Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency

Huemer, Martina; Mulder-Bleile, Regina; Burda, Patricie; Froese, D. Sean; Suormala, Terttu; Zeev, Bruria Ben; Chinnery, Patrick F.; Dionisi‐Vici, Carlo; Dobbelaere, Dries; Gökçay, Gülden; Demirkol, Mübeccel; Häberle, Johannes; Lossos, Alexander; Mengel, Eugen; Morris, Andrew A. M.; Niezen-Koning, Klary E.; Plecko, Barbara; Parini, Rossella; Rokicki, Dariusz; Schiff, Manuel; Schimmel, Mareike; Sewell, A. C.; Sperl, Wolfgang; Spiekerkoetter, Ute; Steinmann, Beat; Taddeucci, Grazia; Trejo-Gabriel-Galán, J.M.; Trefz, Friedrich K.; Tsuji, Megumi; Vilaseca, M. A.; Kleist-Retzow, J. C. von; Walker, Valerie; Zeman, Jiří; Baumgartner, Matthias R.; Fowler, Brian

doi:10.1007/s10545-015-9860-6

Cited by 50 publications

(60 citation statements)

References 38 publications

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“…However, they do not significantly deviate from published case series (Ogier de Baulny et al 1998; Carrillo-Carrasco et al 2012; Fischer et al 2014; Huemer et al 2016). The true prevalence of organ manifestations also depends on the extent of technical investigations, especially in relation to milder forms of microangiopathy and retinopathy that may escape clinical detection.…”

Section: Methodscontrasting

confidence: 44%

“…Neonates and young infants often manifest with feeding difficulties, decreased consciousness, hydrocephalus and muscular hypotonia. Apnoea is a frequent complication (Broomfield et al 2014; Diekman et al 2014; Huemer et al 2016; Schiff et al 2011; Strauss et al 2007). …”

Section: Which Clinical Signs Are Characteristic For Remethylation Dementioning

confidence: 99%

“…The data basis addressing the efficacy of vitamin B6, cobalamin, riboflavin and carnitine is not reliable; various dosages and combinations of these substances have been used and their clinical efficacy cannot be assessed (Huemer et al 2016). …”

Section: The Effects Of Treatment On Clinical Outcomementioning

confidence: 99%

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Guidelines for diagnosis and management of the cobalamin‐related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

Huemer

Diodato

Schwahn

et al. 2016

J of Inher Metab Disea

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212

368

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BackgroundRemethylation defects are rare inherited disorders in which impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions.ObjectiveTo summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management.Data sourcesReview, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach.Key recommendationsWe strongly recommend measuring plasma total homocysteine in any patient presenting with the combination of neurological and/or visual and/or haematological symptoms, subacute spinal cord degeneration, atypical haemolytic uraemic syndrome or unexplained vascular thrombosis. We strongly recommend to initiate treatment with parenteral hydroxocobalamin without delay in any suspected remethylation disorder; it significantly improves survival and incidence of severe complications. We strongly recommend betaine treatment in individuals with MTHFR deficiency; it improves the outcome and prevents disease when given early.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-016-9991-4) contains supplementary material, which is available to authorised users.

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Section: Methodscontrasting

confidence: 44%

Section: Which Clinical Signs Are Characteristic For Remethylation Dementioning

confidence: 99%

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Guidelines for diagnosis and management of the cobalamin‐related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

Huemer

Diodato

Schwahn

et al. 2016

J of Inher Metab Disea

Self Cite

212

368

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“…Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive condition leading to a wide spectrum of neurological symptoms, mainly encephalopathy, hypotonia, microcephaly, seizures, developmental delay and episodes of apnoea Huemer et al 2015). Hydrocephalus is an additional rare but recognised complication.…”

Section: Introductionmentioning

confidence: 99%

Treatment with Mefolinate (5-Methyltetrahydrofolate), but Not Folic Acid or Folinic Acid, Leads to Measurable 5-Methyltetrahydrofolate in Cerebrospinal Fluid in Methylenetetrahydrofolate Reductase Deficiency

2016

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S-adenosyl methionine, which is formed from methionine, is an essential methyl donor within the central nervous system. Methionine is formed by the enzyme methionine synthase for which 5-methyltetrahydrofolate (5-MTHF) and homocysteine are substrates. Patients with severe methylenetetrahydrofolate reductase (MTHFR) deficiency cannot make 5-MTHF and have extremely low levels in the CSF. As a consequence, methylation reactions in the CNS are compromised, and this is likely to play an important role in the neurological abnormalities that occur in MTHFR deficiency. Although treatment with oral betaine can remethylate homocysteine to methionine in the liver, betaine crosses the blood-brain barrier poorly, and CSF levels of methionine remain low. We report three patients with severe MTHFR deficiency (enzyme activity 1% of controls) who had undetectable levels of CSF 5-MTHF at diagnosis and while on treatment with either folic acid or calcium folinate. Only treatment with oral 5-MTHF given as calcium mefolinate at doses of 15-60 mg/kg/day resulted in an increase in CSF 5-MTHF.

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“…The clinical manifestation of the disorder is variable, including severe disease in infancy leading to death, developmental delay, neurological and psychiatric disease, and epilepsy. 2,11 Some patients present with a late childhood onset form, often with developmental delay and varying neurological manifestations. This autosomal recessive disorder is owed to mutations in the MTHFR gene which is located on chromosome 1p36.3.…”

Section: Genetic Basis Of Isolated Remethylation Disordersmentioning

confidence: 99%

Isolated and Combined Remethylation Disorders

Richard

Brasil

Leal

et al. 2017

Journal of Inborn Errors of Metabolism and Screening

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Genetic defects affecting the remethylation pathway cause hyperhomocysteinemia. Isolated remethylation defects are caused by mutations of the 5, 10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), methionine synthase (MTR), and MMADHC genes, and combined remethylation defects are the result of mutations in genes involved in the synthesis of either methylcobalamin or adenosylcobalamin, that is, the active cofactors of MTRR and methylmalonyl-CoA mutase. Diagnosis is based on the biochemical analysis of amino acids, homocysteine, propionylcarnitine, methylmalonic acid, S-adenosylmethionine, and 5-methylentetrahydrofolate in physiological fluids. Gene-by-gene Sanger sequencing has long been the gold standard genetic analysis for confirming the disorder and identifying the gene involved, but massive parallel sequencing is now being used to examine all those potentially involved in one go. Early treatment to rescue metabolic homeostasis is based on the following of an appropriate diet, betaine administration, and, in some cases, oral or intramuscular administration of vitamin B 12 or folate. Elevated ROS levels, apoptosis, endoplasmic reticulum (ER) stress, the activation of autophagy, and alterations in Ca 2þ homeostasis may all contribute toward the pathogenesis of the disease. Pharmacological agents to restore the function of the ER and mitochondria and/or to reduce oxidative stress-induced apoptosis might provide novel ways of treating patients with remethylation disorders.

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Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency

Abstract: 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.

Cited by 50 publications

References 38 publications

Guidelines for diagnosis and management of the cobalamin‐related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

Guidelines for diagnosis and management of the cobalamin‐related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

Treatment with Mefolinate (5-Methyltetrahydrofolate), but Not Folic Acid or Folinic Acid, Leads to Measurable 5-Methyltetrahydrofolate in Cerebrospinal Fluid in Methylenetetrahydrofolate Reductase Deficiency

Isolated and Combined Remethylation Disorders

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