One-Carbon Metabolism in Nepalese Infant-Mother Pairs and Child Cognition at 5 Years Old.

BACKGROUND: One-carbon metabolism (OCM) refers to the transfer of methyl groups central to DNA methylation and histone modification. Insufficient access to methyl donors and B-vitamin cofactors affects epigenetic maintenance and stability, and when occurring in early life may impact future health and neurodevelopment. OBJECTIVE: The objective of this study was to examine the relative associations between one-carbon metabolites in Nepalese mother-infant pairs and child cognition measured at 5 y of age. METHODS: This is a cross-sectional study from Bhaktapur, Nepal, in a population at high risk of subclinical B-vitamin deficiencies and cumulative infection burden. Venous blood samples from 500 mother-infant pairs were collected when the infants were 2 to 12 mo old, and metabolite concentrations measured by microbiological assays and GC-tandem MS. We re-enrolled 321 of these children at 5 y and assessed cognition by the Ages and Stages Questionnaire, 3rd edition, and subtests from the Developmental Neuropsychological Assessment, 2nd edition (NEPSY-II). The associations of the independent metabolites or unobserved metabolic phenotypes (identified by latent class analysis) with the cognitive outcomes were estimated by seemingly unrelated regression. We explored direct and indirect relations between the OCM pathway and the cognitive outcomes using path analysis. RESULTS: Infant cystathionine concentration was inversely associated with 4 cognitive outcomes (standardized ßs ranging from -0.22 to -0.11, P values from <0.001 to 0.034). Infants with a metabolic phenotype indicating impaired OCM and low vitamin B-12 status had poorer cognitive outcomes compared with infants with normal OCM activity and adequate vitamin B-12 status (standardized ßs ranging from -0.80 to -0.40, P < 0.001 and 0.05). In the path analysis, we found several OCM biomarkers were associated with affect recognition through infant plasma cystathionine. CONCLUSIONS: Elevated plasma cystathionine during infancy reflects a metabolic phenotype of impaired OCM and low vitamin B-12 status and is associated with poorer cognitive function when the children are 5 y old.

Vitamin B12 deficiency as a cause of severe neurological symptoms in breast fed infant - a case report.

BACKGROUND: Vitamin B12 (cobalamin, cbl) deficiency in children is rare and may occurs in exclusively breast fed infants of mothers on vegetarian or vegan diet with lack of appropriate supplementation. The clinical manifestation of vitamin B12 deficiency include neurological disorders, megaloblastic anemia and failure to thrive. Routine and commonly used laboratory tests such as cell blood count (CBC) or serum vitamin B12 level are sufficient for appropriate diagnosis. Typical therapy is based on intramuscular cobalamin injections. Early diagnosis and early onset of treatment are crucial factors for long-term prognosis of patients as the duration of deficiency may be correlated with the development of long lasting changes in the nervous system. The purpose of this article is to present influence of maternal vitamin B12 deficiency as a cause of infant psychomotor retardation. CASE PRESENTATION: We report the case of a 7 months old girl whose parents sought medical advice due to pathological somnolence and developmental regression of their daughter with onset approximately 2 months prior to the visit. Following several diagnostic tests it was determined that the infant's symptoms were due to vitamin B12 deficiency which was secondary to the mother's latent Addison-Biermer disease. Apart from neurological symptoms the infant also showed megaloblastic anemia which is typical to cobalamin deficiencies. Intramuscular vitamin B12 supplementation resulted in instant improvement of the patient's general condition and blood morphology. Unfortunately, psychological examination indicated long-term psychomotor retardation due to delayed diagnosis of B12 deficiency. CONCLUSIONS: Vitamin B12 levels should be considered during differential diagnosis of neurological symptoms in exclusively breast-fed infants especially if they co-exist with megaloblastic anemia and psychomotor retardation.

Increased stress and altered expression of histone modifying enzymes in brain are associated with aberrant behaviour in vitamin B12 deficient female mice.

A sub-optimal nutritional environment from early life can be envisaged as a stressor that translates into mental health problems in adulthood. After considering (a) the widespread prevalence of vitamin B12 deficiency especially amongst women in developing countries and (b) the importance of vitamin B12 in normal brain function, in this study we have elucidated the behavioural correlates of chronic severe and moderate vitamin B12 deficiency in C57BL/6 mice. Female weanling mice were assigned to three dietary groups: (a) control AIN-76A diet with cellulose as dietary fibre (b) vitamin B12 restricted AIN-76A diet with pectin as dietary fibre (severe deficiency group) and (c) vitamin B12 restricted AIN-76A diet with cellulose as dietary fibre (moderate deficiency group). The mice received these diets throughout pregnancy, lactation and thereafter. Nest-building, maternal care, anxiety and depressive behaviours were evaluated. Oxidative stress, activities of antioxidant enzymes and expression of various histone modifying enzymes in brain were investigated to unravel the probable underlying mechanisms. Our data suggests that both severe and moderate vitamin B12 deficiency induced anxiety and impaired maternal care. However, only severe vitamin B12 deficiency induced depression. Oxidative stress and poor antioxidant defense underlie the deleterious effects of both severe and moderate vitamin B12 deficiency. Altered expression of histone modifying enzymes in the brain of severely deficient mice is suggestive of epigenetic reprogramming. This study suggests that chronic vitamin B12 deficiency leads to behavioural anomalies in female C57BL/6 mice and the severity of these outcomes can be correlated to the level of deficiency.

[Folic acid and vitamin B12 determination in the assessment of cognitive disorders : Overview and data analysis from a university outpatient memory clinic]. / Folsäure- und Vitamin-B12-Bestimmung in der Diagnostik kognitiver Störungen : Übersicht und Datenanalyse einer universitären Gedächtnisambulanz.

Vitamin B12 and folic acid deficiencies are particularly frequent conditions in older people. Since these metabolic disorders represent relevant dyscognitive factors, the assessment of vitamin B12 and folic acid levels is essential in the diagnostic approach of cognitive disorders, such as mild cognitive impairment and dementia in an outpatient memory clinic. This article summarizes the relevant diagnostic and therapeutic aspects of vitamin B12 and folic acid deficiencies and their effects on cognition. The literature review is supplemented by a data analysis of a naturalistic cohort of 250 patients from this outpatient memory clinic.

Association of vitamin D and vitamin B12 with cognitive impairment in elderly aged 80 years or older: a cross-sectional study.

BACKGROUND: The present study aimed to assess the association of vitamin D and vitamin B12 with cognitive impairment in elderly people. METHODS: The data were obtained from a cross-sectional study that included individuals aged 80 years or older living in the urban and rural areas of the cities of Siderópolis and Treviso in the state of Santa Catarina, Brazil. In total, 165 elderly people were included in the analysis. The outcome of cognitive decline was assessed by the Mini-Mental State Examination. Vitamin D and vitamin B12 levels were measured from blood samples. The socio-demographic, anthropometric and health variables used in the analysis were collected from a questionnaire. Crude and adjusted analyses of the relationship between vitamins D and B12 and cognitive decline were performed using a Poisson regression model. RESULTS: The prevalence of cognitive decline was 35.2%. In the adjusted model, individuals who had vitamin D levels >19 ng mL-1 showed a lower prevalence of cognitive decline (prevalence ratio = 0.59; 95% confidence interval = 0.39-0.87). Those participants who had vitamin B12 levels of ≥496 pg mL-1 had a higher prevalence of cognitive decline (prevalence ratio = 1.90; 95% confidence interval = 1.08-3.36). CONCLUSIONS: The present study showed that individuals aged ≥80 years who had vitamin D levels of ≤18 ng mL-1 had a higher prevalence of cognitive decline even after adjustment for potential confounders. In addition, the study demonstrated that vitamin B12 levels of ≥496 pg mL-1 in this population were also a risk factor for cognitive decline. A cross-sectional analysis does not enable the inference of a cause-effect relationship and additional studies are needed to understand these relationships.

Iron Deficiency, Anemia, and Low Vitamin B-12 Serostatus in Middle Childhood Are Associated with Behavior Problems in Adolescent Boys: Results from the Bogotá School Children Cohort.

BACKGROUND: Iron deficiency (ID) in infancy is related to subsequent behavior problems. The effects of micronutrient status in middle childhood are uncertain. OBJECTIVE: The aim of the study was to examine the associations of micronutrient status biomarkers in middle childhood with externalizing and internalizing behavior problems in adolescence. METHODS: We assessed whether ID (ferritin <15 µg/L), anemia (hemoglobin <12.7 g/dL), or blood concentrations of zinc, vitamins A and B-12, and folate at ages 5-12 y were associated with externalizing or internalizing behavior problems in adolescence in 1042 schoolchildren from Bogotá, Colombia. Behavior problems were assessed with the Youth Self-Report questionnaire after a median 6.2 y of follow-up. Mean problem score differences with 95% CIs were estimated between categories of micronutrient status biomarkers with the use of multivariable linear regression. RESULTS: Mean ± SD externalizing and internalizing problems scores were 52.6 ± 9.6 and 53.8 ± 9.9, respectively. Among boys, middle-childhood ID, anemia, and low plasma vitamin B-12 were associated with 5.9 (95% CI: 1.0, 10.7), 6.6 (95% CI: 1.9, 11.3), and 2.7 (95% CI: 0.4, 4.9) units higher mean externalizing problems scores in adolescence, respectively-after adjustment for baseline age, time spent watching television or playing video games, mother's height, and socioeconomic status. Also in boys, ID was related to an adjusted 6.4 (95% CI: 1.2, 11.6) units higher mean internalizing problems score. There were no associations among girls. Other micronutrient status biomarkers were not associated with behavior problems. CONCLUSIONS: ID, anemia, and low vitamin B-12 in middle childhood are related to behavior problems in adolescent boys.This study was registered at clinicaltrials.gov as NCT03297970.

Severe neurological complication following adjustable gastric banding.

AIM: In the last years with the increase of bariatric surgery, first of all as a result of new indications, a rise in the incidence of nutrient-related complications has been observed. Currently little is known about the impact of post-bariatric malnutrition and neurological complications. Wernicke's encephalopathy is a severe neurological syndrome which occurs as a result of thiamine deficiency. Wernicke-Korsakoff syndrome must be considered a serious neurological complication of bariatric surgery with significant morbidity and mortality, with rapidly progressing neurological symptoms, and must be treated immediately. CASE REPORT: We report the case of a 35 years-old male patient, affected by morbid obesity, anxious-depressive syndrome and alcohol use disorder, who after adjustable gastric banding implanted in another hospital developed a severe malnutrition and neurological syndrome. The patient showed poor adherence to the follow-up and to the dietary indications and after all, we needed to place a PEG for enteral nutrition in order to resolve the malnutrition condition and the neurological syndrome. Our experience emphasizes that preoperative selection and assessment of a patient's nutritional status according to guidelines, is required to identify potential problems, and that bariatric surgeons or physicians caring for patient who have undergone bariatric surgery should be familiar with the constellation of nutritional and neurological disorder that may occur after surgery. CONCLUSION: We want to remark the importance of preoperative selection of the patients, the follow-up and the cooperation between patient and physician in order to obtain the best result and avoid severe complications.

The Lived Experience of Anemia Without a Cause.

This article explores anemia without an obvious cause from two perspectives: a patient and the evidence. Although evidence is required to drive favorable patient outcomes, the focus on evidence often hides the patient experience during diagnosis and treatment. Knowledge of experience with evidence can provide a deeper perspective for clinical decision making and meet nursing's ethical mandate to relieve suffering. Although one patient experience does not reflect every patient experience, this patient's experience demonstrates how difficult and dark anemia can be.

[Neuropsychiatric manifestations ushering pernicious anemia]. / Manifestations neuropsychiatriques inaugurant une maladie de Biermer.

Biermer disease or pernicious anemia is an autoimmune atrophic gastritis characterized by the lack of secretion of gastric intrinsic factor. This leads to an insufficient absorption of vitamin B12 in the ileum. Clinical manifestations are mainly hematologic. Neuropsychiatric manifestations are known but are less frequent especially early in the disease. Inaugural neuropsychiatric arrays are rare and various thus making diagnosis difficult. In this article, we report through two clinical cases different neuropsychiatric manifestations revealing pernicious anemia. Mrs. C.O., aged 56, presented after surgery for gallstones, an acute psychiatric array associated with gait disorders. She had no history of neurological or psychiatric problems. The psychiatric interview revealed delirious syndrome, depressive symptoms and anxiety. Neurological examination noted a flaccid paraplegia with peripheral neuropathic syndrome and myoclonus in the upper limbs. At the full blood count, a macrocytosis (VGM: 112.2fl) without anemia was found. The level of vitamin B12 in the blood was low. Cerebro-spinal MRI was suggestive of a neuro-Biermer and showed hyper signal in the cervical cord on T2-weighted sagittal section. In axial section, hyper signal appears at the posterior columns in the form of V. There were no brain abnormalities. A sensorimotor axonal polyneuropathy was diagnosed. The patient received vitamin B12 intramuscularly for ten days associated with neuroleptic treatment. Mrs. R.M., aged 40, was brought to the psychiatry consultation for acute behavioral disorders progressively worsening over a month. An anxiety syndrome, depressive syndrome and delirious syndrome were identified. Neurological examination showed a posterior cordonal syndrome with quadripyramidal syndrome. Full blood count showed a macrocytic anemia. Serum B12 level was collapsed. Cerebro-spinal MRI was normal. She received vitamin B12 with clinical and biological improvement. Features of pernicious anemia vary according to studies and age range. Digestive and hematological manifestations are well known. Neurological and psychiatric manifestations of pernicious anemia were also described in the early literature. They can be the initial symptoms or the only ones. However, inaugural neuropsychiatric features are often unrecognized. The most common psychiatric symptoms were depression, mania, psychotic symptoms, cognitive impairment and obsessive compulsive disorder. Neurological involvement includes mainly combined spinal sclerosis, peripheral neuropathy and dementia. Cerebellar ataxia and movement disorders are reported less often. Severity of neuropsychiatric features and therapeutic efficacy depends on the duration of signs and level of B12 deficiency. Macrocytic anemia may lack. Neuropsychiatric manifestations could be isolated or be the first manifestation of vitamin deficiency and occur without any hematological or gastrointestinal context. Pernicious anemia and serum B12 assay should be discussed in all patients with organic mental disorders, atypical psychiatric symptoms and fluctuation of symptomatology. Nevertheless, B12 level could be normal in genuine pernicious anemia diseases and macrocytic anemia may lack. Substitutive vitaminotherapy is required when diagnosis is strongly suspected and etiologic assessment is negative.

Nitrous oxide related behavioral and histopathological changes may be related to oxidative stress.

Nitrous oxide (N2O) toxicity can result in myelin loss and hyperhomocysteinemia similar to cobalamin (Cbl) deficiency. Studies on N2O exposure can help in understanding the mechanism of demyelination. In view of paucity of studies on N2O toxicity in rats this study was undertaken. Six male wistar rats were exposed to 1.5L/min N2O with 1:1 O2 for 90 min daily for 1 month. After 1-month exposure blood homocysteine (HCY) and oxidative stress parameters glutathione (GSH) and total antioxidant capacity (TAC) were measured. Brain and spinal cord was subjected to histopathological examination. The neurobehavioral changes, oxidative stress parameters and histopathological changes were correlated with serum B12 and HCY level. After 1-month exposure, the rats appeared sluggish, lethargic and developed predominantly hind limb weakness for 1-1.5h. In the exposed group, the total distance traveled (2001.66 ± 118.27 cm; p=0.037), time moving (80.16 ± 5.7s; p=0.028), number of rearing (10.33 ± 1.45; p=0.014) and grip strength (1042.40 ± 51.3N; p=0.041) were significantly decreased whereas, resting time significantly increased (219.83 ± 5.7s; p=0.030) compared to controls. Serum HCY level was significantly increased (20.56 ± 1.296 µm/ml; p=0.0007) in the exposed group. However, serum B12 and folic acid levels were not significantly different. GSH significantly decreased (2.21 ± 0.60 mg/dl; p=0.018) along with TAC (0.76 ± 0.16 Trolox_Eq_mmol/l; p=0.036). The histopathological studies revealed shrinkage and vacuolation of neurons in cerebral cortex, focal myelin loss, vacuolation in subcortical white matter and spinal cord. N2O exposure results in behavioral alterations, hyperhomocysteinemia, cortical and spinal cord demyelination which were associated with decrease GSH and TAC highlighting pathophysiological role of oxidative stress.

Cobalamin status and its relation with depression, cognition and neuropathy in patients with type 2 diabetes mellitus using metformin.

AIMS: To investigate the associations of vitamin B12 (cobalamin and holotranscobalamin) status with depression, cognition and neuropathy in patients with type 2 diabetes using metformin. METHODS: In an observational study, among 550 type 2 diabetes patients using metformin, cobalamin and holotranscobalamin (holoTCII) levels were measured at the annual diabetes checkup, and deficiencies were defined as <148 and <21 pmol/L, respectively. Depression and cognitive function were assessed with corresponding International Classification of Primary Care codes and questionnaires; neuropathy with medical record data and a questionnaire. Confounding variables were retrieved from medical records. Multivariable logistic and linear regressions were used with cobalamin status as independent variable; depression, cognition and neuropathy as dependent variables. RESULTS: The mean duration of diabetes was 8.4 years (±5.8); mean duration of metformin use was 64.1 months (±43.2), with a mean metformin dose of 1,306 mg/day. A sufficient cobalamin level was independently associated with a decreased risk of depression (OR 0.42; 95 % CI 0.23-0.78) and better cognitive performance (ß = 1.79; 95 % CI 0.07-3.52) adjusted for confounders. This indicates that cobalamin-deficient patients had a 2.4 times higher chance of depression and a 1.79 point lower cognitive performance score. HoloTCII was not associated with any outcome. CONCLUSIONS: Cobalamin deficiency was associated with an increased risk of depression and worse cognitive performance, while holoTCII was not. Screening for cobalamin deficiency may be warranted in diabetes patients using metformin. Physicians should consider a cobalamin deficiency in diabetes patients using metformin with a depression or cognitive decline.

Cobalamin deficiency: clinical picture and radiological findings.

Vitamin B12 deficiency causes a wide range of hematological, gastrointestinal, psychiatric and neurological disorders. Hematological presentation of cobalamin deficiency ranges from the incidental increase of mean corpuscular volume and neutrophil hypersegmentation to symptoms due to severe anemia, such as angor, dyspnea on exertion, fatigue or symptoms related to congestive heart failure, such as ankle edema, orthopnea and nocturia. Neuropsychiatric symptoms may precede hematologic signs and are represented by myelopathy, neuropathy, dementia and, less often, optic nerve atrophy. The spinal cord manifestation, subacute combined degeneration (SCD), is characterized by symmetric dysesthesia, disturbance of position sense and spastic paraparesis or tetraparesis. The most consistent MRI finding is a symmetrical abnormally increased T2 signal intensity confined to posterior or posterior and lateral columns in the cervical and thoracic spinal cord. Isolated peripheral neuropathy is less frequent, but likely overlooked. Vitamin B12 deficiency has been correlated negatively with cognitive functioning in healthy elderly subjects. Symptoms include slow mentation, memory impairment, attention deficits and dementia. Optic neuropathy occurs occasionally in adult patient. It is characterized by symmetric, painless and progressive visual loss. Parenteral replacement therapy should be started soon after the vitamin deficiency has been established.

Vitamin B12 deficiency presenting as an acute confusional state: a case report and review of literature.

BACKGROUND: Vitamin B12 deficiency is associated with a wide spectrum of neuro-psychiatric manifestations. RESULTS: We report a case of a 44 year old female patient referred to the haematology unit with vitamin B12 deficiency presenting as an acute confusional state or delirium. Total resolution of the psychiatric symptoms occurred following parenteral vitamin B12 replacement therapy. CONCLUSION: This case report highlights one of the neuro-psychiatric presentations of vitamin B12 deficiency in a previously healthy individual.

Cobalamin deficiency presenting as obsessive compulsive disorder: case report.

Cobalamin deficiency commonly presents with a wide range of neuropsychiatric manifestations ranging from myelopathy, neuropathy, optic neuritis and dementia to mood disorders, chronic fatigue and psychosis even without classical hematological abnormalities like anemia and macrocytosis. However, obsessive compulsive disorder (OCD) in relation to vitamin B12 deficiency has not been described so far. We report a case of middle-aged man presenting with OCD, low serum cobalamin and a positive family history of vitamin B12 deficiency who responded well to methylcobalamin replacement.

Charles Bonnet syndrome and vitamin B12 deficiency: a case report.

The Charles Bonnet syndrome (CBS) is a condition associated with complex visual hallucinations occurring in the elderly in patients with visual impairment and normal mental health. Here, we report the case of a 78-year-old woman who has a limited visual acuity with a CBS that we postulated to be in relationship to a vitamin B12 deficiency. This case is the first report of vitamin B12 deficiency-associated CBS.

[Diagnosis of vitamin B12 deficiency: a case illustrating diagnostic pitfalls]. / Diagnostic d'une carence en vitamine B12 ou le signe de l'ordonnance.

INTRODUCTION: Vitamin B12 deficiency is a longstanding public health problem which affects more than 20% of the elderly population. Among multiple causes of vitamin B12 deficiency, Biermer's disease is currently mentioned in about 25% of the cases. OBSERVATION: We report the case of a 71-year-old woman, taking folate substitution therapy who, over 2 years, progressively developed spinal combined sclerosis, subacute dementia and severe neuropathy leading to a bedridden state. The initial assessment revealed normocytic anemia, without vitamin B12 deficiency and without increased plasma level of biological markers. The plasma folate level was high. Vitamin B12 assay was repeated leading to the diagnosis of deficiency associated with the presence of intrinsic factor antibodies. DISCUSSION: This observation illustrates the broad spectrum of clinical presentations of vitamin B12 deficiency. In the present case, the lack of sensitivity of biological markers delayed diagnosis and had a dramatic impact on outcome. This case highlights the importance of promoting factors such as isolated folate substitution in B12 deficient patients.