Severe methylenetetrahydrofolate reductase deficiency revealed by a pulmonary embolism in a young adult

Abstract

Summary. Deficiency in methylenetetrahydrofolate reductase (MTHFR), the enzyme involved in the remethylation of homocysteine to methionine using methyltetrahydrofolate as cofactor, induces hyperhomocysteinaemia, homocysteinuria, hypomethioninaemia and low methylfolate levels. Diagnosis usually occurs during infancy because of various neurological abnormalities. We report MTHFR deficiency diagnosed in an adult woman after a pulmonary embolism. Her adult sister, intellectually retarded, suffered from the same disease. Molecular analysis of the MTHFR gene exhibited four different mutations (two missense mutations, one exon skipping and C677T). The impact of these mutations was analysed through the biological abnormalities in the parents and children.Keywords: hyperhomocysteinaemia, pulmonary embolism, MTHFR deficiency, molecular analysis, methylfolate.Among the risk factors of thrombophilia, hyperhomocysteinaemia is responsible for venous and arterial thrombotic diseases (Welch & Loscalzo, 1998).Elevation of plasma homocysteine results from inherited or nutritional factors. Severe hyperhomocysteinaemia is due to enzyme deficiencies. Cystathionine b-synthase, present on the trans-sulphuration pathway, changes homocysteine to cystathionine, by using vitamin B 6 as coenzyme, and is associated with precocious vascular disease. Methylenetetrahydrofolate reductase (MTHFR) catalyses the synthesis of 5-methyltetrahydrofolate, the methyl donor for the vitamin B 12 -dependent remethylation of homocysteine to methionine via methionine synthase (Rosenblatt, 2001). Among various mutations on the MTHFR gene, a thermolabile variant caused by a point mutation in exon 4 of the gene (C677fiT) (AlafiVal) usually induces mild hyperhomocysteinaemia, moderate decreased MTHFR activity and decreased folate status . Nutritional deficiency in the vitamin cofactors (folate, vitamin B 12 and vitamin B 6 ) required for homocysteine metabolism may promote hyperhomocysteinaemia.We report a case of severe pulmonary embolism in a young adult taking oral contraceptives without any known factor of thrombophilia, in whom hyperhomocysteinaemia and hypomethioninaemia related to severe MTHFR deficiency were found. Genetic studies of the family identified three mutations on the MTHFR gene, two of them novel and the C677fiT mutation. The impact of these mutations is discussed. CASE REPORTThe patient, an obese 27-year-old woman, developed dyspnoea 8 months after taking oral contraceptives. One year before, she delivered a healthy child after a normal pregnancy. Since her childhood, she had walking problems, and she encountered difficulties at school. Neurological examination revealed bilateral Babinski signs. Helical computerized tomography showed bilateral pulmonary embolism and duplex ultrasonography revealed left iliac vein thrombosis. When factors associated with thrombophilia (blood levels of antithrombin, protein C, protein S, antiphospholipid antibodies, lupus anticoagulant, analysis of factor V Leiden and prothrombin G20210) were screened, no abnor...

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

“…Vascular problems were found in the patients and revealed the disease in one case [18]; the same missense mutation on exon 1, G167A was found in both families in addition to two other mutations in family 6 and one other in family 7. Because of a progressive and unexplained encephalopathy in the affected child of family 7, homocysteine was assessed in CSF and was 46 lmol/l (normal in CSF <0.7 lmol/l).…”

Methylenetetrahydrofolate reductase deficiency (homocystinuria type II) as a rare cause of rapidly progressive tetraspasticity and psychosis in a previously healthy adult

“…Late onset is rare and is usually associated with a mild course [1,2]. Here we report on an adult who presented with rapidly progressive tetraparesis and psychosis due to previously unrecognized homocystinuria.…”

“…The majority of patients with severe MTHFR deficiency presents in the first few years of life with pronounced neurological symptoms. Adult onset is rare, most of these patients present with thromboembolic events [1,2]. Furthermore, there is some evidence for an association between the MTHFR gene polymorphism c.677C>T and schizophrenia [6].…”

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

“…Arterial and venous thrombosis are generally rare and predominantly encountered in adolescent or adult patients (Visy et al 1991; Tonetti et al 2002). …”