Imerslund-Gräsbeck Syndrome: Clinical Case

Introduction: Imerslund-Gräsbeck syndrome (IGS) is a rare congenital disorder characterized by decreased vitamin B12, megaloblastic anemia, and proteinuria. Clinical case: A 58-year-old woman with four episodes of generalized tonic movements whose paraclinical findings showed cyanocobalamin deficiency. The presence of gait disturbances and constitutional syndrome was reported upon questioning, which required further investigation. The extension tests confirmed type 1 IGS, so it was decided to continue the cyanocobalamin management and nutrition evaluation, with which an adequate evolution was achieved. The patient was eventually discharged. Conclusion: This pathology is low prevalence and mainly affects the first decade of life. It prefers the female sex and is characterized by a decrease in vitamin B12, which can predispose to other disorders such as ataxia and growth retardation.

Introducción: el síndrome de Imerslund-Gräsbeck es un trastorno congénito infrecuente caracterizado por disminución de la vitamina B12, anemia megaloblástica y proteinuria. Caso clínico: mujer de 58 años de edad con cuatro episodios de movimientos tónicos generalizados cuyos paraclínicos mostraban deficiencia de cianocobalamina, por lo que en el interrogatorio se reportaba la presencia de alteraciones en la marcha y síndrome constitucional que requería ampliar los estudios. Los exámenes de extensión confirmaron el síndrome de Imerslund-Gräsbeck tipo 1, de modo que se decidió continuar el manejo con cianocobalamina y valoración con nutrición, con lo que se obtuvo una adecuada evolución y se decidió dar egreso a la paciente. Conclusión: esta patología tiene una baja prevalencia y afecta principalmente a la primera década de la vida, tiene predilección por el sexo femenino y se caracteriza por una disminución de la vitamina B12, que puede predisponer a otras alteraciones como ataxia y retraso en el crecimiento.

Flow cytometry-detected changes in megaloblastic anemia secondary to cobalamin deficiency

Introduction: Megaloblastic anemias secondary to Vitamin B12 deficiency are a group of pathologies produced by defective nuclear DNA synthesis. Objective: To describe the maturation alterations found in hematopoietic precursors of the bone marrow in a series of patients with megaloblastic anemia. Methods: Were included patients attended at the Regional Hospital of Concepción with bone marrow samples sent for the study of cytopenia by flow cytometry whose final diagnosis was megaloblastic anemia. The immunophenotype was performed with CD45, CD34, CD117, HLA-DR, markers of neutrophil (CD13, CD11b, CD10, CD16) and/or erythroblast (CD105, CD71, CD36) maturation. Results: From the flow cytometry laboratory database, 8 patients with megaloblastic anemia were identified, and myelodysplastic syndromes (n=9) and normal or reactive bone marrow (n=10) were used as controls. 44% were men, with a median age of 58 years. Megaloblastic anemia was associated with a higher proportion of size and complexity of erythroid and myeloid progenitors compared to lymphocytes compared to controls. The total percentage of erythroblasts and the proportion of CD34+ myeloid cells associated with erythroid lineage was higher in megaloblastic anemia, associated with a maturation arrest in the CD105+ precursor stage (69% vs 19% and 23%, p<0.001). The heterogeneity of CD36 and CD71 in megaloblastic anemia was similar to myelodysplastic syndromes. Conclusions: Megaloblastic anemia produces a heterogeneous involvement of hematopoiesis, characterized by a greater size and cellular complexity of precursors of the neutrophil and erythroid series and a maturation arrest of the erythroblasts.

Introducción: Anemias megaloblásticas secundarias a la deficiencia de vitamina B12 son patologías producidas por una síntesis defectuosa del ADN nuclear. Objetivo: Describir las alteraciones madurativas encontradas en precursores hematopoyéticos de la médula ósea de una serie de pacientes con anemia megaloblástica. Métodos: Se incluyeron pacientes atendidos en el Hospital Regional de Concepción con muestras de médula ósea enviadas para estudio de citopenias por citometría de flujo cuyo diagnóstico fue anemia megaloblástica. El inmunofenotipo se realizó con CD45, CD34, CD117, HLA-DR, marcadores de maduración de serie de neutrófilo (CD13, CD11b, CD10, CD16) y/o eritroblasto (CD105, CD71, CD36). Resultados: Se identificaron 8 pacientes con anemia megaloblástica y como controles se utilizaron síndromes mielodisplásicos (n=9) y médula ósea normal o reactiva (n=10). El 44% eran hombres, con una mediana de edad de 58 años. La anemia megaloblástica se asoció con una mayor proporción de tamaño y complejidad de progenitores eritroides y mieloides con respecto de los linfocitos en comparación a los controles. El porcentaje total de eritroblastos y la proporción de células mieloides CD34+ comprometidas con el linaje eritroide fue mayor en anemia megaloblástica, asociado a una parada madurativa en la etapa de precursor CD105+ (69% vs 19% y 23%, p <0.001). La heterogeneidad de CD36 y CD71 en anemia megaloblástica fue similar a los síndromes mielodisplásicos. Conclusiones: la anemia megaloblástica produce una afectación heterogénea de la hematopoyesis, caracterizada por un mayor tamaño y complejidad celulares de precursores de la serie neutrófilo y eritroide y una detención madurativa de los eritroblastos.

Trastornos adquiridos y congénitos de la deficiencia de vitamina B12 en niños / Acquired and inherited disorders of vitamin B12 deficiency in children

Vitamin B12 is an essential micronutrient for cell growth and the development of the central nervous system. Its deficiency can manifest clinically as megaloblastic anemia, peripheral neuropathy, myelopathy and neuropsychiatric disorders. Early detection and treatment are essential as it can cause irreversible neurological sequelae. Diagnosis is often challenging as it is based on clinical and biochemical features. Clinically, the symptoms are nonspecific and equivocal. Biochemically, there is no gold standard to detect Cobalamin deficiency. The available biomarkers do not have a defined cut-off value or are not sensitive or specific enough. This article exposes the different causes of vitamin B12 deficiency, analyzes the advantages and disadvantages of biochemical markers and, for the first time, proposes an algorithmic diagnosis using biomarkers and therapeutic tests. The ultimate goal is to alert pediatricians to the difficulties of diagnosing vitamin B12 deficiency and strategies are proposed to differentiate between acquired and congenital cobalamin conditions. Finally, the treatment according to the etiology is described in a practical manner, as well as the expected time for improvement of the biochemical parameters.

La vitamina B12 es un micronutriente fundamental para el crecimiento celular y el desarrollo del sistema nervioso central. Su deficiencia puede manifestarse clínicamente como anemia megaloblástica, neuropatía periférica, mielopatía y trastornos neuropsiquiátricos. La detección y el tratamiento tempranos son esenciales, ya que esta deficiencia puede generar secuelas neurológicas irreversibles. El diagnóstico suele ser un desafío, ya que se basa en pilares clínicos y bioquímicos. Clínicamente, los síntomas son inespecíficos y equívocos. Bioquímicamente no existe un gold standard para diagnosticar la deficiencia de cobalamina. Los biomarcadores existentes no presentan un valor de corte definido o no son lo suficientemente sensibles o específicos. Este trabajo expone las diferentes causas de deficiencia de vitamina B12, analiza las ventajas y desventajas de los marcadores bioquímicos y por primera vez se plantea un algoritmo diagnóstico mediante biomarcadores y pruebas terapéuticas. El objetivo último es alertar a los pediatras acerca las dificultades que representa el diagnóstico de deficiencia de vitamina B12 y se proponen estrategias para diferenciar cuadros adquiridos versus congénitos de la deficiencia de cobalamina. Por último, se describe de manera práctica el tratamiento según la etiología así como el tiempo esperado para la mejoría de los parámetros bioquímicos.

Diagnosis, Treatment and Prevention of Nutritional Anemia in Children: Recommendations of the Joint Committee of Pediatric HematologyOncology Chapter and Pediatric and Adolescent Nutrition Society of the Indian Academy of Pediatrics

Justification: Anemia in children is a significant public health problem in our country. Comprehensive National Nutrition Survey 2016-18 provides evidence that more than 50% of childhood anemia is due to an underlying nutritional deficiency. The National Family Health Survey-5 has reported an increase in the prevalence of anemia in the under-five age group from 59% to 67.1% over the last 5 years. Clearly, the existing public health programs to decrease the prevalence of anemia have not shown the desired results. Hence, there is a need to develop nationally acceptable guidelines for the diagnosis, treatment and prevention of nutritional anemia. Objective: To review the available literature and collate evidence-based observations to formulate guidelines for diagnosis, treatment and prevention of nutritional anemia in children. Process: These guidelines have been developed by the experts from the Pediatric Hematology-Oncology Chapter and the Pediatric and Adolescent Nutrition (PAN) Society of the Indian Academy of Pediatrics (IAP). Key areas were identified as: epidemiology, nomenclature and definitions, etiology and diagnosis of iron deficiency anemia (IDA), treatment of IDA, etiology and diagnosis of vitamin B12 and/or folic acid deficiency, treatment of vitamin B12 and/or folic acid deficiency anemia and prevention of nutritional anemia. Each of these key areas were reviewed by at least 2 to 3 experts. Four virtual meetings were held in November, 2021 and all the key issues were deliberated upon. Based on review and inputs received during meetings, draft recommendations were prepared. After this, a writing group was constituted which prepared the draft guidelines. The draft was circulated and approved by all the expert group members. Recommendations: We recommend use of World Health Organization (WHO) cut-off hemoglobin levels to define anemia in children and adolescents. Most cases suspected to have IDA can be started on treatment based on a compatible history, physical examination and hemogram report. Serum ferritin assay is recommended for the confirmation of the diagnosis of IDA. Most cases of IDA can be managed with oral iron therapy using 2-3 mg/kg elemental iron daily. The presence of macro-ovalocytes and hypersegmented neutrophils, along with an elevated mean corpuscular volume (MCV), should raise the suspicion of underlying vitamin B12 (cobalamin) or folic acid deficiency. Estimation of serum vitamin B12 and folate level are advisable in children with macrocytic anemia prior to starting treatment. When serum vitamin B12 and folate levels are unavailable, patients should be treated using both drugs. Vitamin B12 should preferably be started 10-14 days ahead of oral folic acid to avoid precipitating neurological symptoms. Children with macrocytic anemia in whom a quick response to treatment is required, such as those with pancytopenia, severe anemia, developmental delay and infantile tremor syndrome, should be managed using parenteral vitamin B12. Children with vitamin B12 deficiency having mild or moderate anemia may be managed using oral vitamin B12 preparations. After completing therapy for nutritional anemia, all infants and children should be advised to continue prophylactic iron-folic acid (IFA) supplementation as prescribed under Anemia Mukt Bharat guidelines. For prevention of anemia, in addition to age-appropriate IFA prophylaxis, routine screening of infants for anemia at 9 months during immunization visit is recommended.

Síndrome de Imerslund-Gränsbeck: revisión sistemática de casos clínicos / Imerslund-Gränsbeck Syndrome: systematic review of clinical cases

Resumen Introducción: el Síndrome de Imerslund-Gränsbeck es un trastorno congénito inusual que cursa con disminución de la Vitamina B12, anemia megaloblástica y proteinuria sin afección renal que cual se produce por una mutación de los cromosomas 10 y 14, que condicionan un defecto en el receptor del complejo vitamina B12-factor intrínseco del enterocito ileal. Fue descrita por Olga Imerslund y Armas Gransbeck. Objetivo: caracterizar a la población que ha padecido el Síndrome de Imerslund-Gränsbeck. Metodología: revisión sistemática de la literatura de casos clínicos. Resultados: se incluyeron 68 casos, en la mayoría de los casos el diagnostico en los primeros 10 años de vida, en el que se evidenció una mayor frecuencia en mujeres, y se encontró asociado con antecedentes familiares como consanguinidad entre padres (14,6%). La manifestación más frecuente fue palidez (20,9%), seguido de vomito (10,5%) y anorexia (9,8%). La anemia megaloblástica (66,2%) fue el hallazgo más frecuente y el tratamiento se dio con cianocobalamina (intramuscular u oral) para regular las concentraciones plasmáticas de esta vitamina. Conclusión: el Síndrome de Imerslund Gränsbeck tiene una baja prevalencia y se presenta con mayor frecuencia en el continente europeo, tiene predilección por el sexo femenino y se caracteriza por una disminución de la vitamina B12 que pueden que puede predisponer a otras alteraciones como ataxia y retraso en el crecimiento.

Abstract Introduction: Imerslund-Gränsbeck Syndrome is an unusual congenital disorder that causes a decrease in vitamin B12, megaloblastic anemia and proteinuria without kidney involvement that is caused by a mutation of chromosomes 10 and 14, which determine a defect in the complex receptor vitamin B12-ileal enterocyte intrinsic factor. It was described by Olga Imerslund and Armas Gransbeck. Objective: to characterize the population that has suffered from Imerslund Gränsbeck syndrome. Methodology: systematic review of the clinical case literature. Results: 68 cases were included, in most cases the diagnosis in the first 10 years of life, in which a higher frequency was found in women, and was found to be associated with family history such as consanguinity between parents (14.6%). The most frequent manifestation was paleness (20.9%), followed by vomiting (10.5%) and anorexia (9.8%). Megaloblastic anemia (66.2%) was the most frequent finding and treatment was given with cyanocobalamin (intramuscular or oral) to regulate plasma concentrations of this vitamin. Conclusion: Imerslund-Gränsbeck Syndrome has a low prevalence and occurs more frequently in the European continent, has a predilection for females and is characterized by a decrease in vitamin B12 that may predispose to other disorders such as ataxia and retardation in growth.

Serum Vitamin B12 Level and Dietary intake in Adult Atopic Dermatitis: A Case Control Study

Background@#Vitamin B12 is a contributing factor in pruritus and peripheral nerve regeneration. Its role in atopic dermatitis (AD) is still unclear. This study aimed to compare vitamin B12 level between AD patients and healthy controls, determine its correlation with pruritus and AD severity, and evaluate dietary pattern with energy, macro and micronutrient intakes.@*Methods@#This was a case control study involving adult AD patients and age-, gender-, ethnicity- and body mass index-matched healthy controls. All adult patients who fulfilled UK Working Party AD diagnostic criteria were included. Exclusion criteria include patients on systemic agents, diseases known to affect B12 level and vegan diet. AD severity was determined using SCORing Atopic Dermatitis (SCORAD) index. Serum vitamin B12 level were measured. A three-day 24-hour dietary recall was collected and analyzed.@*Results@#A total of 42 AD patients and 42 controls were recruited. Mean SCORAD index was 39.2±16.6, and AD duration was 12.7 ± 8.1 years. Vitamin B12 was lower among AD (215.6 ± 110.2 pmol/L) versus control (295.1± 119.9 pmol/L), p<0.01 despite similar dietary B12 intake in both groups. There were no significant correlations between AD duration and severity with vitamin B12 level. Energy intake (kcal/ day) was significantly lower in AD (p=0.04). There were no significant differences in proportion of main food groups consumed and other macronutrient and micronutrient intakes.@*Conclusion@#Serum vitamin B12 level was significantly lower in AD patients despite similar dietary pattern and nutrient intake with healthy controls. There were no correlations with AD severity or disease duration. Dietary pattern of AD patients should be routinely assessed to ensure adequate nutrition.

Cobalamin cbiP mutant shows decreased tolerance to low temperature and copper stress in Listeria monocytogenes

BACKGROUND: Listeria monocytogenes is a foodborne pathogen that causes listeriosis in humans. This pathogen activates multiple regulatory mechanisms in response to stress, and cobalamin biosynthesis might have a potential role in bacterial protection. Low temperature is a strategy used in the food industry to control bacteria proliferation; however, L. monocytogenes can grow in cold temperatures and overcome different stress conditions. In this study we selected L. monocytogenes List2-2, a strain with high tolerance to the combination of low temperature +copper, to understand whether the cobalamin biosynthesis pathway is part of the tolerance mechanism to this stress condition. For this, we characterized the transcription level of three cobalamin biosynthesis related genes ( cbiP , cbiB, and cysG ) and the eutV gene, a transcriptional regulator encoding gene involved in ethanolamine metabolism, in L. monocytogenes strain List2-2 growing simultaneously under two environmental stressors: low temperature (8 °C) +copper (0.5 mM of CuSO4 ×5H2O). In addition, the gene cbiP , which encodes an essential cobyric acid synthase required in the cobalamin pathway, was deleted by homologous recombination to evaluate the impact of this gene in L. monocytogenes tolerance to a low temperature (8 °C) +different copper concentrations. RESULTS: By analyzing the KEGG pathway database, twenty-two genes were involved in the cobalamin biosynthesis pathway in L. monocytogenes List2-2. The expression of genes cbiP , cbiB, and cysG, and eutV increased 6 h after the exposure to low temperature +copper. The cobalamin cbiP mutant strain List2-2Δ cbiP showed less tolerance to low temperature +copper (3 mM) than the wild type L. monocytogenes List2-2. The addition of cyanocobalamin (5 nM) to the medium reverted the phenotype observed in List2-2Δ cbiP . CONCLUSION: These results indicate that cobalamin biosynthesis is necessary for L. monocytogenes growth under stress and that the cbiP gene may play a role in the survival and growth of L. monocytogenes List2-2 at low temperature +copper.

Punica granatum and amygdalin extracts plus cobalamin combined with albendazole reduce larval burden and myositis in experimental trichinosis / Extratos de Punica granatum e amígdalina mais cobalamina combinado com albendazol reduzem a carga larvar e a miosite na triquinose experimental

Abstract Trichinellosis is a zoonosis results from eating raw or semi-cooked meat of infected animals. Medicinal plants have been used lately as alternatives and/or combined therapies to resolve some drawbacks of the current regimens. This work analyzed the effect of albendazole monotherapy on Trichinella spiralis experimental infection (group A), in comparison to P. granatum and amygdalin extracts +cobalamin (group B), plus its combination with albendazole (group C). The study revealed that the extracts alone or combined with albendazole had an inferior effect to albendazole monotherapy regarding number of adult worms (40.83 ±3.82, 18.67 ±1.86 and 16.83 ±2.32, respectively). However, their effect was more obvious in muscle phase combined with albendazole, achieving the lower number of larvae/mL tissue homogenate (22.33 ±3.27 in comparison to 39.67 ±2.58 achieved by albendazole monotherapy). The extracts exerted a significant immunomodulatory effect by reducing the local CD4+ expression in the intestine as well as in muscle phase (1.15 ±0.25 and 3.80 ±0.65 in comparison to 4.97 ±0.37 and 12.20 ±0.87 with albendazole monotherapy, respectively). So, these extracts improved the therapeutic efficacy of albendazole, specifically in muscle phase and counteracted the inflammatory reaction caused by albendazole monotherapy, thus extensively alleviating the resulting myositis.

Resumo Trichinellosis é uma zoonose resultante da ingestão de carne crua ou semicozida de animais infectados. As plantas medicinais têm sido usadas, ultimamente, como alternativas e/ou terapias combinadas, para resolver algumas desvantagens dos regimes atuais. Este trabalho analisou o efeito da monoterapia albendazole na infecção experimental por Trichinella spiralis (grupo A), em comparação com extratos de P. granatum e amígdalina +cobalamina (grupo B), além de sua combinação com albendazol (grupo C). O estudo revelou que os extratos sozinho ou combinado com albendazol teve efeito inferior à monoterapia albendazol em relação ao número de vermes adultos (40,83 ±3,82, 18,67 ±1,86 e 16,83 ±2,32, respectivamente). No entanto, seu efeito foi mais óbvio na fase muscular combinado com o albendazol, alcançando o menor número de larvas/mL homogeneizado de tecido (22,33 ±3,27 em comparação com 39,67 ±2,58 obtidos pela monoterapia albendazol). Os extratos exerceram um efeito imunomodulatório significativo, ao reduzir a expressão local CD4+ no intestino, bem como na fase muscular (1,15 ±0,25 e 3,80 ±0,65 em comparação com 4,97 ±0,37 e 12,20 ±0,87 com monoterapia albendazol, respectivamente). Assim, esses extratos melhoraram a eficácia terapêutica do albendazol, especificamente na fase muscular e neutralizaram a reação inflamatória causada pela monoterapia albendazol, aliviando extensivamente a miosite resultante.

Ampliación del tamizaje de errores innatos del metabolismo en Perú: reporte de caso con trastorno del metabolismo de cobalamina / Widened screening for innate metabolism disorders in Peru: report of a case with cobalamin metabolism disorder

RESUMEN El tamizaje neonatal de los errores innatos del metabolismo se instauró hace más de 50 años en el mundo. En Latinoamérica, Uruguay, Costa Rica, Chile, Brasil y Colombia han implementado esta política de salud pública de manera sostenida. La tecnología para detectar estas enfermedades ha ido progresando con un mejor costo/efectividad, haciendo que sea de acceso casi universal. Los trastornos del metabolismo intracelular de la cobalamina es un grupo heterogéneo clasificados en tres fenotipos bioquímicos. Reportamos al primer paciente en Perú con diagnóstico tardío de una variante homocigota c.394 C>T en el gen MMACHC, el cual pertenece al grupo de complementación cblC el cual produce aciduria metilmalónica y homocistinuria, caracterizado por talla baja, hipotonía, retraso del desarrollo psicomotor, convulsiones, anemia megaloblástica, trombocitopenia y neutropenia ondulantes; con homocisteína elevada, acidemia metilmalónica, y contradictoriamente aumento de vitamina B12 en sangre. Es importante el diagnóstico oportuno de enfermedades potencialmente tratables, evitando o disminuyendo la severidad del fenotipo, a través de la implementación de nuevas tecnologías en nuestro país.

ABSTRACT Neonatal screening for innate metabolism disorders was instituted more than 50 years ago. In Latin America, countries like Uruguay, Costa Rica, Chile, Brazil, and Colombia have implemented this public health measurement in a sustained fashion. Technology for detecting these conditions has been steadily progressing, achieving a good cost/effectiveness ratio, so access for such test is practically universal. Intracellular cobalamin metabolism disorders constitute a heterogeneous group that is subdivided in three biochemical phenotypes. We report the first patient in Peru with a late diagnosis of a homozygous c.394 C>T variant in the MMACHC gene, which belongs to the cbIC complementation group, which leads to methyl-malonic aciduria and homocystinuria, characterized by low height, retardation of psychomotor development, seizures, megaloblastic anemia, and variable thrombocytopenia and neutropenia. Also, homocysteine levels are high, there is methyl-malonic academia, and there is a paradoxical vitamin B12 increase in peripheral blood. This paper emphasizes the importance of making a timely diagnosis of potentially treatable conditions, avoiding or reducing the severity of the implied phenotype, with the implementation of new technologies in our country.

Clinical Application of Liquid Chromatography Tandem Mass Spectrometry Using Dried Blood Spot as a More Rapid Method for Determination of Methylmalonic Acid, Propionylcarnitine, and Total Homocysteine

Abstract Methylmalonic acidemia (MMA) should be diagnosed in early infancy and receive appropriate management promptly after the diagnosis to prevent severe complications leading to death. At present, a newborn screening (NBS) method using tandem mass spectrometry (MS/MS) identifies suspected patients with MMA by elevated propionylcarnitine. In addition, a liquid chromatography tandem mass spectrometry (LC/MS/MS) method using dried blood spot is effective to detect some metabolites as a second-tier test, and reduces the false-positive rate in NBS. However, these tests were only used in screening, and not applied as an examination for evaluating treatment. Herein, we describe a 57-day-old girl with MMA under treatment with cobalamin who had elevated urinary methylmalonic acid levels. We applied the LC/MS/MS method with a separation column to evaluate her cobalamin responsiveness, and discovered an insufficient cobalamin dose earlier than would have been possible using other methods. Based on the current data, this method seems to be applicable for the follow-up of the treatment of MMA patients. However, this should be confirmed with more experience with a larger number of cases and a wider spectrum of disorders.

Deficiencia de cobalamina C de inicio temprano: presentación de caso clínico / Early onset cobalamin C deficiency: clinical case presentation

Cobalamin C (CblC) deficiency is an autosomal recessive disorder caused by mutations of the MMACHC gene that results in impaired synthesis of the methylcobalamin and adenosylcobalamin co-factors. This brings an impaired conversion of dietary cobalamin and therefore dysfunction of two key enzymes generating hyperhomocysteinemia, hypometionimemia and methylmalonic aciduria. It is the most common intracellular metabolism disorder of cobalamin. The early clinical form is the most frequent disorder and appears as a multisystemic disease with developmental delay, failure to thrive, and ocular, renal and hematological involvement during the first year of life. The thromboembolic events are associated with small vessel involvement, generating thrombotic microangiopathy responsible for renal involvement and pulmonary thromboembolism. The late-onset form is characterized by leukoencephalopathy, psychiatric disorders, subacute degeneration of the spinal cord, and thromboembolic events of medium to large vessels. The treatment currently available increases the survival of the patient and improves growth, neurological manifestations, biochemical, hematological profile and hydrocephalus. We present the neonatal debut of a case of CblC deficiency that appeared as a multisystem disease with initial neurological, ocular and hematological manifestations. The onset of symptoms was acute, a characteristic that is not frequent in CblC. The patient started treatment early, but in an unsatisfactory fashion, which led to increased neurological deterioration. Due to MRI images performed during the evolution of his condition, a superior and transverse sagittal sinus thrombosis, a rare manifestation of the disease, was observed.

La deficiencia de cobalamina C (CblC) es un defecto autosómico recesivo causado por la mutación del gen MMACHC, que resulta en la síntesis alterada de los cofactores metilcobalamina y adenosilcobalamina. Esto trae aparejado una disfunción de dos enzimas claves, lo cual genera hiperhomocisteinemia, hipometionimemia y aciduria metilmalónica. La presentación clínica de la deficiencia de CblC es heterogénea, y varía desde las formas de inicio temprano graves y potencialmente mortales, hasta los fenotipos más leves de inicio tardío. La forma clínica temprana es la más frecuente y se manifiesta como una enfermedad multisistémica, con restricción del desarrollo, restricción del crecimiento y alteraciones oculares, renales y hematológicas durante el primer año de vida. Las manifestaciones tromboembólicas están asociadas con el compromiso de pequeños vasos, lo que causa microangiopatía trombótica, responsable de compromiso renal y de tromboembolismo pulmonar. La forma tardía se caracteriza por leucoencefalopatía, trastornos psiquiátricos, degeneración subaguda de la médula espinal y eventos tromboembólicos de medianos o grandes vasos. El tratamiento disponible actualmente aumenta la supervivencia de la enfermedad y mejora el crecimiento, las manifestaciones neurológicas, el perfil bioquímico y hematológico y la hidrocefalia. Presentamos el debut neonatal de un caso de deficiencia de CblC que se manifestó con compromiso inicial neurológico, ocular y hematológico. El comienzo de los síntomas fue agudo, característica que no es frecuente en la deficiencia de CblC. El tratamiento se inició tempranamente, pero en forma insatisfactoria, con evolución de deterioro neurológico. En la evolución de su enfermedad en las imágenes de resonancia magnética, se puso de manifiesto trombosis de los senos sagital superior y transversos, una rara manifestación de la deficiencia de CblC.

Deficiencia de vitamina B 12: una presentación atípica / Vitamin B12 deficiency: an atypical presentation

Resumen La importancia de la detección de la deficiencia de vitamina B12 radica en que es una causa reversible de fallo de medula ósea y desmielinización del sistema nervioso. Se puede presentar en hallazgos de laboratorio con datos de hemólisis con recuento reticulocitario disminuido, a diferencia otras formas de anemia hemolítica. La degeneración combinada subaguda medular es una manifestación atípica de la deficiencia de cobalamina; se trata de un proceso desmielinizante asociado a muerte neuronal, que se manifiesta en individuos con niveles muy bajos de esta vitamina y con síntomas inicialmente neurológicos, como parestesias en extremidades y debilidad generalizada. Se reporta el caso de una paciente femenina de 35 años, con hemólisis asociada a bicitopenia, manejada con altas dosis de esteroides sin mejoría clínica, que luego consultó por cuadro de 2 meses de evolución de parestesias e inestabilidad de la marcha. Al examen físico se documentó marcha atáxica, Romberg positivo y estudios de laboratorio que revelaron anemia megaloblástica con datos de hemolisis y reticulocitos disminuidos.

Abstract Vitamin B12 deficiency it's a reversible cause of bone marrow failure and is associated with demyelination of the nervous system, it's important to make the diagnosis correctly and early to prevent irreversible damage. It can present with laboratory findings suggestive of hemolysis with decreased reticulocyte count unlike other forms of hemolytic anemia. The combined subacute marrow degeneration is an atypical manifestation of cobalamin deficiency, it's a demyelinating process associated with neuronal death that occurs with very low levels of this vitamin, the initial manifestations are neurological symptoms like paresthesia in limbs and generalized weakness. This case report analyzes a 35-year-old female with a recent diagnosis of Evans syndrome, due to the presence of hemolysis. Now she comes with a medical record of 2-month presenting with paresthesias and gait instability. The physical examination documented ataxic gait, positive Romberg sing and laboratory findings that reveal macrocytic anemia and hemolysis data with decreased reticulocytes count.

Hipervitaminosis B12: Nuestra experiencia y una revisión / Hypervitaminosis B12. Our experience and a review

Los altos niveles de vitamina B12 o cobalamina, también denominado hipervitaminosis B12 es una anormalidad analítica frecuentemente subestimada. De acuerdo con la literatura algunas de las entidades relacionadas con este hallazgo son las neoplasias sólidas (primarias o metastásicas) y las enfermedades hematológicas agudas o crónicas. Otras causas incluyen la afección hepática, la gammapatía monoclonal de significación indeterminada, la insuficiencia renal y, con menor frecuencia, un exceso de consumo de vitamina B12, enfermedades inflamatorias o autoinmunes y los trastornos hematológicos transitorios (neutrofilia y eosinofilia secundaria). Este artículo informa sobre causas de hipervitaminosis B12, nuestra experiencia y hace una revisión de la literatura.

High serum levels of vitamin B12 or cobalamin, also called hypervitaminemia B12, is a frequently underestimated biological abnormality. According to the literature, some of the entities related to this finding are solid neoplasia (primary or metastatic) and acute or chronic hematological diseases. Other causes include liver disorders, monoclonal gammapathy of undetermined significance, renal failure and, less frequently, excess of vitamin B12 intake, inflammatory or autoimmune diseases, and transient hematological disorders (neutrophilia and secondary eosinophilia). This article reports on causes of hypervitaminosis B12, our experience and a review of the literature.

A case report on hyperpigmentation in vitamin B12 deficiency

Cobalamin (Vitamin B12) is a water-soluble vitamin. Cobalamin is synthesized only by microorganisms. The only source of vitamin B12 for humans is food of animal origin. Hyperpigmentation of skin has been reported only rarely as the presenting manifestation of vitamin B12 deficiency. We report a patient who had hyperpigmentation as her presenting medical complaint and in whom Vitamin B12 deficiency was the cause.  A 36-year-old female presented with generalised weakness and progressive and asymptomatic hyperpigmentation of hand and feet for 5 months. She is vegetarian by diet. On examination, hyperpigmentation was present over dorsal aspect of metacarpophalangeal, proximal and distal interphalangeal joints. Hyperpigmentation were present over dorsum of the foot and over the joints. The tongue was depaillated, and hyperpigmentation was present. Her serum level of vitamin B12 was diminished (83pg/ml). Megaloblastic anemia presents with protean manifestations. The association between vitamin B12 deficiency and hyperpigmentation, although unusual, has been described. Cutaneous manifestations associated with B12 deficiency include characteristic mucocutaneous hyperpigmentation (most common), vitiligo, angular cheilitis, and hair-nail changes. It mainly affects knuckle pads and oral mucosa. It is an under-recognized sign of megaloblastic anemia and should always be looked for in the setting of pallor. Hyperpigmentation could be the earliest manifestation of vitamin B12 deficiency before anemia sets in. It is worthwhile to consider the possibility of vitamin B12 or folate deficiency in a patient with unexplained pigmentary changes. Early detection and adequate treatment will prevent anemia and various neurological manifestations.

A randomized, open labeled study comparing the serum levels of cobalamin after three doses of 500 mcg vs. a single dose methylcobalamin of 1500 mcg in patients with peripheral neuropathy

BACKGROUND: Vitamin B12 deficiency has been associated with peripheral neuropathy, loss of sensation in the peripheral nerves, and weakness in the lower extremities. Methylcobalamin is the most effective analogue of vitamin B12 used to treat or prevent the complications associated with vitamin B12 deficiency. The current study aimed to compare the serum cobalamin levels after administration of two different regimes of methylcobalamin in peripheral neuropathy patients. METHODS: The present study was a prospective, randomized, comparative study. The study consisted of two parallel groups, group A (methylcobalamin 500 µg injection intramuscularly three times a week) and group B (methylcobalamin 1500 µg injection intramuscularly once a week). A control group of healthy volunteers was also included. RESULTS: A total of 24 patients (12 in each group) were included in the study. Five healthy volunteers were also included as a control in each group. At the end of treatment, serum cobalamin levels were significantly (P = 0.028) higher in group A (1892.08 ± 234.50) as compared with group B (1438.5 ± 460.32). The serum cobalamin levels in Group A healthy volunteers were also two times higher than that of group B (P = 0.056). Both the LANSS scale and DN4 questionnaire reported similar results at end of treatment. CONCLUSIONS: The 500 µg methylcobalamin thrice weekly regime is more effective in increasing the serum cobalamin levels as compared to the 1500 µg methylcobalamin once weekly regime.

Demencia reversible por déficit de vitamina B12 en un adulto mayor / Reversible dementia caused by vitamin B12 deficiency in an older adult

Se presenta el caso de un paciente adulto mayor con antecedente de haber presentado úlcera gástrica hace 40 años, cuyos familiares observaron desde hace dos meses cambios en el comportamiento, los cuales incluyeron progresivamente desorientación, agitación psicomotriz, negativismo, delirio de persecución, lo que motivó ser traído al servicio de emergencia. Así mismo presentó palidez marcada y equimosis múltiple, por lo cual fue admitido posteriormente en nuestro servicio y diagnosticado de demencia reversible por anemia perniciosa. También se le detectó pancitopenia y cambios neurológicos. El paciente respondió favorablemente a la administración de vitamina B12.

This is the case of an elderly patient with a 40-year history of stomach ulcer, whose relatives perceived behavioral changes for the last two months. Those changes progressively included disorientation, psychomotor agitation, negativism and delirium of persecution, which caused him to be brought to the emergency room. He also showed marked pallor and multiple ecchymosis, due to which he was hospitalized in our service and diagnosed with reversible dementia caused by pernicious anemia. Pancytopenia and neurological changes were also found. The patient responded favorably to the administration of vitamin B12.

Evaluation of the ability to metabolize 1, 2-propanediol by heterofermentative bacteria of the genus Lactobacillus

Background: New directions of research on lactic acid bacteria include investigation of metabolic pathways for the synthesis and/or metabolism of 1,2-propanediol, commonly used in the food and chemical industry, medicine, pharmacy and cosmetology as well as agriculture. The objective of this study was to compare the capacity of strains representing three diverse heterofermentative species belonging to the genus Lactobacillus to synthesize and/or transform 1,2-PD as well as to suggest new directions of research aimed at commercial use of this metabolite. Results: The novel strain of Lactobacillus buchneri A KKP 2047p, characterized as exhibiting an unusual trait for that species in the form of capacity to metabolize 1,2-PD, grew poorly in a medium containing 1,2-PD as a sole carbon source. The supplementation with glucose facilitated rapid growth of bacteria and use of 1,2-PD for the synthesis of propionic acid. A similar observation was noted for Lactobacillus reuteri. On the other hand, Lactobacillus diolivorans effectively metabolized 1,2-PD which was the sole carbon source in the medium, and the addition of glucose inhibited the synthesis of propionic acid. The experiments also investigated the effect of cobalamin as a diol dehydratase coenzyme involved in the propionic acid synthesis from 1,2-PD whose addition promoted the yield of the reaction in the case of all tested strains. Conclusions: All tested isolates showed the ability to effectively metabolize 1,2-PD (in the presence of cobalamin) and its conversion to propionic acid, which reveals that investigated bacteria meet the essential requirements of microorganisms with a potential application.

Hampered Vitamin B12 Metabolism in Gaucher Disease?

Abstract Untreated vitamin B12 deficiency manifests clinically with hematological abnormalities and combined degeneration of the spinal cord and polyneuropathy and biochemically with elevated homocysteine (Hcy) and methylmalonic acid (MMA). Vitamin B12 metabolism involves various cellular compartments including the lysosome, and a disruption in the lysosomal and endocytic pathways induces functional deficiency of this micronutrient. Gaucher disease (GD) is characterized by dysfunctional lysosomal metabolism brought about by mutations in the enzyme beta-glucocerebrosidase (Online Mendelian Inheritance in Man (OMIM): 606463; Enzyme Commission (EC) 3.2.1.45, gene: GBA1). In this study, we collected and examined available literature on the associations between GD, the second most prevalent lysosomal storage disorder in humans, and hampered vitamin B12 metabolism. Results from independent cohorts of patients show elevated circulating holotranscobalamin without changes in vitamin B12 levels in serum. Gaucher disease patients under enzyme replacement therapy present normal levels of Hcy and MMA. Although within the normal range, a significant increase in Hcy and MMA with normal serum vitamin B12 was documented in treated GD patients with polyneuropathy versus treated GD patients without polyneuropathy. Thus, a functional deficiency of vitamin B12 caused by disrupted lysosomal metabolism in GD is a plausible mechanism, contributing to the neurological form of the disorder but this awaits confirmation. Observational studies suggest that an assessment of vitamin B12 status prior to the initiation of enzyme replacement therapy may shed light on the role of vitamin B12 in the pathogenesis and progression of GD.

Efectividad de la administración oral versus intramuscular de vitamina B12 en pacientes con deficiencia: revisión sistemática / Efectiviness of the oral administration versus intramuscular of B12 vitamin in patients with deficiency: systematic review

La deficiencia de la vitamina B12 o cobalamina es una condición muy común y es una de las causas más importantes de la anemia. Puede ser tratada con un tratamiento oral o intramuscular. Se realizó una síntesis de la evidencia a través de una revisión sistemática de ensayos clínicos aleatorizados que hayan comparado ambos tratamientos para el manejo de estos pacientes. La estrategia de búsqueda incluyó ensayos clínicos aleatorizados (ECA); las bases de datos usadas fueron: Medline, Cochrane Central, Lilacs y Cinahl. Además se realizó una búsqueda electrónica en Google Scholar. Los resultados obtenidos fueron de tres artículos que cumplían con nuestros criterios de elegibilidad. El objetivo de esta revisión fue determinar si existe evidencia científica que avale la efectividad de la administración oral versus intramuscular de la vitamina B12 para el tratamiento de su deficiencia. Se concluyó que existe moderada evidencia que la administración de la vitamina B12 oral es más efectiva que la administración intramuscular a mediano plazo en el volumen sérico de cobalamina en pacientes con déficit de vitamina B12.

Vitamin B12 or cobalamin deficiency is a very common condition and is one of the most important causes of anemia. It can be treated with oral or intramuscular treatment. A summary of the evidence will be made through a systematic review of rando-mized clinical trials that have compared both treatments for the management of these patients. The objective of this review was to determine whether there is scientific evidence supporting the effectiveness of oral versus intramuscular vitamin B12 treatment ofits deficiency. The search strategy included randomized clinical trials (RCTs); databases used were: Medline, Cochrane Central, Lilacs and CINAHL. Also an electronic search in Google Scho-lar was performed. The results were three articles that met our eligibility criteria. We conclude that there is moderate evidence that the administration of oral vitamin B12 is most effective in the medium term increment serum cobalamin volume in patients with vitamin B12 deficiency.

Vitamin B supplementation for diabetic peripheral neuropathy

Vitamin B12 deficiency has been associated with significant neurological pathology, especially peripheral neuropathy. This review aims to examine the existing evidence on the effectiveness of vitamin B12 supplementation for the treatment of diabetic peripheral neuropathy. A search of PubMed and the Cochrane Central Register of Controlled Trials for all relevant randomised controlled trials was conducted in December 2014. Any type of therapy using vitamin B12 or its coenzyme forms was assessed for efficacy and safety in diabetics with peripheral neuropathy. Changes in vibration perception thresholds, neuropathic symptoms and nerve conduction velocities, as well as the adverse effects of vitamin B12 therapy, were assessed. Four studies comprising 363 patients met the inclusion criteria. This review found no evidence that the use of oral vitamin B12 supplements is associated with improvement in the clinical symptoms of diabetic neuropathy. Furthermore, the majority of studies reported no improvement in the electrophysiological markers of nerve conduction.