Methylmalonic Acid Levels Research Articles

Improving Bariatric Patient Aftercare Outcome by Improved Detection of a Functional Vitamin B12 Deficiency.

Vitamin B12 deficiency is common after bariatric surgery. Vitamin B12 is a poor predictor of functional vitamin B12 status, since deficiencies might even occur within the reference limits. Therefore, vitamin B12 deficiencies with serum vitamin B12 levels are between 140 and 200pmol/L remain undetected. Methylmalonic acid (MMA), however, will detect these deficiencies as accumulates due to functional intracellular vitamin B12 deficiencies. MMA is a relative expensive analysis and is therefore not generally available. To lower the costs, we only request MMA when vitamin B12 levels are between these levels. As a result, more biochemical deficiencies are found. However, it was not known whether bariatric patients with vitamin B12 levels between 140 and 200pmol/L would benefit from supplementation. Bariatric patients with vitamin B12 levels between 140 and 200pmol/L with (n = 45) and without (n = 45) intramuscular hydroxocobalamin injections were compared. Treated patients showed a significant increase of vitamin B12 levels (P < 0.001) and a significant decrease in MMA levels (P < 0.001). Biochemical improvement occurs in both patients with and without clinical symptoms. The control group showed a significant increase of MMA levels (P < 0.001). To examine whether biochemical benefits of vitamin B12 supplementation are correlated with clinical improvement, patient records were checked for complaints. Complaints were disappeared after treatment, while no improvement was seen in untreated patients. This study shows that all bariatric patients with vitamin B12 levels between 140 and 200pmol/L benefit clinical and biochemical from vitamin B12 supplementation, regardless the MMA levels.

Vitamin B2, vitamin B12 and total homocysteine status in children and their associations with dietary intake of B-vitamins from different food groups: the Healthy Growth Study

To examine the associations between the dietary intakes of certain B-vitamins from different food sources with the relevant plasma status indices in children. A representative subsample of 600 children aged 9-13years from the Healthy Growth Study was selected. Dietary intakes of vitamins B2, B12, B6 and folate derived from different food sources were estimated. Plasma levels of vitamin B2 (or riboflavin), methylmalonic acid (MMA) and total homocysteine (tHcy) were also measured. Plasma concentrations of vitamin B2 below 3μg/L were found in 22.8% of the children. Children in the lower quartile of dietary vitamin B2 intake were found to have the lowest plasma vitamin B2 levels compared to children in the upper three quartiles (5.06±7.63 vs. 6.48±7.88, 6.34±7.63 and 6.05±4.94μg/L respectively; P=0.003). Regarding vitamin B12 children in the lower quartile of dietary intake had higher mean plasma tHcy levels compared to children in the upper two quartiles, respectively (6.00±1.79 vs. 5.41±1.43 and 5.46±1.64μmol/L; P=0.012). Positive linear associations were observed between plasma vitamin B2 levels and dietary vitamin B2 derived from milk and fruits (β=0.133; P=0.001 and β=0.086; P=0.037). Additionally, nonlinear associations were also observed between plasma vitamin B2 levels and vitamin B2 derived from red meat, as well as between tHcy levels and vitamins B12 and B6 derived from milk; vitamins B12, B6 and folate derived from cereal products and folate derived from fruits. A considerably high prevalence of poor plasma vitamin B2 status was observed in children. The intake of milk, fruits and cereals was associated with more favorable tHcy levels, while the intake of milk and fruits with more favorable plasma B2 levels. However, these findings need to be further confirmed from controlled dietary intervention studies examining the modulation of biomarkers of B-vitamins.

Nutritional Supplementation with Chlorella pyrenoidosa Lowers Serum Methylmalonic Acid in Vegans and Vegetarians with a Suspected Vitamin B₁₂ Deficiency.

Since vitamin B12 occurs in substantial amounts only in foods derived from animals, vegetarians and particularly vegans are at risk of developing deficiencies of this essential vitamin. The chlorella used for this study is a commercially available whole-food supplement, which is believed to contain the physiologically active form of the vitamin. This exploratory open-label study was performed to determine if adding 9 g of Chlorella pyrenoidosa daily could help mitigate a vitamin B12 deficiency in vegetarians and vegans. Seventeen vegan or vegetarian adults (26-57 years of age) with a known vitamin B12 deficiency, as evidenced by a baseline serum methylmalonic acid (MMA) level above 270 nmol/L at screening, but who otherwise appeared healthy were enrolled in the study. Each participant added 9 g of C. pyrenoidosa to their daily diet for 60 ± 5 days and their serum MMA, vitamin B12, homocysteine (Hcy) levels as well as mean corpuscular volume (MCV), hemoglobin (Hgb), and hematocrit (Hct) were measured at 30 and 60 days from baseline. After 30 and 60 days, the serum MMA level fell significantly (P < .05) by an average ∼34%. Fifteen of the 17 (88%) subjects showed at least a 10% drop in MMA. At the same time, Hcy trended downward and serum vitamin B12 trended upward, while MCV, Hgb, and Hct appeared unchanged. The results of this work suggest that the vitamin B12 in chlorella is bioavailable and such dietary supplementation is a natural way for vegetarians and vegans to get the vitamin B12 they need.

“Whippet” Into Your Differential

SESSION TITLE: Critical Care Case Report Posters SESSION TYPE: Affiliate Case Report Poster PRESENTED ON: Tuesday, October 27, 2015 at 01:30 PM - 02:30 PM INTRODUCTION: The differential diagnosis of a patient presenting with confusion and neurologic abnormalities is broad. Recreational drug use is a common etiology while vitamin deficiency is more rare. Here we present a case of recreational drug abuse precipitating severe vitamin deficiency resulting in neurologic abnormalities. CASE PRESENTATION: A 60-year-old male presented with altered mental status and ataxia. He had a history of deteriorating mental status and progressive ataxia for several months. Notably he had been a chronically abusing nitrous oxide (N2O), known recreationally as “whippits”. In the ED the patient's mental status worsened, requiring intubation for airway protection. Physical exam was limited due to sedation. Diagnostic investigations revealed negative toxicology, pancytopenia, severely low vitamin B12 level with elevated methylmalonic acid and homocysteine levels. MRI of the spine revealed increased T2 signal intensity at the C3-C4 and C4-C5 levels. The patient was diagnosed with N2O induced severe vitamin B12 deficiency and neurotoxicity. He was treated with vitamin B12, leucovorin and thiamine, which yielded rapid improvement in hematologic abnormalities. He was discharged to inpatient rehabilitation with mild improvement in his neurologic abnormalities. DISCUSSION: N2O is used as an inhalational dissociative anesthetic and is available as a propellant in pressurized containers. N2O is a commonly abused inhalant. Abuse resulting in severe vitamin B12 deficiency and injury to the dorsal column of the spinal cord and peripheral nervous system has been described; however, it is uncommon likely due to a dose-response correlation. Mechanistically nitrous oxide irreversibly inactivates vitamin B12 leading to a functional deficiency ultimately inhibiting myelin formation in the spinal cord and peripheral nerves. Diagnostic imaging may reveal lesions on T2 weighted MRI. Treatment consists of vitamin B12 replacement and discontinuation of N2O use. Hematologic abnormalities normalize with vitamin supplementation; however, the neurologic prognosis varies. CONCLUSIONS: The clinician should consider N2O induced vitamin B12 deficiency when a patient presents with neurologic deficits, altered mental status and/or pancytopenia with a history of N2O abuse. Reference #1: Hsu C et al. Myelopathy and polyneuropathy caused by nitrous oxide toxicity:a case report. Am Jour of Emer Med.2012;30:1016.e3-e6 Reference #2: Baum VC.When Nitrous Oxide is No Laughing Matter. Pediatr Anessthesia.2007;17(9):824-830 DISCLOSURE: The following authors have nothing to disclose: Matthew Anderson, Trina Hollatz No Product/Research Disclosure Information

Clinical characteristics of hemolytic uremic syndrome secondary to cobalamin C disorder in Chinese children.

The present study was undertaken to investigate the clinical characteristics of hemolytic uremic syndrome (HUS) secondary to cobalamin C disorder (cbl-C disorder). We reviewed retrospectively the medical records of 3 children with HUS secondary to cbl-C disorder who had been treated between April 1, 2009 and October 31, 2013. The 3 patients with HUS secondary to cbl-C disorder presented with progressive hemolytic anemia, acute renal failure, thrombocytopenia, poor feeding, and failure to thrive. Two of the 3 patients once had high blood pressure. The mutations of c.609G>A (p.W203X), c.217C>T (p.R73X) and c.365A>T (p.H122L) in the methylmalonic aciduria (cobalamin deficiency) cbl-C type, with homocystinuria gene were detected in the 3 patients. In these patients the levels of lactate dehydrogenase and homocysteine in serum were elevated and the level of methylmalonic acid (MMA) in urine was also elevated. After treatment with hydroxocobalamin, 2 patients were discharged with no obvious abnormal growth and neurological development and 1 patient died of multiple organ failure. The results of this study demonstrated that cbl-C disorder should be investigated in any child presenting with HUS. The high concentrations of homocysteine and MMA could be used for timely recognization of the disease. Once the high levels of plasma homocystein and/or plasma or urine MMA are detected, the treatment with parenteral hydroxocobalamin should be prescribed immediately. The early diagnosis and treatment would contribute to the good prognosis of the disease.

Vitamin B12 and folate levels in healthy Swiss senior citizens: a prospective study evaluating reference intervals and decision limits.

BackgroundThe vitamin B12 and folate status in nonanaemic healthy older persons needs attention the more so as decrease in levels may be anticipated from reduced haematinic provision and/or impaired intestinal uptake.MethodsA total of 1143 subjectively healthy Swiss midlands participants (637 females and 506 males), ≥60 years of age were included in this study. Levels of vitamin B12, holotranscobalamin (holoTC), methylmalonic acid (MMA), homocysteine (Hcy), serum folate, red blood cell (RBC) folate were measured. Further, Fedosov’s wellness score was determined. Associations of age, gender, and cystatin C/creatinine-based estimated kidney function, with the investigated parameters were assessed. Reference intervals were calculated. Further, ROC analysis was done to assess accuracy of the individual parameters in recognizing a deficient vitamin B12 status. Finally, decision limits for sensitive, specific and optimal recognition of vitamin B12 status with individual parameters were derived.ResultsThree age groups: 60–69, 70–79 and ≥ 80 had median B12 (pmol/L) levels of 237, 228 and 231 respectively (p = 0.22), holoTC (pmol/L) of 52, 546 and 52 (p = 0.60) but Hcy (μmol/L) 12, 15 and 16 (p < 0.001), MMA (nmol/L) 207, 221 and 244 (p < 0.001). Hcy and MMA (both p < 0.001), but not holoTC (p = 0.12) and vitamin B12 (p = 0.44) were found to be affected by kidney function. In a linear regression model Fedosov’s wellness score was independently associated with kidney function (p < 0.001) but not with age. Total serum folate and red blood cell (RBC) folate drift apart with increasing age: whereas the former decreases (p = 0.01) RBC folate remains in the same bandwidth across all age groups (p = 0.12) A common reference interval combining age and gender strata can be obtained for vitamin B12 and holoTC, whereas a more differentiated approach seems warranted for serum folate and RBC folate.ConclusionWhereas the vitamin B12 and holoTC levels remain steady after 60 years of age, we observed a significant increment in MMA levels accompanied by increments in Hcy; this is better explained by age-related reduced kidney function than by vitamin B12 insufficiency. Total serum folate levels but not RBC folate levels decreased with progressing age.Electronic supplementary materialThe online version of this article (doi:10.1186/s12877-015-0060-x) contains supplementary material, which is available to authorized users.

Methylmalonic Aciduria Secondary to Selective Cobalamin Malabsorption in a Yorkshire Terrier

An 8 wk old male Yorkshire terrier was presented with a 2 wk history of recurrent hypoglycemia, lethargy, and seizures. Investigations revealed a marked increase in blood ammonia, low serum cobalamin, and increased levels of urinary methylmalonic acid (MMA) excretion. No liver vascular abnormality was detected. The patient was diagnosed with methylmalonic aciduria due to cobalamin malabsorption. The patient responded well to parenteral cobalamin administration, and the urinary MMA levels normalized rapidly following instigation of treatment. Due to the suspected hereditary nature of selective cobalamin deficiency, one sibling of this dog was screened and found to be normal. This is the first reported case of MMA secondary to hypocobalaminemia in Yorkshire terriers, and the second report of this disease in a dog in the United Kingdom. Given the fact that clinical signs of MMA are similar to those seen in dogs with portosystemic shunts and that Yorkshire terriers are predisposed to liver vascular abnormalities, this case report adds important clinical information to the current available literature.

PTU-125 The prevalence of vitamin b12 deficiency in patients with oesophagogastric cancer: Abstract PTU-125 Table 1

<h3>Introduction</h3> Vitamin B12 deficiency is a recognised problem in patients after surgery for OG cancer owing to the implications of surgery on gastric acid and intrinsic factor (IF) production (which are needed for Vitamin B12 metabolism). However it is postulated that for some patients with OG cancer their deficiency predates surgery. This study investigates the prevalence of preoperative Vitamin B12 deficiency in patients with OG cancer. <h3>Method</h3> A retrospective observational study was undertaken of patients who had surgery for OG cancer between January–December 2014. Active Vitamin B12 levels considered ‘borderline deficiency’ are sent for Methylmalonic acid (MMA) analysis. MMA levels above the normal range for age indicate deficiency. Weight loss data was also collected. <h3>Results</h3> Active Vitamin B12 ±MMA levels were available for 89 patients. 16% of patients had a proven Vitamin B12 deficiency. 27% of patients with Gastric Adenocarcinoma (AC) had a deficiency. Table 1Demographics, prevalence of Vitamin B12 deficiency and weight loss in the study: <h3>Conclusion</h3> OG cancer most commonly affects people &gt;65 years of age. The prevalence of Vitamin B12 deficiency increases with age. This is attributed to a reduction in stomach acid and pepsin production. However the study population has a higher prevalence of Vitamin B12 deficiency than the general population (65–74 years age 1 in 6 vs 1 in 20).¹Implications of deficiency include anaemia, which can have significant consequences for surgery, but also symptoms such as fatigue; depression; problems with memory and understanding; all of which can negatively impact on patients’ Quality of Life. Deficiency can be masked as symptoms which may be attributed to the cancer and/or its treatment. Older age, weight loss and poor nutrition can contribute to Vitamin B12 deficiency in these patients with OG cancer. However 1/5 of the deficient subgroup had stable/gained weight suggesting other possible causes of deficiency such as the use of antacid medication. The high prevalence of Vitamin B12 deficiency in patients with Gastric AC maybe related to the possible presence of gastritis, leading to malabsorption of Vitamin B12, and undiagnosed Pernicious Anaemia; both of which are risk factors for Gastric cancer. Assessment of Vitamin B12 preoperatively is therefore an important component of nutritional assessment in OG cancer. <h3>Disclosure of interest</h3> None Declared. <h3>Reference</h3> Clarke, <i>et al</i>. Vitamin B12 and folate deficiency in later life. Age Ageing 2004;33:34–41

Whippits, nitrous oxide and the dangers of legal highs

Nitrous oxide is increasingly being used as a recreational drug. Prolonged use of nitrous oxide can have disabling neurological sequelae due to functional inactivation of vitamin B12. We present three...

P84 – 2801: Two novel, disease-causing mutations in the ACSF3 gene in a patient with combined malonic and methylmalonic aciduria

Background Combined malonic and methylmalonic aciduria (CMAMMA) is a rare inborn error of metabolism with elevated excretion of malonic acid (MA) and methylmalonic acid (MMA) in urine commonly caused by mutations in the MLYCD gene leading to malonyl-CoA decarboxylase (MCD) deficiency. Clinical features are metabolic acidosis, seizures, axial hypotonia, developmental delay, failure to thrive, microcephaly, cardiomyopathy, elevated transaminases and gastrointestinal symptoms. Benign clinical courses and asymptomatic patients summarized as non-classical phenotype with mostly normal MCD activity are described. In these patients mutations in the ACSF3 gene encoding a methylmalonyl-CoA and malonyl-CoA synthetase are frequently detected. Case report We describe a 3-year-old boy diagnosed with CMAMMA at the age of 26 months. After an uneventful pregnancy a boy of unrelated Afghan parents was born at term with a birth weight of 2955 g. At three weeks he presented with two generalized seizures and metabolic acidosis. Plasma lactat level was normal. Initially moderately elevated levels of MMA were found in urine. Plasma amino acids, carnitine levels, acylcarnitine profile, homocysteine, folate, vitamin B12, liver and renal function parameters were normal. Initial electroencephalogram (EEG) was pathologic and anticonvulsive therapy with phenobarbital was initiated. No further seizures occurred, EEG normalized at the age of three months and antiepileptic medication was stopped. Besides microcephaly the development is age-appropriate up to now. Asymptomatic cholelithiasis persisted despite therapy with ursodeoxycholic acid. Echocardiography was normal. Genetic analysis revealed two novel, disease-causing mutations in the ACSF3 gene and led to the diagnosis auf CMAMMA. Excretion of MMA in urine decreased spontaneously. A mild protein restricted diet was started. A younger sister also presented generalized seizure and elevated MMA in urine at the age of four weeks. Her genetic analysis is in progress. Conclusion We found two novel mutations in the ACSF3 gene which we assume to cause a non-classic CMAMMA phenotype.

Diagnosis of Vitamin B12 Deficiency in Patients With Myeloproliferative Disorders

BackgroundMyeloproliferative disorders are characterized by proliferation of 1 or more lineage of hematologic cells. Rapid proliferation of cells may lead to depletion of vitamin B12, which may be falsely elevated...

Vitamin B12 deficiency in the elderly: is it worth screening?

Vitamin B12 deficiency is common among the elderly. Elderly people are particularly at risk of vitamin B12 deficiency because of the high prevalence of atrophic gastritis-associated food-cobalamin (vitamin B12) malabsorption, and the increasing prevalence of pernicious anaemia with advancing age. The deficiency most often goes unrecognised because the clinical manifestations are highly variable, often subtle and non-specific, but if left undiagnosed the consequences can be serious. Diagnosis of vitamin B12 deficiency, however, is not straightforward as laboratory tests have certain limitations. Setting a cut-off level to define serum vitamin B12 deficiency is difficult; though homocysteine and methylmalonic acid are more sensitive for vitamin B12 deficiency, it may give false result in some conditions and the reference intervals are not standardised. At present, there is no consensus or guideline for diagnosis of this deficiency. It is most often based on the clinical symptoms together with laboratory assessment (low serum vitamin B12 level and elevated serum homocysteine or methylmalonic acid level) and the response to treatment to make definitive diagnosis. Treatment and replacement with oral vitamin B12 can be as effective as parenteral administration even in patients with pernicious anaemia. The suggested oral vitamin B12 dose is 1 mg daily for a month, and then maintenance dose of 125 to 250 µg for patients with dietary insufficiency and 1 mg daily for those with pernicious anaemia. Vitamin B12 replacement is safe and without side-effects, but prompt treatment is required to reverse the damage before it becomes extensive or irreversible. At present, there is no recommendation for mass screening for vitamin B12 in the elderly. Nevertheless, the higher prevalence with age, increasing risk of vitamin B12 deficiency in the elderly, symptoms being difficult to recognise, and availability of safe treatment options make screening a favourable option. However, the unavailability of reliable diagnostic tool or gold standard test makes screening difficult to carry out.

Predictors of survival in children with methymalonic acidemia with homocystinuria in Beijing, China: a prospective cohort study.

(i) To determine whether clinical features and biochemical parameters help to predict survival of methylmalonic acidemia with homocystinuria; (ii) To find the cutoff values of biochemical parameters for predicting survival of methylmalonic acidemia with homocystinuria. A prospective cohort study. A pediatric tertiary hospital in Beijing; all patients were followed until death or June 2013. 45 pediatric patients diagnosed with methylmalonic acidemia with homocystinuria between 2006 and 2012. The data of clinical characteristics and pretreatment biochemical parameters were collected. The Cox regression analysis was performed to identify independent risk factors for survival of patients with methylmalonic acidemia and homocystinuria. The best cutoff values for these independent factors were determined by the receiver characteristic curve. Newborn onset (OR=6.856, 95%CI=2.241-20.976, P=0.001), high level of methylmalonic acid in urine (OR=1.022, 95%CI=1.011-1.033, P<0.001), and high level of urea in serum (OR=1.083, 95%CI=1.027-1.141, P=0.003) were independent negative risk factors for survival of patients with methylmalonic acidemia and homocystinuria. The cutoff values of maximum predictive accuracy of methylmalonic acid in urine and urea in serum were respectively 5.41 mmol/mmol creatinine and 7.80 mmol/L by receiver operating characteristic curve analysis. The patients of methylmalonic acidemia with homocystinuria tend to have an adverse outcome if they have newborn onsets. Elevated urea and urinary methylmalonic acid are predictors of adverse outcomes for the patients. They show similar effect for predicting severe adverse prognosis. The combination of methylmalonic acid in urine concentration and urea in serum concentration provided the most accurate predictive tool.

Mutation analysis of methylmalonyl CoA mutase gene exon 2 in Egyptian families: Identification of 25 novel allelic variants

Methylmalonic aciduria (MMA) is an autosomal recessive disorder of methylmalonate and cobalamin (cbl; vitamin B12) metabolism. It is an inborn error of organic acid metabolism which commonly results from a defect in the gene encoding the methylmalonyl-CoA mutase (MCM) apoenzyme. Here we report the results of mutation study of exon 2 of the methylmalonyl CoA mutase (MUT) gene, coding MCM residues from 1 to 128, in ten unrelated Egyptian families affected with methylmalonic aciduria. Patients were presented with a wide-anion gap metabolic acidosis. The diagnosis has established by the measurement of C3 (propionylcarnitine) and C3:C2 (propionylcarnitine/acetylcarnitine) in blood by using liquid chromatography–tandem mass spectrometry (LC/MS–MS) and was confirmed by the detection of an abnormally elevated level of methylmalonic acid in urine by using gas chromatography–mass spectrometry (GC/MS) and isocratic cation exchange high-performance liquid-chromatography (HPLC). Direct sequencing of gDNA of the MUT gene exon 2 has revealed a total of 26 allelic variants: ten of which were intronic, eight were located upstream to the exon 2 coding region, four were novel modifications predicted to affect the splicing region, three were novel mutations within the coding region: c.15G>A (p.K5K), c.165C>A (p.N55K) and c.7del (p.R3EfsX14), as well as the previously reported mutation c.323G>A (p.R108H).

Subacute Combined Degeneration of the Dorsal Columns in A Patient With Nitrous Oxide Induced B12 Inactivation: A Case Report

Nitrous oxide (N2O) toxicity is a well-known entity. It is capable of inactivating vitamin B12, producing a relative B12 deficiency. Vitamin B12 is needed for neurologic development and is necessary for the body to complete vital biologic functions. We look at a case of a 28 year old patient who abused N2O, then went on to develop neurologic symptoms of ataxia, numbness and subacute combined degeneration of the dorsal columns as seen on MRI. Her symptoms were consistent with vitamin B12 deficiency despite having normal vitamin B12 levels by conventional lab measurements. Her methylmalonic acid (MMA) levels however were elevated. After administering daily B12 injections for 2 weeks and complete abstinence from N2O, her neurologic deficits have nearly resolved.

Methylmalonic acidemia and diabetic ketoacidosis: An unusual association.

Sir, We read with interest the recently published article “methylmalonic acidemia (MMA) mimicking diabetic ketoacidosis (DKA) and septic shock in infants” by Saini et al.[1] and would like to make some important comments. Methylmalonic acidemia commonly presents as acute metabolic decompensation with hypoglycemia.[2] MMA manifesting as hyperglycemia or DKA is rare, only nine cases have been reported till date including one by Saini et al.[1] Boeckx and Hicks[3] for the first time reported a female neonate with severe and persistent metabolic acidosis and hyperglycemia, despite large doses of insulin, who had increased methylmalonic acid levels in urine, but she died before any further investigations. Mathew and Hamdan[4] reported a newborn girl with transient diabetes mellitus in association with MMA, and she died at the age of 6 months. Another interesting case was described by Abramowicz et al.[5] with a mut0 form of MMA with complete absence of pancreatic β cells causing insulin-dependent diabetes mellitus (IDDM). Ciani et al.[6] reported a case of late-onset MMA in a 12-year-old female who presented with vomiting, fever, bronchopneumonia and coma associated with hyperglycemia, ketoacidosis, and hyperammonemia. She was misdiagnosed as a case of IDDM and died 3 days later despite receiving insulin. Filippi et al.[7] reported a newborn suffering from acute neonatal-onset MMA presented with dehydration, ketoacidosis and hyperammonemia and insulin-resistant hyperglycemia and later on died. A 13-month-old girl was presented with DKA and later on diagnosed as MMA.[8] Imen et al.[9] reported a 14-month-old male child who presented with an acute generalized dystonia and lethargy. Investigations revealed hyperglycemia, lactic acidosis, hyperammonemia, and increased urinary methylmalonic acid, tiglylglycine and methylcitrate leading to the diagnosis of MMA. With symptomatic treatment, there was rapid improvement in general condition, consciousness and gradual normalization of glucose after 6 days without using insulin. Sharda et al.[10] reported a 13-month-old boy who presented with vomiting, dehydration, coma, hyperglycemia, high anion gap metabolic acidosis (HAGMA) and ketosis. He was treated in line of DKA with parenteral fluid, electrolytes, and insulin infusion that resulted in an improvement in hyperglycemia, but the persistence of HAGMA and lack of improvement of neurologic status. Urinary organic acid analysis revealed increased methylmalonic acid levels. He also had hyperhomocysteinemia and homocystinuria in the presence of normal Vitamin B12 levels. There was some improvement in the neurologic status and metabolic parameters after treatment with low-protein diet, vitamin B12, folic acid, and L-carnitine, but he succumbed to polymicrobial nosocomial sepsis. Six of these nine (2/3rd) reported cases of MMA presented as DKA died, without any information on long term outcome of those who survived. So, DKA is an exceptional manifestation of MMA and could be a marker of poor prognosis.[9,10,11] The unusual presentation of MMA as DKA reminds us of the wide clinical spectrum of inborn errors of metabolism. In very young patients, who present with DKA and on being treatment with fluid and insulin show rapid improvement in hyperglycemia and/or poor response in metabolic acidosis or neurological status should be worked up for organic acidemia in particular MMA.

Reliable and powerful laboratory markers of cobalamin deficiency in the newborn: plasma and urinary methylmalonic acid

Background: Diagnosing cobalamin deficiency is critical, given the high prevalence of cobalamin deficiency particularly in developing countries. Measuring serum cobalamin levels is of limited diagnostic sensitivity, in other words its specificity and sensitivity are low. The present study investigated the changes in the levels of metabolic markers – plasma homocysteine, plasma methylmalonic acid (MMA) and urinary MMA – of cobalamin metabolism.Methods: Plasma cobalamin and serum folic acid were studied in 206 pregnant women over the last four prenatal weeks. Plasma cobalamin, folic acid, homocysteine, MMA from umbilical cord blood and urinary MMA in newborns were studied.Results: Plasma cobalamin values were low in 66% of the mothers. There was a positive correlation between maternal and neonatal plasma cobalamin values (r = 0.72, p < 0.001). B12 was strongly inversely associated with plasma MMA, urine MMA and plasma homocysteine. To predict cobalamin deficiency, sensitivities of plasma MMA, urinary MMA and homocysteine were 96.4%, 95.6% and 88.2%, respectively. And positive predictive values (PPV) were 96.2%, 96.9% and 86% for plasma MMA, urinary MMA and plasma homocysteine levels, respectively.Conclusion: Plasma MMA and urinary MMA B12 are the most robust markers of cobalamin deficiency. As a non-invasive method, urinary MMA is a sensitive method in demonstrating cobalamin deficiency in the newborn.

Anemias due to essential nutrient deficiencies.

• Iron deficiency results from decreased intake in the setting of increased loss due to menstruation, childbirth or gastrointestinal bleeding. • Diets low in animal source foods are deficient in both iron and vitamin B 12 . • Atrophic gastritis (pernicious anemia) and other malabsorption syndromes are the major cause of vitamin B 12 deficiency megaloblastic anemia. • Folate deficiency megaloblastic anemia is often the result of alcoholism, drug therapy or malabsorption syndromes. • Vitamin B 12 deficiency causes elevated methylmalonic acid levels, and both B 12 deficiency and folate deficiency cause elevated homocysteine levels.

IT'S NO LAUGHING MATTER

Background Nitrous oxide abuse is on the increase and can cause neurological dysfunction by inactivation of Vitamin B12 resulting in manifestations such as Sub-acute combined degeneration of spinal cord and Peripheral neuropathy. Case report We report two young patients who presented to emergency neurology clinic with progressive dysasthesia. Both had history of smoking, alcohol and had inhaled nitrous oxide from whipped cream canisters. Examination of both patients revealed unremarkable cranial nerves but case 1 had sluggish reflexes in the lower limbs with thoracic sensory level while case 2 had mild weakness distally in the upper limbs, global areflexia and cervical sensory level. MRI spine in both cases showed posterior cervico-thoracic cord high signal change. Case 1 had low Vitamin B12 and high Methylmalonic acid levels. Case 2 declined blood tests but had a demyelinating sensorimotor neuropathy on nerve conduction studies. Both patients were advised on abstinence from nitrous oxide and treated with Vitamin B12 supplementation. Conclusion Neurological sequelae of Nitrous oxide toxicity are under-recognised. It is a common recreational drug and its use should be specifically sought in young patients presenting with signs of a myelo-neuropathy.

The Mmachc gene is required for pre-implantation embryogenesis in the mouse

Patients with mutations in MMACHC have the autosomal recessive disease of cobalamin metabolism known as cblC. These patients are unable to convert cobalamin into the two active forms, methylcobalamin and adenosylcobalamin and consequently have elevated homocysteine and methylmalonic acid in blood and urine. In addition, some cblC patients have structural abnormalities, including congenital heart defects. MMACHC is conserved in the mouse and shows tissue and stage-specific expression pattern in midgestation stage embryos. To create a mouse model of cblC we generated a line of mice with a gene-trap insertion in intron 1 of the Mmachc gene, (MmachcGt(AZ0348)Wtsi). Heterozygous mice show a 50% reduction of MMACHC protein, and have significantly higher levels of homocysteine and methylmalonic acid in their blood. The MmachcGt allele was inherited with a transmission ratio distortion in matings with heterozygous animals. Furthermore, homozygous MmachcGt embryos were not found after embryonic day 3.5 and these embryos were unable to generate giant cells in outgrowth assays. Our findings confirm that cblC is modeled in mice with reduced levels of Mmachc and suggest an early requirement for Mmachc in mouse development.