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Background: Pancytopenia is characterized by a decrease in all three types of blood cells. Instead of being a standalone disease, it acts as a common outcome resulting from various factors, including infections, autoimmune disorders, genetic issues, nutritional deficiencies, and malignancies. Pinpointing the root cause of pancytopenia poses a challenge but is essential for devising an effective treatment plan and predicting the likely prognosis. Vitamin B12 deficiency is a common cause of megaloblastic anemia, pancytopenia, and various neuropsychiatric symptoms. However, diagnosing vitamin B12 deficiency lacks a definitive gold standard. Case Presentation: We present two cases where patients initially exhibited pancytopenia with seemingly normal vitamin B12 levels. Based on a bone marrow biopsy, they were initially diagnosed with myelodysplastic syndrome (MDS). Subsequent investigations revealed elevated serum methylmalonic acid (MMA) levels, leading to a revised diagnosis of vitamin B12 deficiency. Both patients showed positive responses to adequate vitamin B12 supplementation. Conclusion: Our case series highlights the importance of ruling out alternative causes of dysplasia in MDS when solely morphological abnormalities are observed on a bone marrow biopsy. It also underscores the crucial aspect of assessing MMA and homocysteine levels in individuals with normal vitamin B12 levels when there is a high clinical suspicion of B12 deficiency. [ABSTRACT FROM AUTHOR]

Deficiency of cofactors for various enzymes can lead to inborn errors of metabolism. These conditions frequently occur as seizures, which lead to permanent brain damage. Newborn screening for biomarkers associated with these disorders can help in early detection and treatment. Our objective was to establish a liquid chromatography mass spectrometry technique for quantifying biomarkers in dried urine spots to detect specific vitamin‐responsive inborn errors metabolism. Biomarkers were extracted from dried urine spots using a methanol:0.1% v/v formic acid solution (75:25) containing an internal standard mixture. Separation was achieved using a Luna PFP column (150 mm × 4.6 mm, 3 µm) under gradient elution conditions. The LC–MS technique was validated as per ICH M10 guidelines. Urine samples from healthy newborns in Udupi district, South India, were analyzed to establish reference values for these biomarkers. The method demonstrated excellent linearity (R2 > 0.99) with low limits of quantification: 0.1 µg/mL for leucine, isoleucine, valine, proline, hydroxyproline, methylmalonic acid, and 3‐hydroxyisovaleric acid; 0.01 µg/mL for pipecolic acid and α‐aminoadipic semialdehyde; and 0.03 µg/mL for piperideine‐6‐carboxylate. Interconvertibility between urine and dried urine spot assays was observed from the results of the regression and Bland–Altman analyses. Reference intervals for these biomarkers in the Udupi neonatal population were established using the validated dried urine spot method. [ABSTRACT FROM AUTHOR]

Enteropathies are prevalent in dog internal medicine, and their diagnosis involves a lengthy process. One of the tests requested is for biomarkers, which are important as they can provide data on intestinal functionality, intensity of inflammation, and response to treatment, and can help determine the prognosis. This study aimed to conduct a literature review on the main serum and fecal intestinal biomarkers in dogs and proposed to refine the correlations between these indicators and enteropathies. It was observed that the main biomarkers used in the intestinal evaluation of dogs were alpha 1‐proteinase inhibitory factor, immunoglobulin A, methylmalonic acid, serum folate, serum cobalamin, C‐reactive protein, fecal and serum calprotectin, and dysbiosis index. However, we suggest that more research be carried out to clarify the relationship between enteropathies and intestinal biomarkers. We noticed a lack of studies on specific intestinal markers and indicator variables in healthy dogs and those with various enteropathies; moreover, no data are available on the association of these laboratory parameters. [ABSTRACT FROM AUTHOR]

Background: No prospective study has evaluated the efficacy of oral supplementation with cobalamin in hypocobalaminemic cats. Objectives: To investigate the efficacy of oral or SC supplementation with cyanocobalamin in normalizing serum cobalamin and methylmalonic acid (MMA) concentrations in hypocobalaminemic cats with chronic gastrointestinal disease (CGID) or exocrine pancreatic insufficiency (EPI). Animals: Forty‐eight client‐owned hypocobalaminemic (<290 ng/L) cats with normal or abnormally high serum MMA concentrations. Methods: This study was conducted based on the prospective randomized clinical trial method. Cats with CGID or EPI were randomly assigned to 2 groups that received either oral or SC supplementation with cobalamin (250 μg/cat) for 12 and 10 weeks, respectively, in addition to other medical and dietary interventions. Each cat was evaluated 3 times (baseline, 6‐week postsupplementation, and 1‐week postcompletion) by measuring serum cobalamin and MMA concentrations. Results: In cats with CGID or EPI, cobalamin concentrations were normalized in all cats that received either oral or SC supplementation (mean 100% [95% CI: 80.6%‐100%] in both groups in cats with CGID and 100% [67.6%‐100%] in both groups in cats with EPI). Among 37 cats with elevated MMA concentrations at baseline (21 cats with CGID and 16 cats with EPI), MMA concentrations were normalized in most cats with CGID (70% in oral and 82% in SC group) or EPI (88% in both groups). Conclusions and Clinical Importance: In hypocobalaminemic cats with CGID or EPI, in conjunction with other medical and dietary interventions, both oral and SC supplementation are effective at normalizing serum cobalamin and MMA concentrations. [ABSTRACT FROM AUTHOR]

Aim: Vitamin B12 deficiency is common in the elderly population. Standard treatment via intramuscular injections, however, has several disadvantages. Safer and more convenient dosage forms such as intranasal are therefore being explored. This study compares the effects of two intranasal vitamin B12 dosage regimens in elderly vitamin B12‐deficient patients. Methods: Sixty patients ≥65 years were randomly assigned to either a loading dose (daily administration for 14 days followed by weekly administration) or a no loading dose (administration every 3 days) regimen for 90 days. Each dose contained 1000 μg cobalamin. Total vitamin B12, holotranscoblamin (holoTC), methylmalonic acid (MMA) and total homocysteine (tHcy) levels in serum were measured on days 0, 7, 14, 30, 60 and 90. Results: Both dosage regimens resulted in a rapid increase of vitamin B12 and holoTC concentrations and normalization of initial high, MMA and tHcy concentrations. The loading dose regimen resulted in the fastest and greatest increase to a median vitamin B12 of 1090 pmol/L (reference 350‐650 pmol/L) concentration after 14 days. Following weekly administration, B12 rapidly decreased to a median concentration of 530 pmol/L after 90 days. The no loading dose regimen resulted in a steady increase to a median vitamin B12 of 717 pmol/L after 90 days. Conclusions: Intranasal vitamin B12 administration is an effective and suitable way to replenish and sustain vitamin B12 levels in elderly patients. [ABSTRACT FROM AUTHOR]

Summary: In this study, the changes in volatile compounds, lipids, and small molecule compounds during the curing and drying processes were examined. The results showed that lipid oxidation was enhanced during curing and drying processes. A total of fifty‐two types of volatile compounds in the dry‐cured fish were detected, and the contents of alcohols (such as 3‐methyl‐1‐butanol, 1‐octen‐3‐ol), ketones (such as 2‐heptanone, 2‐octanone), and aldehydes (such as 3‐methylbutyraldehyde, hexanal, nonanal, decanal) were increased during curing and drying processes. A total of 812 metabolites were identified. The metabolites in linoleate, arachidonate, nucleotide, amino acid, and other metabolic pathways showed significant differences between drying stage and curing stage. The oxidative degradation of arachidonate acid, linoleate acid, and amino acid may contribute to the changes in volatile compounds during the curing and drying stages. Seven compounds including shikimic acid, carnitine C5: DC, carnitine C7: DC, 2‐hydroxybutanoic acid, 3‐hydroxybutanoic acid, malonic acid, and methylmalonic acid could be key small molecule compounds in curing and drying processing. These findings are valuable for understanding the mechanisms underlying flavour changes occurring during fish curing and drying processes. [ABSTRACT FROM AUTHOR]

Background and purpose: Nitrous oxide (N2O) induced neurological symptoms are increasingly encountered. Our aim is to provide clinical and diagnostic characteristics with a focus on electrodiagnostic studies. Methods: Patients with neurological sequelae due to N2O presenting in our hospital between November 2018 and December 2021 reporting clinical and diagnostic data were retrospectively reviewed. Results: Seventy patients (median 22 years) were included. Median N2O usage was 4 kg/week during 12 months. Patients' history revealed a higher rate of sensory symptoms compared to motor (97% vs. 57%) and 77% walking difficulties. Clinical diagnosis was polyneuropathy (PNP) in 44%, subacute combined degeneration (SCD) of the spine in 19%, both in 37%. Median vitamin B12 level was low (159 pmol/L), normal in 16%. The median methylmalonic acid was increased (2.66 μmol/L). Electrodiagnostic abnormalities were observed in 91%, with 72% fulfilling axonal PNP criteria, 20% showing mild to intermediate slowing. One patient fulfilled demyelinating PNP criteria not related to N2O abuse (Charcot−Marie−Tooth type 1a). More prominent motor nerve conduction abnormalities were found; lower limbs were more affected. In 64% with normal conduction, myography showed signs of axonal loss. Magnetic resonance imaging showed cervical myelopathy in 58% involving generally five to six segments. Conclusions: Nitrous oxide (N2O) leads to neurological symptoms by causing PNP and/or SCD primarily involving the legs. Distinguishing PNP and SCD clinically was shown to be insufficient. Electrodiagnostic studies showed axonal PNP. Demyelinating PNP due to N2O abuse was not present in our cohort. Therefore, further diagnostic work‐up is warranted if demyelinating features are present. [ABSTRACT FROM AUTHOR]

A simple and rapid HPLC‐MS/MS analytical method was developed and validated for the determination of methylmalonic acid (MMA) in human serum without a derivatization step. Serum samples (200 μl) were pretreated using a simple method based on ultrafiltration using a VIVASPIN 500 ultrafiltration column. Chromatographic separation was achieved on a Luna Omega C18 column with a PS C18 precolumn guard by gradient elution using 0.1% (v/v) formic acid in water (mobile phase A) and 0.5% (v/v) formic acid in acetonitrile (mobile phase B) at a flow rate of 0.2 ml min−1. The total run time of the analysis was 4.5 min. Negative electrospray ionization and multiple reaction monitoring mode were used. The lower limit of detection and lower limit of quantification for MMA were determined to be 13.6 and 42.3 nmol L−1, respectively. The developed method enabled the quantification of MMA in a wide linear range of 42.3–4230 nmol L−1 with a correlation coefficient of 0.9991. [ABSTRACT FROM AUTHOR]

Background: Low serum cobalamin concentrations have been associated with ileal malabsorption in dogs with chronic enteropathy. Increased serum methylmalonic acid (MMA) concentrations indicate cobalamin deficiency on a cellular level. Few studies have evaluated serum cobalamin concentrations or methylmalonic acid concentrations in juvenile dogs with parvoviral enteritis or nonparvoviral acute enteropathies. Objectives: Evaluate serum cobalamin and methylmalonic acid concentrations in juvenile dogs (6 weeks to 10 months old) with parvoviral enteritis or nonparvoviral acute enteropathy. Animals: Thirty‐one juvenile dogs with parvoviral enteritis, 29 dogs with nonparvoviral acute diarrhea (NPVAD), and 40 healthy juvenile control dogs. Methods: Single‐center, prospective, observational, cross‐sectional study. Serum cobalamin and, when sufficient serum was available, MMA concentrations were measured. Results: Most serum cobalamin concentrations were within the adult reference interval. Serum cobalamin concentrations in healthy dogs (median, 848 ng/L; range, 293‐1912 ng/L) were significantly higher than in dogs with parvoviral enteritis (P =.0002; median, 463 ng/L; range, <150‐10 000 ng/L) or dogs with NPVAD (P =.02; median, 528 ng/L; range, 160‐8998 ng/L). Serum MMA concentrations were not significantly different between groups (healthy dogs: median, 796 nmol/L; range, 427‐1933 nmol/L; parvoviral enteritis: median, 858 nmol/L; range, 554‐3424 nmol/L; NPVAD: median, 764 nmol/L; range, 392‐1222 nmol/L; P =.1). Conclusions and Clinical Importance: Juvenile dogs with parvoviral enteritis or NPVAD had lower serum cobalamin concentrations than healthy juvenile dogs. However, based on serum MMA concentrations cellular cobalamin deficiency was not apparent. [ABSTRACT FROM AUTHOR]

Background: Elevated plasma methylmalonic acid (MMA) is reported in patients with established coronary heart disease (CHD) and is considered a marker of vitamin B12 deficiency. Moreover, MMA‐dependent reactions have been linked to alterations in mitochondrial energy metabolism and oxidative stress, key features in the pathophysiology of cardiovascular diseases (CVDs). Objectives: We examined whether plasma MMA prospectively predicted the long‐term risk of acute myocardial infarction (AMI) and mortality. Methods and results: Using Cox modeling, we estimated hazard ratios (HRs) for endpoints according to per 1‐SD increment of log‐transformed plasma MMA in two independent populations: the Western Norway Coronary Angiography Cohort (WECAC) (patients evaluated for CHD; n = 4137) and the Norwegian Vitamin Trial (NORVIT) (patients hospitalized with AMI; n = 3525). In WECAC and NORVIT, 12.8% and 18.0% experienced an AMI, whereas 21.8% and 19.9% died, of whom 45.5% and 60.3% from CVD‐related causes during follow‐up (range 3–11 years), respectively. In WECAC, age‐ and gender‐adjusted HRs (95% confidence interval) were 1.18 (1.09–1.28), 1.25 (1.18–1.33), and 1.28 (1.17–1.40) for future AMI, total mortality, and CVD mortality, respectively. Corresponding risk estimates were 1.19 (1.10–1.28), 1.22 (1.14–1.31), and 1.30 (1.19–1.42) in NORVIT. These estimates were only slightly attenuated after multivariable adjustments. Across both cohorts, the MMA‐risk association was stronger in older adults, women, and non‐smokers. Conclusions: Elevated MMA was associated with an increased risk of AMI and mortality in patients with suspected or verified CHD. [ABSTRACT FROM AUTHOR]

Background: Methylmalonic acid (MMA) is linked to progression and aggressiveness of tumours. A recent study showed that high levels of circulatory MMA directed genetic programs promoting cancer progression. Purpose: To evaluate in vivo two‐dimensional correlated spectroscopy (2D COSY) data from women at elevated risk of breast cancer to determine if resonances consistent with MMA are present, and if so to correlate levels with breast density, menopausal status and risk categories. Materials and methods: With institutional review board approval, 106 women at elevated risk (mean age 47), including 46 participants at medium risk, 43 at high risk with no known mutation and 17 BRCA‐mutation carriers, were recruited. Breast density was assessed using a T2 sequence. A T1 sequence was used to place the voxel for the 2D COSY data. Peak volumes were normalized to the methylene peak at (1.30, 1.30) ppm. Chi‐squared and Mann–Whitney tests were used. Results: Two resonances are assigned on the diagonal at 3.15 ppm and 3.19 ppm consistent with and denoted MMA1 and MMA2 respectively. MMA1 and MMA2 increased in parallel with increased risk. BRCA‐mutation carriers recorded an increase in mean MMA1 of 120% (p = 0.033) and MMA2 of 127% (p = 0.020) in comparison with participants with no known mutation. BRCA‐mutation carriers with dense breasts recorded a significant increase in mean MMA1 of 137% (p = 0.002) and in mean MMA2 of 143% (p = 0.004) compared with BRCA‐mutation participants with low‐density breast tissue. MMA1 and MMA2 were higher in premenopausal women with dense breasts compared with those with low‐density tissue. The highest values of MMA were recorded in BRCA‐mutation carriers. Conclusion: Two tentative assignments are made for MMA in breast tissue of women at elevated risk for cancer. BRCA‐mutation carriers exhibited higher values of MMA than those with no known mutation. Premenopausal women with BRCA mutation and dense breasts recorded the highest levels of MMA compared with other categories. [ABSTRACT FROM AUTHOR]

Aim: Risk factors for vitamin B12 deficiency in infants are not fully understood. The aim of the study was to assess predictors of total homocysteine and methylmalonic acid analysed in newborn screening dried blood spots. Methods: In a Norwegian case control study, we analysed total homocysteine and methylmalonic acid in newborn screening dried blood spots of 86 infants clinically diagnosed with vitamin B12 deficiency during 2012–2018. Results were compared to 252 healthy infants and 400 dried blood spot controls. Medical records were reviewed, and mothers completed questionnaires. Results: Both total homocysteine and methylmalonic acid were significantly higher on newborn screening dried blood spots in infants later clinically diagnosed with vitamin B12 deficiency than controls. Multiple regression analysis showed that the dose of nitrous oxide during labour was the strongest predictor for total homocysteine level in newborn screening dried blood spots for all infants, with larger effect in infants later clinically diagnosed with vitamin B12 deficiency than controls. Conclusion: Nitrous oxide dose during labour was a predictor for total homocysteine and may impact the interpretation of total homocysteine analysis in newborn screening. Nitrous oxide is suggested as a contributing risk factor for infants prone to develop vitamin B12 deficiency. [ABSTRACT FROM AUTHOR]

Background: Recent studies have shown similar efficacy of oral supplementation of cobalamin compared to injectable supplementation in dogs, but few prospective, randomized studies have been published. Objectives: To evaluate efficacy of oral or injectable supplementation with cobalamin in normalizing serum cobalamin and methylmalonic acid (MMA) concentrations in dogs with hypocobalaminemia caused by either chronic enteropathy (CE) or exocrine pancreatic insufficiency (EPI). Animals: Forty‐six client owned dogs with hypocobalaminemia. Methods: Prospective randomized clinical trial. Dogs were divided into 2 groups (CE or EPI), and randomized to receive oral or injectable supplementation of cobalamin. Each dog had 3 visits and serum cobalamin and MMA concentrations were measured at each visit. Results: In dogs with CE, serum cobalamin concentrations increased with oral (P =.02; median 149 [range 149‐231] to 733 [166‐1467] ng/L, median difference 552 [95% CI: 181‐899] ng/L) or injectable (P <.01; 168 [149‐233] to 563 [234‐965] ng/L, 367 [187‐623] ng/L) supplementation. In dogs with EPI, serum cobalamin concentrations increased with oral (P =.01; 162 [149‐214] to 919 [643‐3863] ng/L, 705 [503‐3356] ng/L) or injectable (P =.01; 177 [149‐217] to 390 [243‐907] ng/L, 192 [89‐361] ng/L) supplementation. Serum MMA concentrations decreased with oral or injectable supplementation in dogs with CE, but only with oral supplementation in dogs with EPI. Conclusions and Clinical Importance: Oral supplementation is an alternative for cobalamin supplementation in dogs with hypocobalaminemia caused by CE or EPI. [ABSTRACT FROM AUTHOR]

Background: To summarize the relationship between different MMUT gene mutations and the response to vitamin B12 in MMA. Methods: This was a retrospective study of patients diagnosed with mut‐type MMA. All patients with mut‐type MMA were tested for responsiveness to vitamin B12. Results: There were 81, 27, and 158 patients in the completely responsive, partially responsive, and nonresponsive groups, respectively, and the proportions of symptom occurrence were 30/81 (37.0%), 21/27 (77.8%), and 131/158 (82.9%), respectively (p <.001). The median levels of posttreatment propionyl carnitine (C3), C3/acetyl carnitine (C2) ratio in the blood, and methylmalonic acid in the urine were all lower than pretreatment, and the median level of C3/C2 ratio in the completely responsive group was within the normal range. In 266 patients, 144 different mutations in the MMUT gene were identified. Patients with the mutations of c.1663G>A, c.2080C>T, c.1880A>G, c.1208G>A, etc. were completely responsive and with the mutations of c.1741C>T, c.1630_1631GG>TA, c.599T>C, etc. were partially responsive. The proportions of healthy/developmental delay outcomes in the three groups were 63.0%/23.5%, 33.3%/40.7%, and 13.3%/60.1%, respectively (p <.001). Conclusion: Different mutations in the MMUT gene are associated with the effect of vitamin B12 treatment. [ABSTRACT FROM AUTHOR]

Hydroxycobolamine supplementation in hereditary cobolamine deficiency and serial biochemical follow-up allow uncomplicated pregnancy outcome. [ABSTRACT FROM AUTHOR]

Background: Peripheral neuropathy (PN) is common in patients with diseases that are in turn associated with deficiency of the B‐vitamins, and vitamin treatment has shown mixed results. Methods: This systematic review and meta‐analysis studied the association between PN/pain and B‐vitamin biomarkers and investigated whether vitamin treatment can ameliorate the symptoms. PubMed and Web of Science were searched according to the study protocol. Results: A total of 46 observational and seven interventional studies were identified and included in the data synthesis. The presence of PN was associated with lowered B12 levels (pooled estimate [95% CIs] = 1.51 [1.23–1.84], n = 34, Cochran Q Test I2 = 43.3%, p = 0.003) and elevated methylmalonic acid (2.53 [1.39–4.60], n = 9, I2 = 63.8%, p = 0.005) and homocysteine (3.48 [2.01–6.04], n = 15, I2 = 70.6%, p < 0.001). B12 treatment (vs. the comparators) showed a non‐significant association with symptom improvement (1.36 (0.66–2.79), n = 4, I2 = 28.9%). Treatment with B1 was associated with a significant improvement in symptoms (5.34 [1.87–15.19], n = 3, I2 = 64.6%, p = 0.059). Analysis of seven trials combined showed a non‐significant higher odds ratio for improvement under treatment with the B‐vitamins (2.58 [0.98–6.79], I2 = 80.0%, p < 0.001). Conclusions: PN is associated with lowered plasma vitamin B12 and elevated methylmalonic acid and homocysteine. Overall, interventional studies have suggested that B‐vitamins could improve symptoms of PN. Available trials have limitations and generally did not investigate vitamin status prior to treatment. Well‐designed studies, especially in non‐diabetes PN, are needed. This meta‐analysis is registered at PROSPERO (ID: CRD42020144917). [ABSTRACT FROM AUTHOR]

Cobalamin J disease (CblJ) is an ultra‐rare autosomal recessive disorder of intracellular cobalamin metabolism associated with combined methylmalonic acidemia and homocystinuria. It is caused by pathogenic variants in ABCD4, which encodes an ATP‐binding cassette (ABC) transporter that affects the lysosomal release of cobalamin (Cbl) into the cytoplasm. Only six cases of CblJ have been reported in the literature. Described clinical features include feeding difficulties, failure to thrive, hypotonia, seizures, developmental delay, and hematological abnormalities. Information on clinical outcomes is extremely limited, and no cases of presymptomatic diagnosis have been reported. We describe a now 17‐month‐old male with CblJ detected by newborn screening and confirmed by biochemical, molecular, and complementation studies. With early detection and initiation of treatment, this patient has remained asymptomatic with normal growth parameters and neurodevelopmental function. To the best of our knowledge, this report represents the first asymptomatic and neurotypical patient with CblJ. [ABSTRACT FROM AUTHOR]

Background: Iron deficiency and cobalamin deficiency, as sequelae to chronic gastrointestinal (GI) disease, could result in anemia and increased morbidity in cats with chronic enteropathies. Objective: To evaluate iron deficiency in cats with chronic GI disease and its relationship with hypocobalaminemia, anemia, and disease severity. Animals Twenty client‐owned cats with primary GI disease. Methods: Prospective, cross‐sectional study. Cats were enrolled at the time of evaluation for chronic GI disease, after exclusion of comorbidities. CBC with reticulocyte indices, iron metabolism (serum iron and ferritin concentrations, total iron binding capacity [TIBC]), serum methylmalonic acid (MMA), cobalamin, and folate concentrations, pancreatic lipase and trypsin‐like immunoreactivity, and disease severity were evaluated. Results: Anemia (hematocrit <30%), iron deficiency, and cobalamin deficiency were diagnosed in 4/20, 7/20, and 8/20 cats, respectively. Hematocrit (rs = −.45; P <.05) and body condition score (rs = −.60; P <.01) negatively correlated with MMA. Median TIBC was lower in cats with increased vs normal MMA (218 μg/mL; range, 120‐466 μg/mL vs 288 μg/mL; range, 195‐369 μg/mL; P =.02). Hematocrit (rs =.51; P =.02), reticulocyte MCV (rs =.52; P =.02), reticulocyte hemoglobin content (rs =.71; P <.001), and percent transferrin saturation (rs =.79; P <.0001) positively correlated with serum iron concentration. Conclusions and Clinical Importance: Functional iron deficiency was common in cats with chronic GI disease. Associations between hypocobalaminemia, iron parameters, and hematologic parameters warrant further investigation on the impact of iron deficiency on chronic GI disease morbidity in cats. [ABSTRACT FROM AUTHOR]

Background: Migraine, especially migraine with aura (MA), has been linked to increased risk for ischemic cerebrovascular disease. The possible role of elevated serum homocysteine (Hcy, a cause of thrombophilia) in migraine has been demonstrated by several studies. Objective: The present study aims to review and meta‐analyze data from studies investigating the difference of serum Hcy and Hcy lowering vitamins between migraine patients and healthy controls (HC), as well as between patients with MA and migraine without aura (MO). Methods: Literature search involved MEDLINE, Embase, CENTRAL, Google Scholar, and trial registries. The Newcastle‐Ottawa Scale was used to evaluate the quality of the retrieved studies. Standardized mean differences (SMDs) and 95% confidence intervals (95%CIs) were calculated. Funnel‐plots were utilized for the evaluation of publication bias. Results: Overall, 29 (28 case‐control and 1 cross‐sectional) studies were retrieved. Meta‐analysis was indicative of higher Hcy concentration in migraine patients vs HC overall [adults and children: 16 studies, I2 = 81%, SMD = 0.41, 95%CI = (0.20, 0.61)]. Hcy was consistently elevated in adults with migraine [adults: 12 studies, I2 = 76%, SMD = 0.35, 95%CI = (0.15, 0.54); children: 1 study, SMD = 0.37, 95%CI = (−0.05, 0.79)]. Subgroup analyses reproduced the results for both adults with MA [7 studies, I2 = 83%, SMD = 0.37, 95%CI = (0.03, 0.71)] and MO [5 studies, I2 = 84%, SMD = 0.46, 95%CI = (0.03, 0.89)]. Figures for serum folate were lower in the overall comparison of migraine patients with HC [adults and children: 11 studies, I2 = 87%, SMD = −0.36, 95%CI = (−0.68, −0.05); adults: 8 studies, I2 = 6%, SMD = −0.11, 95%CI = (−0.22, 0.01); children: 1 study, SMD = −0.71, 95%CI = (−1.14, −0.29); MA adults: 4 studies, I2 = 44%, SMD = −0.16, 95%CI = (−0.35, 0.04); MO adults: 4 studies, I2 = 47%, SMD = −0.17, 95%CI = (−0.44, 0.10)]. Serum vitamin B12 levels were not different between migraine patients and HC [adults and children: 11 studies, I2 = 88%, SMD = −0.24, 95%CI = (−0.57, 0.09); adults: 8 studies, I2 = 57%, SMD = −0.10, 95%CI = (−0.28, 0.08); children: 1 study, SMD = 0.29, 95%CI = (−0.13, 0.71); MA adults: 4 studies, I2 = 63%, SMD = −0.14, 95%CI = (−0.48, 0.20); MO adults: 4 studies, I2 = 59%, SMD = −0.15, 95%CI = (−0.45, 0.15)]. Serum Hcy was lower in MO than MA [adults and children: 10 studies, I2 = 39%, SMD = 0.30, 95%CI = (0.14, 0.46), adults: 6 studies, I2 = 29%, SMD = 0.21, 95%CI = (0.09, 0.36), children: 1 study, SMD = 0.51, 95%CI = (0.22, 0.80)]. Serum folate and vitamin B12 did not differ between MA and MO. Conclusions: Our results suggest that there is a possible link between migraine, mainly MA, and elevated serum Hcy. [ABSTRACT FROM AUTHOR]

Background: Measurement of vitamin B12 (B12) levels is routinely used to monitor B12 sufficiency. However, its accuracy may not be reliable in patients with short‐bowel syndrome (SBS). The presence of elevated methylmalonic acid (MMA) levels can also be used as a marker for B12 deficiency. Therefore, our aim was to analyze serum B12 and MMA levels simultaneously in a cohort of children with SBS to evaluate the accuracy of these markers in the assessment of B12 status. Methods: Children ages 1–18 with intestinal failure were eligible for enrollment. MMA and B12 levels were checked simultaneously in all patients, with 93 sets of labs obtained over 2 years. Fifty percent of the patients were receiving parenteral nutrition. B12 injections were administered to 14 patients who had simultaneously elevated MMA and B12, and a repeat MMA level was measured 4–6 weeks after injection. Data were collected retrospectively. Results: Forty‐eight percent of the lab pairs showed evidence of both elevated MMA and high or normal B12, which contradicted the expected inverse relationship of these markers. There was a statistically significant decrease in mean MMA values after treatment with B12 injections (412.7 vs 1037.5, P = 0.001). Conclusion: Paradoxical elevation of MMA with normal or elevated serum B12 is common in children with SBS. Caution should be used when interpreting serum B12 and MMA values in this setting. This may be related to effects of small‐bowel bacterial overgrowth, a condition commonly seen in these patients. [ABSTRACT FROM AUTHOR]

Two isostructural CdII frameworks, [Cd2(MMA)2(bpy)(H2O)2]n (1) and [Cd2(MMA)2(bpe)(H2O)2]n (2), were synthesized solvothermally with hybrid flexible methylmalonic acid (H2MMA) and rigid 4,4'‐bipyridine (bpy) or trans‐1,2‐bis(4‐pyridyl)ethylene (bpe) as coligands. Single‐crystal X‐ray diffraction analyses reveal that complexes 1 and 2 display a three‐dimensional (3D) framework structure composed of 2D [Cd(MMA)] layer unit and bpy/bpe linker, and exhibit a (3,4)‐connected topological network with Schläfli symbol of {63}{65.8}. The solid‐state luminescent properties were studied, and 1 and 2 show a distinct emission centered at 465 and 531 nm, respectively. [ABSTRACT FROM AUTHOR]

Methylmalonic acidemia (MMA) is the most common organic acidemia in China. This study aimed to characterise the genotypic and phenotypic variabilities, and the molecular epidemiology of Chinese patients with isolated MMA. Patients (n = 301) with isolated MMA were diagnosed by clinical examination, biochemical assays, and genetic analysis. Fifty‐eight patients (19.3%) were detected by newborn screening and 243 patients (80.7%) were clinically diagnosed after onset. Clinical onset ranged from the age of 3 days to 23 years (mean age = 1.01 ± 0.15 years). Among 234 MMA patients whose detailed clinical data were available, 170 (72.6%) had early onset disease (before the age of 1 year), and 64 (27.4%) had late‐onset disease. The 234 MMA patients manifested with neuropsychiatric impairment (65.4%), haematological abnormality (31.6%), renal damage (8.5%), and metabolic crises (67.1%). Haematological abnormality was significantly more common in early‐onset patients than that in late‐onset patients. The incidence of metabolic crises was significantly high (P < 0.001) in patients with mut type than those with other types of isolated MMA. Variations (n = 122) were identified in MMUT, MMAA, MMAB, MMADHC, SUCLG1, and SUCLA2, of which 45 were novel. c.729_730insTT was the most frequent MMUT mutation, with a significantly higher frequency in our patients than that in 151 reported European patients. The frequency of c.914T>C in MMUT in our cohort was also higher than that in 151 European patients. MMUT mutations c.729_730insTT and c.914T>C are specific for the Chinese population. Our study expanded the spectrum of phenotypes and genotypes in isolated MMA. [ABSTRACT FROM AUTHOR]

Disorders of cobalamin (vitamin B12) metabolism are increasingly recognized in small animal medicine and have a variety of causes ranging from chronic gastrointestinal disease to hereditary defects in cobalamin metabolism. Measurement of serum cobalamin concentration, often in combination with serum folate concentration, is routinely performed as a diagnostic test in clinical practice. While the detection of hypocobalaminemia has therapeutic implications, interpretation of cobalamin status in dogs can be challenging. The aim of this review is to define hypocobalaminemia and cobalamin deficiency, normocobalaminemia, and hypercobalaminemia in dogs, describe known cobalamin deficiency states, breed predispositions in dogs, discuss the different biomarkers of importance for evaluating cobalamin status in dogs, and discuss the management of dogs with hypocobalaminemia. [ABSTRACT FROM AUTHOR]

Background: Although the exact pathophysiological mechanistic pathways that result in the initiation of migraine attacks remain unclear, there are some proposed mechanisms including neurogenic inflammation, trigeminovascular system activation, vascular dysfunction, and augmented release of nitric oxide (NO) and homocysteine (Hcy). Vitamin B12 is thought to be involved in important pathways that seem to be related to the pathogenesis of migraine including scavenging against NO and prevention of hyperhomocysteinemia. Therefore, the aim of the current study was to evaluate the serum vitamin B12 and methylmalonic acid (MMA) status in a group of migraine patients compared to healthy controls. Methods: After the recruitment of cases and controls, demographic data and migraine characteristics (including the number of headache days, severity of headaches, and duration of each attack in hours) were recorded. Serum vitamin B12 and MMA levels were measured using the enzyme‐linked immunosorbent assay technique. Results: Seventy migraine patients and 70 healthy subjects were enrolled in this case control study. The serum levels of B12 were found to be significantly lower in migraine patients than in healthy subjects (512 ± 300 vs 667 ± 351 pg/mL, P =.007); whereas migraineurs had higher levels of MMA than controls (1.39 [0.59,4.01] vs 1.01 [0.49,1.45] µg/dL, P =.027). In the fully adjusted multiple regression model, those in the highest vs the lowest serum B12 quartile had 80% decrease in the odds of having migraine ([OR = 0.20, 95% CI = 0.05‐0.73], [P for trend =.008]); while, patients in the highest quartile of MMA had more than 5 times increased risk of having migraine ([OR = 5.44, 95% CI = 1.49‐19.87] [P for trend =.002]). There was no association between serum B12 and MMA levels and headache characteristics. Conclusion: Taken together, these findings suggest that participants with lower vitamin B12 and higher MMA levels that considered as lower functional activity of B12 had higher odds of migraine. [ABSTRACT FROM AUTHOR]

Background: Efficacy of PO cobalamin (Cbl) supplementation in dogs with hereditary Cbl malabsorption (Imerslund‐Gräsbeck syndrome, IGS) is unknown. Objectives: To evaluate PO Cbl supplementation in Beagles with IGS previously treated parenterally. We hypothesized that 1 mg cyano‐Cbl daily PO would maintain clinical and metabolic remission. Animals: Three client‐owned Beagles with IGS and 48 healthy control dogs. Methods: Prospective study. Daily PO cyanocobalamin (cyano‐Cbl; 1 mg) supplementation was monitored for 13 (2 dogs) and 8 months (1 dog). Health status was assessed by owner observations. Methylmalonic acid (MMA)‐to‐creatinine concentrations were measured using an ultra‐performance liquid chromatography‐tandem mass spectrometry (UPLC‐TMS) method on urine samples collected monthly. Concurrent measurements of serum MMA concentration (n = 7; UPLC‐TMS) were available for 1 dog. Results: All dogs remained in excellent health during PO supplementation. Urine MMA remained consistently low in 2 dogs (median, 2.5 mmol/mol creatinine; range, 1.2‐9; healthy dogs [n = 30], median, 2.9 mmol/mol creatinine; range, 1.3‐76.5). Urine MMA ranged from 38.9‐84.9 mmol/mol creatinine during the first 6 months in 1 dog already known to excrete comparable amounts when supplemented parenterally. Brief antibiotic treatment for an unrelated condition after 6 months resulted in low urine MMA (median, 2.8 mmol/mol creatinine; range, 1.9‐4.8) for the next 7 months. All concurrent serum MMA concentrations (median, 651 nmol/L; range, 399‐919) before and after month 6 were within the established reference interval (393‐1476 nmol/L; n = 48). Conclusions and Clinical Importance: One milligram of cyano‐Cbl daily PO appears efficacious for maintaining normal clinical status and normal cellular markers of Cbl metabolism in Beagles with IGS. [ABSTRACT FROM AUTHOR]

Background: Prospective studies on maintenance treatment for Beagles with hereditary selective cobalamin (Cbl) malabsorption (Imerslund-Gräsbeck syndrome, IGS) are lacking. In our experience, measurement of methylmalonic acid (MMA), a Cbl-dependent metabolite, seems more helpful to monitor Cbl status as compared with serum Cbl concentrations. Objectives: To evaluate a standardized Cbl supplementation scheme in Beagles with IGS. We hypothesized that a single parenteral dose of 1 mg hydroxocobalamin (OH-Cbl) would maintain clinical and metabolic remission for up to 2 months. Animals: Six client-owned juvenile Beagles with genetically confirmed IGS and 28 healthy control dogs. Methods: Prospective study. Monthly IM OH-Cbl (1 mg) supplementation was done over a median of 9 months (range, 6-13) in 6 dogs, followed by bimonthly (every 2 months) injections in 5 dogs over a median of 6 months (range, 3-10). Health status was assessed by routine clinical examinations at injection time points and owner observations. Voided urine samples were collected immediately before OH-Cbl injections for measurement of MMA-to-creatinine concentrations using a gas-liquid chromatography-tandem mass spectrometry (GC-MS) method. Results: All dogs were clinically healthy while receiving monthly and bimonthly OH-Cbl supplementation. Urinary MMA results in healthy dogs ranged from 1.3 to 76.5 mmol/mol creatinine (median, 2.9). Median urinary MMA concentrations did not differ between dogs with IGS receiving monthly (n=49; 5.3 mmol/mol creatinine; range, 2.3-50.4) and bimonthly (n=31; 5.3 mmol/mol creatinine; range, 1.6-50) injections. Conclusions and Clinical Importance: A maintenance parenteral dose of 1 mg OH-Cbl monthly or bimonthly appears adequate in Beagles with IGS monitored by metabolic testing [ABSTRACT FROM AUTHOR]

Abstract: Background: Physical frailty and loss of mobility in elderly individuals lead to reduced independence, quality of life, and increased mortality. Vitamin B12 deficiency has been linked to several age‐related chronic diseases, including in the musculo‐skeletal system, where vitamin B12 deficiency is generally believed to be linked to poor nutritional intake. In the present study, we asked whether aging and frailty associate with altered vitamin B12 homeostasis in humans and investigated the underlying molecular mechanisms using preclinical models. Methods: We analysed a subset of the Singapore Longitudinal Aging Study and stratified 238 participants based on age and Fried frailty criteria. Levels of methyl‐malonic acid (MMA), a marker for vitamin B12 deficiency, and amnionless, the vitamin B12 co‐receptor that anchors the vitamin B12 transport complex to the membrane of epithelial cells, were measured in plasma. In addition, vitamin B12 levels and the molecular mechanisms of vitamin B12 uptake and excretion were analysed in ileum, kidney, liver, and blood using a rat model of natural aging where nutritional intake is fully controlled. Results: We demonstrate that aging and frailty are associated with a higher prevalence of functional vitamin B12 deficiency that can be detected by increased levels of MMA in blood (ρ = 0.25; P = 0.00013). The decline in circulating vitamin B12 levels is recapitulated in a rat model of natural aging where food composition and intake are stable. At the molecular level, these perturbations involve altered expression of amnionless in the ileum and kidney. Interestingly, we demonstrate that amnionless can be detected in serum where its levels increase during aging in both rodents and human (P = 3.3e‐07 and 9.2e‐07, respectively). Blood amnionless levels negatively correlate with vitamin B12 in rats (r2 = 0.305; P = 0.0042) and positively correlate with the vitamin B12 deficiency marker MMA in humans (ρ = 0.22; P = 0.00068). Conclusions: Our results demonstrate that aging and frailty cause intrinsic vitamin B12 deficiencies, which can occur independently of nutritional intake. Mechanistically, vitamin B12 deficiency involves the physio‐pathological decline of both the intestinal uptake and the renal reabsorption system for vitamin B12. Finally, amnionless is a novel biomarker which can detect perturbed vitamin B12 bioavailability during aging and physical frailty. [ABSTRACT FROM AUTHOR]

Purpose To describe the retinal structure of a group of patients affected by methylmalonic aciduria with homocystinuria cblC type, caused by mutations in the MMACHC gene, using spectral domain optical coherence tomography ( SD- OCT). Methods Young patients ( n = 11, age 0-74 months) with cblC disease, detected by newborn screening or clinically diagnosed within 40 days of life, underwent molecular analysis and complete ophthalmic examination, including fundus photography and SD- OCT. In one case, we also performed fluorescein angiography (FA) and standard electroretinography ( ERG). Results Molecular analysis of the MMACHC gene fully confirmed cblC disease in nine of 11 patients. Two patients harboured only a single heterozygous pathogenic MMACHC mutation and large unbalanced rearrangements were excluded by array- CGH analysis in both. All patients except two showed a bilateral maculopathy. In general, retinal changes were first observed before one year of age and progressed to a well-established maculopathy. Measurable visual acuities ranged from normal vision, in keeping with age, to bilateral, severe impairment of central vision. Nystagmus was present in six patients. Spectral domain optical coherence tomography (SD-OCT) showed macular thinning with severe alterations in outer, and partial sparing of inner, retinal layers. Conclusion Patients affected by cblC disease may frequently show an early onset maculopathy with variable ophthalmoscopic appearance. Spectral domain optical coherence tomography (SD-OCT) broadens the knowledge of subtle retinal alterations during the disease's progression and helps to shed light on the pathological mechanism of maculopathy development. [ABSTRACT FROM AUTHOR]

Methylmalonic acidemia (MMA) is an autosomal recessive disorder that can be classified into two types: (1) vitamin B12-responsive and (2) vitamin B12-non-responsive. In MMA cases with long-term survival, renal failure is often a problem, and timing for kidney transplantation for MMA is controversial. We encountered a vitamin B12-non-responsive MMA case for which regular hemodialysis for renal failure was initiated; the patient was 16 years old when she first received regular hemodialysis and 35 years old when she developed pulmonary artery hypertension (PAH). PAH can complicate regular hemodialysis; however, PAH in this case was considered to be a complication of MMA because it was responsive to medical treatment and reversible. In this report, we discuss the role of regular hemodialysis in MMA and the causal relationship between MMA and regular hemodialysis for PAH. [ABSTRACT FROM AUTHOR]

Mononuclear {Cu(Me2mal)2}2- dianion has been used as a building block for the synthesis of six new coordination polymers: {Li2(H2O)2(µ-H2O)[Cu(µ4-Me2mal)(µ-Me2mal)]} n ( 1), {Na2(µ-EtOH)2[Cu(µ5-Me2mal)2]} n ( 2), {K8(µ-H2O)6[Cu(µ-H2O)(µ3-Me2mal)(µ6-Me2mal)]2[Cu2(µ5-Me2mal)4]} n ( 3), {K2M(H2O)5(µ-H2O)3[Cu(µ-Me2mal)(µ3-Me2mal)][Cu(µ-H2O)(µ-Me2mal)(µ3-Me2mal)]} n (M = MgII ( 4) or NiII ( 5); isostructural compounds), and {K4Co3(H2O)8(µ-H2O)4(µ3-OH)2[Cu(H2O)(µ-Me2mal)(µ3-Me2mal)]2[Cu(µ-H2O)(µ3-Me2mal)2]2} n ( 6). It was shown that the structures of the compounds depend on the nature and ionic radius of the heterometal. In particular, the dimensionality of the complexes increases from 1D to 2D and 3D with increasing radius of the s-metal in compounds 1, 2, and 3, respectively. Partial replacement of K+ in 3 by Mg2+, Ni2+, or Co2+ leads to the formation of heterometallic coordination polymers 4 and 5, with 2D structure, and 3D complex 6. The compounds were characterized by single-crystal X-ray diffraction and EPR spectroscopy, and the magnetic properties of compounds 1, 2, and 4- 6 were also studied. Further, the topological analysis of the structures and another 794 known mal-derivatives complexes from Cambridge Structural Database (CSD, version 5.36) was performed. The main regularities determining the coordination modes of ligands and metal cations in relation to structure topology have been established and are discussed. [ABSTRACT FROM AUTHOR]

Specific mitochondrial enzymatic deficiencies in the catabolism of branched-chain amino acids cause methylmalonic aciduria ( MMA), propionic acidemia ( PA) and maple syrup urine disease ( MSUD). Disease-causing mutations were identified in nine unrelated branched-chain organic acidurias (BCOA) patients. We detected eight previously described mutations: p. Asn219Tyr, p. Arg369His p. Val553Glyfs*17 in MUT, p. Thr198Serfs*6 in MMAA, p.Ile144_Leu181del in PCCB, p. Gly288Valfs*11, p. Tyr438Asn in BCKDHA and p. Ala137Val in BCKDHB gene. Interestingly, we identified seven novel genetic variants: p. Leu549Pro, p.Glu564*, p. Leu641Pro in MUT, p. Tyr206Cys in PCCB, p. His194Arg, p. Val298Met in BCKDHA and p.Glu286_Met290del in BCKDHB gene. In silico and/or eukaryotic expression studies confirmed pathogenic effect of all novel genetic variants. Aberrant enzymes p. Leu549Pro MUT, p. Leu641Pro MUT and p. Tyr206Cys PCCB did not show residual activity in activity assays. In addition, activity of MUT enzymes was not rescued in the presence of vitamin B12 precursor in vitro which was in accordance with non-responsiveness or partial responsiveness of patients to vitamin B12 therapy. Our study brings the first molecular genetic data and detailed phenotypic characteristics for MMA, PA and MSUD patients for Serbia and the whole South-Eastern European region. Therefore, our study contributes to the better understanding of molecular landscape of BCOA in Europe and to general knowledge on genotype-phenotype correlation for these rare diseases. [ABSTRACT FROM AUTHOR]

Methymalonic acidemia ( MMA) is a hereditary metabolic disorder characterized by a defect of the methylmalonyl-CoA mutase that breaks down propionate. The efficacy of liver transplantation for MMA was recently reported. However, the anesthetic management of liver transplant for MMA is not clear. The aim of this article is to describe an anesthetic management algorithm of liver transplant for MMA by reviewing our cases of liver transplant for MMA. Fourteen patients received a liver transplant; three cases showed metabolic decompensation during the transplant and two of the patients died. In the two patients who expired, propofol was used for maintenance anesthesia and preoperative continuous hemodiafiltration was used to reduce plasma methylmalonic acid level in one case, and to control severe metabolic decompensation before transplant for the other case. Their renal function was also worse than others and they were already experiencing metabolic decompensation before induction of anesthesia. Based on our experience of these 14 cases, we have established an anesthetic algorithm for patients with MMA undergoing liver transplant or other procedures. There are three important points in our experience: propofol should be avoided, dextrose infusion therapy should be continued to prevent metabolic decompensation, and liver transplant or other procedures should be avoided during metabolic decompensation. [ABSTRACT FROM AUTHOR]

Introduction This study aimed to investigate the utility of methylmalonic acid ( MMA) and neutrophil Cell Population Data, available on the Beckman Coulter LH750 Analyser (Miami, FL, USA), in laboratory assessment of cobalamin status in patients at risk of cobalamin deficiency, without macrocytosis and inflammation. Methods The study group included 189 patients. Neutrophil Cell Population Data along with vitamin B12 and homocysteine were assessed in regard to MMA tertile groups. Results Statistically significant differences were between lower and upper MMA tertile in serum B12 ( P ˂ 0.001), homocysteine ( P = 0.001) and neutrophil morphometric index, NeS- DW ( P = 0.029). Also, serum B12 concentrations were significantly different between lower and middle MMA tertile, P = 0.005. Receiver operating characteristic analysis of NeS- DW ability to detect MMA˃367 nmol/L revealed a significant area under the curve AUC = 0.761 P ˂ 0.001 95% CI 0.693-0.830. Optimal cut-off value was NeS- DW˃3.51% with sensitivity of 74.19% and specificity of 68.87%. Conclusion In patients at risk of cobalamin deficiency and normal MCV, classification according to MMA revealed cobalamin status differences. Neutrophil morphometric index may be an indicator of early changes in neutrophil nucleus morphology caused by impaired cobalamin status. [ABSTRACT FROM AUTHOR]

Accumulation of 2-methylcitric acid (2 MCA) is observed in methylmalonic and propionic acidemias, which are clinically characterized by severe neurological symptoms. The exact pathogenetic mechanisms of brain abnormalities in these diseases are poorly established and very little has been reported on the role of 2 MCA. In the present work we found that 2 MCA markedly inhibited ADP-stimulated and uncoupled respiration in mitochondria supported by glutamate, with a less significant inhibition in pyruvate plus malate respiring mitochondria. However, no alterations occurred when α-ketoglutarate or succinate was used as respiratory substrates, suggesting a defect on glutamate oxidative metabolism. It was also observed that 2 MCA decreased ATP formation in glutamate plus malate or pyruvate plus malate-supported mitochondria. Furthermore, 2 MCA inhibited glutamate dehydrogenase activity at concentrations as low as 0.5 mM. Kinetic studies revealed that this inhibitory effect was competitive in relation to glutamate. In contrast, assays of osmotic swelling in non-respiring mitochondria suggested that 2 MCA did not significantly impair mitochondrial glutamate transport. Finally, 2 MCA provoked a significant decrease in mitochondrial membrane potential and induced swelling in Ca2+-loaded mitochondria supported by different substrates. These effects were totally prevented by cyclosporine A plus ADP or ruthenium red, indicating induction of mitochondrial permeability transition. Taken together, our data strongly indicate that 2 MCA behaves as a potent inhibitor of glutamate oxidation by inhibiting glutamate dehydrogenase activity and as a permeability transition inducer, disturbing mitochondrial energy homeostasis. We presume that 2 MCA-induced mitochondrial deleterious effects may contribute to the pathogenesis of brain damage in patients affected by methylmalonic and propionic acidemias. [ABSTRACT FROM AUTHOR]

Background Hyperthyroidism, the most common endocrine disorder in cats, has been associated with low serum cobalamin concentrations. Whether this is a functional cobalamin deficiency of clinical importance has not been assessed. Hypothesis/Objectives Cats with hyperthyroidism experience a functional cobalamin deficiency which correlates with their clinical catabolic state and is reversible with return of the euthyroid state. Animals Thirty-nine client-owned hyperthyroid cats. Methods Prospective observational study. Serum cobalamin, methylmalonic acid, and clinical scores were determined in each hyperthyroid cat at enrollment and when euthyroid (60 days after radioiodine treatment). Results Five of the 39 hyperthyroid cats (13%) had a low serum cobalamin concentration ranging from <150 to 290 ng/L. Serum cobalamin concentrations normalized to >350 ng/L in 2 of the hypocobalaminemic cats once euthyroid. None of the hyperthyroid/hypocobalaminemic cats had increased serum methylmalonic acid concentrations (175-601 nmol/L). In cats with clinical and biochemical hyperthyroidism, there was no correlation between serum cobalamin concentrations with total T4 concentration ( P = .12) or clinical scores including body weight ( P = .11) and BCS ( P = .54). Conclusions and Clinical Importance In this population of hyperthyroid cats, the prevalence of hypocobalaminemia was low. Specifically, hyperthyroid cats, in which concurrent gastrointestinal disease is unlikely. Hypocobalaminemia is not a functional deficiency requiring supplementation in hyperthyroid cats without gastrointestinal disease. [ABSTRACT FROM AUTHOR]

Background. Anaemia is a common complication of human immunodeficiency virus (HIV) infection. The aim of this study was to investigate the impact of HIV infection and zidovudine on red blood cells (RBC) parameters and urine methylmalonic acid (UMMA) levels in patients with HIV infection. Material and Methods. A cross-sectional study involving 114 subjects, 94 of which are HIV-infected nonanaemic and 20 HIV negative subjects (Cg) as control. Full blood count parameters and urine methylmalonic acid (UMMA) level of each subject were determined. Associations were determined by Chi-square test and logistic regression statistics where appropriate. Results. Subjects on zidovudine-based ART had mean MCV (93 fL) higher than that of control group (82.9 fL) and ART-naïve (85.9 fL) subjects and the highest mean RDW. Mean UMMA level, which reflects vitamin B12 level status, was high in all HIV-infected groups but was significantly higher in ART-naïve subjects than in ART-experienced subjects. Conclusion. Although non-zidovudine therapy may be associated with macrocytosis (MCV > 95 fL), zidovudine therapy and ART naivety may not. Suboptimal level of vitamin B12 as measured by high UMMA though highest in ART-naïve subjects was common in all HIV-infected subjects. [ABSTRACT FROM AUTHOR]

Methylmalonic aciduria ( MMA) is an inborn error of metabolism associated with many complications despite treatment. Chronic renal failure is the most common problem, and patients may eventually require kidney transplant. Therefore, it is worth investigating whether living donor kidney transplant offers a better option than deceased kidney donors; and the value of novel vascular risk biomarkers in the assessment of transplanted MMA patients. We report a case of a 26-year-old man with MMA, who progressed to end-stage renal disease and received kidney transplant from a heterozygous next-of-kin living donor at 20 years of age. Although post-transplant urinary levels of methylmalonic acid decreased, this reduction was lower than previously reported for deceased donors. No episodes of metabolic decompensation were observed after transplantation. During his clinical progress, vascular complications appeared; and finally, pancreatitis was the cause of death. After kidney transplant, we evaluated novel vascular risk factors, such as asymmetric dimethylarginine ( ADMA) and symmetric dimethylarginine ( SDMA), which were used as early biomarkers of progression and metabolic management for this transplanted patient. This case report illustrates the disadvantage of transplantation with an allograft from a heterozygous living donor, and the utility of vascular risk biomarkers in renal transplant assessment. [ABSTRACT FROM AUTHOR]

Methylmalonic aciduria ( MMA) cblB type is caused by mutations in the MMAB gene, which codes for the enzyme adenosine triphosphate ( ATP): cobalamin adenosyltransferase ( ATR). This study reports differences in the metabolic and disease outcomes of two pairs of siblings with MMA cblB type, respectively harbouring the novel changes p. His183Leu/p.Arg190dup ( P1 and P2) and the previously described mutations p. Ile96Thr/p.Ser174fs ( P3 and P4). Expression analysis showed p. His183Leu and p.Arg190dup to be destabilizing mutations. Both were associated with reduced ATR stability and a shorter half-life than wild-type ATR. Analysis of several parameters related to oxidative stress and mitochondrial function showed an increase in reactive oxygen species ( ROS) content, a decrease in mitochondrial respiration and changes in mitochondria morphology and structure in patient-derived fibroblasts compared to control cells. The impairment in energy production and the presence of oxidative stress and fission of the mitochondrial reticulum suggested mitochondrial dysfunction in cblB patients' fibroblasts. The recovery of mitochondrial function should be a goal in efforts to improve the clinical outcome of MMA cblB type. [ABSTRACT FROM AUTHOR]

Hutchinson-Gilford progeria syndrome is a rare genetic disorder characterized by premature aging of the skin, bones, heart, and blood vessels. We report a 6-year-old boy who was born at full term but presented with scleroderma-like appearance at 1 month of age and gradually developed clinical manifestations of progeria. He had characteristic facial features of prominent eyes, scalp, and leg veins; loss of scalp hair, eyebrows, and eyelashes; stunted growth; scleroderma-like changes of the skin; and a premature aged appearance. Metabolic investigations showed transient methylmalonic aciduria, and genetic testing of the peripheral blood identified the c.1824C>T heterozygous LMNA mutation. The present case is reported because of its rarity. [ABSTRACT FROM AUTHOR]

In this study, we showed that cyanocobalamin dodecylamine, a ribose 5′-carbamate derivative of cyanocobalamin, was absorbed and accumulated to significant levels by Caenorhabditis elegans and was not further metabolized. The levels of methylmalonic acid and homocysteine, which serve as indicators of cobalamin deficiency, were significantly increased in C. elegans treated with the dodecylamine derivative, indicating severe cobalamin deficiency. Kinetic studies show that the affinity of the cyanocobalamin dodecylamine derivative was greater for two cobalamin-dependent enzymes, methylmalonyl-CoA mutase and methionine synthase, compared with their respective coenzymes, suggesting that the dodecylamine derivative inactivated these enzymes. The dodecylamine derivative did not affect the levels of mRNAs encoding these enzymes or those of other proteins involved in intercellular cobalamin metabolism, including methylmalonyl-CoA mutase ( mmcm - 1 ), methylmalonic acidemia cobalamin A complementation group ( mmaa - 1 ), methylmalonic aciduria cblC type ( cblc - 1 ), and methionine synthase reductase ( mtrr - 1 ). In contrast, the level of the mRNAs encoding cob(I)alamin adenosyltransferase ( mmab - 1 ) was increased significantly and identical to that of cobalamin-deficient C. elegans . These results indicate that the cyanocobalamin-dodecylamine derivative acts as a potent inhibitor of cobalamin-dependent enzymes and induces severe cobalamin deficiency in C. elegans . [ABSTRACT FROM AUTHOR]

Background Increased serum concentrations of homocysteine ( HCY) and methylmalonic acid ( MMA), the 2 main cobalamin-dependent metabolites, as well as decreased serum albumin and canine alpha1-proteinase inhibitor (cα1- PI) concentrations have previously been described in hypocobalaminemic dogs with gastrointestinal disease. However, no studies have been conducted to evaluate potential relationships between these serum biomarkers. Objective The aim of this study was to evaluate the relationship between HCY and MMA, 2 cobalamin-dependent metabolites, and both serum albumin and cα1- PI concentrations in hypocobalaminemic dogs. Methods Serum samples from 285 dogs including 7 different breeds (Beagle, Boxer, Cocker Spaniel, German Shepherd, Labrador Retriever, Chinese Shar-Pei, and Yorkshire Terrier) with hypocobalaminemia were used. Serum HCY, MMA, albumin, and cα1- PI concentrations were determined. Results There was a significant correlation between serum HCY and albumin concentrations, as well as serum HCY and cα1- PI concentrations (ρ = 0.62 and ρ = 0.37, respectively; P < .0001). No correlations were observed between serum MMA and albumin concentrations, or cα1- PI concentrations (ρ = 0.01 and ρ = 0.08, respectively; P > .05). In addition, significant breed-specific correlations were observed between serum MMA and albumin concentrations in German Shepherds, and serum HCY and MMA concentrations in Chinese Shar-Peis with hypocobalaminemia. Conclusions This study shows a correlation between serum albumin and cα1- PI and HCY concentrations, but not with serum MMA concentration in dogs with hypocobalaminemia. In addition, significant breed-specific correlations were observed between serum MMA and albumin concentrations in German Shepherds, as well as serum HCY and MMA concentrations in Chinese Shar-Peis, emphasizing the unique metabolic interactions in those dog breeds affected by hypocobalaminemia. [ABSTRACT FROM AUTHOR]

of key recommendations The clinical picture is the most important factor in assessing the significance of test results assessing cobalamin status because there is no 'gold standard' test to define deficiency., Serum cobalamin currently remains the first-line test, with additional second-line plasma methylmalonic acid to help clarify uncertainties of underlying biochemical/functional deficiencies. Serum holotranscobalamin has the potential as a first-line test, but an indeterminate 'grey area' may still exist. Plasma homocysteine may be helpful as a second-line test, but is less specific than methylmalonic acid. The availability of these second-line tests is currently limited., Definitive cut-off points to define clinical and subclinical deficiency states are not possible, given the variety of methodologies used and technical issues, and local reference ranges should be established., In the presence of discordance between the test result and strong clinical features of deficiency, treatment should not be delayed to avoid neurological impairment., Treatment of cobalamin deficiency is recommended in line with the British National Formulary. Oral therapy may be suitable and acceptable provided appropriate doses are taken and compliance is not an issue., Serum folate offers equivalent diagnostic capability to red cell folate and is the first-line test of choice to assess folate status. [ABSTRACT FROM AUTHOR]

Methylmalonic acidemia (MMA) is an autosomal-recessive inborn metabolic disorder that results from a deficiency in methylmalonyl-coenzyme A mutase or its cofactor, adenosylcobalamin. Currently, neurological manifestations in MMA are thought to be associated with neural apoptosis. BCL2L11, which is a proapoptotic Bcl-2 family member, is resident in the outer mitochondrial membrane, where this protein acts as a central regulator of the intrinsic apoptotic cascade and mediates excitotoxic apoptosis. MicroRNAs (miRNAs) are a class of non-coding RNAs that function as endogenous triggers of the RNA interference pathway. Currently, little is known regarding the role of miRNA in MMA. In our previous study, we preliminarily found that the expression of miR-9 was significantly down-regulated in MMA patient plasma and sensitively changed after VitB12 treatment, which may act as a potential "competitor" of gas chromatography-mass spectrometry for the diagnosis of MMA. In the present study, we first confirmed that miR-9 inhibited BCL2L11 expression by directly targeting its 3'-untranslated region, and the up-regulation of miR-9 reduced neural apoptosis induced by methylmalonate via targeting BCL2L11. Taken together, our results suggested that miR-9 might act as a monitor of changes in MMA and might provide new insights into a therapeutic entry point for treating MMA. [ABSTRACT FROM AUTHOR]

The rising incidence of diabetes and its negative impact on quality of life highlights the urgent need to develop biomarkers of early nerve damage. Measurement of total vitamin B12 has some limitations. We want to determine the levels of urinary methylmalonic acid and its relationships with serum vitamin B12 and polyneuropathy. The 176 Chinese patients with Type 2 diabetes mellitus were divided into 3 groups according to the levels of vitamin B12. A gas chromatography mass spectrometric technique was used to determine blood methylmalonic acid and urinary methylmalonic acid. The diagnosis of distal diabetic polyneuropathy was based on the determination of bilateral limb sensory and motor nerve conduction velocity and amplitude with electromyogram. Multiple regression analysis revealed that urinary methylmalonic acid/creatinine, blood methylmalonic acid, and so forth were variables that influenced diabetic polyneuropathy significantly. Nerve sensory conduction velocity and nerve amplitude in the group of urinary methylmalonic acid/creatinine >3.5 mmol/mol decreased significantly. Superficial peroneal nerve sensory and motor conduction velocity and ulnar nerve compound motor active potential amplitude were inversely correlated with urinary methylmalonic acid/creatinine. Urinary methylmalonic acid correlates with serum vitamin B12 levels in person with diabetes and is a sensitive marker of early polyneuropathy. [ABSTRACT FROM AUTHOR]

Abstract: Vitamin B12 (B12) deficiency has been linked to developmental disorders, metabolic abnormalities, and neuropathy; however, the mechanisms involved remain poorly understood. Caenorhabditis elegans grown under B12-deficient conditions for five generations develop severe B12 deficiency associated with various phenotypes that include decreased egg-laying capacity (infertility), prolonged life cycle (growth retardation), and reduced lifespan. These phenotypes resemble the consequences of B12 deficiency in mammals, and can be induced in C. elegans in only 15 days. Thus, C. elegans is a suitable animal model for studying the biological processes induced by vitamin deficiency. [Copyright &y& Elsevier]

Background Serum cobalamin concentration [ CBL] suggests CBL deficiency in cats but serum methylmalonic acid concentration [ MMA] more accurately indicates CBL deficiency. Objective To examine the ability of [ CBL] to predict CBL deficiency defined by increased [ MMA], and relationships of [ CBL] and [ MMA] with select clinical and clinicopathological variables. Animals One hundred sixty-three client-owned cats with [ CBL] measurements, 114 cats with simultaneous [ MMA] measurements; 88 cats with medical information. Methods Prospectively collected [ CBL] and [ MMA] were compared using scatter plots, receiver operating characteristic and correlative analyses with historical [ CBL] thresholds and those identified in the study. [ CBL] and [ MMA] were compared retrospectively to specific clinical and clinicopathological variables. Results [ CBL] correlated negatively with [ MMA] (τ = −0.334, P < .0001). [ MMA] ≥ 1,343 nmol/L identified CBL deficiency. [ CBL] = 209 pg/mL optimized sensitivity (0.51), specificity (0.96), PPV (0.89), and NPV (0.74) for detecting [ MMA] ≥ 1,343 nmol/L. Prevalence of CBL deficiency was 42% (48/114) when defined by [ MMA] ≥ 1,343 nmol/L versus 23% (27/114) by [ CBL] ≤ 209 pg/mL. Unexpectedly, 23 and 45% of 48 cats with [ MMA] ≥ 1,343 nmol/L had [ CBL] > 900 pg/mL and 290 pg/mL (historical thresholds). [ CBL] correlated with mean corpuscular volume (τ = −0.199, P = .013) and [MMA] with hematocrit (τ = −0.28, P = .006). Conclusions and Clinical Importance Cobalamin deficiency ([ MMA] ≥ 1,343 nmol/L) occurred in 42% of cats and is predicted with high specificity by [ CBL] ≤ 209 pg/mL. CBL status correlates with microcytosis and anemia. Discordance between [ CBL] and [ MMA] cautions against relying on any single marker for determining CBL status. [ABSTRACT FROM AUTHOR]

The membrane receptor (TCbIR/CD320) for transcobalamin (TC)-bound cobalamin (Cbl) facilitates the cellular uptake of Cbl. A genetically modified mouse model involving ablation of the CD320 gene was generated to study the effects on cobalamin homeostasis. The nonlethal nature of this knockout and the lack of systemic cobalamin deficiency point to other mechanisms for cellular Cbl uptake in the mouse. However, severe cobalamin depletion in the central nervous system (CNS) after birth (P<0.01) indicates that TCbIR is the only receptor responsible for Cbl uptake in the CNS. Metabolic Cbl deficiency in the brain was evident from the increased methylmalonic acid (P< 0.01 - 0.04), homocysteine (P<0.01), cystathionine (P<0.01), and the decreased S-adenosylmethionine/S-adenosyl homocysteine ratio (P<0.01). The CNS pathology of Cbl deficiency seen in humans may not manifest in this mouse model; however, it does provide a model with which to evaluate metabolic pathways and genes affected. [ABSTRACT FROM AUTHOR]

Abstract: The influence of acute renal failure induced by gentamicin administration on the effects of MMA on mitochondrial respiratory chain complexes, citrate synthase, succinate dehydrogenase and creatine kinase activities in cerebral cortex and kidney of young rats were investigated. Animals received one intraperitoneal injection of saline or gentamicin (70mg/kg). One hour after, the animals received three consecutive subcutaneous injections of MMA (1.67μmol/g) or saline (11h interval between injections) and 60min after the last injection the animals were killed. Acute MMA administration decreased creatine kinase activity in both tissues and increased complexes I–III activity in cerebral cortex. Creatine kinase activity was also inhibited by gentamicin administration. Simultaneous administration of MMA and gentamicin increased the activities of citrate synthase in cerebral cortex and kidney and complexes II–III in cerebral cortex. The other enzyme activities in cerebral cortex and kidney of animals receiving MMA plus gentamicin did not significantly differ from those observed in animals receiving only MMA. Our present data is line with the hypothesis that MMA acts as a toxin in brain and kidney of rats and suggest that renal injury potentiates the toxicity of MMA on the Krebs cycle and respiratory chain in brain and peripheral tissues. [Copyright &y& Elsevier]

Objectives To determine whether high serum folate levels contribute to metabolite changes in elderly subjects with normal cobalamin levels. Design Case series. Setting Outpatient clinic at a university-based staff model health maintenance organization. Participants Two hundred thirty-three ambulatory individuals without diabetes mellitus with normal renal function and normal cobalamin levels evaluated for cobalamin deficiency. Measurements Cobalamin, serum folate, methylmalonic acid ( MMA), and homocysteine. Results Older individuals (≥60) with low-normal cobalamin levels (201-300 pg/mL) had higher MMA and lower homocysteine levels when serum folate levels were high (>20 ng/mL) than when serum folate levels were normal ( P < .02), but serum folate levels within the normal range were not a determinant of either metabolite. In younger subjects with low-normal cobalamin levels, high serum folate levels were not associated with significant differences in either metabolite. At mid-normal cobalamin levels (301-600 pg/mL), high serum folate levels were associated with lower homocysteine levels in older adults ( P < .001) but not with differences in MMA in either age group. Cobalamin therapy decreased or normalized MMA and homocysteine in 89% or more of participants even at pretherapy cobalamin levels greater than 600 pg/mL. Conclusion High serum folate levels are associated with higher MMA levels when cobalamin levels are low-normal, and this effect is age dependent, not progressive within the normal serum folate range (suggesting a threshold effect), and reversed by cobalamin therapy. Because MMA may be neurotoxic, these findings suggest caution in the use of folic acid supplements in elderly adults. [ABSTRACT FROM AUTHOR]

Background There is an urgent need for proper utilization of laboratory markers to diagnose vitamin B12 deficiency that should reduce false negative cases. We worked out a diagnostic algorithm that provides a two-step detection of vitamin B12 deficiency using holotranscobalamin as a first line marker and methylmalonic acid (MMA) as a second line marker. Materials and Methods We tested 1359 serum samples sent to our laboratory for total vitamin B12 assay. Serum samples were used for the determination of holotranscobalamin, MMA and creatinine. Results Compared with total B12, holotranscobalamin showed a higher area under the receiver operating characteristic curve for detecting MMA levels > 300 nM. However, the distribution of holotranscobalamin in individuals with elevated creatinine irrespective of MMA and in individuals with elevated MMA irrespective of creatinine was shifted into the higher ranges. In the grey zone of holotranscobalamin between 23 and 75 pM (the range extending from the 90% diagnostic sensitivity to the 90% diagnostic specificity), MMA testing as a second line marker would help detecting 18% of deficient cases. Lowering MMA after vitamin B12 treatment may help setting the diagnosis of B12 deficiency in individuals with elevated creatinine. Discussion Testing for vitamin B12 deficiency should start with holotranscobalamin measurement. Holotranscobalamin between 23 and 75 pM should be followed by MMA testing that can filter substantial number of deficient cases in the grey range in individuals with normal renal function. This diagnostic strategy may significantly improve assessing vitamin B12 deficiency. [ABSTRACT FROM AUTHOR]