med Genet, 1993, 45(5): 572-576.
[9]
Prasad AN, Rupar CA, Prasad C. Methylenetetrahydrofolate reductase (MTHFR) deficiency and infantile epilepsy[J]. Brain Dev, 2011, 33(9): 758-769.
[10]
Arn PH, Williams CA, Zori RT, et al. Methylenetetrahydrofolate reductase deficiency in a patient with phenotypic findings of Angelman syndrome[J]. Am J Med Genet, 1998, 77(3): 198-200.
[11]
Engelbrecht V, Rassek M, Huismann J, et al. MR and proton MR spectroscopy of the brain in hyperhomocysteinemia caused by methylenetetrahydrofolate reductasedeficiency[J]. AJNR Am J Neuroradiol, 1997, 18(3): 536-539.
Rosenblatt DS, Lue-Shing H, Arzoumanian A, et al. Methylenetetrahydrofolate reductase deficiency: thermolability of residual MR activity,methionione synthase activity, and methylcobalamin levels in cultured fibroblasts[J]. Biochem Med Met Biol, 1992, 47(3): 221-225.
[15]
Goyette P, Christensen B, Rosenblatt DS, et al. Severe and mild mutations in cis for the methyleneterahydrofolate gene, and descripyion of 5 novel mutations in MTHFR[J]. Am J Hum Genet, 1996, 59(6): 1268-1275.
[16]
Klerk M, Verhoef P, Clarke R, et al. MTHFR 677C-T polymorphism and risk of coronary heart disease: a meta-analysis[J]. JAMA, 2002, 288(16): 2023-2031.
Qian X, Lu Z, Tan M, et al. A meta-analysis of association between C677T polymorphism in the methylenetetrahydrofolate reductase gene and hypertension[J]. Eur J Hum, Genet, 2007, 15(12): 1239-1245.
[19]
Ronge E, Kjellman B. Long term treatment with betaine in methylenetetrahydrofolate reductase deficiency[J]. Arch Dis Child, 1996, 74(3): 239-241.
[20]
Schiff M, Benoist JF, Tilea B, et al. Isolated remethylation disorders: do our treatments benefit patients?[J]. J Inherit Metab Dis, 2011, 34(1):137-145.
Christensen E, Brandt NJ. Prenatal diagnosis of 5,10-methylenete-trahydrofolate reductase deficiency[J]. New Eng J Med, 1985, 313(1): 50-51.
[23]
Morel CF, Scott P, Christensen E, et al. Prenatal diagnosis for severe methylenetetrahydrofolate reductase deficiency by linkage analysis and enzymatic assay[J]. Mol Genet Metab, 2005, 85(2):115-120.
Fredriksen A, Meyer K, Ueland PM, et al. Large-scale population-based metabolic phenotyping of thirteen genetic polymorphisms related to one-carbon metabolism[J]. Hum Mutat, 2007, 28(9): 856-865.
[26]
Freeman JM, Finkelstein JD, Mudd SH. Folate-responsive homocystinuria and "schizophrenia". A defect in methylation due to deficient 5,10-methylenetetrahydrofolate reductase activity[J]. N Engl J Med, 1975, 292(10): 491-496.
[27]
Lewis SJ, Zammit S, Gunnell D, et al. A meta-analysis of the MTHFR C677T polymorphism and schizophrenia risk[J]. Am J Med Genet B Neuropsychiatr Genet, 2005, 135B(1): 2-4.
[28]
Allen NC, Bagade S, McQueen MB, et al. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database[J]. Nat Genet, 2008, 40(7): 827-834.
Wilcken B, Bamforth F, Li Z, et al. Geographical and ethnic variation of the 677C-T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas world wide[J]. J Med Genet, 2003, 40(8): 619-625.
[31]
Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase[J]. Nat Genet, 1995, 10(1): 111-113.
