The effect of vitamin B12-supplementation on actigraphy measured sleep pattern; a randomized control trial.

BACKGROUND: Vitamin B12 deficiency is common worldwide and has been associated with poor sleep. The effect of vitamin B12 supplementation on sleep in infants is not known. AIMS: To measure the effect of daily supplementation of vitamin B12 for one year on sleep in infants at risk of deficiency. METHODS: This was an individually randomized double-blind placebo-controlled trial in 600 infants in low-to middle-income neighborhoods in Bhaktapur, Nepal of daily supplementation of vitamin B12 for one year. Infants were included if they were 6-11 month year-old and with a length-for-age less than one z-score. Sleep was a predefined, secondary outcome, and was measured by actigraphy including sleep duration at night and total sleep duration (day and night), sleep onset latency (SOL), and wake after sleep onset (WASO). The effect of vitamin B12 on sleep was additionally assessed in predefined subgroups defined by stunting, underweight, vitamin B12 status, low birthweight, anemia and exclusive breastfeeding for 3 months. RESULTS: There was no effect of vitamin B12 supplementation on sleep duration at night, total sleep duration, or WASO. There was a small significant negative effect for SOL. None of the included subgroup analyses revealed effect modification on any of the sleep outcomes. CONCLUSION: Overall, vitamin B12 supplementation did not have an effect on sleep in infants or for high-risk subgroups, with the exception of a small negative effect for SOL. The present study does not support vitamin B12 supplementation to improve sleep in infants. TRIAL REGISTRATION: clinicaltrials.gov: NCT02272842. UNIVERSAL TRIAL NUMBER: U1111-1161-5187.

Association of Maternal Vitamin B12 Status With Infant Findings and Neurodevelopment in Vitamin B12-Deficient Breast-fed Babies.

Few studies have examined the association between maternal vitamin B12 status and their breast-fed infants' findings. The objective of this study was to analyze the association of maternal B12 status with infant findings including neurodevelopmental outcome in breast-fed babies with B12 deficiency. Correlation analyses between the laboratory findings of infants with B12 deficiency (n=120) and their mothers were performed and the association of maternal B12 status with infant findings including the Denver-II developmental screening test (DDST II) results was examined. There was a significant correlation between infant and maternal B12 levels (r=0.222; P=0.030), and between infant and maternal homocysteine (Hcy) levels (r=0.390; P<0.001). Among the babies 4 months of age or older, maternal Hcy levels were significantly correlated with infant mean corpuscular hemoglobin (r=0.404; P=0.001) and infant mean corpuscular volume (r=0.461; P<0.001). Mothers of infants with abnormal DDST II had lower vitamin B12 (196.9±41.2 vs. 247.0±77.0 pg/mL; P=0.018) and higher Hcy levels (17.3±5.0 vs. 10.7±3.1 µmol/L; P<0.001) than mothers of infants with normal DDST II. A lower maternal vitamin B12 status may be related to impaired neurodevelopment in breast-fed infants with vitamin B12 deficiency. Pregnant and lactating women should be offered easy access to healthy nutrition and vitamin B12 supplements.

Late-onset methylmalonic acidemia and homocysteinemia / Acidemia metilmalónica y homocisteinemia de inicio tardío

Introduction: cobalamin C (Cbl C) deficiency is the most common defect in intracellular cobalamin metabolism, associated with methylmalonic acidemia and homocystinuria. Its late clinical presentation is heterogeneous and may lead to a diagnostic delay. Case report: we report the case of a 45-year-old man with a 20-year history of chronic kidney disease and recently diagnosed spastic paraparesis, both of unknown origin. Metabolic studies revealed elevated levels of homocysteine and methylmalonic acid in the blood and urine. A genetic study confirmed cobalamin C deficiency. Treatment with hydroxocobalamin, betaine, carnitine, and folic acid was started. The patient eventually received a kidney transplant. Discussion: early diagnosis and appropriate treatment improve the clinical evolution of patients with Cbl C deficiency. Determination of homocysteine, organic acids, and other amino acids should be included in the differential diagnosis of patients with nephrological-neurological symptoms without a clear etiology. (AU)

Introducción: la deficiencia de cobalamina C (Cbl C) es el defecto más común en el metabolismo intracelular de la cobalamina, asociado a acidemia metilmalónica y homocistinuria. Su presentación clínica tardía es heterogénea y puede llevar a un retraso en el diagnóstico. Caso clínico: presentamos el caso de un varón de 45 años con 20 años de evolución de enfermedad renal crónica y paraparesia espástica de reciente diagnóstico, ambos de origen desconocido. Los estudios metabólicos revelaron niveles elevados de homocisteína y ácido metilmalónico en sangre y orina. El estudio genético confirmó el déficit de cobalamina C. Se inició tratamiento con hidroxocobalamina, betaína, carnitina y ácido fólico. El paciente pudo recibir un trasplante renal. Discusión: el establecimiento de un diagnóstico precoz y un tratamiento adecuado mejora la evolución clínica de los pacientes con déficit de Cbl C. La determinación de homocisteína, ácidos orgánicos y otros aminoácidos debe incluirse en el diagnóstico diferencial de los pacientes con síntomas nefrológico-neurológicos sin una etiología clara. (AU)

Vitamin B12 Deficiency Dysregulates m6A mRNA Methylation of Genes Involved in Neurological Functions.

INTRODUCTION: Vitamin B12 deficiency presents various neurological manifestations, such as cognitive dysfunction, mental retardation, or memory impairment. However, the involved molecular mechanisms remain to date unclear. Vitamin B12 is essential for synthesizing S-adenosyl methionine (SAM), the methyl group donor used for almost all transmethylation reactions. Here, we investigate the m6A methylation of mRNAs and their related gene expression in models of vitamin B12 deficiency. METHODS AND RESULTS: This study observes two cellular models deficient in vitamin B12 and hippocampi of mice knock-out for the CD320 receptor. The decrease in SAM levels resulting from vitamin B12 deficiency is associated with m6 A reduced levels in mRNAs. This is also potentially mediated by the overexpression of the eraser FTO. We further investigate mRNA methylation of some genes involved in neurological functions targeted by the m6A reader YTH proteins. We notably observe a m6A hypermethylation of Prkca mRNA and a consistently increased expression of PKCα, a kinase involved in brain development and neuroplasticity, in the two cellular models. CONCLUSION: Our data show that m6A methylation in mRNA could be one of the contributing mechanisms that underlie the neurological manifestations produced by vitamin B12 deficiency.

Late-onset methylmalonic acidemia and homocysteinemia.

INTRODUCTION: Introduction: cobalamin C (Cbl C) deficiency is the most common defect in intracellular cobalamin metabolism, associated with methylmalonic acidemia and homocystinuria. Its late clinical presentation is heterogeneous and may lead to a diagnostic delay. Case report: we report the case of a 45-year-old man with a 20-year history of chronic kidney disease and recently diagnosed spastic paraparesis, both of unknown origin. Metabolic studies revealed elevated levels of homocysteine and methylmalonic acid in the blood and urine. A genetic study confirmed cobalamin C deficiency. Treatment with hydroxocobalamin, betaine, carnitine, and folic acid was started. The patient eventually received a kidney transplant. Discussion: early diagnosis and appropriate treatment improve the clinical evolution of patients with Cbl C deficiency. Determination of homocysteine, organic acids, and other amino acids should be included in the differential diagnosis of patients with nephrological-neurological symptoms without a clear etiology.

INTRODUCCIÓN: Introducción: la deficiencia de cobalamina C (Cbl C) es el defecto más común en el metabolismo intracelular de la cobalamina, asociado a acidemia metilmalónica y homocistinuria. Su presentación clínica tardía es heterogénea y puede llevar a un retraso en el diagnóstico. Caso clínico: presentamos el caso de un varón de 45 años con 20 años de evolución de enfermedad renal crónica y paraparesia espástica de reciente diagnóstico, ambos de origen desconocido. Los estudios metabólicos revelaron niveles elevados de homocisteína y ácido metilmalónico en sangre y orina. El estudio genético confirmó el déficit de cobalamina C. Se inició tratamiento con hidroxocobalamina, betaína, carnitina y ácido fólico. El paciente pudo recibir un trasplante renal. Discusión: el establecimiento de un diagnóstico precoz y un tratamiento adecuado mejora la evolución clínica de los pacientes con déficit de Cbl C. La determinación de homocisteína, ácidos orgánicos y otros aminoácidos debe incluirse en el diagnóstico diferencial de los pacientes con síntomas nefrológico-neurológicos sin una etiología clara.

Myeloradiculoneuropathy due to vitamin B12 deficiency: an unusual clinical and radiological presentation.

A 42-year-old man from rural India presented with asymmetric progressive paraparesis mimicking compressive dorsal myelopathy, followed by distal upper limb, truncal and neck-flexor weakness, further complicated by acute urinary retention. His sensory deficits were marked by loss of joint position sense (JPS) and graded loss of vibration sense, along with a definite sensory level. Deep tendon jerks were hypo-to-areflexic, plantar was bilaterally extensor. He had become less attentive and occasionally failed to keep track with conversations. A syndromic diagnosis of myeloradiculoneuropathy with cognitive impairments was made. Further tailored investigations revealed vitamin B12 deficiency with positive anti-parietal cell antibody. Diagnosis of subacute combined cord degeneration (SACD) was confirmed. Neuro-imaging revealed intramedullary intensity changes only along lateral aspect of spinal cord instead of characteristic posterior involvement. Following parenteral vitamin B12 supplementation, patient started showing improvement in motor power and subjective sensory symptoms. His bladder symptoms persisted initially, however recovered finally after 6 months.

Vestibular Evoked Myogenic Potentials in Patients With Low Vitamin B12 Levels.

OBJECTIVE: Vitamin B12 deficiency-induced hyperhomocysteinemia has been associated with impaired microarterial flow, demyelization, and neuronal damage, resulting in cochlear damage and auditory dysfunction. Therefore, we aimed to evaluate the possible vestibular-evoked myogenic potential (VEMP) abnormalities in patients with vitamin B12 deficiency. MATERIAL AND METHOD: In this prospective study, 37 patients diagnosed with vitamin B12 deficiency (<220 pg/mL) were compared with 31 audiologically healthy participants with normal B12 levels. Burst-evoked cervical VEMP (cVEMP) measurements were performed on all participants. Additionally, cVEMP responses were analyzed for P1-N1 latency, interpeak amplitude, and amplitude asymmetry ratio. The results of audiometric examination and VEMP records as well as absent responses were evaluated and compared between groups. RESULTS: The rate of absent VEMP responses was twice as high in the patient group than in the healthy control group (12 vs 6 cases, respectively). Moreover, the mean values of interpeak amplitude in both right and left ears were statistically shorter in the patient group than the control group (P values = .024 and .007, respectively). Similarly, the mean amplitude asymmetry ratio was statistically higher in the patient group than the control group (P = .050). There were no statistically significant differences in latency responses between groups. Furthermore, positive, statistically significant correlation was detected between values of the left P1-N1 interpeak amplitude and vitamin B12 levels (r = 0.287, P = .037). CONCLUSIONS: Increased rates of absent VEMPs and decreased amplitudes with normal latencies are attributed to peripheral vestibular hypofunction in patients with vitamin B12 deficiency.

Glucocorticoid Receptor Activation Restores Learning Memory by Modulating Hippocampal Plasticity in a Mouse Model of Brain Vitamin B12 Deficiency.

Cobalamin (Cbl, vitamin B12) deficiency or inborn errors of Cbl metabolism can produce neurologic disorders resistant to therapies, including cognitive dysfunction, mild mental retardation, memory impairment, and confusion. We used Cd320 KO mouse as a model for studying the pathological mechanisms of these disorders. Cd320 encodes the receptor (TCblR) needed for the cellular uptake of Cbl in the brain. The Cd320-/- mouse model presented an impaired learning memory that could be alleviated by a moderate stress, which produced also a greater increase of plasma corticosterone, compared to wild type animals. The present study investigated such a putative rescue mechanism in Cbl-deficient mice. At the molecular level in the brain of Cd320-/- mouse, the decreased methylation status led to a downregulation of glucocorticoid nuclear receptor (GR)/PPAR-gamma co-activator-1 alpha (PGC-1α) pathway. This was evidenced by the decreased expression of GR, decreased methylation of GR and PGC1α, and decreased dimerization and interaction of GR with PGC1α. This led to altered synaptic activity evidenced by decreased interaction between the NMDA glutamatergic receptor and the PSD95 post-synaptic protein and a lower expression of Egr-1 and synapsin 1, in Cd320-/- mice compared to the wild type animals. Intraperitoneal injection of hydrocortisone rescued these molecular changes and normalized the learning memory tests. Our study suggests adaptive influences of moderate stress on loss of memory and cognition due to brain Cbl deficiency. The GR pathway could be a potential target for innovative therapy of cognitive manifestations in patients with poor response to conventional Cbl treatment.

Reducing the Risk of Stroke in Patients with Impaired Renal Function: Nutritional Issues.

Patients with renal failure have extremely high cardiovascular risk; in dialysis patients the risk of stroke is increased approximately 10-fold over that in the general population. Reasons include not only a high prevalence of traditional risk factors such as diabetes, hypertension and dyslipidemia, but also the accumulation of toxic substances that are eliminated by the kidneys, so have very high levels in patients with renal failure. These include plasma total homocysteine, asymmetric dimethylarginine, thiocyanate, and toxic products of the intestinal microbiome (Gut-Derived Uremic Toxins; GDUT), which include trimethylamine N- oxide (TMAO), produced from phosphatidylcholine (largely from egg yolk) and carnitine (largely from red meat). Other GDUT are produced from amino acids, largely from meat consumption. Deficiency of vitamin B12 is very common, raises plasma tHcy, and is easily treated. However, cyanocobalamin is toxic in patients with renal failure. To reduce the risk of stroke in renal failure it is important to limit the intake of meat, avoid egg yolk, and use methylcobalamin instead of cyanocobalamin, in addition to folic acid.

Effects of vitamin B12 supplementation on neurodevelopment and growth in Nepalese Infants: A randomized controlled trial.

BACKGROUND: Vitamin B12 deficiency is common and affects cell division and differentiation, erythropoiesis, and the central nervous system. Several observational studies have demonstrated associations between biomarkers of vitamin B12 status with growth, neurodevelopment, and anemia. The objective of this study was to measure the effects of daily supplementation of vitamin B12 for 1 year on neurodevelopment, growth, and hemoglobin concentration in infants at risk of deficiency. METHODS AND FINDINGS: This is a community-based, individually randomized, double-blind placebo-controlled trial conducted in low- to middle-income neighborhoods in Bhaktapur, Nepal. We enrolled 600 marginally stunted, 6- to 11-month-old infants between April 2015 and February 2017. Children were randomized in a 1:1 ratio to 2 µg of vitamin B12, corresponding to approximately 2 to 3 recommended daily allowances (RDAs) or a placebo daily for 12 months. Both groups were also given 15 other vitamins and minerals at around 1 RDA. The primary outcomes were neurodevelopment measured by the Bayley Scales of Infant and Toddler Development 3rd ed. (Bayley-III), attained growth, and hemoglobin concentration. Secondary outcomes included the metabolic response measured by plasma total homocysteine (tHcy) and methylmalonic acid (MMA). A total of 16 children (2.7%) in the vitamin B12 group and 10 children (1.7%) in the placebo group were lost to follow-up. Of note, 94% of the scheduled daily doses of vitamin B12 or placebo were reported to have been consumed (in part or completely). In this study, we observed that there were no effects of the intervention on the Bayley-III scores, growth, or hemoglobin concentration. Children in both groups grew on an average 12.5 cm (SD: 1.8), and the mean difference was 0.20 cm (95% confidence interval (CI): -0.23 to 0.63, P = 0.354). Furthermore, at the end of the study, the mean difference in hemoglobin concentration was 0.02 g/dL (95% CI: -1.33 to 1.37, P = 0.978), and the difference in the cognitive scaled scores was 0.16 (95% CI: -0.54 to 0.87, P = 0.648). The tHcy and MMA concentrations were 23% (95% CI: 17 to 30, P < 0.001) and 30% (95% CI: 15 to 46, P < 0.001) higher in the placebo group than in the vitamin B12 group, respectively. We observed 43 adverse events in 36 children, and these events were not associated with the intervention. In addition, 20 in the vitamin B12 group and 16 in the placebo group were hospitalized during the supplementation period. Important limitations of the study are that the strict inclusion criteria could limit the external validity and that the period of vitamin B12 supplementation might not have covered a critical window for infant growth or brain development. CONCLUSIONS: In this study, we observed that vitamin B12 supplementation in young children at risk of vitamin B12 deficiency resulted in an improved metabolic response but did not affect neurodevelopment, growth, or hemoglobin concentration. Our results do not support widespread vitamin B12 supplementation in marginalized infants from low-income countries. TRIAL REGISTRATION: ClinicalTrials.gov NCT02272842 Universal Trial Number: U1111-1161-5187 (September 8, 2014) Trial Protocol: Original trial protocol: PMID: 28431557 (reference [18]; study protocols and plan of analysis included as Supporting information).

Mouse models to study the pathophysiology of combined methylmalonic acidemia and homocystinuria, cblC type.

Combined methylmalonic acidemia and homocystinuria, cblC type, is the most common inherited disorder of cobalamin metabolism and is characterized by severe fetal developmental defects primarily impacting the central nervous system, hematopoietic system, and heart. CblC was previously shown to be due to mutations in the MMACHC gene, which encodes a protein thought to function in intracellular cobalamin trafficking and biosynthesis of adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). These coenzymes are required for the production of succinyl-CoA and methionine, respectively. However, it is currently unclear whether additional roles for MMACHC exist outside of cobalamin metabolism. Furthermore, due to a lack of sufficient animal models, the exact pathophysiology of cblC remains unknown. Here, we report the generation and characterization of two new mouse models to study the role of MMACHC in vivo. CRISPR/Cas9 genome editing was used to develop a Mmachc floxed allele (Mmachcflox/flox), which we validated as a conditional null. For a gain-of-function approach, we generated a transgenic mouse line that over-expresses functional Mmachc (Mmachc-OE+/tg) capable of rescuing Mmachc homozygous mutant lethality. Surprisingly, our data also suggest that these mice may exhibit a partially penetrant maternal-effect rescue, which might have implications for in utero therapeutic interventions to treat cblC. Both the Mmachcflox/flox and Mmachc-OE+/tg mouse models will be valuable resources for understanding the biological roles of MMACHC in a variety of tissue contexts and allow for deeper understanding of the pathophysiology of cblC.

Subacute Combined Degeneration of the Spinal Cord Caused by Autoimmune Gastritis.

A 68-year-old woman presented with a 2-year history of worsening unsteady gait. Her neurological examination revealed peripheral neuropathy with lower limb sensory dominance. T2-weighted imaging revealed a disorder of the posterior cervical cord. Blood test findings revealed vitamin B12 deficiency, and gastroscopy revealed typical findings of autoimmune gastritis. She received vitamin B12 supplementation, but some peripheral neuropathy symptoms persisted due to longstanding vitamin B12 deficiency. Asymptomatic patients should undergo gastroscopy to detect autoimmune gastritis, as chronic vitamin B12 deficiency causes irreversible peripheral neuropathy.

Vitamin B12 and Folate Concentrations in Recent-onset Type 2 Diabetes and the Effect of Metformin Treatment.

CONTEXT: Vitamin B12 and folate deficiency are not only linked to hematological, neurological, and cardiovascular diseases, but are also associated with insulin resistance. Metformin can decrease vitamin B12 and folate concentrations. OBJECTIVE: To examine (1) effects of short-term metformin treatment on serum holotranscobalamin (holoTC) and folate and (2) their association with insulin sensitivity in recent-onset type 2 diabetes. DESIGN: This cross-sectional analysis comprised patients (known disease duration <12 months) on metformin monotherapy (MET, n = 123, 81 males, 53 ±â€…12 years) or nonpharmacological treatment (NPT, n = 126, 77 males, 54 ±â€…11 years) of the German Diabetes Study. MAIN OUTCOME MEASURES: HoloTC (enzyme-linked immunosorbent assay), cobalamin, and folate (electrochemiluminescence); beta-cell function and whole-body insulin sensitivity, measured during fasting (HOMA-B, HOMA-IR) and intravenous glucose tolerance tests combined with hyperinsulinemic-euglycemic clamp tests. RESULTS: HoloTC (105.4 [82.4, 128.3] vs 97 [79.7, 121.9] pmol/L) and folate concentrations (13.4 [9.3, 19.3] vs 12.7 [9.3, 22.0] nmol/L) were similar in both groups. Overall, holoTC was not associated with fasting or glucose-stimulated beta-cell function and insulin-stimulated glucose disposal. Cobalamin measurements yielded similar results in representative subgroups. In NPT but not MET, folate levels were inversely correlated with HOMA-IR (r = -0.239, P = .007). Folate levels did not relate to insulin sensitivity or insulin secretion in the whole cohort and in each group separately after adjustment for age, body mass index, and sex. CONCLUSIONS: Metformin does not affect circulating holoTC and folate concentrations in recent-onset type 2 diabetes, rendering monitoring of vitamin B12 and folate dispensable, at least during the first 6 months after diagnosis or initiation of metformin.

Early neurodevelopmental characterization in children with cobalamin C/defect.

Cobalamin C (cblC) defect is the most common inherited disorder of cobalamin metabolism. Developmental delay, behavioral problems, and maculopathy are common, but they have not been systematically investigated. The aim of this study was to define early neurodevelopment in cblC patients and the possible contribution of different factors, such as mode of diagnosis, age at diagnosis, presence of brain lesions and epilepsy. Children up to the age of 4 years with a visual acuity ≥1/10 were evaluated using the Griffiths' Mental Development Scales. Eighteen children were enrolled (age range 12-48 months). Four were diagnosed by newborn screening (NBS); in the others mean age at diagnosis was 3.5 months (range 0.3-18 months). Eight had seizures: three in the first year, and five after the second year of life. Fourteen had brain lesions on magnetic resonance imaging (MRI). Neurovisual assessment evidenced low visual acuity (<3/10) in 4/18. NBS diagnosed patients had higher general and subquotients neurodevelopmental scores, normal brain MRI, and no epilepsy. The others showed a progressive reduction of the developmental quotient with age and language impairment, which was evident after 24 months of age. Our findings showed a progressive neurodevelopmental deterioration and a specific fall in language development after 24 months in cblC defect. The presence of brain lesions and epilepsy was associated with a worst neurodevelopmental outcome. NBS, avoiding major disease-related events and allowing an earlier treatment initiation, appeared to have a protective effect on the development of brain lesions and to promote a more favorable neurodevelopment.

Discovering metformin-induced vitamin B12 deficiency in patients with type 2 diabetes in primary care.

BACKGROUND: Although metformin is the preferred initial pharmacological choice in type 2 diabetes, there is evidence that reveals a link between metformin use and vitamin B12 deficiency. The American Diabetes Association (ADA) has recently recommended periodic measurement of B12 levels for all patients on metformin. LOCAL PROBLEM: Medical record data collected for the preintervention period showed that only 5% (n = 23) of patients diagnosed with diabetes and on metformin had B12 levels checked at an internal medicine primary care practice. METHODS: This was a quasi-experimental project of preintervention and postintervention design using a checklist containing important measures of diabetes control. The project sample population consisted of data of adults with type 2 diabetes aged 18 years and older who were prescribed metformin in the previous year at the primary care practice. INTERVENTIONS: The intervention focused on revising an existing diabetes measures checklist to include a prompt for an annual measurement of B12 levels. RESULTS: There was significant improvement in monitoring vitamin B12 levels and discovery of low vitamin B12 levels. These data show that the number of B12 levels checked increased from 23 during the preintervention to 155 during the intervention (p ≤ 0.0000). CONCLUSIONS: This project supports a conclusion that including a prompt to check B12 levels to an existing checklist increases B12 monitoring in this patient population. Results may encourage other providers to follow the ADA guidelines for monitoring vitamin B12 levels for patients taking metformin.

[Kidney disease in cobalamin C deficiency]. / Atteintes rénales au cours du déficit en cobalamine C.

Cobalamin C deficiency (cblC) is the most common inborn error of vitamin B12 metabolism. This autosomal recessive disease is due to mutations in MMACHC gene, encoding a cyanocobalamin decyanase. It leads to hyperhomocysteinemia associated with hypomethioninemia and methylmalonic aciduria. Two distinct phenotypes have been described : early-onset forms occur before the age of one year and are characterized by a severe multisystem disease associating failure to thrive to neurological and ophthalmological manifestations. They are opposed to late-onset forms, less severe and heterogeneous. CblC deficiency-associated kidney lesions remain poorly defined. Thirty-eight cases have been described. Age at initial presentation varied from a few days to 28 years. Most of the patients presented renal thrombotic microangiopathy (TMA) associated with acute renal failure, and 21 patients presented typical lesions of renal thrombotic microangiopathy on kidney biopsy. Prognosis was poor, leading to death in the absence of treatment, and related to the severity of renal lesions in the early-onset forms. Late-onset disease had better prognosis and most of patients were weaned off dialysis after treatment initiation. We suggest that all the patients with renal TMA be screened for cobalamin metabolism disorder, regardless of age and even in the absence of neurological symptoms, to rapidly initiate the appropriate treatment.

Age-specific reference ranges are needed to interpret serum methylmalonic acid concentrations in the US population.

BACKGROUND: Serum vitamin B-12 is measured to evaluate vitamin B-12 status. Serum methylmalonic acid (MMA) is a specific functional indicator of vitamin B-12 status; however, concentrations increase with impaired renal function. OBJECTIVE: The aim of this study was to describe the distribution of serum vitamin B-12 and MMA in US adults, and estimate age-specific reference intervals for serum MMA in a healthy subpopulation with replete vitamin B-12 status and normal renal function. METHODS: We examined cross-sectional data for serum vitamin B-12 and MMA in adults participating in the NHANES from 2011 to 2014. Vitamin B-12 was measured by electrochemiluminescence assay and MMA by isotope-dilution liquid chromatography-tandem mass spectrometry. RESULTS: In both bivariate and multivariate analyses, age, race/Hispanic origin, and vitamin B-12 supplement use were generally significantly associated with serum vitamin B-12 and MMA concentrations. Serum MMA concentrations increased with age, particularly in persons aged ≥70 y. Non-Hispanic white persons had lower vitamin B-12 and higher MMA concentrations than non-Hispanic black persons. Shorter fasting times and impaired renal function were significantly associated with higher serum MMA concentrations, but not with serum vitamin B-12 concentrations after controlling for covariates. The central 95% reference intervals for serum vitamin B-12 and MMA concentrations were widest for persons aged ≥70 y compared with younger age groups. Compared with the overall population, the central 95% reference intervals for serum MMA concentrations were considerably narrower for a vitamin B-12-replete subpopulation with normal renal function, but still age-dependent. Serum vitamin B-12 showed little, whereas serum MMA showed notable, increases with impaired renal function. CONCLUSIONS: The higher serum MMA concentrations throughout the entire distribution in older persons (especially persons aged ≥70 y) who are vitamin B-12-replete and have normal renal function indicate the need for age-specific MMA reference intervals to better interpret vitamin B-12 status in epidemiologic research.