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14 p., [EN]Hereditary diseases constitute a major group within the rare diseases that includes those caused by mutations in a single gene (monogenic) or in more than one gene (multigenic). The discovery that a certain gene is associated with the development of a disease has become a paradigm of current biomedical research with huge implications in clinical practice. Hence, molecular diagnosis based on the search for mutations in genes associated with a disease, has not only become essential to support the clinical diagnosis, but often provides diagnostic criteria that allow customized patient management. Although we have become familiar with terms like genes, Human Genome or DNA Sequencing, we often forget that the identification of a gene responsible for a disease is only the starting point of a long process whose main objectives are to establish the molecular mechanisms underlying the pathology and the development of strategies to prevent or cure the disease. Here, we will review recent advances in two rare diseases, one multigenic, the atypical hemolytic uremic syndrome, and the other one monogenic, the hereditary hemorrhagic telangiectasia, to illustrate the model of multidisciplinary research that characterizes current biomedical research and how the knowledge generated in this area has been transferred to clinical practice., [ES]Dentro de las enfermedades raras, las enfermedades hereditarias constituyen un grupo mayoritario que incluye las ocasionadas por mutaciones en un solo gen (monogénicas) o aquellas ocasionadas por más de un gen (poligénicas). Descubrir que un determinado gen se asocia con el desarrollo de una patología se ha convertido en un paradigma de la investigación biomédica actual que tiene enormes repercusiones en la práctica clínica. Así, el diagnóstico molecular, basado en la búsqueda de mutaciones en los genes asociados a una patología, no solo se ha convertido en un refuerzo imprescindible del diagnóstico clínico, sino que frecuentemente aporta criterios a ese diagnóstico que permiten un manejo personalizado de los pacientes. Sin embargo, nos hemos familiarizado tanto con términos como genes, genoma humano o secuenciación de ADN que frecuentemente olvidamos que la identificación de un gen como responsable de una enfermedad es a menudo solo el punto de partida de un largo proceso cuyos objetivos fundamentales son establecer los mecanismos moleculares que determinan la patología y el desarrollo de estrategias que la eviten o la remedien. En este artículo revisaremos los avances recientes en dos patologías raras, una poligénica, el síndrome hemolítico urémico atípico, y otra monogénica, la telangiectasia hemorrágica hereditaria, para ilustrar el modelo de investigación multidisciplinar que caracteriza a la investigación biomédica actual y cómo el conocimiento generado en esta área se ha trasladado a la práctica clínica.

La activación de la vía alternativa del complemento interviene en el desarrollo de varias enfermedades renales, como el síndrome hemolítico urémico atípico o la glomerulopatía C3. En esta última enfermedad un elevado porcentaje de los pacientes presentan niveles circulantes de un autoanticuerpo denominado C3NeF, causante de la desregulación del complemento a nivel sistémico. En ciertos casos, la presencia de este anticuerpo se asocia con alteraciones en el tejido adiposo, causando lipodistrofia parcial adquirida (síndrome de Barraquer-Simons), una enfermedad ultra-rara que afecta a la distribución del tejido adiposo subcutáneo y que comienza principalmente durante la infancia. Estos pacientes, además de poder presentar los problemas metabólicos asociados al defecto en el tejido adiposo, presentan hipocomplementemia C3 junto con la presencia de C3NeF y, en un 25% de los casos desarrollan una glomerulopatía C3. Aunque se sabe desde hace tiempo cómo la desregulación del sistema del complemento afecta al riñón, se desconoce de forma precisa cómo lo hace en el tejido adiposo; no obstante, su relación está bastante clara. En este artículo se va a describir la relación del sistema del complemento con la biología del tejido adiposo y supatogenia reflejada a partir de la lipodistrofia parcial adquirida., The activation of the alternative pathway of the complement is involved in the development of several renal diseases, such as atypical haemolytic uremic syndrome and C3 glomerulopathy. In C3 glomerulopathy, a high percentage of patients have circulating levels of the autoantibody called C3NeF, which causes systemic dysregulation of the complement system. In some cases, the presence of this antibody has been related with abnormalities of adipose tissue, causing acquired partial lipodystrophy (Barraquer-Simons syndrome). Acquired partial lipodystrophy is an extremely rare disorder affecting the distribution of subcutaneous adipose tissue and that mainly onsets during childhood. These patients, in addition to possibly presenting with all the metabolic disorders associated with the adipose tissue defect, present with C3 hypocomplementemia and C3NeF and 25% have developed C3 glomerulopathy. Although it has been known for some time how the dysregulation of the complement system affects the kidneys, it remains unknown how it exactly affects adipose tissue; nevertheless, the relationship is quite clear. In this paper, we describe the connection between the complement system with the biology of the adipose tissue and its pathogenesis reflected from acquired partial lipodystrophy, Este trabajo ha sido financiado por el Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (PI15-00255), la Sociedad Española de Nefrología (Ayuda para la Investigación de la Fundación SENEFRO, 2016) y CIBERER (ACCI-2015)

ResumenEl síndrome hemolítico urémico (SHU) es una entidad clínica definida por la tríada anemia hemolítica no inmune, trombocitopenia e insuficiencia renal aguda, en la que las lesiones subyacentes están mediadas por un proceso de microangiopatía trombótica (MAT) sistémico. Distintas causas pueden desencadenar el proceso de MAT que caracteriza el SHU. En este documento consideramos SHU atípico (SHUa) como el subtipo de SHU en el que los fenómenos de MAT son fundamentalmente consecuencia del daño producido en el endotelio de la microvasculatura renal y de otros órganos por desregulación de la actividad del sistema del complemento. En los últimos años se han identificado diversas mutaciones en genes del sistema del complemento asociados a SHUa, que explicarían aproximadamente el 60% de los casos de SHUa, y se han caracterizado funcionalmente numerosas mutaciones y polimorfismos asociados a SHUa que han permitido determinar que la patología se produce como consecuencia de la deficiente regulación de la activación del complemento sobre las superficies celulares y que lleva al daño endotelial mediado por la activación del C5 y de la vía terminal del complemento. Eculizumab es un anticuerpo monoclonal humanizado que inhibe la activación del C5, bloqueando la generación de la molécula proinflamatoria C5a y la formación del complejo de ataque de membrana. En estudios prospectivos en pacientes con SHUa su administración ha demostrado la interrupción rápida y sostenida del proceso de MAT, con una mejora significativa de la función renal a largo plazo y una reducción importante de la necesidad de diálisis y el cese de la terapia plasmática. En función de las evidencias científicas publicadas y la experiencia clínica acumulada, el Grupo Español de SHUa publicamos un documento de consenso con recomendaciones para el tratamiento de la enfermedad (Nefrología 2013;33(1):27-45). En la presente versión online del documento se actualizan los contenidos sobre la clasificación etiológica de las MAT, la fisiopatología del SHUa, su diagnóstico diferencial y su manejo terapéutico.AbstractHaemolytic uraemic syndrome (HUS) is a clinical entity defined as the triad of nonimmune haemolytic anaemia, thrombocytopenia, and acute renal failure, in which the underlying lesions are mediated by systemic thrombotic microangiopathy (TMA). Different causes can induce the TMA process that characterizes HUS. In this document we consider atypical HUS (aHUS) a sub-type of HUS in which the TMA phenomena are the consequence of the endotelial damage in the microvasculature of the kidneys and other organs due to a disregulation of the activity of the complement system. In recent years, a variety of aHUs-related mutations have been identified in genes of the the complement system, which can explain approximately 60% of the aHUS cases, and a number of mutations and polymorphisms have been functionally characterized. These findings have stablished that aHUS is a consequence of the insufficient regulation of the activiation of the complement on cell surfaces, leading to endotelial damage mediated by C5 and the complement terminal pathway. Eculizumab is a monoclonal antibody that inhibits the activation of C5 and blocks the generation of the pro-inflammatory molecule C5a and the formation of the cell membrane attack complex. In prospective studies in patients with aHUS, the use of Eculizumab has shown a fast and sustained interruption of the TMA process and it has been associated with significative long-term improvements in renal function, the interruption of plasma therapy and important reductions in the need of dialysis. According to the existing literature and the accumulated clinical experience, the Spanish aHUS Group published a consensus document with recommendations for the treatment of aHUs (Nefrologia 2013;33[1]:27-45). In the current online version of this document, we update the aetiological classification of TMAs, the pathophysiology of aHUS, its differential diagnosis and its therapeutic management.

CD55 e CD59 são proteínas de membrana ancoradas por glicosilfosfatidilinositol que apresentam propriedades reguladoras da ativação da cascata do complemento. Essa regulação ocorre através da inibição da C3 convertase pelo CD55 e prevenção da etapa final de polimerização do complexo de ataque à membrana pelo CD59. Deficiência na expressão dessas proteínas pode estar associada a uma maior ativação do sistema complemento, inclusive do complexo de ataque à membrana, levando à morte celular. Pacientes com lúpus eritematoso sistêmico, com anemia hemolítica e linfopenia, parecem apresentar uma deficiência adquirida de CD55 e CD59. Contudo, os mecanismos que modulam essa diminuída expressão continuam desconhecidos e o seu impacto nas manifestações do lúpus eritematoso sistêmico precisa ser mais bem estudado. CD55 and CD59 are glycosylphosphatidylinositol-anchored proteins with regulatory properties on the activating cascades of the complement system. This regulation occurs through inhibition of the C3-convertase formation by CD55, and prevention of the terminal polymerization of the membrane attack complex by CD59. Deficiency in the expression of these proteins can be associated with increased susceptibility to complement-mediated cell death. Systemic lupus erythematosus patients with hemolytic anemia and lymphopenia seem to have an acquired deficiency of CD55 and CD59 proteins. However, the mechanisms involved in this deficiency and its impact on the clinical manifestation of SLE needs to be further investigated.

La presente comunicación se refiere a la presencia de la tele en la sociedad en general y a su potencial como agente importante de formación y educación, junto con la escuela y la familia, en la vida de los niños y de los jóvenes. Actualmente vivimos inmersos en un mundo complejo de imágenes con sonido, que recibimos muy especialmente a través de la tele, del cine y de Internet, los cuales hacen parte del cotidiano del universo infantil. Así, a fin de organizar algunos de los contenidos desde los que es posible enfocar el tema, estructuramos este artículo en cuatro partes. La primera parte describe la presencia de la tele a diario de los niños y su relación con la caja mágica, incluso la identificación que hacen de sus personajes favoritos, a fin de comprender el espacio que ocupa la tele en su cotidianidad. La segunda parte presenta los distintos mensajes transmitidos por la tele. Es importante analizar las principales riesgos y ventajes de la televisión, o sea, a pesar de algunos programas muestran antivalores de la tele: fomentar excesivamente el consumo, exponer a los niños a un ambiente de violencia y pornografía también entretiene, acompaña, educa, informa, favorece el acceso a la cultura y permite unir a la familia en torno a un programa. Cuanto a la tercera parte, plantea la necesidad de incorporar la tele como recurso curricular en la escuela, para que enseñe a los alumnos a analizar crítica y reflexivamente los textos mediáticos. La televisión es considerada como una herramienta poderosa, determinante en la comunicación, tanto en la formación de valores e ideas, como en la transmisión de cultura; la función de la escuela no es permanecer ajena a este factor, pero procurar reflexionar para comprender y decidir mejor su impacto en el desarrollo de los niños y jóvenes. Como conclusión podemos añadir que hemos tratado de apuntar algunas estrategias que educadores y padres podrán trabajar junto con los niños y los jóvenes, para que éstes tengan una nueva mirada del mundo de la tele y para que sepan hacer su propia selección y tener una actitud crítica ante el producto visionado, The present article is about the presence of the tv in the society, in general, and its potential as an important agent, such as the family and the school, on the children’s and young people’s development and education. Nowadays we live in a complex world of images with sound, the most of them transmitted by the tv, the cinema and the internet. The infantile universe is full of those images. This way we structured this article in four parts, refering some of the contents related with this subject. The first part describes the presence of the television in the children's daylife and their relationship with the magic box, even the identification that they make with its favourites characters, in order to understand the space that the TV occupies in their lives. The second part presents the different messages transmitted by the television. It is important to analyze the main risks and advantages of television, that is to say, in spite of some programs show bad values, foment the excessive consumption, expose the children to an atmosphere of violence and pornography, also entertains, accompanies, educates, informs, favours the access to the culture and allows to unite the family around a program. At last the third part, this one outlines the necessity to put the tele as a curricular resource in the school, to teaches the students how to analyze, how to criticize and to think about the texts and the news of the world today. The television, considered a powerful tool, is decisive in the communication, such in the formation of values and ideas as in the culture transmission. The function of the school is not to remain far from this factor, but to try to meditate, to understand and to decide its impact, in a better way, on the development of the children and youngs. As conclusion we can add that we’ve tried to aim some strategies that educators and parents will be able to work, united to the children and the youngs, so they could have a new look of the Tv’s world and that they could know how to make their own selection and how to have a critical attitude before the watched product

OBJETIVO: determinar se os alótipos do Fator B (BF), C2 e C4 (C4A e C4B) do sistema complemento poderiam ser marcadores para a doença cardíaca reumática (DCR) na população brasileira. MÉTODOS: foram estudados 49 pacientes com DCR crônica. Os controles incluíram 65 indivíduos saudáveis, não aparentados, pareados com a amostra dos pacientes de acordo com o sexo, idade e grupo racial. Os alótipos de BF, C2, C4A e C4B foram determinados por técnicas-padrão, incluindo Western blot para a determinação das variantes de C2 e C4, utilizando-se anticorpos monoclonais e policlonais. RESULTADOS: este estudo demonstrou um significante aumento do alelo raro C4A*6 (p=0,003 RR=11,85) e diminuição de C4A*3 nos pacientes, quando comparados com os controles. Além disso, alelos nulos de C4 e raros de C4 e BF foram observados com maior freqüência nos pacientes. CCONCLUSÕES: considerando-se que foram avaliados somente pacientes com DCR, mais estudos serão necessários para que se possa esclarecer se o alelo C4A6 pode ser um marcador da forma cardíaca ou da própria doença. OBJECTIVE: to determine whether the allotypes of complement proteins Factor B (BF), C2, C4A and C4B could be markers of rheumatic heart disease (RHD) in the Brazilian population. METHODS: forty-nine patients with chronic RHD were studied. The controls included 65 healthy individuals, matched with the patients according to sex, age and ethnical background. BF, C2, C4A and C4B allotypes were studied by standard techniques including Western blots for C2 and C4 variants with monoclonal and polyclonal antibodies. RESULTS: this study showed a significantly elevated frequency of the rare C4A6 allotype (p=0.03 RR=11.85) and a decrease of C4A3 in the patients when compared to controls. In addition, C4 null and BF and C4 rare allotypes were more frequent in patients than in controls. CONCLUSIONS: considering that only RHD patients were included, further investigations are necessary in order to clarify whether C4A6 may be a marker of the cardiac form or of the disease itself.

The complement system is an important humoral defense mechanism that plays a relevant role against microbial agents, inflammatory response control, and immunocomplex clearance. Classical complement pathway activation is antibody-dependent. The C4 component participates in the initial step of activation, and C4 expression is determined by 2 pairs of allotypes: C4A and C4B. Deficiencies in C4 allotypes have been associated with several diseases. The aim of the present review is evaluate the reported data in the literature regarding specific C4A and C4B deficiencies and characterize their clinical relevance. We searched the MEDLINE and LILACS databases. Papers referring to total C4 deficiency without allotype evaluation and case reports of primary C4 deficiency were not included. Deficiencies in C4 allotypes have been associated with Mycobacterium leprae infection, erythema nodosum, systemic sclerosis with anti-topoisomerase I antibodies, intermediate congenital adrenal hyperplasia with DR5 genotype, diabetes mellitus type 1 with DR3,4 genotype, and diabetes mellitus with antibodies against islet cells. C4 allotype deficiency is also related to C4B deficiency and autoimmune-associated diseases, such as systemic lupus erythematosus, or diseases with an autoimmune component, such as autism. Some reports associate C4A with thyroiditis after delivery as well as limited and systemic sclerosis without anti-topoisomerase I antibodies. However, the studies with C4A and C4B have been concentrated in isolated populations, and some of the studies could not be reproduced by other authors. O sistema complemento constitui um importante sistema de defesa humoral, exercendo papel relevante na resposta contra agentes microbianos, no controle da resposta inflamatória e na depuração de imunocomplexos. A ativação da via clássica é dependente da formação do complexo antígeno-anticorpo. O componente C4 do complemento participa da etapa inicial de ativação desta via e a sua expressão é determinada por dois alótipos : C4A e C4B. A deficiência dos alótipos de C4 tem sido relacionada a várias doenças. O objetivo do presente estudo foi avaliar os dados de literatura que descrevem as deficiências específicas de C4A e C4B com a finalidade de caracterizar seu significado clínico. Foi realizada uma ampla revisão bibliográfica através do MEDLINE e LILACS, avaliando-se os dados de literatura. Excluiu-se estudos com a avaliação de C4 total sem a análise dos alótipos e relatos de caso isolados de deficiência total de C4. Verificou-se que a deficiência dos alótipos de C4 está relacionada com algumas doenças: hanseníase, esclerose sistêmica com anticorpos anti-topoisomerase I, hiperplasia adrenal congênita intermediária com genótipo DR5, diabetes mellitus tipo 1 com genótipo DR3,4 e diabetes mellitus tipo 1 com anticorpos anti-células das ilhotas. Também foram observadas algumas associações entre C4B e doenças auto-imunes como lupus eritematoso sistêmico, ou que se supõe terem um componente auto-imune como o autismo. Estudos demonstraram associações do C4A com tireoidite pós-parto, esclerose limitada e esclerose sistêmica sem anticorpos anti-topoisomerase I. Porém, os estudos dos alótipos de C4 se concentraram em populações isoladas e alguns destes não conseguiram ser reproduzidos por outros autores.

Background: Membranoproliferative glomerulonephritis (MPGN type I, II and III) was reclassified in 2013 as MPGN and C3 glomerulopathy (C3G) based on the complement system activation mechanism. Objectives: To evaluate whether C4d, a component of the classical pathway, could be a diagnostic tool in differentiating between MPGN and C3G. Methods: We conducted a retrospective study of 15 MPGN type I, II and III and 13 minimal change disease (MCD) patients diagnosed between 2000 and 2012. C4d staining using the peroxidase method was employed. Results: Using the 2013 C3G consensus classification, the 15 MPGN types I, II and III biopsies were re-classified as MPGN (8) and C3G (7). Following C4d staining, of the 8 biopsies diagnosed as MPGN, 4 had classical pathway involvement [C1q (+), C3 (+), C4d (+)]; two had lectin pathway involvement [C1q (−), C3 (+), C4d (+)]; and, two were reclassified as C3G because the absence of C4d and C1q suggested the presence of the alternative pathway [C1q (−), C3 (+), C4d (−)]. Three of the seven C3G biopsies presented classical pathway involvement and were reclassified as MPGN. The alternative pathway was present in one of the other 4 biopsies considered to be C3G. Two C3G biopsies involved the lectin pathway and the one case of dense deposit disease had lectin pathway involvement. Conclusions: C4d staining may help to differentiate between MPGN and C3G. In addition, the lectin pathway could play a role in the pathogenesis of these glomerulopathies.