Adverse Event Associated With Methionine Loading Test

Abstract

Abstract-The death of a control subject after an oral load of methionine for a study of the possible relationship between homocysteine and Alzheimer's disease is reported. The subject developed postload plasma concentrations of methionine far beyond those reported previously in humans given the usual oral loading dose of methionine (100 mg/kg body wt). Her preload plasma metabolite values rule out known genetic diseases that might predispose one to unusually high methionine concentrations. The most likely explanation for these events is that the subject received a substantial overdose of methionine. The possibility that extremely high methionine concentrations may lead to severe cerebral effects is discussed, and it is recommended that any move to increase the sensitivity of the usual methionine loading test by increasing the dose of methionine either not be undertaken or be taken only with extreme care. Key Words: methionine load elevation Ⅲ cerebral death T he present article reports the death of a control subject after an oral methionine load for a study of the possible relationship between elevation of plasma total homocysteine (tHcy) 1 and Alzheimer's disease. Elevation of plasma or serum tHcy (hyperhomocysteinemia) is widely recognized to be an independent risk factor for vascular disease. 2 Such elevations have also been associated with Alzheimer's disease. [3][4][5] Although this finding is consistent with the hypothesis that vascular disease may be a contributing factor in the pathogenesis of Alzheimer's disease, 3,6 it is presently uncertain whether the elevated tHcy is a cause or a consequence of the disease. 5 Administration of an oral load of methionine, the ultimate metabolic precursor of homocysteine, at a dose of 100 mg/kg body wt is a widely used means to test for a tendency to manifest hyperhomocysteinemia. 7,8 The available evidence, based on the results of at least many hundreds of such tests, indicates they are generally very safe (see Discussion for further details). In the present case study, we report a death after what seems very likely to have been an overdose of methionine. MethodstHcy, methylmalonic acid, sarcosine (N-methylglycine), cystathionine, total cysteine, and N,N-dimethylglycine were assayed as previously described by using gas chromatography/mass spectrometry. 9 -12 Because the undeproteinized samples were initially treated with a reducing reagent that cleaves all disulfide bonds, tHcy and total cysteine were measured in this assay. Methionine was assayed by column chromatography. S-Adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy) were assayed as described. 13 Methionine transamination (TAM) metabolites, the sum of methanethiol released sequentially into the gas phase at pH 7 (protein-S-S-CH 3 ), pH 10 (X-S-S-CH 3 ), and pH 12.5 to 13 (chiefly 4-methylthio-2-oxobutyrate), 14 were determined as described. 15 Phosphatidylcholine and free choline were assayed as described. 16 Betaine was assayed by an unpublished method with the use of liquid chromatography/elec...

Cerebral edema associated with betaine treatment in classical homocystinuria

“…The patient of Yaghmai et al 6 had exceptionally high plasma methionine concentrations (2272-3037 lmol/L) while taking betaine, and the authors suggested that methionine toxicity might have caused the cerebral edema. Acute cerebral problems have also been associated with very high methionine concentrations in a normal control after a methionine load (plasma methionine 5760 lmol/L) 9 and in infants with a high methionine intake (plasma concentrations 6830 and 2154 lmol/L). 10 In contrast, our patient's plasma methionine levels were no higher than in some patients who tolerate betaine without problems.…”

“…He had poor speech articulation, clumsiness, and frequent falls, but development was otherwise normal. Baseline plasma tHcy concentrations ranged from 334 to 430 lmol/L (normal, [5][6][7][8][9][10][11][12][13][14][15][16][17]. The plasma methionine concentration was 203 lmol/L (normal, 10-54) with a normal vitamin B 12 level and a normal urinary organic acid profile.…”

Facts and Recommendations about Total Homocysteine Determinations: An Expert Opinion

“…A 2-h postmethionine tHcy has been validated and may be more practical in the clinical setting (89 ), but it probably has greater within-person variability than the 4-or 6-h test (90 ). There are few side effects of methionine loading (91 ), but one possible death from severe overdose was reported recently (92 ).…”

Murine Models of Hyperhomocysteinemia and Their Vascular Phenotypes

“…46 Massive methionine excess also can be fatal in humans. 47 Diets Deficient in Folate, Vitamin B12, or Vitamin B6 Another common dietary approach to induce hyperhomocysteinemia in mice is to restrict the dietary intake of the B *In several cases, the primary authors were contacted to obtain the complete formulation of the diets used in their studies.…”