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.

Galactic Cosmic Rays Throughout the Heliosphere and in the Very Local Interstellar Medium.

We review recent observations and modeling developments on the subject of galactic cosmic rays through the heliosphere and in the Very Local Interstellar Medium, emphasizing knowledge that has accumulated over the past decade. We begin by highlighting key measurements of cosmic-ray spectra by Voyager, PAMELA, and AMS and discuss advances in global models of solar modulation. Next, we survey recent works related to large-scale, long-term spatial and temporal variations of cosmic rays in different regimes of the solar wind. Then we highlight new discoveries from beyond the heliopause and link these to the short-term evolution of transients caused by solar activity. Lastly, we visit new results that yield interesting insights from a broader astrophysical perspective.

Clinical, Biochemical and Molecular Characterization of a Cohort of Glycogen Storage Disease Type I Patients in a High Complexity Hospital in Argentina

Abstract Glycogen storage disease type I is an autosomal recessive disorder of carbohydrate metabolism that manifests mainly by hepatomegaly and hypoglycemia with short fasts. Despite strict therapy, patients present long-term renal and liver complications. Data of 36 patients,29 GSD Ia and 7 Ib from a high complexity Hospital in Argentina was collected retrospectively. Collected data included diagnosis, anthropometric, biochemical parameters, therapy and follow-up. Treatment increased Height SDS (p=0.012). Patients with good adherence to therapy presented better growth parameters (p=0.049). Instead, admissions were detrimental (p =0.031) and were more common in Ib patients (p=0.002). The early appearance of complications (liver adenomas and nephropathy) was related to sustained triglyceride values > 500mg / dl (p=0.009 and 0.046 respectively). With intensive dietary treatment, clinical and biochemical status improves but cannot be completely corrected in most patients. Growth improves with treatment and this is optimized with adequate adherence. We must take into account that with ageing, more complications will develop.

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.

Hiperamonemia secundaria a infección urinaria en un paciente con malformación del tracto urinario en pediatría: a propósito de un caso / Hyperammonemia secondary to urinary tract infection in patients with pediatric urinary tract malformation: a case report

Ammonium is an important source of nitrogen for amino acid synthesis and is necessary for normal acid base balance. When ammonium concentrations are high it becomes a toxic compound. Hyperammonemia is a metabolic emergency. When underdiagnosed and not treated appropriately, it produces severe neurological sequelae and/or death. The clinical presentation of hyperammonemic encephalopathy varies, and includes from personality disorders, psychiatric disorders, confusion, irritability, lethargy, seizures to coma. Hyperammonemia occurs with an increase in ammonium production, as in intestinal hemorrhage, or with a decrease in the elimination of ammonium, such as in congenital metabolic errors, hepatic insufficiency or drug intoxication. As we can see, it may have multiple origins, but congenital errors of metabolism are always suspected as one of the causes. However, there are less frequent causes, such as urinary tract infection, especially in predisposing conditions. We describe the case of a 2-year-old boy with a history of horseshoe kidney and right ureterohydronephrosis, surgical correction of imperforate anus and rectal bladder fistula. This patient presented hyperammonemia with encephalopathy (Glasgow 7/15) while undergoing a urinary infection with Corynebacterium riegelii. Hyperammonemia is the result of the production in the dilated urinary tract of large amounts of ammonium due to bacterial urease and its subsequent reabsorption in the systemic circulation. The patient improved clinically (Glasgow 15/15) after parenteral antibiotic therapy and urinary tract clearance

El amonio es una fuente importante de nitrógeno para la síntesis de aminoácidos y necesario para el balance ácido base; si se encuentra elevado, se convierte en un compuesto tóxico. La hiperamoniemia es una urgencia metabólica; cuando no es diagnosticada y tratada de manera oportuna, produce graves secuelas de tipo neurológico o la muerte. La presentación clínica de la encefalopatía hiperamoniémica es variable, pudiéndose observar trastornos en la personalidad, trastornos psiquiátricos, confusión e irritabilidad, letargia, convulsión y coma. La hiperamoniemia se presenta por aumento en la producción de amonio, como en la hemorragia intestinal, o por disminución de la eliminación del mismo, como ocurre en los errores congénitos del metabolismo, en la insuficiencia hepática o en la intoxicación por fármacos. Puede tener múltiples orígenes, pero los errores congénitos del metabolismo son una de las causas que siempre se sospechan. Sin embargo, existen causas menos frecuentes, como la infección del tracto urinario (sobre todo en condiciones que predispongan a las mismas). Describimos aquí el caso de un niño de 2 años, con antecedentes de riñón en herradura y ureterohidronefrosis derecha, corrección quirúrgica de ano imperforado y fistula recto vesical. Este paciente presentó hiperamoniemia con encefalopatía (Glasgow 7/15) mientras cursaba una infección urinaria por Corynebacterium riegelii. La hiperamoniemia es el resultado de la producción en el tracto urinario dilatado de grandes cantidades de amonio, debido a la ureasa bacteriana y su posterior reabsorción en la circulación sistémica. El paciente mejoró clínicamente (Glasgow 15/15) después de la terapia antibiótica parenteral y desobstrucción de tracto urinario

Citrulinemia tipo I con insuficiencia hepática recurrente en un niño / Citrullinemia type I with recurrent liver failure in a child

La citrulinemia tipo I es un desorden autosómico recesivo causado por la mutación del gen ASS1, que expresa argininosuccinato sintetasa, enzima limitante del ciclo de la urea. Las variantes clásicas están asociadas con la forma neonatal/infantil, que llevan a hiperamoniemia y a la muerte si el tratamiento no es instaurado. Los síntomas iniciales de los trastornos del ciclo de la urea incluyen deterioro neurológico con leve o moderado daño hepático. Reportamos un caso de falla hepática recurrente en un lactante con diagnóstico de citrulinemia tipo I sin compromiso neurológico grave, que fue derivado a nuestro centro para trasplante hepático. La falla hepática aguda puede ser causada por una gran variedad de desórdenes, dentro de los que se incluyen errores congénitos del metabolismo. El tratamiento adecuado de los trastornos del ciclo de la urea y, en particular, la citrulinemia I puede evitar la necesidad de un trasplante.

Citrullinemia type I is an autosomal recessive disorder caused by mutation of the gene expressing ASS1 argininosuccinate synthetase, limiting enzyme of the urea cycle. The classic variants are associated with neonatal/infantile forms that cause hyperammonemia leading to death if treatment is not established. Initial symptoms of disorders of the urea cycle include neurological impairment with mild or moderate liver damage. We report a case of recurrent liver failure in an infant diagnosed with type I citrullinemia without severe neurological involvement that was referred to our center for liver transplantation. Acute liver failure can be caused by a wide range of disorders in which inborn errors ofmetabolism are included. Appropriate treatment of disorders of the urea cycle and in particular citrullinemia I can avoid the need for a transplant.

[Citrullinemia type I with recurrent liver failure in a child]. / Citrulinemia tipo I con insuficiencia hepática recurrente en un niño.

Citrullinemia type I is an autosomal recessive disorder caused by mutation of the gene expressing ASS1 argininosuccinate synthetase, limiting enzyme of the urea cycle. The classic variants are associated with neonatal/infantile forms that cause hyperammonemia leading to death if treatment is not established. Initial symptoms of disorders of the urea cycle include neurological impairment with mild or moderate liver damage. We report a case of recurrent liver failure in an infant diagnosed with type I citrullinemia without severe neurological involvement that was referred to our center for liver transplantation. Acute liver failure can be caused by a wide range of disorders in which inborn errors of metabolism are included. Appropriate treatment of disorders of the urea cycle and in particular citrullinemia I can avoid the need for a transplant.

La citrulinemia tipo I es un desorden autosómico recesivo causado por la mutación del gen ASS1, que expresa argininosuccinato sintetasa, enzima limitante del ciclo de la urea. Las variantes clásicas están asociadas con la forma neonatal/ infantil, que llevan a hiperamoniemia y a la muerte si el tratamiento no es instaurado. Los síntomas iniciales de los trastornos del ciclo de la urea incluyen deterioro neurológico con leve o moderado daño hepático. Reportamos un caso de falla hepática recurrente en un lactante con diagnóstico de citrulinemia tipo I sin compromiso neurológico grave, que fue derivado a nuestro centro para trasplante hepático. La falla hepática aguda puede ser causada por una gran variedad de desórdenes, dentro de los que se incluyen errores congénitos del metabolismo. El tratamiento adecuado de los trastornos del ciclo de la urea y, en particular, la citrulinemia I puede evitar la necesidad de un trasplante.

Galactic cosmic ray simulation at the NASA Space Radiation Laboratory.

Most accelerator-based space radiation experiments have been performed with single ion beams at fixed energies. However, the space radiation environment consists of a wide variety of ion species with a continuous range of energies. Due to recent developments in beam switching technology implemented at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory (BNL), it is now possible to rapidly switch ion species and energies, allowing for the possibility to more realistically simulate the actual radiation environment found in space. The present paper discusses a variety of issues related to implementation of galactic cosmic ray (GCR) simulation at NSRL, especially for experiments in radiobiology. Advantages and disadvantages of different approaches to developing a GCR simulator are presented. In addition, issues common to both GCR simulation and single beam experiments are compared to issues unique to GCR simulation studies. A set of conclusions is presented as well as a discussion of the technical implementation of GCR simulation.