Enzyme replacement therapy interruption in mucopolysaccharidosis type IVA patients and its impact in different clinical outcomes.

Mucopolysaccharidosis type IVA (MPS IVA) is an autosomal recessive lysosomal storage disorder caused by mutations in the GALNS gene, which leads to deficient activity of N-acetylglucosamine-6-sulfate sulfatase. MPS IVA patients usually present skeletal dysplasia, coarse features, short stature, airway obstruction, cervical spinal cord compression, dental abnormalities, and cardiac valvular alterations. Enzyme replacement therapy (ERT) with elosulfase alfa is the only disease-specific treatment available for MPS IVA patients and has been shown to improve important clinical and biochemical parameters; however, little is known about the effects of ERT interruption on these patients. In this article, we report the impact of different periods of treatment interruption on clinical outcomes of 18 MPS IVA patients. All MPS IVA patients included in this case series were treated and followed up in Latin American centers and had been receiving elosulfase alfa intravenously for at least 8 months before ERT was interrupted. Different clinical parameters and assessments were evaluated at variable timepoints following therapy interruption. Altogether, our report indicates that some beneficial ERT effects in MPS IVA patients may last after different periods of treatment interruption, as cardiac and respiratory function improvements. However, worsening of important disease parameters after ERT interruption, such as the increase in uGAGs, pain, joint and skeletal aspects, and surgery indications suggests that treatment discontinuation should be avoided in order to maintain the disease as stable as possible, aiming to optimize these patients' life expectancy and quality of life.

Molecular Characterization of the GBA Gene in Patients from Southwest of Colombia with Gaucher Disease

Abstract Introduction Gaucher's disease (GD) is an autosomal-recessive lysosomal storage disorder that results from hereditary deficiency of the acid glucocerebrosidase enzyme, encoded by the GBA gene necessary for the degradation of glucosylceramide. Objective molecularly characterize the variants found in the GBA gene present in patients from the Southwest of Colombia with GD. Material and methods 19 patients were included in the study, clinically and enzymatically diagnosed with GD. A molecular analysis of the GBA gene was performed and the variants were subsequently searched in different population and clinical databases. A bioinformatic analysis was performed. Results The variants in the GBA gene reported were classified into: 14/19 homozygous patients, 4/19 compound heterozygote and 1/19 heterozygous. The presence of 7 variants coding for 8 different genotypes was reported. Also the known mutations like Asn409Ser, p.Leu483Pro, p.Lys237Glu, p.Glu427Lys, and p.Arg535His were identified in these patients. The most frequent genotype was p. Asn409Ser / Asn409Ser (36%). All the variants presented a pathogenic clinical significance. Conclusion The given study will make it possible to understand the susceptibility to GD in the population. This can help maintain the health quotient of the population through premarital counseling and therefore minimize the burden of disease among the population.

Determination of the Population Allelic Frequency of the Variants of the MPS Complex in Southwestern Colombia

Abstract Mucopolysaccharidoses are lysosomal storage diseases characterized by the excessive accumulation of glycosaminoglycan sulfate in organs and tissues. To determine the population allelic frequency of the MPS complex variants in a population without clinical and molecular diagnosis of MPS. An observational descriptive study was carried out where the allelic frequency of variants presents in the IDUA, IDS, SGSH, NAGLU, HGSNAT, GNS, GALNS, GLB1, ARSB, GUSB, HYAL1 genes was determined by means of the sequencing of 320 exomes from patients without a clinical diagnosis of MPS; the results were tabulated, and allelic frequency formulas were used to determine the values associated with each of the genes. 509 alleles associated with the MPS complex were reported, of which 262 have not been previously reported. Genes with the most frequent allelic presence were IDUA, GLB1 and GALNS, involved in MPS I and MPS IV A / B. The total frequencies ranged between 0.00393 (2 alleles) and 0.47937 (248 alleles). These studies make it possible to determine polymorphisms that circulate in the country, present in patients not affected with MPS, allowing to expand the knowledge about the characteristics of the alleles that are present in affected patients.

Enzyme replacement therapy interruption in patients with Mucopolysaccharidoses: Recommendations for distinct scenarios in Latin America.

BACKGROUND: Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders, leading to the progressive accumulation of glycosaminoglycans (GAGs) and the subsequent compromising of tissues and organ malfunction. Although incurable, most types of MPS can be treated with enzyme replacement therapy (ERT), an approach that has had positive effects on the natural clinical evolution and which impact has been extensively investigated. Unfortunately, to date, there is relatively little data regarding the effects of ERT interruption, especially in Latin America, where such interruption may be frequent due to a variety of issues (for instance, difficulties involving logistics, reimbursement and/or payment withdrawal). METHOD: A group of medical professionals from Latin America with experience in Genetics, Pediatrics and Neurology held an Advisory Board Meeting in the city of São Paulo, in October 2018, to discuss the issue of ERT interruptions in the region and recommendations health care professionals on how to deal with these interruptions and better assess the therapeutic effects of ERT. CONCLUSION: Recommendations provided by the experts may support physicians in dealing with the most common reasons for ERT interruptions in Latin America. Most importantly, recommendations for data collection at specific timepoints (at baseline, throughout the treatment and during the interruption period of ERT and after its resumption) can significantly improve the collection of real world evidence on the effects of ERT and its interruptions, supporting health care professionals and policy makers in the decision making regarding the provision of these therapies for MPS patients.

Variantes del gen GBA en el Suroccidente Colombiano / Variants of the GBA gene in the Southwest of Colombia

Introducción: La Enfermedad de Gaucher (EG) es un trastorno genético autosómico recesivo, causado por la deficiencia de la enzima B-Glucocerebrosidasa acida (GBA). En Colombia se ha estimado una prevalencia de 1:266.441 habitantes. Sin embargo, el país no cuenta con datos exactos sobre la incidencia, prevalencia y carga poblacional de esta enfermedad. Objetivo: Con el objetivo de caracterizar molecularmente las variantes encontradas en el gen GBA presentes en pacientes del Suroccidente Colombiano con enfermedad de Gaucher. Materiales y métodos: Se incluyeron 19 pacientes en el estudio, 57,8% de género masculino, con intérvalo de edad entre 4 y 71 años, diagnosticados clínica y enzimáticamente con EG. Se realizó un análisis molecular del gen GBA y posteriormente se buscaron las variantes en diferentes bases de datos poblacionales y clínicas; además se realizó análisis bioinformático para evaluar el posible impacto de las variantes de interés en la estructura y funcionalidad de la proteína. Resultados: Se encontraron 14/19 pacientes homocigotos; 4/19 heterocigotos compuestos y 1/19 heterocigotos). Se reportó la presencia de 7 variantes que codifican para 8 genotipos diferentes. El genotipo más frecuente es p.Asn409Ser/p.Asn409Ser (36%). De las 7 variantes encontradas, se reportó que específicamente p. Asn409Ser (10/23 alelos) y p.Leu483Pro (3/23 alelos) y p.Lys237Glu (3/23 alelos), están presentes en el 69,5% de los alelos. Todas las variantes presentaron una significancia clínica patogénica. Conclusiones: Este trabajo contribuye al establecimiento de las bases moleculares de la EG en los pacientes del Suroccidente Colombiano, permitiendo realizar una correlación genotipo-endotipo-fenotipo. Así mismo, se determina que los algoritmos de diagnóstico que incluyen análisis molecular y herramientas predictivas bioinformáticas permiten mejorar el diagnóstico, el tratamiento y el pronóstico de los pacientes afectados por EG, generando un impacto positivo en el seguimiento de los afectados, de la mano de una correcta consejería genética y estudios de portadores.

Introduction:Gaucher's disease (EG) is an autosomal recessive genetic disorder, caused by a deficiency of the acid B-Glucocerebrosidase (GBA) enzyme. In Colombia, a prevalence of 1: 266.441 inhabitants have been estimated. However, the country does not have exact data on the incidence, prevalence and population burden of this disease. Objective: molecularly characterize the variants found in the GBA gene present in patients from the Southwest of Colombia with Gaucher disease. Material and methods: 19 patients were included in the study, 57,8% male, with an age range between 4 and 71 years, clinically and enzymatically diagnosed with GD. A molecular analysis of the GBA gene was performed and the variants were subsequently searched in different population and clinical databases; In addition, a bioinformatic analysis was performed to evaluate the possible impact of the variants of interest on the structure and functionality of the protein. Results: 14/19 homozygous patients were found; 4/19 compound heterozygotes and 1/19 heterozygotes). The presence of 7 variants coding for 8 different genotypes was reported. The most frequent genotype was p.Asn409Ser/p.Asn409Ser (36%). Of the 7 variants found, it was reported that specifically p. Asn409Ser (10/23 alleles) and p.Leu483Pro (3/23 alleles) and p.Lys237Glu (3/23 alleles), are present in 69,5% of the alleles. All the variants presented a pathogenic clinical significance. Conclusion: This work contributes to the establishment of the molecular bases of GD in patients from the Southwest of Colombia, allowing a genotype-endotype-phenotype correlation to be carried out. Likewise, it is determined that diagnostic algorithms that include molecular analysis and bioinformatic predictive tools allow improving the diagnosis, treatment and prognosis of patients affected by GD, generating a positive impact on the follow-up of those affected, hand in hand with correct genetic counseling and carrier studies.

Presencia de duplicación 2p25.3 y síndrome de microdeleción 2q37.3 en un mismo individuo / Presence of 2p25.3 Duplication and 2q37.3 Microdeletion Syndrome in the Same Individual / Presença de duplicação 2p25.3 e síndrome da microdeleção 2p25.3 no mesmo indivíduo

Resumen: El estudio del cromosoma 2 en los seres humanos ha permitido reconocer que su alteración, basada en una localización específica, puede conducir a diversas enfermedades asociadas. Mediante la identificación fenotípica, sustentada en el estudio molecular de hibridación genómica comparativa y un estudio bioinformático posterior, se detectó la presencia de una duplicación patogénica en la región cromosómica 2p25.3p24.3, relacionada con la afección de 36 genes. Adicionalmente, se identificó una deleción patogénica en la citobanda 2q37.3, relacionada con la afección de 36 genes. El análisis bioinformático demostró interacciones entre genes que explican características sintomatológicas. Esta es la primera vez que se presentan estas dos variantes en un mismo individuo. Ambas alteraciones se han asociado con retraso psicomotor moderado, autismo, neurohipófisis ectópica, aracnodactilia, cardiopatía congénita y alteraciones cardiovasculares. Se ha propuesto que la mutación HDAC4 es la causante de la mayoría de las características del síndrome de microdeleción 2q37. El fenotipo clínico heterogéneo es el resultado del reordenamiento cromosómico encontrado, lo cual permite describir, interpretar y dar un tratamiento oportuno y dirigido a la paciente y la respectiva conserjería genética familiar. Finalmente, esta es la primera vez que se reporta este tipo específico de reordenamiento cromosómico.

Abstract: The study of chromosome 2 in humans has allowed recognizing that its alteration, based on a specific location, can lead to various associated diseases. Through the phenotypic identification, supported by comparative genomic hybridization and subsequent bioinformatic analysis, the presence of a pathogenic duplication was detected in the chromosomal region 2p25.3p24.3 affecting 36 genes. Additionally, a pathogenic deletion was identified in cytoband 2q37.3 affecting 36 genes. The bioinformatic analysis showed interactions among genes that explain symptomatic characteristics. This is the first time that these two variants are present in the same individual. Both disorders have been associated with moderate psychomotor retardation, autism, ectopic neurohypophysis, arachnodactyly, congenital heart disease, and cardiovascular disorders. The hdac4 mutation has been suggested to cause most of the features of 2q37 microdeletion syndrome. The heterogeneous clinical phenotype derives from the chromosomal rearrangement found, which allows describing, interpreting, and providing the patient with timely targeted treatment and the respective family genetic counseling. Finally, this specific type of chromosomal rearrangement has been reported for the first time.

Resumo: O estudo do cromossomo 2 em seres humanos nos permitiu reconhecer que sua alteração, com base em uma localização específica, pode levar a diversas doenças associadas. Por meio da identificação fenotípica, apoiada no estudo molecular da hibridação genômica comparativa e em um estudo bioinformático posterior, foi detectada a presença de uma duplicação patogénica na região cromossômica 2p25.3p24.3, relacionada a 36 genes afetados. Além disso, uma deleção patogénica foi identificada na citobanda 2q37.3, relacionada a 36 genes afetados. A análise bioinformática mostrou interações entre genes que explicam características sintomáticas. É a primeira vez que essas duas variantes são apresentadas no mesmo indivíduo. Ambos os distúrbios tém sido associados a retardo psicomotor moderado, autismo, neuro-hipófise ectópica, aracnodactilia, doenças cardíacas congénitas e distúrbios cardiovasculares. Propõe-se que a mutação hdac4 é a causa da maioria das características da síndrome de microdeleção 2q37. O fenótipo clínico heterogéneo é o resultado do rearranjo cromossômico encontrado, que permite descrever, interpretar e oferecer um tratamento oportuno direcionado ao paciente e ao respectivo aconselhamento genético familiar. Finalmente, também é a primeira vez que esse tipo específico de rearranjo cromossômico é relatado.

Complejidad de la expresión de genes asociados a obesidad en el tejido adiposo humano / Complexity of the expression of genes associated with obesity in human adipose tissue / Complexidade da expressão de genes associados à obesidade no tecido adiposo humano

Resumen Objetivo: Analizar la complejidad de la expresión génica en tejido adiposo de genes asociados con obesidad, mediante simulación computacional con diferentes herramientas bioinformáticas. Métodos: Después de una búsqueda bibliográfica en PubMed, se seleccionaron 37 genes asociados con obesidad con fold change mayor a 1,5. A partir del cálculo de valores de los z-score obtenidos de experimentos de micromatrices de ADN de muestras de tejido adiposo de personas obesas y de control, se construyó una red de interacción con el programa Cytoscape 3.2. La información detallada sobre las características genómicas de estos genes se extrajo de las bases de datos Genome Browser de la UCSC y del NCBI. Utilizando herramientas de análisis de multivariado, se hizo un análisis de componentes principales y uno de agrupación. Resultados: La red construida mostró que los genes con mayor número de interacciones fueron: 1) el factor nuclear respiratorio (NRF1), 2) el canal activado de potasio activado por calcio alfa 1 (KCNMA1) y 3) la sintasa de ácidos grasos (FASN). Los que tuvieron mayores valores de expresión fueron: 1) el factor de crecimiento endotelial vascular A (VEGFA), 2) la dioxigenasa dependiente de alfa-cetoglutarato (FTO) y 3) el regulador de crecimiento neuronal 1 (NEGR1). Las proteínas IL6, BDNF y HLC tuvieron los mayores valores de interacción con IL6R, NRF1 y ACACB, respetivamente. Las categorías ontológicas más importantes se relacionaron con procesos metabólicos de lipoproteínas, el ciclo de los ácidos tricarboxílicos, la activación de las MAP-quinasas y la cascada JNK. Conclusiones: En su conjunto los resultados obtenidos de sobreexpresión diferencial de genes asociados con el metabolismo de lípidos en el tejido adiposo de personas obesas podría ser un criterio para discriminar a nivel de diagnóstico esta patología.

Summary Objective: To analyze the complexity of gene expression in the adipose tissue of genes associated with obesity, by computer simulation with different bioinformatics tools. Methods: After conducting a PubMed literature search, 37 genes associated with obesity with a fold change greater than 1.5 were selected. An interaction network was cons tructed using the Cytoscape 3.2 program from the calculation of z-score values obtained from DNA microarray experiments of adipose tissue samples collected from obese and control people. Detailed information on the genomic characteristics of these genes was extracted from the UCSC and NCBI Genome Browser databases. Using multivariate analysis tools, a principal component analysis and a cluster analysis were carried out. Results: The constructed network showed that the genes with the greatest number of interactions were: 1) the nuclear respiratory factor (NRF1), 2) the activated channel of potassium activate by calcium alpha 1 (KCNMA1), and 3) the fatty acid synthase (FASN). Those with the higher expression values were: 1) vascular endothelial growth factor A (VEGFA), 2) alpha-ketoglutarate-dependent dioxygenase (FTO), and 3) neuronal growth regulator 1 (NEGR1). The IL6, BDNF and HLC proteins had the highest interaction values with IL6R, NRF1 and ACACB, respectively. The most important ontological categories were related to lipoprotein metabolic processes, the tricarboxylic acid cycle, the activation of the MAP kinases, and the JNK cascade. Conclusions: As a whole, the results obtained from differential overexpression of genes associated with lipid metabolism in the adipose tissue of obese people could be a criterion to discriminate this pathology at a diagnostic level.

Resumo Objetivo: Analisar a complexidade da expressão gênica no tecido adiposo de genes associados com obesidade, por meio de simulação por computador com diferentes ferramentas bioinformáticas. Métodos: Após uma busca bibliográfica em PubMed, foram selecionados 37 genes associados com obesidade com fold change superior a 1,5. A partir do cálculo de valores dos z-score obtidos de experimentos de micro matrizes de ADN de amostras de tecido adiposo de pessoas obesas e de controle, construiu-se uma rede de interação com o programa Cytoscape 3.2. A informação detalhada sobre as características genômicas destes genes foi obtida das bases de dados Genome Browser da UCSC e do NCBI. Utilizando ferramentas de análise de multivariado, fez-se uma análise de componentes principais e um de agrupação. Resultados: A rede construída mostrou que os genes com maior número de interações foram: 1) o fator nuclear respiratório (NRF1), 2) o canal ativado de potássio ativado por cálcio alfa 1 (KCNMA1) e 3) ácido graxo sintase (FASN). Os que tiveram maiores valores de expressão foram: 1) o fator de crescimento endo-telial vascular A (VEGFA), 2) a dioxigenase dependente de alfa-cetoglutarato (FTO) e 3) o regulador de crescimento neuronal 1 (NEGR1). As proteínas IL6, BDNF e HLC tiveram os maiores valores de interação com IL6R, NRF1 e ACACB, respectivamente. As categorias ontológicas mais importantes se relacionaram com processos metabólicos de lipoproteínas, o ciclo dos ácidos tri carboxílicos, a ativação das MAP-quinases e a cascata JNK. Conclusões: Em seu conjunto, os resultados obtidos de superexpressão diferencial de genes associados com o metabolismo de lipídios no tecido adiposo de pessoas obesas poderia ser um critério para discriminar a nível de diagnóstico esta patologia.

Caracterización funcional y estructural de genes asociados a preeclampsia expresados en la placenta humana / Structural and functional characterization of genes associated with preeclampsia expressed in human placenta / Caracterização estrutural e funcional de genes associados à pré-eclâmpsia expressaram em humanos placenta

Introducción: La preeclampsia continúa siendo la primera causa de morbimortalidad perinatal. El conocimiento sobre su etiología molecular se ha incrementado en los últimos años debido al avance en la aplicación de las ciencias "ómicas". Ello ha llevado a identificar genes candidatos que participarían en su patogénesis. Objetivo: Identificar y caracterizar estructural y funcionalmente genes expresados en placenta que se asocian con preeclampsia. Métodos: A partir de una revisión de literatura de los últimos diez años, se identificaron 16 genes cuya expresión en placenta estaba asociada con la patología. Se realizó la minería de datos incluyendo las siguientes variables: número de genes, tamaño de los genes, número de exones codificantes, islas CpG y las familias de los diferentes elementos repetidos en una ventana de 100Kbp. Mediante un análisis bioinformático, usando los diferentes recursos del NCBI (www.ncbi.nlm.nih.gov) y del Genome Browser de UCSC (http://genome.ucsc.edu/). Adicionalmente se usó el portal BioGPS (http://biogps.gnf.org/#goto=welcome) se determinaron los niveles de expresión de cada gen por tejidos. Resultados: Se registraron diferencias en la cromatina que contiene las familias de elementos no codificantes de los genes asociados en comparación con los controles (Prueba de Kruskall-Wallis, P= 0.0341824). Los genes LEP, EBI3, PROCR, FSTL3, HEXB, INHBA y ENG fueron los que registraron el mayor puntaje z en placentas preeclámpsicas. Conclusión:La aplicación de las herramientas bioinformáticas se convierte en un instrumento potente para el análisis integrado de la expresión de genes y su papel en la patogénesis de la PE. Esto conllevaría a la identificación temprana de mujeres afectadas.

Introduction: Preeclampsia still is the main cause of perinatal morbi-mortality; due to the advance in the application of the omics sciences the knowledge about its molecular etiology has increased in the last years, this has led to the identification of candidate genes, which would be involved in its pathogenesis. Objective: To identify those genes, expressed in placenta that are associated with preeclampsia and compare their structural and functional characteristics. Methods: From a literature review, 16 genes were found, whose expression in placenta was associated to the pathology. Data mining was performed including the following genomic variables: number of genes, genomic size, coding exon count, CpG islands and repeat elements in a 100Kbp window. For the Bioinformatics analysis, we used different resources of the NCBI (www.ncbi.nlm.nih.gov) and the UCSC Genome Browser (http://genome.ucsc.edu/). Furthermore, the portal BioGPS (http://biogps.gnf.org/#goto=welcome) Was used to determine the expression levels of each gene per tissue. Results: Significant differences were found for the non-coding elements of the chromatin in that associated genes, in comparison with controls (Kruskall-Wallis test, P= 0.0341824). The genes LEP, EBI3, PROCR, FSTL3, HEXB, INHBA and ENG were the ones with the highest z- score values in preeclampsic placenta. Conclusion: The application of computational tools has become a powerful instrument for the integrated analysis of gene expression and its role in the pathogenesis of PE. This would lead to an early detection of affected women.

Introdução: A pré-eclâmpsia ainda é a principal causa perinatal Morbi-mortalidade; devido ao avanço na aplicação das ciências "ómicas" o conhecimento sobre sua etiologia molecular tem aumentado nos últimos anos, Isto levou à identificação de genes candidatos, que estariam envolvidos na sua Patogênese. Objetivo: Para identificar esses genes, Expresso em placenta que está associada à pré-eclâmpsia e comparar as suas características estruturais e funcionais. Métodos: A partir de uma revisão da literatura, foram encontrados 16 genes, cuja expressão na placenta foi asociada à patología. Extração de dados Foi realizada incluindo as seguintes variáveis genómicas: Número de genes, tamanho genômico, exon contagem de codificação, CpG ilhas e repetir elementos em uma janela de 100Kbp. Para a análise bioinformática, Utilizamos diferentes recursos do NCBI (www.ncbi.nlm.nih.gov) e do UCSC Genome Browser (http://genome.ucsc.edu/). Além disso, o portal BioGPS (http://biogps.gnf.org/#goto=welcome) foi utilizado para determinar os níveis de expressão de cada gene por tecido. Resultados: Se encontrou diferenças significativas para os elementos não codificantes da cromatina nos genes associados, Em comparação com os controlos (teste de Kruskall-Wallis, P = 0,0341824). Os genes LEP, EBI3, PROCR, FSTL3, HEXB, INHBA e ENG foram os que apresentaram os maiores valores de z-score na placenta pré-eclâmpsica. Conclusão: A aplicação de ferramentas computacionais tornou-se um poderoso instrumento para a análise integrada da expressão gênica e seu papel na patogênese da PE. Isso levaria a uma detecção precoce das mulheres afetadas.

Global differential expression of genes located in the Down Syndrome Critical Region in normal human brain / Expresión diferencial global de genes localizados en la Región Crítica del Síndrome de Down en el cerebro humano normal

Background: The information of gene expression obtained from databases, have made possible the extraction and analysis of data related with several molecular processes involving not only in brain homeostasis but its disruption in some neuropathologies; principally in Down syndrome and the Alzheimer disease. Objective: To correlate the levels of transcription of 19 genes located in the Down Syndrome Critical Region (DSCR) with their expression in several substructures of normal human brain. Methods: There were obtained expression profiles of 19 DSCR genes in 42 brain substructures, from gene expression values available at the database of the human brain of the Brain Atlas of the Allen Institute for Brain Sciences", (http://human.brain-map.org/). The co-expression patterns of DSCR genes in brain were calculated by using multivariate statistical methods. Results: Highest levels of gene expression were registered at caudate nucleus, nucleus accumbens and putamen among central areas of cerebral cortex. Increased expression levels of RCAN1 that encode by a protein involved in signal transduction process of the CNS were recorded for PCP4 that participates in the binding to calmodulin and TTC3; a protein that is associated with differentiation of neurons. That previously identified brain structures play a crucial role in the learning process, in different class of memory and in motor skills. Conclusion: The precise regulation of DSCR gene expression is crucial to maintain the brain homeostasis, especially in those areas with high levels of gene expression associated with a remarkable process of learning and cognition.

Introducción: La información de la expresión de genes consignada en bases de datos, ha permitido extraer y analizar información acerca procesos moleculares implicados tanto en la homeostasis cerebral y su alteración en algunas neuropatologías. Objetivos: Correlacionar los niveles de transcripción de 19 genes localizados en la región crítica del cromosoma 21, asociada a Síndrome de Down (DSCR), con la localización cerebral y su coexpresión en diferentes subestructuras del cerebro humano. Métodos: A partir de valores de expresión génica disponibles en la base de datos del proyecto cerebro humano del Atlas del Cerebro del "Allen Institute for Brain Sciences" (http://human.brain-map.org/), se construyeron perfiles de expresión de 19 genes DSCR en 42 subestructuras cerebrales. Además, utilizando métodos estadísticos multivariados se analizaron los patrones de coexpresión de genes DSCR en el cerebro normal. Resultados: En el núcleo caudado, el núcleo accumbens y el putamen además de las Áreas centrales 2, 3 y 4, se determinaron los valores de expresión más elevados para los genes incluidos RCAN1, que codifica para una proteína involucrada en el proceso de transducción de señales de SNC; PCP4 cuya proteína interviene en la unión a la calmodulina y TTC3 una proteína que interviene en la diferenciación de neuronas. Las subestructuras identificadas con una elevada expresión de estos genes, están asociadas con procesos de aprendizaje, en diferentes tipos de memoria y habilidades motoras. Conclusiones: La regulación de la expresión de los genes DSCR es clave para mantener la homeostasis cerebral, especialmente en aquellas áreas de mayor expresión, las cuales están asociadas con procesos sumamente importantes.

Global differential expression of genes located in the Down Syndrome Critical Region in normal human brain.

BACKGROUND: The information of gene expression obtained from databases, have made possible the extraction and analysis of data related with several molecular processes involving not only in brain homeostasis but its disruption in some neuropathologies; principally in Down syndrome and the Alzheimer disease. OBJECTIVE: To correlate the levels of transcription of 19 genes located in the Down Syndrome Critical Region (DSCR) with their expression in several substructures of normal human brain. METHODS: There were obtained expression profiles of 19 DSCR genes in 42 brain substructures, from gene expression values available at the database of the human brain of the Brain Atlas of the Allen Institute for Brain Sciences", (http://human.brain-map.org/). The co-expression patterns of DSCR genes in brain were calculated by using multivariate statistical methods. RESULTS: Highest levels of gene expression were registered at caudate nucleus, nucleus accumbens and putamen among central areas of cerebral cortex. Increased expression levels of RCAN1 that encode by a protein involved in signal transduction process of the CNS were recorded for PCP4 that participates in the binding to calmodulin and TTC3; a protein that is associated with differentiation of neurons. That previously identified brain structures play a crucial role in the learning process, in different class of memory and in motor skills. CONCLUSION: The precise regulation of DSCR gene expression is crucial to maintain the brain homeostasis, especially in those areas with high levels of gene expression associated with a remarkable process of learning and cognition.

INTRODUCCIÓN: La información de la expresión de genes consignada en bases de datos, ha permitido extraer y analizar información acerca procesos moleculares implicados tanto en la homeostasis cerebral y su alteración en algunas neuropatologías. OBJETIVOS: Correlacionar los niveles de transcripción de 19 genes localizados en la región crítica del cromosoma 21, asociada a Síndrome de Down (DSCR), con la localización cerebral y su coexpresión en diferentes subestructuras del cerebro humano. MÉTODOS: A partir de valores de expresión génica disponibles en la base de datos del proyecto cerebro humano del Atlas del Cerebro del "Allen Institute for Brain Sciences" (http://human.brain-map.org/), se construyeron perfiles de expresión de 19 genes DSCR en 42 subestructuras cerebrales. Además, utilizando métodos estadísticos multivariados se analizaron los patrones de coexpresión de genes DSCR en el cerebro normal. RESULTADOS: En el núcleo caudado, el núcleo accumbens y el putamen además de las Áreas centrales 2, 3 y 4, se determinaron los valores de expresión más elevados para los genes incluidos RCAN1, que codifica para una proteína involucrada en el proceso de transducción de señales de SNC; PCP4 cuya proteína interviene en la unión a la calmodulina y TTC3 una proteína que interviene en la diferenciación de neuronas. Las subestructuras identificadas con una elevada expresión de estos genes, están asociadas con procesos de aprendizaje, en diferentes tipos de memoria y habilidades motoras. CONCLUSIONES: La regulación de la expresión de los genes DSCR es clave para mantener la homeostasis cerebral, especialmente en aquellas áreas de mayor expresión, las cuales están asociadas con procesos sumamente importantes.

Estudio genómico de la región crítica del cromosoma 21 asociada con el síndrome de Down / Genomic study of the critical region of chromosome 21 associated to Down syndrome

Introduction: Previous reports have identified a region of chromosome 21 known as Down syndrome critical region (DSCR) in which the expression of some genes would modulate the main clinical characteristics of this pathology. In this sense, there is currently limited information on the architecture of the DSCR associated. Objective: To obtain in silico a detailed vision of the chromatin structure associated with the evaluation of genomic covariables contained in public data bases. Methods: Taking as reference the information consigned in the National Center for Biotechnology Information, the Genome Browser from the University of California at Santa Cruz and from the HapMap project, a chromosome walk along 21 Mb of the distal portion of chromosome 21q arm was performed. In this distal portion, the number of single nucleotide polymorphisms (SNP), number of CpG islands, repetitive elements, recombination frequencies, and topographical state of that chromatin were recorded. Results: The frequency of CpG islands and Ref genes increased in the more distal 1.2 Mb DSCR that contrast with those localized near to the centromere. The highest level of recombination calculated for women was registered in the 21q22.12 to 22.3 bands. DSCR 6 and 9 genes showed a high percentage of methylation in CpG islands in DNA from normal and trisomic fibroblasts. The DSCR2 gene exhibited high levels of open chromatin and also methylation in some lysine residues of the histone H3 as relevant characteristics. Conclusion: The existence of a genomic environment characterized by high values of recombination frequencies and CpG methylation in DSCR 6 and 9 and also DSCR2 genes led us to postulate that in non-disjunction detected in Down syndrome, complex genomic, epigenetic and environmental relationships regulate some processes of meiosis.

Introducción: Análisis previos han identificado una región del cromosoma 21, conocida como región crítica del síndrome de Down (DSCR) en donde se localizan algunos genes cuya expresión modularía las principales características clínicas de este síndrome. En este sentido, existe poca información detallada sobre la arquitectura de la cromatina asociada con la DSCR. Objetivo: Obtener in silico, a partir de la evaluación de covariables genómicas contenidas en bases de datos públicas, una visión detallada de la estructura cromatina asociada con la DSCR. Métodos: Tomando como referencia la información consignada en el National Center for Biotechnology Information, el Genome Browser de la Universidad de California en Santa Clara y el proyecto internacional HapMap, se efectuó un paseo cromosómico a lo largo de 21Mb de la porción distal del brazo q del cromosoma 21, para registrar el número de polimorfismos de nucleótido único, el de islas CpG, de secuencias repetidas, las tasas de recombinación y el estado topológico de la cromatina asociada. Resultados: La frecuencia de islas CpG y de genes referenciados se incrementó en los últimos 1,2 Mb de la región distal en contraste con su distribución pericentromérica. La mayor tasa de recombinación calculada en este estudio para mujeres se registró en las bandas 21q22.13 y 21q22.3. Los genes DSCR 6 y 9 presentaron un elevado grado de metilación en islas CpG tanto en fibroblastos normales como en trisómicos. En el gen DSCR2 se observó un alto grado de descondensación cromatínica, además de metilación de diferentes residuos de lisina de la histona H3. Conclusiones: La existencia de un ambiente genómico caracterizado por tener elevadas tasas de recombinación y de metilación de genes DSCR 6 y 9, permite postular que en la no disyunción asociada con el SD, operarían complejas interacciones genómicas, epigenéticas y ambientales que actuarían en algunos procesos meióticos.

Efecto del estrés al nacimiento sobre el perfil lipídico del neonato / Effect of stress on the lipid profile at birth

OBJETIVO: en el presente trabajo se establecido el efecto del estres al nacimiento sobre el perfil lipidico. Metodo: se realizó un estudio del tipo caso y control, con un nivel de confianza de 95 por ciento, y significancia de p<0,05. Los datos fueron analizados utilizando una prueba t de student. Se obtuvieron muestras de un grupo control de 32 niños nacidos mediante parto espontaneo normal y de un grupo problema conformado por 32 niños que nacieron en condiciones que generaron estrés. Las muestras fueron tomadas de cordón umbilical inmediatamente después del nacimiento, y las determinaciones de laboratorio se realizaron por el método enzimático colorimérico. RESULTADOS: no se encontré diferencia significativa entre sexos. Las concentraciones de triglicéridos, colesterol-VLDL y colesterol-HDL estuvieron más elevadas en el grupo problema. Además se midieron como indicadores de estrés los niveles de albumina, glucosa y lactato, siendo representativos los niveles de albumina, los cuales se encontraron deprimidos en el grupo problema, y los niveles de glucosa estando elevados en el mismo grupo. CONCLUSIÓN: el estrés al nacimiento produce cambios en varios parametros bioquimicos, los cuales se deben posteriormente analizar buscando su posible implicación en la presentación de complicaciones futuras.

OBJECTIVE: This study established the effect of stress on the lipid profile at birth. METHODS: a case and control study was performed using the student t-test for analyzing the data, with a confidence interval of 95 percent, and significance of p<0.05. Samples from a control group of 32 newborn babies from normal spontaneous birth and a problem group of 32 babies born in stress conditions were obtained. The samples were taken from the umbilical cord immediately at birth, and the laboratory measurements were performed using the enzymatic-colorimetric method. RESULTS: a significant difference was not found between se...