Life-threatening methylenetetrahydrofolate reductase (MTHFR) deficiency with extremely early onset: characterization of two novel mutations in compound heterozygous patients

Mol Genet Metab. 2010 Jun;100(2):143-8. doi: 10.1016/j.ymgme.2010.03.002. Epub 2010 Mar 6.


Methylenetetrahydrofolate reductase (MTHFR) is a key enzymatic component of the folate cycle, converting 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, the methyl donor for remethylation of homocysteine into methionine. Severe MTHFR deficiency is a rare recessive disease leading to major hyperhomocysteinemia, homocystinuria, and progressive neurological distress within the two first decades of life. More than 50 mutations have been reported so far in affected patients but only a few cases with very early onset of symptoms during the first weeks have been described, most of them showing a particular severe clinical course. We detected two novel mutations by direct sequencing of MTHFR in compound heterozygous patients with extremely low or undetectable enzyme activity; one of them had clinical onset during the first week of life and fatal issue at the age of six weeks. Prenatal diagnosis of his sibling allowed for early treatment with B vitamins and betaine and a favorable outcome. One of these mutations (c.523G>A) led to an Ala>Thr transition in the catalytic domain of the enzyme, the other (c.1166G>A) induced alternative splicing of exon 7 at the junction of the catalytic and regulatory domains. Both parents carried only one of these mutations and presented with moderate and intermediate hyperhomocysteinemia, respectively, without neurological symptoms. Severe MTHFR deficiency thus has to be taken into consideration when investigating neurological distress even in the newborn, regarding the need for an earliest possible treatment. Characterization of the relatives further allows for preventive measure to limit the risks of chronic hyperhomocysteinemia.

Publication types

  • Case Reports

MeSH terms

  • Base Sequence
  • Codon, Nonsense
  • Fatal Outcome
  • Female
  • Heterozygote
  • Humans
  • Hyperhomocysteinemia / genetics
  • Infant
  • Infant, Newborn
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2) / deficiency*
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
  • Mutation
  • Prenatal Diagnosis


  • Codon, Nonsense
  • Methylenetetrahydrofolate Reductase (NADPH2)