scholarly journals Pilot Study on Neonatal Screening for Methylmalonic Acidemia Caused by Defects in the Adenosylcobalamin Synthesis Pathway and Homocystinuria Caused by Defects in Homocysteine Remethylation

2021 ◽  
Vol 7 (3) ◽  
pp. 39
Author(s):  
Reiko Kagawa ◽  
Go Tajima ◽  
Takako Maeda ◽  
Fumiaki Sakura ◽  
Akari Nakamura-Utsunomiya ◽  
...  
Keyword(s):  
Neonatal Screening ◽  
Vitamin B12 Deficiency ◽  
Methylmalonic Acidemia ◽  
Methylene Tetrahydrofolate Reductase ◽  
B12 Deficiency ◽  
Total Homocysteine ◽  
Index 2 ◽  
Second Tier ◽  
Positive Results ◽  
Primary Index

Neonatal screening (NS) for methylmalonic acidemia uses propionylcarnitine (C3) as a primary index, which is insufficiently sensitive at detecting methylmalonic acidemia caused by defects in the adenosylcobalamin synthesis pathway. Moreover, homocystinuria from cystathionine β-synthase deficiency is screened by detecting hypermethioninemia, but methionine levels decrease in homocystinuria caused by defects in homocysteine remethylation. To establish NS detection of methylmalonic acidemia and homocystinuria of these subtypes, we evaluated the utility of indices (1) C3 ≥ 3.6 μmol/L and C3/acetylcarnitine (C2) ≥ 0.23, (2) C3/methionine ≥ 0.25, and (3) methionine < 10 μmol/L, by retrospectively applying them to NS data of 59,207 newborns. We found positive results in 116 subjects for index (1), 37 for (2), and 15 for (3). Second-tier tests revealed that for index 1, methylmalonate (MMA) was elevated in two cases, and MMA and total homocysteine (tHcy) were elevated in two cases; for index 2 that MMA was elevated in one case; and for index 3 that tHcy was elevated in one case. Though data were anonymized, two cases identified by index 1 had been diagnosed with maternal vitamin B12 deficiency during NS. Methylene tetrahydrofolate reductase deficiency was confirmed for the case identified by index 3, which was examined because an elder sibling was affected by the same disease. Based on these data, a prospective NS study is underway.

scholarly journals Polymorphisms in the Transcobalamin Gene: Association with Plasma Homocysteine in Healthy Individuals and Vascular Disease Patients

2002 ◽  
Vol 48 (9) ◽  
pp. 1383-1389 ◽  
Author(s):  
Karin JA Lievers ◽  
Lydia A Afman ◽  
Leo AJ Kluijtmans ◽  
Godfried HJ Boers ◽  
Petra Verhoef ◽  
...  
Keyword(s):  
Vitamin B12 ◽  
Vascular Disease ◽  
Vitamin B12 Deficiency ◽  
Potential Effect ◽  
Sequence Variants ◽  
Cvd Risk ◽  
Plasma Thcy ◽  
B12 Deficiency ◽  
Total Homocysteine ◽  
Plasma Total Homocysteine

Abstract Background: Hyperhomocysteinemia is an independent risk factor for cardiovascular disease (CVD). Intracellular vitamin B12 deficiency may lead to increased plasma total homocysteine (tHcy) concentrations and because transcobalamin (TC) is the plasma transporter that delivers vitamin B12 to cells, genetic variation in the TC gene may affect intracellular vitamin B12 availability and, consequently, tHcy concentrations. Methods: We examined five sequence variants, i.e., I23V, G94S, P259R, S348F, and R399Q, in the TC gene as possible determinants of tHcy and, concordantly, as possible risk factors for CVD in 190 vascular disease patients and 601 controls. We also studied potential effect-modification of vitamin B12 by genotype. Results: In individuals with high vitamin B12, 259PP individuals had lower tHcy concentrations than 259PR and 259RR individuals. Homozygous 23VV individuals had lower fasting tHcy concentrations than their 23IV and 23II peers. None of the genotypes defined by the three other sequence variants showed an association with tHcy concentrations, nor was any TC genotype associated with an increased CVD risk. Conclusions: In individuals in the highest quartile of the vitamin B12 distribution (&gt;299 pmol/L), tHcy concentrations are lower in 259PP homozygotes than in 259PR and 259RR individuals. Therefore, 259PP individuals, who represent &gt;25% of the general population, may be more susceptible to reduction of plasma tHcy concentrations by increasing the vitamin B12 status.

scholarly journals A Dietary Vitamin B12 Deficiency Impairs Balance and Coordination After Ischemic Injury to the Sensorimotor Cortex in Adult Male and Female Mice

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 932-932
Author(s):  
Gyllian Yahn ◽  
Brandi Wasek ◽  
Terry Bottiglieri ◽  
Nafisa Jadavji
Keyword(s):  
Risk Factor ◽  
Ischemic Stroke ◽  
Vitamin B12 ◽  
Vitamin B12 Deficiency ◽  
Stroke Outcome ◽  
Deficient Diet ◽  
Male And Female ◽  
Female Mice ◽  
B12 Deficiency ◽  
Total Homocysteine

Abstract Objectives The majority of the world's population is growing older, in 2000, 10% of the total population of the world was over 60 years old and is projected to increase to 21% by 2050. Brain vasculature is unique, and its aging has been scarcely investigated at the cellular, and molecular levels, as well as in the context of age-related comorbidities. Nutrition is a modifiable risk factor for stroke, as people age their ability to absorb some nutrients decreases. A primary example is vitamin B12, the majority of older adults are deficient in vitamin B12 because of changes in breakdown and absorption of the vitamin. Furthermore, a vitamin B12 deficiency results in elevated levels of homocysteine which is a risk factor for cardiovascular diseases, such as stroke. Using a mouse model system, the aim of this study was to understand the role of vitamin B12 deficiency in ischemic stroke outcome and investigate mechanistic changes in the brain. Methods At 10-weeks of age male and female C57Bl/6J mice were put on control (0.025 mg/kg of vitamin B12) or vitamin B12 deficient (0 mg/kg of vitamin B12) diets for 4-weeks prior to ischemic damage. At 14 weeks of age we induced ischemic stroke in the sensorimotor cortex using the photothrombosis model, all animals received damage. Animals continued on diets for 4 weeks after damage. At 18 weeks of age we assessed stroke outcome using the accelerating rotarod and forepaw placement task. After the collection of behavioral data, we euthanized animals and collected brain, blood, and liver tissue to assess histological and biochemical measurements. Plasma was used to measure total homocysteine and methylmalonic acid. Results All animals maintained on the vitamin B12 deficient diet had increased levels of total homocysteine in plasma and liver tissue. Male and female mice maintained on a vitamin B12 deficient diet had impairments in balance and coordination on the accelerating rotarod compared to animals maintained on a control diet. Conclusions Vitamin B12 deficiency impacts motor function in older adult male and female mice. We are investigating damage volume and potential mechanisms within the damage brain tissue. Funding Sources Midwestern University Start-Up Funds.

scholarly journals Functional Biomarkers of Vitamin B12 Status, Diet, and Metabolic Control in Women with Phenylketonuria (P24-005-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Meriah Schoen ◽  
Kathryn Coakley ◽  
Teresa Douglas ◽  
Rani Singh
Keyword(s):  
Vitamin B12 ◽  
Metabolic Control ◽  
Vitamin B12 Deficiency ◽  
Dietary Compliance ◽  
Funding Sources ◽  
Regular Consumption ◽  
B12 Deficiency ◽  
Total Homocysteine ◽  
Private Donations ◽  
Functional Biomarkers

Abstract Objectives Metabolic control in Phenylketonuria (PKU) requires a protein-restricted diet, which elevates the risk of vitamin B12 deficiency. Neurological sequelae driven by suboptimal B12 status in PKU may be overlooked due to concomitant elevations in phenylalanine and B12 monitoring techniques that lack sensitivity. The aim of this analysis was to assess the effectiveness of functional biomarkers of B12 status, methylmalonic acid (MMA) and total homocysteine (tHcy), in the early identification of B12 deficiency in PKU. Methods Diet and blood measures (plasma amino acids, B6; serum B12, folate, MMA, tHcy) were assessed in 31 females with PKU who attended the Emory Metabolic Camp in 2012 (N = 14) or 2018 (N = 17). The prevalence of functional B12 deficiency (MMA > 378 nmol/L and B12 < 914 pg/mL) was determined, and Spearman rank correlations between dietary intake, metabolic control, and biochemical indicators of B12 status were assessed (SAS 9.4, α = 0.05). Results All characteristics were similar for 2012 and 2018 participants except tHcy, which was higher among females in 2012 (P = 0.01). Median age was 20 years (IQR: 16–24) and mean BMI was 29.6 ± 8.3 kg/m2. Of the 31 participants, 13 (41.9%) were on a phenylalanine-lowering medication (Kuvan). Five females (16%) had low B12 concentrations (<230 pg/mL), and one of these five had elevated MMA. Dietary consumption of B12 was below the RDA in seven females (22.6%), five of which also had suboptimal consumption of B6 and folate. Low B12 was associated with increased MMA (r = −0.49, P = 0.01) and tHcy (r = −0.42, P = 0.02) levels. Whereas, higher serum B12 was associated with elevated plasma B6 (r = 0.86, P < 0.01), dietary compliance (r = 0.41, P = 0.03), and increased intake of B12 (r = 0.63, P < 0.01), B6 (r = 0.47, P = 0.01), folate (r = 0.46, P = 0.01), and total protein (r = 0.43, P = 0.02). Conclusions Vitamin B12 has a moderate correlation with MMA and tHcy in females with PKU. Functional B12 deficiency, however, is not prevalent in this sample. This may reflect the regular consumption of fortified medical food among the females in this sample. Monitoring MMA and tHcy, regardless of B12 levels, may still have utility in this population for the detection of early deficiency. Funding Sources National Center for Advancing Translational Sciences of the NIH, private donations.

Abstract P807: Vitamin B12 Deficiency Impairs Balance and Coordination After Photothrombotic Damage to the Sensorimotor Cortex in Adult Male and Female Mice After Ischemic Stroke

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Gyllian Yahn ◽  
Teodoro Bottiglieri ◽  
Brandi Wasek ◽  
Nafisa Jadavji
Keyword(s):  
Ischemic Stroke ◽  
Vitamin B12 ◽  
Control Diet ◽  
Vitamin B12 Deficiency ◽  
Stroke Outcome ◽  
Deficient Diet ◽  
Male And Female ◽  
Female Mice ◽  
B12 Deficiency ◽  
Total Homocysteine

Introduction: The majority of the world’s population is growing older, in 2000, 10% of the total population of the world was over 60 years old and is projected to increase to 21% by 2050. Brain vasculature is unique, and its aging has been scarcely investigated at the cellular, and molecular levels, as well as in the context of age-related comorbidities. Nutrition is a modifiable risk factor for stroke, as people age their ability to absorb some nutrients decreases. A primary example is vitamin B12, the majority of older adults are deficient in vitamin B12 because of changes in breakdown and absorption of the vitamin. Furthermore, a vitamin B12 deficiency results in elevated levels of homocysteine which is a risk factor for cardiovascular diseases, such as stroke. Using a mouse model system, the aim of this study was to understand the role of vitamin B12 deficiency in ischemic stroke outcome and investigate mechanistic changes in the brain. Hypothesis: Vitamin B12 deficient mice will exhibit worse stroke outcome compared to control diet mice through increased apoptosis. Methods: At 10-weeks of age male and female C57Bl/6J mice were put on control (0.025 mg/kg of vitamin B12) or vitamin B12 deficient (0 mg/kg of vitamin B12) diets for 4-weeks prior to ischemic damage. At 14 weeks of age we induced ischemic stroke in the sensorimotor cortex using the photothrombosis model, all animals received damage. Animals continued on diets for 4 weeks after damage. At 18 weeks of age we assessed stroke outcome using the accelerating rotarod and forepaw placement task. After the collection of behavioral data, we euthanized animals and collected brain and liver tissue to assess histological and biochemical measurements. Plasma was used to measure total homocysteine and methylmalonic acid. Results: All animals maintained on the vitamin B12 deficient diet had increased levels of total homocysteine in plasma and liver tissue. Male and female mice maintained on a vitamin B12 deficient diet had impairments in balance and coordination on the accelerating rotarod compared to animals maintained on a control diet. Conclusions: Vitamin B12 deficiency impacts motor function in older adult male and female mice. We are investigating damage volume and potential mechanisms within the damage brain tissue.

Chemotherapy-induced suppression of serum holotranscobalamin

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e20639-e20639
Author(s):  
G. Tisman ◽  
S. J. Kutik ◽  
Y. A. Khan
Keyword(s):  
Vitamin B12 ◽  
Methylmalonic Acid ◽  
Statistical Significance ◽  
Active Form ◽  
Vitamin B12 Deficiency ◽  
Total Serum ◽  
Significant Drop ◽  
Before And After ◽  
B12 Deficiency ◽  
Total Homocysteine

e20639 Purpose: Chemotherapy-induced damage to the stomach and small intestine may inhibit the absorption of vitamin B12. To assess the risk of chemotherapy causing acute vitamin B12 deficiency, we primarily measured the active form of vitamin B12, holotranscobalamin, but also total serum B12, methylmalonic acid, and total homocysteine. Experimental Design: We studied 21 patients that were actively on chemotherapy and recorded values for holotranscobalamin, total serum B12, methylmalonic acid, total homocysteine, and cystatin-c. Measurements were taken both before and after four doses of chemotherapy. T-tests were employed to determine statistical significance. Results: There was a statistically significant drop in holotranscobalamin after chemotherapy in eighteen out of twenty-one patients (p = 2.64x10–3). Three patients were vitamin B12 deficient as defined by total B12 < 300 pg/ml. Neither methylmalonic acid (p = 3.95x10–1), nor total homocysteine (p = 4.34x10–1), showed any significant changes. Conclusions: Chemotherapy caused an acute deficiency of the only metabolically active form of vitamin B12, holotranscobalamin, despite B12 supplementation. We suggest monitoring patients for changes in holotranscobalamin to ensure that prolonged deficiency does not occur. The clinical implications of acute lowering of holotranscobalamin remain unknown. No significant financial relationships to disclose.

Diagnostic Challenges Using a 2-Tier Strategy for Methylmalonic Acidurias: Data from 1.2 Million Dried Blood Spots

2020 ◽  
Vol 76 (4) ◽  
pp. 268-276 ◽  
Author(s):  
Katharina J. Weiss ◽  
Wulf Röschinger ◽  
Holger Blessing ◽  
Amelie S. Lotz-Havla ◽  
Katharina A. Schiergens ◽  
...  
Keyword(s):  
Vitamin B12 ◽  
Methylmalonic Acid ◽  
Vitamin B12 Deficiency ◽  
Dried Blood Spots ◽  
Maternal Vitamin ◽  
B12 Deficiency ◽  
Second Tier ◽  
Genetically Determined ◽  
Moderate Elevation

<b><i>Background:</i></b> The detection of methylmalonic acid (MMA) by second-tier analysis has been shown to reduce the number of false positives in newborn screening (NBS) for genetically determined methylmalonic acidurias (MMAuria). In addition to genetic conditions, MMA is an indicator of vitamin B12 status, thus applicable to detect maternal vitamin B12 deficiency in the newborns screened. <b><i>Methods:</i></b> Biochemical and clinical follow-up data of a 7.5-year pilot study with 1.2 million newborns screened were reviewed. <b><i>Results:</i></b> Among 1,195,850 NBS samples, 3,595 (0.3%) fulfilled criteria for second-tier analysis of MMA. In 37 (0.003%; 1/32,000) samples, elevated concentrations of MMA were detected, resulting in diagnostic workup at a metabolic center in 21 newborns. In 6 infants (1/199,000), genetic conditions were established, 1 infant with cobalamin C deficiency (CblC) showed only a moderate elevation of MMA. The remaining 15 newborns (1/79,000) displayed significantly lower concentrations of MMA and were evaluated for maternal vitamin B12 deficiency. In 9 mothers, vitamin B12 deficiency was verified, and 6 showed no indication for vitamin B12 deficiency. Treatment with vitamin B12 normalized biochemical parameters in all 15 infants. <b><i>Conclusions:</i></b> Applying a 2-tier strategy measuring MMA in NBS identified genetic conditions of MMAuria. It was possible to separate severe, early-onset phenotypes from maternal vitamin B12 deficiency. However, the detection of CblC deficiency with mildly elevated MMA interferes with impaired vitamin B12 status of unknown relevance and thus burdens possibly healthy newborns. Regarding maternal vitamin B12 deficiency, testing and supplementing mothers-to-be is preferable. This might decrease straining follow-up of newborns and improve quality and overall perception of NBS.

Sign in / Sign up

Export Citation Format

Share Document