Population screening.
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Amino Acid Metabolism, Inborn Errors↗
Biomedical subjects
Sally P Stabler
Publications and source records attributed to Sally P Stabler.
Infantile hypermethioninemia and hyperhomocysteinemia due to high methionine intake: a diagnostic trap.
Studies were carried out to identify the cause of combined severe hypermethioninemia and moderate hyperhomocysteinemia in a cluster of 10 infants ascertained between 1999 and early 2001. Although several were thought initially to have cystathionine beta-synthase (CBS) deficiency and treated accordingly, CBS deficiency and other known genetic causes of hypermethioninemia were ruled out by assay of CBS activity in fibroblasts of four patients and by assays of plasma cystathionine and S-adenosylmethionine. Retrospective data on dietary methionine intakes and plasma concentrations of methionine and related metabolites established that the hypermethioninemia in nine of the 10 babies was related to ingestion of an infant protein hydrolysate formula, the methionine content of which had been increased from May 1998 to February 2001. The formula in question has now been reformulated and is no longer available. The 10th infant manifested similar metabolic abnormalities while receiving TPN containing excessive methionine. Brain MRI abnormalities indicative of cerebral edema, most marked in the cerebral cortex and posterior brainstem, occurred in two patients near times of extreme hypermethioninemia. Metabolic and MRI abnormalities resolved when the methionine intake decreased. A third infant had a normal MRI 1 day after the formula was changed. The possible relationship between extreme hypermethioninemia and cerebral edema is discussed and a working hypothesis offered to explain the relative sensitivity of the inferior colliculi, based upon the facts that this is the region most active in glucose utilization and that Na(+),K(+)-ATPase is inhibited by methionine and related metabolites.
Brain Edema↗
Hyperhomocysteinemia and vitamin B-12 deficiency in elderly using Title IIIc nutrition services.
BACKGROUND: The effect of the folate food fortification program on the prevalence of hyperhomocysteinemia in the older population with coexisting vitamin B-12 deficiency is not known. OBJECTIVE: The objective was to determine the prevalence of hyperhomocysteinemia and vitamin B-12 deficiency in elderly who were using Title IIIc nutrition services, after folate food fortification in the United States. DESIGN: Demographic, nutritional, cognitive, routine diagnostic, and serum methylmalonic acid (MMA) and total homocysteine (tHcy) tests were performed in a convenience sample of 103 elderly enrolled in nutrition service programs in rural northeast Georgia. A subgroup (n = 27) was treated with vitamin B-12, 2.5 mg, and a multivitamin with 400 micro g folic acid, 2 mg vitamin B-6, and 27 mg ferrous fumarate. RESULTS: The total cohort included 103 participants (+/- SD age: 76.4 +/- 8.1; 80% female; 68% white, 32% African American). Vitamin B-12 deficiency (serum vitamin B-12 < 258 pmol/L and MMA > 271 nmol/L) was present in 23%. Mean serum folate was high, 39.3 nmol/L, and no subject had serum folate < 6.8 nmol/L. Mean tHcy was 17.6 +/- 7.2 micro mol/L in vitamin B-12-deficient subjects and 10.8 +/- 3.6 micro mol/L in those who were nondeficient. Determinants of high tHcy were vitamin B-12 deficiency, high serum creatinine, and low red blood cell folate. Those with vitamin B-12 deficiency were more likely to have poor cognition (58% compared with 20%, P < 0.001) and anemia (38% compared with 18%, P = 0.042). High-dose oral B-12 therapy lowered mean MMA and tHcy by 49% and 32%, respectively. CONCLUSION: Vitamin B-12 deficiency was prevalent and was associated with poor cognition, anemia, and hyperhomocysteinemia.
Activities of Daily Living↗
Vitamins, homocysteine, and cognition.
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Biomarkers↗
Adverse event associated with methionine loading test: a case report.
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.
Administration, Oral↗
Progressive cerebral edema associated with high methionine levels and betaine therapy in a patient with cystathionine beta-synthase (CBS) deficiency.
Cystathionine beta-synthase (CBS) deficiency, the most common form of homocystinuria, is an autosomal recessive inborn error of homocysteine metabolism. Treatment of B6-nonresponsive patients centers on lowering homocysteine and its disulfide derivatives (tHcy) by adherence to a methionine-restricted diet. However, lifelong dietary control is difficult. Betaine supplementation is used extensively in CBS-deficient patients to lower plasma tHcy. With betaine therapy, methionine levels increase over baseline, but usually remain below 1,500 micromol/L, and these levels have not been associated with adverse affects. We report a child with B6-nonresponsive CBS deficiency and dietary noncompliance whose methionine levels reached 3,000 micromol/L on betaine, and who subsequently developed massive cerebral edema without evidence of thrombosis. We investigated the etiology by determining methionine and betaine metabolites in our patient, and several possible mechanisms for her unusual response to betaine are discussed. We conclude that the cerebral edema was most likely precipitated by the betaine therapy, although the exact mechanism is uncertain. This case cautions physicians to monitor methionine levels in CBS-deficient patients on betaine and to consider betaine as an adjunct, not an alternative, to dietary control.
Betaine↗
High homocysteine and thrombosis without connective tissue disorders are associated with a novel class of cystathionine beta-synthase (CBS) mutations.
Cystathionine beta-synthase (CBS) is a crucial regulator of plasma levels of the thrombogenic amino acid homocysteine (Hcy). Homocystinuria due to CBS deficiency confers a dramatically increased risk of thrombosis. Early diagnosis usually occurs after the observation of ectopia lentis, mental retardation, or characteristic skeletal abnormalities. Homocystinurics with this phenotype typically carry mutations in the catalytic region of the protein that abolish CBS activity. We describe a novel class of missense mutations consisting of I435T, P422L, and S466L that are located in the non-catalytic C-terminal region of CBS that yield enzymes that are catalytically active but deficient in their response to S-adenosylmethionine (AdoMet). The P422L and S466L mutations were found in patients suffering premature thrombosis and homocystinuric levels of Hcy but lacking any of the connective tissue disorders typical of homocystinuria due to CBS deficiency. The P422L and S466L mutants demonstrated a level of CBS activity comparable to that of the AdoMet stimulated wild-type CBS but could not be further induced by the addition of AdoMet. In terms of temperature stability, oligomeric organization, and heme saturation the I435T, P422L, and S466L mutants are indistinguishable from wild-type CBS. Our findings illustrate the importance of AdoMet for the regulation of Hcy metabolism and are consistent with the possibility that the characteristic connective tissue disturbances observed in homocystinuria due to CBS deficiency may not be due to elevated Hcy.
Adult↗
Screening for cobalamin deficiency in geriatric outpatients: prevalence and influence of synthetic cobalamin intake.
OBJECTIVES: To describe the prevalence of cobalamin (Cbl) deficiency in older adult outpatients and to determine whether regular intake of a synthetic source of cobalamin confers protection against Cbl deficiency. DESIGN: Cross-sectional study. SETTING: Two university-affiliated geriatric medicine outpatient clinics. PARTICIPANTS: Three hundred fifteen older adults (age range 65-100) without a history of previously diagnosed or treated Cbl deficiency, severe anemia, or a life-threatening illness. MEASUREMENTS: Detailed information on total synthetic Cbl intake (from vitamins, fortified cereal, and supplemental nutritional formula sources) and laboratory measures of serum Cbl, metabolite panel (serum methylmalonic acid, homocysteine, cystathionine, and 2-methylcitric acid), complete blood count, and serum creatinine levels. RESULTS: Cbl deficiency (serum Cbl < or =300 pg/mL and methylmalonic acid (MMA)>271 nmol/L) was found in 13% of screened patients. Forty-six percent of screened patients reported regularly taking a source of synthetic Cbl. Serum Cbl correlated with synthetic Cbl intake, and patients regularly taking synthetic Cbl were significantly less likely to be Cbl deficient than persons not taking supplemental Cbl (8% vs 17%, P =.02). CONCLUSION: Regular use of a multivitamin/synthetic Cbl source confers some degree of protection against Cbl deficiency in older adults. The relatively high prevalence rates and benefit of synthetic Cbl intake in this study reinforce recommendations that older adults should be screened for Cbl deficiency and should incorporate synthetic sources of Cbl as part of a balanced diet. Appropriate screening intervals and the optimal dose of supplemental Cbl to prevent Cbl deficiency remains to be determined.
Aged↗
Response of elevated methylmalonic acid to three dose levels of oral cobalamin in older adults.
OBJECTIVES: Because the effects of lower-dose oral cobalamin (Cbl) supplements on older people with cobalamin deficiency are not known, we determined whether oral Cbl supplements at three different dose levels would normalize elevated serum methylmalonic acid (MMA) and total homocysteine (tHcy) concentrations. DESIGN: Sequential nonrandomized intervention study of three dose levels. SETTINGS: Two university-based senior care clinics. PARTICIPANTS: Twenty-three older adults (aged >/=65) with serum Cbl levels of 221 pmol/L (300 pg/mL) or lower and serum MMA greater than 271 nmol/L who had been enrolled in a previous screening study for Cbl deficiency (mean age 79 +/- 9; 17 male, 6 female; 17 white, 6 other). INTERVENTION: Sequential daily treatment with 25 microg oral cobalamin, followed by 100 microg and 1,000 microg cobalamin each for a 6-week period. MEASUREMENTS: Serum MMA, tHcy, and other metabolites at baseline and after each 6-week dosing interval. RESULTS: Treatment with 25 microg and 100 microg lowered but did not normalize MMA levels in most subjects. A dose of 1,000 microg/day proved to be the most effective in lowering MMA levels to within normal limits. Serum tHcy was normalized in six of 11 subjects who had elevated tHcy pretreatment with oral Cbl alone and in one subject in combination with a multivitamin. CONCLUSIONS: Most Cbl-deficient older people require more than 100 microg of oral Cbl to normalize serum MMA, which is a larger dose than is available in most standard multivitamins and Cbl supplements.
Administration, Oral↗
Elevated plasma total homocysteine in severe methionine adenosyltransferase I/III deficiency.
Abnormal elevation of plasma methionine may result from several different genetic abnormalities, including deficiency of cystathionine beta-synthase (CBS) or of the isoenzymes of methionine adenosyltransferase (MAT) I and III expressed solely in nonfetal liver (MAT I/III deficiency). Classically, these conditions have been distinguished most readily by the presence or absence, respectively, of elevated plasma free homocystine, detected by amino acid chromatography in the former condition, but absent in the latter. During the present work, we have assayed methionine, S-adenosylmethionine, S-adenosylhomocysteine, total homocysteine (tHcy), cystathionine, N-methylglycine (sarcosine), and total cysteine (tCys) in groups of both MAT I/III- and CBS-deficient patients to provide more evidence as to their metabolite patterns. Unexpectedly, we found that MAT I/III-deficient patients with the most markedly elevated levels of plasma methionine also had elevations of plasma tHcy and often mildly elevated plasma cystathionine. Evidence is presented that methionine does not inhibit cystathionine beta-synthase, but does inhibit cystathionine gamma-lyase. Mechanisms that may possibly underlie the elevations of plasma tHcy and cystathionine are discussed. The combination of elevated methionine plus elevated tHcy may lead to the mistaken conclusion that an MAT I/III-deficient patient is instead CBS-deficient. Less than optimal management is then a real possibility. Measurements of plasma cystathionine, S-adenosylmethionine, and sarcosine should permit ready distinction between the 2 conditions in question, as well as be useful in several other situations involving abnormalities of methionine and/or homocysteine derivatives.
Adolescent↗
Homocysteine and methylmalonic acid: markers to predict and avoid toxicity from pemetrexed therapy.
The purpose of this study was to identify predictive factors for severe toxicity caused by antifolate-chemotherapy using pemetrexed (ALIMTA, LY231514), as a model. Data on potential predictive factors for severe toxicity from pemetrexed were collected from 246 patients treated between 1995 and 1999. Multivariate stepwise regression methods were used to identify markers predictive of severe toxicity. Using a multiple logistic regression model allowed us to quantify the relative risk of developing toxicities and to generate a validated clinical hypothesis on ways to improve the safety profile of pemetrexed. Pretreatment total plasma homocysteine (tHcy) levels significantly predict severe thrombocytopenia and neutropenia with or without associated grade 3/4 diarrhea, mucositis, or infection. Pretreatment methylmalonic acid (MMA) levels significantly and independently predict grade 3/4 diarrhea and mucositis; however, these toxicities are still predicted by tHcy alone. Patients with elevated baseline levels of tHcy alone, or of both tHcy and MMA, were found to have a high risk of severe toxicity that led us to postulate that reducing tHcy would result in a reduction of severe toxicity with no harm to efficacy. This study points out for the first time the importance of pretreatment tHcy levels in predicting severe toxicity associated with an antifolate and sets the stage for a prospective clinical intervention to protect patients from pemetrexed-induced severe toxicity and possibly improve the drug's efficacy. Antifolates as a class have been associated with sporadic severe myelosuppression with gastrointestinal toxicity. Although infrequent, a combination of such toxicities can carry a high risk of mortality. This phenomenon had been unpredictable until now. Our work shows that by measuring tHcy, one can identify patients that are at risk of toxicity before treatment. Most importantly, decreasing homocysteine levels via vitamin supplementation leads to a better safety profile of pemetrexed and possibly to an improved efficacy.
Adult↗