Homocysteinemia and schizophrenia as a case of methylation deficiency

Abstract

A 27-year-old woman is described whose disorder meets the DSM-III-R criteria for a diagnosis of schizophrenia and who was found to have a significantly increased serum level of homocysteine. Repeatedly, she improved on frequent cobalamin injections and deteriorated in periods without treatment. The effects of prolonged weekly treatment appeared to diminish as time went on, suggesting that the abnormality was not wholly cobalamin-dependent. It was found that methylenetetrahydrofolate reductase (MR) activity in cultured skin fibroblasts was reduced to a magnitude that is found among people with heterozygous deficiency. A defect in MR activity indicates a deficiency in methyltetrahydrofolate (MTHF), with a consequent reduction of the remethylation of homocysteine to methionine. Thus, reduced methylation may explain the increased levels of homocysteine and the transient effects of cobalamin treatment in the patient. Theoretically, MTHF should be the optimal treatment for her. The case reported highlights the importance of assessing the serum homocysteine level in order to detect methylation deficiency in patients with schizophrenia.

Homocysteinemia is a common feature of schizophrenia

“…Methionine synthase requires methyltetrahydrofolate as methyl donor and cobalamin as cofactor. Methyltetrahydrofolate, in turn, is synthesized by the catalytic action of MR. Deficient activity of this enzyme has been associated with schizophrenia (Freeman et al, 1975;Regland et al, 1994), although such a deficiency is not a general feature of schizophrenia (Berger et al, 1977).…”

“…There are studies suggesting that a substantial proportion of schizophrenic patients have an abnormal methyl metabolism (Andreoli et al, 1975;Smythies et al, 1986;Sargent et al, 1992). We recently described the case of a female schizophrenic who had a significantly raised level of homocysteine in serum as the probable marker of insufficient methylation, a notion supported by her reduced activity of the enzyme methylenetetrahydrofolate reductase (MR) and the fact that she responded favourably to cobalamin treatment (Regland et al, 1994). In the present study, we investigated the prevalence of hyperhomocysteinemic levels in schizophrenic patients.…”

Association between the methylenetetrahydrofolate reductase 677C→T missense mutation and schizophrenia

“…7 Several reports indicate that a high plasma level of homocysteine may be a risk factor for various pathological conditions, such as pregnancies complicated by neural tube defects 8 or abortions 9 and has been previously reported in schizophrenic patients. 10 Casereports of treatment of hyperhomocysteinemia and psychotic symptoms using folate 11,12 have been described. Furthermore, some patients with homocysteinuria, an inborn error metabolism that can be caused by rare and severe mutations in the MTHFR gene, have exhibited schizophrenia-like symptoms in addition to severe hyperhomocysteinemia, hypomethioninemia and various neurological manifestations.…”

Redox Dysregulation and Oxidative Stress in Schizophrenia: Nutrigenetics as a Challenge in Psychiatric Disease Prevention

“…Indeed, the enzymes and metabolites of the methionine and folate cyle are associated with schizophrenia [152][153][154][155]. However, we do not know yet whether an observed disturbance is a primary event that is fundamentally related to the pathogenesis or a secondary phenomenon reflecting a nonpathogenic mechanism.…”

“…In one case report, cobalamine treatment alleviated psychotic symptoms [152]. However, this clinical effect diminished with time, and the metabolic abnormality was thus not wholly cobalamin dependent.…”