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Biomedical subjects

R H Allen

Publications and source records attributed to R H Allen.

At least 55 records · Page 3Linked to original sources
PubMed1996

Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate.

Elevated plasma homocyst(e)ine levels are an independent risk factor for vascular disease. In a case-control study, the authors studied the associations of fasting plasma homocyst(e)ine and vitamins, which are important cofactors in homocysteine metabolism, with the risk of myocardial infarction. The cases were 130 Boston area patients hospitalized with a first myocardial infarction and 118 population controls, less than 76 years of age, enrolled in 1982 and 1983. Dietary intakes of vitamins B6, B12, and folate were estimated from a food frequency questionnaire. After adjusting for sex and age, the authors found that the geometric mean plasma homocyst(e)ine level was 11% higher in cases compared with controls (p = 0.006). There was no clear excess of cases with extremely elevated levels. The age- and sex-adjusted odds ratio for each 3-mumol/liter (approximately 1 standard deviation) increase in plasma homocyst(e)ine was 1.35 (95% confidence interval 1.05-1.75; p trend = 0/007). After further control for several risk factors, the odds ratio was not affected, but the confidence interval was wider and the p value for trend was less significant. Dietary and plasma levels of vitamin B6 and folate were lower in cases than in controls, and these vitamins were inversely associated with the risk of myocardial infarction, independently of other potential risk factors. Vitamin B12 showed no clear association with myocardial infarction, although methylmalonic acid levels were significantly higher in cases. Comparing the mean levels of several homocysteine metabolites among cases and controls, the authors found that impairment of remethylation of homocyst(e)ine (dependent of folate and vitamin B12 rather than on vitamin B6-dependent transsulfuration) was the predominant cause of high homocyst(e)ine levels in cases. Accordingly, plasma folate and, to a lesser extent, plasma vitamin B12, but not vitamin B6, correlated inversely with plasma homocyst(e)ine, even for concentrations at the high end of normal values. These data provide further evidence that plasma homocyst(e)ine is an independent risk factor for myocardial infarction. In this population, folate was the most important determinant of plasma homocyst(e)ine, even in subjects with apparently adequate nutritional status of this vitamin.

Case-Control Studies↗
PubMed1996

Elevated methylmalonic acid and total homocysteine levels show high prevalence of vitamin B12 deficiency after gastric surgery.

OBJECTIVE: To determine the prevalence of vitamin B12 deficiency in patients who have had gastric surgery. DESIGN: Cross-sectional study. SETTING: Philadelphia Veterans Affairs Medical Center. PARTICIPANTS: 61 patients who had had gastric surgery and 107 controls. MEASUREMENTS: Serum levels of vitamin B12, folate, methylmalonic acid, and total homocysteine measured before and after treatment in participants with vitamin B12 deficiency. Vitamin B12 deficiency was defined as one of the following: 1) a serum vitamin B12 level less than 221 pmol/L and an elevated methylmalonic acid level; 2) a serum vitamin B12 level less than 221 pmol/L and an elevated total homocysteine level that decreased with vitamin B12 treatment; or 3) in patients unavailable for treatment, a serum vitamin B12 level less than 221 pmol/L, a folate level greater than 9 nmol/L, and an elevated total homocysteine level. RESULTS: Study patients and controls were similar in age, sex, and racial distribution. Nineteen patients (31%) and 2 controls (2%) had vitamin B12 deficiency (P < 0.001). Twelve (63%) of the 19 vitamin B12-deficient patients had elevated total homocysteine levels. In all participants with vitamin B12 deficiency who received treatment (15 of 21), methylmalonic acid and total homocysteine levels decreased substantially, confirming the deficiency before treatment. CONCLUSION: Patients who have had gastric surgery have a high prevalence of vitamin B12 deficiency. Prompt recognition and treatment of the deficiency with resultant normalization of elevated total homocysteine and methylmalonic acid levels may prevent the development of cardiovascular, hematologic, and neurologic abnormalities. Our data support both frequent screening and vitamin B12 replacement therapy in patients who have had gastric surgery and have serum vitamin B12 levels less than 221 pmol/L.

Adult↗
PubMed1996

Ethanol feeding of micropigs alters methionine metabolism and increases hepatocellular apoptosis and proliferation.

Chronic alcoholism is associated with increased cancer risk that may be related to ethanol-induced alterations in methionine and deoxynucleotide metabolism. These metabolic relationships were studied in micropigs fed diets for 12 months that contained 40% ethanol or cornstarch control with adequate folate. Ethanol feeding altered methionine metabolism without changing mean terminal liver folate levels. After initial equilibration to diet, ethanol feeding significantly increased monthly serum homocysteine levels while reducing serum methionine levels over the time course of the experiment. After 12 months, hepatic methionine synthase activity and the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) were significantly reduced in ethanol-fed animals, whereas the ratio of liver deoxyuridine triphosphate (dUTP) to deoxythymidine triphosphate (dTTP) was increased and correlated inversely with methionine synthase activity. These findings were associated with increased frequency of hepatocytes with apoptotic bodies and positivity for proliferating cell nuclear antigen (PCNA) in livers from ethanol-fed minipigs. These studies suggest that chronic ethanol feeding perturbs methionine metabolism by impairment of methionine synthase activity, resulting in deoxynucleoside triphosphate (dNTP) imbalance, increased apoptosis, and regenerative proliferation. These biochemical alterations may provide a promoting environment for carcinogenesis during long-term ethanol exposure.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1996

Vitamin supplementation and other variables affecting serum homocysteine and methylmalonic acid concentrations in elderly men and women.

OBJECTIVE: An elevated serum concentration of the metabolite, homocysteine (Hcys): 1) can indicate folate or vitamin B12 deficiency, 2) is an independent risk factor for vascular disease. The metabolite, methylmalonic acid (MMA), is elevated in deficiency of vitamin B12, but not folate. The purpose of this study was to determine the effect of self-selected vitamin supplementation and other variables on serum Hcys and MMA concentrations in elderly men and women. METHODS: Serum concentrations of Hcys, MMA, folate and vitamin B12 were measured for elderly volunteers, age 68-96 years, and compared for those consuming (26 men, 25 women) and not consuming (24 men, 25 women) self-selected vitamin supplements. RESULTS: Compared with the nonsupplemented group, the supplemented group had lower mean serum MMA (208 +/- 162 vs. 241 +/- 98 nmol/L [+/- SD]) and Hcys (9.5 +/- 2.6 vs. 11.2 +/- 2.7 mumol/L); and higher serum vitamin B12 (391 +/- 174 vs 292 +/- 107 pmol/L), and serum folate (46 +/- 15 vs. 24 +/- 10 nmol/L) p < 0.05. Among all 100 subjects, the prevalence of serum vitamin B12 < 221 pmol/L (300 pg/mL) was 18; MMA > 271 nmol/L, 16; Hcys > 16.2 mumol/L, 3; folate < 5.0 nmol/L, none. Based on serum vitamin B12 < 221 nmol/L with elevated serum MMA, vitamin B12 deficiency was probable in seven subjects, of whom two were supplemented. All three subjects with elevated serum Hcys had elevated serum MMA as well, suggesting vitamin B12 deficiency or renal insufficiency. A stepwise linear regression model for serum Hcys explained 61.7% of the variance, and included (in order) serum creatinine, folate, vitamin B12, albumin, age and body mass index (BMI). A model with serum MMA replacing serum vitamin B12 explained 64.1% of the variance in serum Hcys. Folate did not enter the model for supplemented subjects, supporting a "threshold effect": serum Hcys was inversely related to serum folate at lower serum folate (nonsupplemented subjects), but at higher serum folate (supplemented subjects), the relationship was flat. In supplemented subjects, serum Hcys was still related to vitamin B12 status, confirming that tissue deficiency of the vitamin was present. CONCLUSIONS: Results showed potential usefulness of serum MMA and Hcys in identifying subclinical or tissue deficiency of vitamin B12. Clinicians should be aware of the risk of vitamin B12 deficiency in older people and of current screening algorithms using serum metabolites. These elderly volunteers had generally good folate status; nevertheless, some subjects seemed likely to benefit from an improvement in folate status that would reduce their serum Hcys within the normal range. The role of serum creatinine in the normal range in predicting serum Hcys, a vascular disease risk factor, remains unexplained.

Aged↗
PubMed1996

Relationship among homocyst(e)ine, vitamin B-12 and cardiac disease in the elderly: association between vitamin B-12 deficiency and decreased left ventricular ejection fraction.

We evaluated the association of moderate hyperhomocyst(e)inemia and vitamin B-12 status with coronary artery disease (CAD) and left ventricular ejection fraction in 367 elderly patients undergoing coronary angiography. The extent of CAD was scored, left ventricular ejection fraction was assessed and vitamins B-12 and folate and the metabolites homocyst(e)ine, methylmalonic acid and 2-methylcitric acid were measured. There was no significant trend in change in homocyst(e)ine as the extent of CAD increased. There was an association between vitamin B-12 deficiency, i.e., vitamin B-12 < 221 pmol/l and homocyst(e)ine > 16 nmol/ml and low left ventricular ejection fraction (P = 0.014). Of 105 samples, selected for vitamin B-12 < 221 pmol/l or high normal vitamin B-12 and folate levels, metabolites including methylmalonic acid revealed a specific diagnosis of vitamin B-12 deficiency in 18 patients. The trend among these vitamin B-12-deficient patients and low left ventricular ejection fraction was significant (P = 0.028). In vitro studies on rat heart revealed that nitrous oxide in the presence of 200 microM/l methionine reduced contractility of the heart. In conclusion, vitamin B-12-deficient patients had significantly lower left ventricular ejection fractions than nonvitamin B-12-deficient patients. Whether low left ventricular ejection fraction results in malabsorption of vitamin B-12 and vitamin B-12 deficiency, or conversely, whether vitamin B-12 and its marker, elevated homocyst(e)ine, depress left ventricular function warrants further evaluation.

Aged↗
PubMed1996

The use of homocysteine and other metabolites in the specific diagnosis of vitamin B-12 deficiency.

Vitamin B-12 (cobalamin) is a cofactor for only two enzymes, methionine synthase and L-methylmalonyl-CoA mutase. The serum vitamin B-12 concentration has been shown to have limitations in specificity and sensitivity in diagnosing vitamin B-12 deficiency and predicting response to therapy in subjects with clinical deficiency syndromes. Serum methylmalonic acid and/or total homocysteine concentrations have been shown to be elevated in almost every patient who has a clinical response to vitamin B-12. In elderly populations serum methylmalonic acid concentrations are elevated in the majority (60-66%) of subjects who have elevated total homocysteine concentrations, suggesting that vitamin B-12 deficiency (with or without associated folate deficiency) and/or chronic renal insufficiency may be the primary cause of most of the elevated total homocysteine concentrations in elderly populations. In such subjects vitamin B-12 and folate concentrations are both frequently in the low or low normal range, making differentiation of the clinical syndromes by use of serum vitamin concentrations problematic. Elevations of 2-methylcitric acid and cystathionine also result from vitamin B-12 deficiency. Serum N-methylglycine concentrations are normal in cobalamin deficiency but are increased in 40% of patients deficient in folate. In conclusion, elevations of methylmalonic acid and total homocysteine are very sensitive and specific in diagnosing vitamin B-12 deficiency and can be used to help differentiate vitamin B-12 deficiency from folate deficiency. Elevated total homocysteine concentrations that may have been attributed to folate deficiency in elderly subjects may in many instances be the result of vitamin B-12 deficiency even though serum vitamin B-12 concentrations are within normal limits.

Adolescent↗
PubMed1996

High prevalence of cobalamin deficiency in the elderly.

In summary, we have shown that there is a high prevalence of Cbl deficiency in the elderly. This observation is based on an increase in the number of low and low normal serum Cbl levels, an increase in elevated serum total homocysteine levels that correct with Cbl therapy, and an increase in elevated serum methylmalonic acid levels that also correct with Cbl therapy. These observations may be of great clinical importance since Cbl deficiency may be a common and treatable cause of vascular disease.

Aged↗
PubMed1995

Effects of vitamin B12, folate, and vitamin B6 supplements in elderly people with normal serum vitamin concentrations.

In a prospective, multicentre, double-blind controlled study, the effect of an intramuscular vitamin supplement containing 1 mg vitamin B12, 1.1 mg folate, and 5 mg vitamin B6 on serum concentrations of methylmalonic acid (MMA), homocysteine (HCYS), 2-methylcitric acid (2-MCA), and cystathionine (CYSTA) was compared with that of placebo in 175 elderly subjects living at home and 110 in hospital. Vitamin supplement and placebo were administered eight times over a 3-week period. Vitamin supplement but not placebo significantly reduced all four metabolite concentrations at the end of the study in both study groups. The maximum effects of treatment were usually seen within 5-12 days. Initially elevated metabolite concentrations returned to normal in a higher proportion of the vitamin than of the placebo group: 92% vs 20% for HYCS; 82% vs 20% for MMA; 62% vs 25% for 2-MCA; and 42% vs 25% for CYSTA. The response rate to vitamin supplements supports the notion that metabolic evidence of vitamin deficiency is common in the elderly, even in the presence of normal serum vitamin levels. Metabolite assays permit identification of elderly subjects who may benefit from vitamin supplements.

Aged↗
PubMed1995

Simulating birth to investigate clinician-applied loads on newborns.

This report describes the design, development and testing of a force-measuring birth stimulator. Designed to mimic the feel of an obstetric emergency, the simulator is named shoulder dystocia birth model (SDBM). The SDBM consists of a simply supported overhung beam, instrumented with two strain gauges and one commercially-available sensor, all of which are embedded in a maternal manikin that rests on a height-adjustable scissors jack. Rigidly affixed to the free end of the beam, a model of a newborn head protrudes from the manikin to allow physicians to simulate the loads they exert when delivering a newborn. A microcomputer-based data acquisition system monitors, analyses and processes the output from the gauges and the sensor in real time. The system measures axial force and vertical force to within 2% accuracy and the end-moment to within 5% accuracy. Testing with 15 University of Maryland clinicians simulating routine, difficult and SD deliveries reveals average peak force magnitudes of 68 N, 118 N and 172 N and average peak moment magnitudes of 138 N. cm, 384 N.cm and 621 N.cm, respectively. The standard deviations for these average peak values are large indicating wide variation in perceived loads required to deliver. Confirming clinical observation, average peak forces for some difficult and many shoulder dystocia deliveries exceed the force necessary to induce clavicle fracture at birth.

Delivery, Obstetric↗
PubMed1994

Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies.

PURPOSE: Patients with cobalamin (vitamin B12) deficiency usually lack many of the classic features of severe megaloblastic anemia; because of the low diagnostic specificity of decreased serum cobalamin levels, demonstrating the deficiency unequivocally is often difficult. We examined the sensitivity of measuring serum concentrations of methylmalonic acid and total homocysteine for diagnosing patients with clear-cut cobalamin deficiency and compared the results with those of patients with clear-cut folate deficiency. PATIENTS AND METHODS: Serum metabolites were measured for all patients seen from 1982 to 1989 at two university hospitals who met the criteria for cobalamin and folate deficiency states and for such patients seen from 1968 to 1981 from whom stored sera were available. In all, 406 patients had 434 episodes of cobalamin deficiency and 119 patients had 123 episodes of folate deficiency. Criteria for deficiency states included serum vitamin levels, hematologic and neurologic findings, and responses to therapy. Responses were documented in 97% of cobalamin-deficient patients and 76% of folate-deficient patients. Metabolite levels were measured by modified techniques using capillary-gas chromatography and mass spectrometry. RESULTS: Most of the cobalamin-deficient patients had underlying pernicious anemia; two thirds were blacks or Latinos. Hematocrits were normal in 28% and mean cell volumes in 17%. Of the 434 episodes of cobalamin deficiency, 98.4% of serum methylmalonic acid levels and 95.9% of serum homocysteine levels were elevated (greater than 3 standard deviations above the mean in normal subjects). Only one patient had normal levels of both metabolites. Serum homocysteine levels were increased in 91% of the 123 episodes of folate deficiency. Methylmalonic acid was elevated in 12.2% of the folate-deficient patients; in all but one, the elevation was attributable to renal insufficiency or hypovolemia. CONCLUSIONS: For the cobalamin-deficient patients, measuring serum metabolite concentrations proved to be a highly sensitive test of deficiency. We conclude that normal levels of both methylmalonic acid and total homocysteine rule out clinically significant cobalamin deficiency with virtual certainty.

Female↗
PubMed1994

Comparing clinician-applied loads for routine, difficult, and shoulder dystocia deliveries.

OBJECTIVE: Our goal was to examine and compare clinician-applied loads during simulated vaginal delivery. STUDY DESIGN: We developed a birthing model and a microcomputer data acquisition system and used them to measure clinician-applied extraction forces, moment, and rates for three perceived categories of delivery. In 39 experiments, clinicians simulated delivery of the fetal shoulders during vaginal delivery for routine, difficult, and shoulder dystocia deliveries. RESULTS: Clinicians averaged 84 N combined force and 473 N-cm neck-bending moment for routine deliveries, 122 N and 697 N-cm for difficult deliveries, and 163 N and 700 N-cm for shoulder dystocia deliveries (p < 0.002). No force or moment parameter was associated with clinician gender or experience. Force levels exceeding 100 N are reached for many clinicians (74% and 82%) for difficult and shoulder dystocia deliveries and for some clinicians (31%) for routine deliveries (p < 0.0001). CONCLUSION: We conclude that simulating shoulder dystocia in the laboratory may be useful in measuring extraction forces and neck-bending moment and that birthing models can be used to train clinicians in force, moment, and rate perception.

Delivery, Obstetric↗
PubMed1994

Plasma cysteine concentrations in infants with respiratory distress.

Because factors that predispose infants to persistent pulmonary hypertension of the newborn (PPHN) may cause oxidant stress, which in turn may increase demands for cysteine and glutathione, we investigated the availability of cysteine and its precursors in PPHN and related disorders. Plasma concentrations of four sulfur-containing and two non-sulfur-containing amino acids were measured by gas chromatography-mass spectrometry in blood from infants with PPHN, both those managed conventionally (PPHN group) and those treated with extracorporeal membrane oxygenation, as well as from infants with hyaline membrane disease. Concentrations also were measured in umbilical venous cord blood samples from a healthy control population, in venous plasma from infants receiving only intravenously administered glucose-containing solutions because they had noncardiopulmonary illnesses ("fasted" group), and from otherwise healthy, orally fed infants ("fed" group). The plasma total cyst(e)ine concentration was markedly lower in the three groups (PPHN, PPHN and extracorpeal membrane oxygenation, and hyaline membrane disease) receiving an elevated inspired oxygen concentration (0.6 to 1.0) than in fasted or fed control infants. In contrast, levels of plasma methionine, the other major sulfur amino acid, were low in the three groups receiving an elevated inspired oxygen concentration, as well as in fasted infants. Glycine and serine, two non-sulfur-containing amino acids, had a pattern similar to that of plasma methionine. Thus infants with PPHN and hyaline membrane disease have low plasma total cyst(e)ine levels, an effect that does not appear to result primarily from nutritional deprivation. We speculate that the role of cysteine in bioactivation of nitric oxide and as a precursor of glutathione may be relevant to the pathogenesis and evolution of PPHN and respiratory distress syndrome. Further studies are needed to determine whether increased demands for cysteine exist in these disorders.

Algorithms↗
PubMed1994

Prevalence of cobalamin deficiency in the Framingham elderly population.

To determine whether the increased prevalence of low serum cobalamin concentrations in elderly people represents true deficiency, serum concentrations of cobalamin and folate and of metabolites that are sensitive indicators of cobalamin deficiency were measured in 548 surviving members of the original Framingham Study cohort. Serum cobalamin concentrations < 258 pmol/L were found in 222 subjects (40.5%) compared with 17.9% of younger control subjects (P < 0.001). Serum methylmalonic acid and total homocysteine concentrations were markedly elevated in association with cobalamin values < 258 pmol/L in 11.3% and 5.7%, respectively, of the cohort. Both metabolites were increased in 3.8% of the cohort, associated with significantly lower erythrocyte counts and higher mean cell volumes. Serum metabolites correlated best with serum cobalamin values, even when subnormal determinations were excluded. The prevalence of cobalamin deficiency was > or = 12% in a large sample of free-living elderly Americans. Many elderly people with "normal" serum vitamin concentrations are metabolically deficient in cobalamin or folate.

Adult↗
PubMed1993

Elevation of serum cystathionine levels in patients with cobalamin and folate deficiency.

Homocysteine can be methylated to form methionine by the cobalamin- (Cbl) and folate-dependent enzyme, methionine synthase; serum levels of total homocysteine are elevated in greater than 95% of patients with either Cbl or folate deficiency. Homocysteine can also condense with serine to form cystathionine in a pyridoxal phosphate-dependent reaction catalyzed by cystathionine beta-synthase. Cystathionine is subsequently cleaved to cysteine and alpha-ketobutyrate by the pyridoxal phosphate-dependent enzyme gamma-cystathionase. To assess levels of cystathionine in Cbl and folate deficiency, we developed a new capillary gas chromatographic-mass spectrometric assay and measured cystathionine in the serum of normal subjects and patients with clinically confirmed deficiencies of these vitamins. The normal range for serum cystathionine was 65 to 301 nmol/L (median = 126 nmol/L) for 50 normal blood donors. In 30 patients with clinically confirmed Cbl deficiency, values for cystathionine ranged from 208 nmol/L to 2,920 nmol/L (median = 816 nmol/L) and 26 (87%) had levels above the normal range. In 20 patients with clinically confirmed folate deficiency, cystathionine concentrations ranged from 138 nmol/L to 4,150 nmol/L (median = 1,560 nmol/L) and 19 (95%) had values above the normal range. Five homozygotes for cystathionine beta-synthase deficiency had high values for serum-total homocysteine and low or low-normal values for serum cystathionine that ranged from 30 nmol/L to 114 nmol/L even though they were on treatment with pyridoxine and had partially responded. One patient with a defect in the synthesis of 5-CH3-tetrahydrofolate and five patients with defects in the synthesis of CH3-Cbl had high values for serum-total homocysteine and high values for cystathionine that ranged from 311 nmol/L to 1,500 nmol/L even though they were on treatment with folic acid and Cbl, respectively, and had partially responded. We conclude that levels of cystathionine are evaluated in the serum of most patients with Cbl and folate deficiency and that they are useful in the differential diagnosis of an elevated serum-total homocysteine level.

Animals↗
PubMed1993

Identification and perturbation of mutant human fibroblasts based on measurements of methylmalonic acid and total homocysteine in the culture media.

Human and mammalian cells contain two cobalamin-dependent enzymes. Methylmalonyl-CoA mutase isomerizes L-methylmalonyl-CoA to succinyl-CoA in the propionyl-CoA pathway while methionine synthase catalyzes the transfer of the methyl group of 5-methyltetrahydrofolate to homocysteine to form methionine. Decreased activity of mutase leads to an increased methylmalonic acid in the serum of humans while decreased activity of methionine synthase leads to increased homocysteine in the serum of humans. In current studies of cultured fibroblasts, methylmalonic acid levels were specifically increased in media of normal fibroblasts exposed to propionate or in fibroblasts with mutations involving mutase. Homocysteine levels were specifically increased in media of normal fibroblasts exposed to reduced folate concentrations or in fibroblasts involving mutations of methionine synthase. In addition, exposure of normal cells to inhibitory cobalamin analogues resulted in an increase of both methylmalonic acid and homocysteine in the media. This method of analysis appears to be both specific and sensitive for reduced activity of these two enzymes in tissue culture.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1993

Elevation of 2-methylcitric acid I and II levels in serum, urine, and cerebrospinal fluid of patients with cobalamin deficiency.

Citrate synthase catalyzes the condensation of acetyl-coenzyme A (CoA) and oxaloacetic acid to form citric acid. The enzyme also catalyzes the condensation of propionyl-CoA and oxaloacetic acid with a maximal reaction velocity (Vmax) approximately 10(-4) times that of acetyl-CoA to form 2-methylcitric acid, which contains two asymmetric carbon atoms and exists as two pairs of related enantiomers designated as 2-methylcitric acid I and II. Cobalamin (Cbl) deficiency can lead to increases in intracellular levels of propionyl-CoA. To assess the magnitude of increased synthesis of 2-methylcitric acid in Cbl deficiency, we developed a new capillary gas chromatographic-mass spectrometric assay and measured 2-methylcitric acid levels in serum and cerebrospinal fluid (CSF) of normal subjects and patients with clinically confirmed Cbl deficiency. The normal range for 2-methylcitric acid level was 60 to 228 nmol/L for serum in 50 normal blood donors and 323 to 1,070 nmol/L for CSF in 19 normal subjects. In 50 patients with clinically confirmed Cbl deficiency, values for 2-methylcitric acid in serum ranged from 93 to 13,500 nmol/L; 44 (88%) had values above the normal range. In five patients with clinically confirmed Cbl deficiency, levels of the sum of 2-methylcitric acid I and II ranged from 1,370 to 16,300 nmol/L in CSF, and all five (100%) patients had levels above the normal range. We conclude that levels of 2-methylcitric acid are elevated in serum and CSF of most patients with Cbl deficiency.

Adolescent↗