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Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Synonym(s) MTHFR deficiency
Methylene tetrahydrofolate reductase deficiency
Prevalence Unknown
Inheritance Autosomal recessive
Age of onset Infancy
  • E72.1
MeSH -
MedDRA -


Homocystinuria due to methylene tetrahydrofolate reductase (MTHFR) deficiency is a metabolic disorder characterised by neurological manifestations. The prevalence is unknown. Onset usually occurs during the first year of life with severe neurological signs, recurrent apnoea, microcephaly and convulsions. There is no megaloblastic anaemia. There are some forms with onset during childhood, adolescence, or adulthood beginning with mental regression, ataxia, and, most often, common psychiatric disorders of the schizophrenic type that may be linked to cerebrovascular accidents. Other symptoms such as subacute degeneration of the spinal chord have been reported. The disorder is transmitted as an autosomal recessive trait and is caused by mutations in the MTHFR gene (1p36.3). MTHFR deficiency results in abnormal intracellular folic acid metabolism and prevents reduction of 5-10 methylenetetrahydrofolate to 5-methyltetrahydrofolate, the methyl donor for the remethylation of homocysteine into methionine. As a result, the disorder leads to methyltetrahydrofolate deficiency and consequently to homocystinuria and hypomethioninemia. Diagnosis may be suspected after analysis of amino acids by chromatography and measurements of total plasma homocysteine levels revealing highly elevated values of >100 micromol/L. Other biological findings include low levels of methyltetrahydrofolate in both the plasma and cerebrospinal fluid. Diagnosis is confirmed by measuring enzyme activity in lymphocytes or fibroblasts. The differential diagnosis should include other homocysteine remethylation disorders. Prenatal diagnosis is feasible through molecular or enzymatic analysis. Treatment of severe deficiency revolves around the administration of high-dose betaine, in combination with methionine, pyridoxine, vitamin B12 and folic or folinic acid supplements. The prognosis is variable.

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  • Pr Pascale DE LONLAY

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