Relations between molecular and biological abnormalities in 11 families from siblings affected with methylenetetrahydrofolate reductase deficiency

Methylenetetrahydrofolate reductase (MTHFR) deficiency is an autosomal recessive disorder resulting in elevated homocysteine levels in plasma and urine. MTHFR catalyses the reduction of methylenetetrahydrofolate to methyltetrahydrofolate, a cofactor for homocysteine remethylation to methionine. MTHFR deficiency may be diagnosed from infancy to adulthood with a broad spectrum of clinical symptoms. A molecular analysis of the MTHFR gene combined with an assessment of MTHFR activity, plasma homocysteine and folate in plasma and red blood cells (RBC), especially methylfolate, was assessed in the members of 11 families from children affected with this disorder. This study was performed to try to define the impact of the mutations found in the MTHFR gene on symptoms and biological abnormalities. A total of 14 mutations were found and 10 of them were identified for the first time. Two were found in two families, two more in two other families and one in three families. The position of the mutation spread all over the gene does not predict the degree of biological abnormalities found in parents or healthy siblings bearing the mutation. Two different mutations located not far apart on the same exon may cause mild or severe abnormalities. The thermolabile variant C677T when expressed in an homozygote state in some parents was associated with lower MTHFR activity, higher homocysteine levels, lower folate levels, mainly methylfolate in RBC than in parents without the mutation; conversely, two or more mutations on the same allele had mild effects when the other allele was normal. Conclusion: given the heterogeneity of mutations, no one seems preponderant to predict neurological and/or vascular symptoms.