Severe deficiency of methylenetetrahydrofolate reductase (MTHFR) is the most 
common inborn error of folate metabolism. Patients are characterized by severe 
hyperhomocysteinemia, homocystinuria and a variety of neurological and vascular 
problems. Eighteen rare mutations have been reported in this group of patients. 
Two polymorphisms which cause mild enzyme deficiencies have been described 
(677C-->T and 1298A-->C). The first sequence change encodes a thermolabile 
enzyme and is associated with mild hyperhomocysteinemia. Six novel point 
mutations are described in patients with severe deficiency of MTHFR, along with 
their associated polymorphisms and clinical phenotypes. Of the two nonsense 
mutations (1762A-->T, 1134C-->G) and four missense mutations (1727C-->T, 
1172G-->A, 1768G-->A, and 358G-->A), one was identified in the N-terminal 
catalytic domain, while the others were located in the regulatory C-terminal 
region. All four residues affected by missense mutations are conserved in one or 
more MTHFRs of other species. This report brings the total to 24 mutations 
identified in severe MTHFR deficiency, with two mutations identified in each of 
22 patients.