Abstract
Background
Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inborn defect disturbing the remethylation of homocysteine to methionine (<200 reported cases). This retrospective study evaluates clinical, biochemical genetic and in vitro enzymatic data in a cohort of 33 patients.
Methods
Clinical, biochemical and treatment data was obtained from physicians by using a questionnaire. MTHFR activity was measured in primary fibroblasts; genomic DNA was extracted from cultured fibroblasts.
Results
Thirty-three patients (mean age at follow-up 11.4 years; four deceased; median age at first presentation 5 weeks; 17 females) were included. Patients with very low (<1.5 %) mean control values of enzyme activity (n = 14) presented earlier and with a pattern of feeding problems, encephalopathy, muscular hypotonia, neurocognitive impairment, apnoea, hydrocephalus, microcephaly and epilepsy. Patients with higher (>1.7–34.8 %) residual enzyme activity had mainly psychiatric symptoms, mental retardation, myelopathy, ataxia and spasticity. Treatment with various combinations of betaine, methionine, folate and cobalamin improved the biochemical and clinical phenotype. During the disease course, patients with very low enzyme activity showed a progression of feeding problems, neurological symptoms, mental retardation, and psychiatric disease while in patients with higher residual enzyme activity, myelopathy, ataxia and spasticity increased. All other symptoms remained stable or improved in both groups upon treatment as did brain imaging in some cases. No clear genotype-phenotype correlation was obvious.
Discussion
MTHFR deficiency is a severe disease primarily affecting the central nervous system. Age at presentation and clinical pattern are correlated with residual enzyme activity. Treatment alleviates biochemical abnormalities and clinical symptoms partially.
Similar content being viewed by others
References
Abeling NG, van Gennip AH, Blom H et al (1999) Rapid diagnosis and methionine administration: basis for a favourable outcome in a patient with methylene tetrahydrofolate reductase deficiency. J Inherit Metab Dis 22:240–242
Al-Essa MA, Al Amir A, Rashed M et al (1999) Clinical, fluorine-18 labeled 2-fluoro-2-deoxyglucose positron emission tomography of the brain, MR spectroscopy, and therapeutic attempts in methylenetetrahydrofolate reductase deficiency. Brain Dev 21:345–349
Bathgate D, Yu-Wai-Man P, Webb B, Taylor RW, Fowler B, Chinnery PF (2012) Recessive spastic paraparesis associated with complex I deficiency due to MTHFR mutations. J Neurol Neurosurg Psychiatry 83:115
Birnbaum T, Blom HJ, Prokisch H, Hartig M, Klopstock T (2008) Methylenetetrahydrofolate reductase deficiency (homocystinuria type II) as a rare cause of rapidly progressive tetraspasticity and psychosis in a previously healthy adult. J Neurol 255:1845–1846
Burda P, Schäfer A, Suormala T et al (2015) Insights into severe 5,10-methylenetetrahydrofolate reductase deficiency: molecular genetic and enzymatic characterization of 76 patients. Hum Mutat. doi:10.1002/humu.22779
Clayton PT, Smith I, Harding B, Hyland K, Leonard JV, Leeming RJ (1986) Subacute combined degeneration of the cord, dementia and Parkinsonism due to an inborn error of folate metabolism. J Neurol Neurosurg Psychiatry 49:920–927
Crushell E, O’Leary D, Irvine AD, O’Shea A, Mayne PD, Reardon W (2012) Methylenetetrahydrofolate reductase (MTHFR) deficiency presenting as a rash. Am J Med Genet A158:2254–2257
D’Aco KE, Bearden D, Watkins D, Hyland K, Rosenblatt DS, Ficicioglu C (2014) Severe 5,10-methylenetetrahydrofolate reductase deficiency and two MTHFR variants in an adolescent with progressive myoclonic epilepsy. Pediatr Neurol 51:266–270
Diekman EF, de Koning TJ, Verhoeven-Duif NM, Rovers MM, van Hasselt PM (2014) Survival and psychomotor development with early betaine treatment in patients with severe methylenetetrahydrofolate reductase deficiency. JAMA Neurol 71:188–194
Engelbrecht V, Rassek M, Huismann J, Wendel U (1997) MR and proton MR spectroscopy of the brain in hyperhomocysteinemia caused by MethylenetetrahydrofolateReductase deficiency. AJNR 18:536–539
Ertan S, Tanriverdi T, KiziltanG TG (2002) Complete resolution of myelopathy in a patient with vitamin B12 deficiency: a case report. Internet J Neurol 2:1
Fattal-Valevski A, Bassan H, Korman SH, Lerman-Sagie T, Gutman A, Harel S (2000) Methylenetetrahydrofolate reductase deficiency: importance of early diagnosis. J Child Neurol 15:539–543
Fischer S, Huemer M, Baumgartner M et al (2014) Clinical presentation and outcome in a series of 88 patients with the cblC defect. J Inherit Metab Dis 37:831–840
Forges T, Chery C, Audonnet S, Feillet F, Gueant JL (2010) Life-threatening methylenetetrahydrofolate reductase (MTHFR) deficiency with extremely early onset: characterization of two novel mutations in compound heterozygous patients. Mol Genet Metab 100:143–148
Goyette P, Frosst P, Rosenblatt DS, Rozen R (1995) Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency. Am J Hum Genet 56:1052–1059
Goyette P, Pai A, Milos R et al (1998) Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR). Mamm Genome 9:652–6
Haworth JC, Dilling LA, Surtees RA et al (1993) Symptomatic and asymptomatic methylenetetrahydrofolate reductase deficiency in two adult brothers. Am J Med Genet 45:572–576
Holme E, Kjellmann B, Ronge E (1989) Betaine for treatment of homocystinuria caused by methylenetetrahydrofolate reductase deficiency. Arch Dis Child 64:1060–1094
Huemer M, Bürer C, Ješina P et al (2014a) Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data. J Inherit Metab Dis. doi:10.1007/s10545-014-9803-7
Huemer M, Scholl-Bürgi S, Hadaya K et al (2014b) Three new cases of late-onset cblC defect and review of the literature illustrating when to consider inborn errors of metabolism beyond infancy. Orphanet J Rare Dis 15:161
Hyland K, Shoffner J, Heales SJ (2010) Cerebral folate deficiency. J Inherit Metab Dis 33:563–70
Kishi T, Kawamura I, Harada Y et al (1994) Effect of betaine on S-adenosylmethionine levels in the cerebrospinal fluid in a patient with methylenetetrahydrofolate reductase deficiency and peripheral neuropathy. J Inherit Metab Dis 17:560–565
Lawrance AK, Racine J, Deng L, Wang X, Lachapelle P, Rozen R (2011) Complete deficiency of methylenetetrahydrofolate reductase in mice is associated with impaired retinal function and variable mortality, hematological profiles, and reproductive outcomes. J Inherit Metab Dis 34:147–157
Lossos A, Teltsh O, Milman T et al (2014) Severe methylenetetrahydrofolate reductase deficiency clinical clues to a potentially treatable cause of adult-onset hereditary spastic paraplegia. JAMA Neurol 71:901–904
Michot JM, Sedel F, Giraudier S, Smiejan JM, Papo T (2008) Psychosis, paraplegia and coma revealing methylenetetrahydrofolate reductase deficiency in a 56-year-old woman. J Neurol Neurosurg Psychiatry 79:963–964
Naughten ER, Yap S, Mayne PD (1998) Newborn screening for homocystinuria: Irish and world experience. Eur J Pediatr 157:S84–87
Outteryck O, De Seze J, Stojkovic T et al (2012) Methionine synthase deficiency (cblG): a rare cause of adult onset leukoencephalopathy with reversible neurological deficit. Neurology 78:01.124
Ronge E, Kjellman B (1996) Long term treatment with betaine in methylenetetrahydrofolate reductase deficiency. Arch Dis Child 74:239–241
Roschitz B, Plecko B, Huemer M, Biebl A, Foerster H, Sperl W (2005) Nutritional infantile vitamin B12 deficiency: pathobiochemical considerations in seven patients. Arch Dis Child Fetal Neonatal Ed 90:F281–282
Schiff M, Blom HJ (2012) Treatment of inherited homocystinurias. Neuropediatrics 43:295–304
Schiff M, Benoist JF, Tilea B, Royer N, Giraudier S, Ogier de Baulny H (2011) Isolated remethylation disorders: do our treatments benefit patients? J Inherit Metab Dis 34:137–145
Smith DEC, Smulders YM, Blom HJ, Popp J, Jessen F, Semmler A, Farkas M, Linnebank M (2012) Determinants of the essential one-carbon metabolism metabolites, homocysteine, S-adenosylmethionine, S-adenosylhomocysteine and folate, in cerebrospinal fluid. Clin Chem Lab Med 50:1641–1647
Steinmann B, Sigg P, Gitzelmann R et al (1984) Homocystinuria due to methylene-tetrahydrofolate-(THF-) reductase deficiency. Helv Paediatr Acta Suppl 50:38–39
Strauss KA, Morton DH, Puffenberger EG et al (2007) Prevention of brain disease from severe 5,10-methylenetetrahydrofolatereductase deficiency. Mol Genet Metab 91:165–75
Suormala T, Gamse G, Fowler B (2002) 5,10-Methylenetetrahydrofolate reductase (MTHFR) assay in the forward direction: residual activity in MTHFR deficiency. Clin Chem 48:835–843
Surtees R, Leonard J, Austin S (1991) Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway. Lancet 338:1550–1554
Tallur KK, Johnson DA, Kirk JM, Sandercock PA, Minns RA (2005) Folate-induced reversal of leukoencephalopathy and intellectual decline in methylene-tetrahydrofolate reductase deficiency: variable response in siblings. Dev Med Child Neurol 47:53–56
Thomas MA, Rosenblatt DS (2005) Severe methylenetetrahydrofolate deficiency. In: Ueland PM, Rozen R (eds) MTHFR polymorphisms and disease. Landes Bioscience, Georgetown, Texas; USA
Tonetti C, Saudubray JM, Echenne B, Landrieu P, Giraudier S, Zittoun J (2003) Relations between molecular and biological abnormalities in 11 families from siblings affected with methylenetetrahydrofolate reductase deficiency. Eur J Pediatr 162:466–475
Tsuji M, Takagi A, Sameshima K et al (2011) 5,10-Methylenetetrahydrofolate reductase deficiency with progressive polyneuropathy in an infant. Brain Dev 33:521–524
Urreizti R, Moya-Garcia AA, Pino-Angeles A et al (2010) Molecular characterization of five patients with homocystinuria due to severe methylenetetrahydrofolate reductase deficiency. Clin Genet 78:441–448
Watkins D, Rosenblatt DS (2012) Update and new concepts in vitamin responsive disorders of folate transport and metabolism. J Inherit Metab Dis 35:665–670
Weisfeld-Adams JD, Bender HA, Miley-Åkerstedt A et al (2013) Neurologic and neurodevelopmental phenotypes in young children with early-treated combined methylmalonicacidemia and homocystinuria, cobalamin C type. Mol Genet Metab 110:241–247
Acknowledgments
We are indebted to the patients and their families who participated in this study.
Compliance with Ethics Guidelines
ᅟ
Conflict of interest
None.
Human rights and informed concent
All procedures followed were in accordance with the ethical standards of the responsible local committees on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained by the reporting physicians from their patients for being included in the study.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Communicated by: Bridget Wilcken
Martina Huemer, Regina Mulder-Bleile, Matthias R. Baumgartner and Brian Fowler contributed equally to this work.
Electronic supplementary material
Below is the link to the electronic supplementary material.
ESM 1
(DOC 65 kb)
Rights and permissions
About this article
Cite this article
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 Inherit Metab Dis 39, 115–124 (2016). https://doi.org/10.1007/s10545-015-9860-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10545-015-9860-6