Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes

Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si le hubiere, y los autores pertenecientes a la UAMAromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogeni

The Genetic Landscape and Epidemiology of Phenylketonuria

Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si lo hubiere, y los autores pertenecientes a la UAMPhenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]–1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066−11G>A (IVS10−11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066−11G>A];[1066−11G>A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcomeThis work was funded in part by the Fundacio´n Isabel Gemio-Fundacion La Caixa (LCF/PR/PR16/11110018), the Regional Government of Madrid (CAM, B2017/BMD3721), and by NIH, United States grants R01DK117916 and R01NR016991

New and potential strategies for the treatment of PMM2-CDG

Background: Mutations in the PMM2 gene cause phosphomannomutase 2 deficiency (PMM2; MIM# 212065), which manifests as a congenital disorder of glycosylation (PMM2-CDG). Mutant PMM2 leads to the reduced conversion of Man-6-P to Man-1-P, which results in low concentrations of guanosine 5′-diphospho-D-mannose, a nucleotide-activated sugar essential for the construction of protein oligosaccharide chains. To date the only therapeutic options are preventive and symptomatic. Scope of review: This review covers the latest advances in the search for a treatment for PMM2-CDG. Major conclusions: Treatments based on increasing Man-1-P levels have been proposed, along with the administration of different mannose derivates, employing enzyme inhibitors or repurposed drugs to increase the synthesis of GDP-Man. A single repurposed drug that might alleviate a severe neurological symptom associated with the disorder is now in clinical use. Proof of concept also exists regarding the use of pharmacological chaperones and/or proteostatic regulators to increase the concentration of hypomorphic PMM2 mutant proteins. General significance: The ongoing challenges facing the discovery of drugs to treat this orphan disease are discussedThe authors are grateful to the Spanish families affected by PMM2- CDG who actively participated in this work. Financial support was provided by grant PI19/01155, PI17/00101, B2017/BMD-3721, the Fundación Isabel Gemio/Fundación La Caixa (LCF/PR/PR16/11110018), and the European Regional Development Fund. MS research is supported by the Generalitat de Catalunya (PERIS SLT008/18/0019

Sensoring a Generative System to Create User-Controlled Melodies

[EN] The automatic generation of music is an emergent field of research that has attracted the attention of countless researchers. As a result, there is a broad spectrum of state of the art research in this field. Many systems have been designed to facilitate collaboration between humans and machines in the generation of valuable music. This research proposes an intelligent system that generates melodies under the supervision of a user, who guides the process through a mechanical device. The mechanical device is able to capture the movements of the user and translate them into a melody. The system is based on a Case-Based Reasoning (CBR) architecture, enabling it to learn from previous compositions and to improve its performance over time. The user uses a device that allows them to adapt the composition to their preferences by adjusting the pace of a melody to a specific context or generating more serious or acute notes. Additionally, the device can automatically resist some of the user’s movements, this way the user learns how they can create a good melody. Several experiments were conducted to analyze the quality of the system and the melodies it generates. According to the users’ validation, the proposed system can generate music that follows a concrete style. Most of them also believed that the partial control of the device was essential for the quality of the generated music

Nuevas técnicas de evaluación en el Trastorno por Déficit de Atención e Hiperactividad (TDAH)

Este estudio pretende conocer la evolución general del proceso de diagnóstico y cuál será su futuro inmediato en el TDAH, profundizando en dos nuevas técnicas objetivas como son el EEG y el HEG. En primer lugar se pretende situar las perspectivas futuras en TDAH a corto y medio plazo. Intentando entender la realidad actual y el nuevo espectro de oportunidades que se nos abre en este sentido. En segundo lugar, específicamente se plantea el objetivo de conocer específicamente la técnica de la hemoencefalografía HEG y su antecedente inmediato EEG. Intentando mostrar sus bases biológicas, su utilidad y su accesibilidad en el diagnóstico. Así como también, completándolo con otras medidas relacionadas como puede ser el TOVA test, con una gran eficiencia y fiabilidad en el diagnóstico y seguimiento del TDAH. Todas las aportaciones teóricas, tratan de condensarse en las conclusiones aportando nuevas medidas más objetivas en el diagnóstico del TDAH, así como más sencillas de aplicar. Se discuten las implicaciones educativas de las ideas relatadas

La mejora de la convivencia desde los centros educativos a través de la educación en resolución de conflictos

Este texto tiene como objetivo presentar una de las líneas de intervención para la mejora de la convivencia más relevantes en la actualidad, la Educación en Resolución de Conflictos . Se expondrán, en primer lugar, los contenidos que deben ser trabajados para enseñar a abordar conflictos adecuadamente y, en segundo lugar, las principales formas de integrar esos contenidos en el currículum educativo. Respecto a la primera cuestión, educar en resolución de conflictos supone enseñar al alumnado a negociar, mediar o consensuar en grupo. Y, para ello, se deben enseñar tanto las fases del proceso, como las actitudes, principios y habilidades necesarias para su desarrollo. Respecto a la segunda cuestión, estos contenidos pueden introducirse en el centro educativo de cuatro maneras básicamente: mono-curricular, cross-curricular, extra-curricular o trans-curricular, es decir, en tutoría, integrándolos en las diferentes áreas, fuera del trabajo ordinario del aula o mediante la interacción cotidiana, respectivament

Determinación de la variabilidad espacial de parámetros de calidad y rendimiento en viñedos a partir de índices de vegetación obtenidos con un espectro- radiómetro de campo

El objetivo de este trabajo consistió en desarrollar un procedimiento para la representación de la variabilidad espacial de parámetros que determinan la calidad y cantidad de uva, a partir de índices de vegetación medidos sobre las cepas. El trabajo de campo se hizo en viñedos de la Denominación de Origen Bierzo. La metodología se basó en la obtención de cartografía continua de los índices de vegetación a partir de datos puntuales (obtenidos en muestreos de campo) mediante técnicas de interpolación espacial. Se estudiaron varios índices con el fin de encontrar el más adecuado para la zona de estudio. Los datos de campo para el cálculo de los índices espectrales fueron tomados con un espectro-radiómetro de campo. También se crearon mapas continuos de parámetros de medida de vigor de las cepas. Partiendo estos datos se consiguieron resultados importantes i) identificar las variables vitivinícolas más relacionadas con los índices de vegetación ii) identificar de áreas homogéneas en los viñedos. Los análisis espaciales fueron llevados a cabo con herramientas SIG. Mediante este trabajo se ha conseguido implementar un protocolo para cartografiar la variabilidad espacial de la uva permitiendo planificar la vendimia para conseguir la calidad y cantidad de vino fijada por la bodega.The aim of this work was to develop a methodology for the representation of spatial variability of parameters that determine the quality and quantity of grapes, using vegetation indices measured on the vines. The field work was done in the vineyards in the Designation of Origin Bierzo. The methodology was based on mapping of vegetation indices from data vines by spatial interpolation techniques. Several indices were studied to find the most suitable for the study area. The field data were taken by a field spectro-radiometer. Based on these data were achieved results useful for the vine-grower i) identify the variables most related to wine vegetation indices ii) identification of homogeneous areas in the vineyards. Spatial analysis was conducted with GIS tools. A protocol for mapping the spatial variability of the grape has been carried out. This information will be useful to manage a harvest plan to achieve the quality and quantity of wine fixed by the winery

PMM2-CDG caused by uniparental disomy: Case reportand literature review

Background Phosphomannomutase 2 deficiency (PMM2-CDG) affects glycosylation pathways such as the N-glycosylation pathway, resulting in loss of function of multiple proteins. This disorder causes multisystem involvement with a high variability among patients. PMM2-CDG is an autosomal recessive disorder, which can be caused by inheriting two pathogenic variants, de novo mutations or uniparental disomy. Case Presentation Our patient presented with multisystem symptoms at an early age including developmental delay, ataxia, and seizures. No diagnosis was obtained till the age of 31 years, when genetic testing was reinitiated. The patient was diagnosed with a complete maternal mixed hetero/isodisomy of chromosome 16, with a homozygous pathogenic PMM2 variant (p.Phe119Leu) causing PMM2-CDG. A literature review revealed eight cases of uniparental disomy as an underlying cause of CDG, four of which are PMM2-CDG. Conclusion Since the incidence of homozygosity for PMM2 variants is rare, we suggest further investigations for every homozygous PMM2-CDG patient where the segregation does not fit. These investigations include testing for UPD or a deletion in one of the two alleles, as this will have an impact on recurrence risk in genetic counselingWe thank the patient described in this case report for all-owing us to share her details, and we thank C. Pérez-Cerdá of the Center of Molecular Biology-Severo Ochoa,Madrid, for her contribution. This work is funded by thegrant titled Frontiers in Congenital Disorders of Glycosylation (1U54NS115198-01) from the National Institute ofNeurological Diseases and Stroke (NINDS) and theNational Center for Advancing Translational Sciences(NCATS), and the Rare Disorders Consortium DiseaseNetwork (E.M. and S.K.

El difícil equilibrio entre eficiencia energética y conservación de los valores patrimoniales en edificios históricos

La gestión eficiente de la energía en el patrimonio arquitectónico es un tema plenamente actual, que surge del consenso social y político sobre la necesidad de reducir progresivamente el consumo energético de los edificios. El texto que presentamos, a propósito de unas jornadas organizadas para finales de este año 2013, reflexiona sobre la necesaria búsqueda de un equilibrio entre las consideraciones de la eficiencia energética, la imprescindible conservación del patrimonio arquitectónico y la satisfacción de las necesidades de los ocupantes. Sus autores forman parte de un equipo de investigadores de la Universidad Politécnica de Cataluña que está desarrollando un proyecto de investigación al respecto.Postprint (published version

The assessment of the ASD (Autism Spectrum Disorder) classrooms in early children’s education: the voice of teachers and families

Es sabido que el avance hacia culturas, políticas y prácticas más inclusivas es un proceso complejo y dilemático. Los obstáculos se acrecientan cuando se trata de alumnado con mayores dificultades como es el caso del Trastorno del Espectro del Autismo (TEA). La Comunidad de Madrid, al igual que otras comunidades autónomas, viene desarrollando un programa de escolarización preferente para este alumnado, en un intento de incluir al alumnado con TEA, que hasta el momento se situaba en centros específicos, en centros educativos ordinarios. La investigación desarrollada trata de identificar y analizar la concreción de las dimensiones de la inclusión en Educación Infantil (Booth y Ainscow, 2006) en el marco de la propuesta educativa que desarrollan estos centros. Para ello, una estrategia necesaria es tener muy presentes “las voces” (Susinos y Ceballos, 2012) de familias y docentes como expresión de sus anhelos y expectativas, y también de sus logros, dificultades y propuestas de mejora que subyacen en la labor que realizan diariamente. Conocer la percepción por parte de familias y docentes en relación a las características que definen la inclusión en los centros, la importancia de un liderazgo pedagógico en los equipos directivos, el alto compromiso y satisfacción del profesorado con el trabajo que desarrolla, así como los altos índices en la participación de las familias en los centros son algunos de los resultados que se muestran en el artículo como indicadores clave para favorecer los procesos de inclusión educativa.It is well known that progress towards more inclusive cultures, policies and practices is a complex and dilemmatic process. The obstacles increase when dealing with students with greater difficulties as is the case of Autism Spectrum Disorder (ASD). The Community of Madrid, like other Autonomous Communities, has developed a preferential schooling program for these students, in an attempt to include students with ASD, which until now was located in specific centers, in ordinary educational centers. The research developed aims to identify and analyze the concretion of the dimensions of inclusion in Early Childhood Education (Booth and Ainscow, 2006) within the framework of the educational proposal developed by these centers. For this, a necessary strategy is to keep in mind “the voices” (Susinos and Ceballos, 2012) of families and teachers as an expression of their desires and expectations, and also of their achievements, difficulties and proposals for improvement that underlie the work they perform daily. The fact of knowing the perception by families and teachers in relation to the characteristics that define inclusion in the centers, the importance of a pedagogical leadership in the management teams, teacher’s high commitment and satisfaction with the work they develop, as well as the high rates in the participation of families in the centers are some of the results that are shown in the article as key indicators to favor the processes of educational inclusion