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Background and purpose Definitive radiation therapy (RT) with or without chemotherapy has become the standard treatment for non-metastatic unresectable non-small cell lung cancer (NSCLC). However, treatment outcomes can differ substantially and patients’ genetic background could play a crucial role. Potential associations between single-nucleotide polymorphisms (SNP) in Heat shock protein beta-1 (HSPB1) and survival have been reported in prior single-institution retrospective reports. Materials and methods The current assay aims to validate such connection in a prospective multicenter study in a European cohort including 181 NSCLC patients. Median follow-up time for all patients was 13 months (range, 3–57 months). Results The results obtained show an association between the rs2868371 GG genotype and better overall survival (HR: 0.35; 95%CI: 0.13–0.96; p = 0.042) in multivariate analysis. Two-year overall survival rate was 72% for patients carrying the rs2868371 GG genotype versus 36% for those patients harboring the rs2868371 CC/CG genotypes (p = 0.013). Additionally, the rs2868371 GG genotype was found to be associated with better disease-free survival in the multivariate analysis (HR: 0.36; 95%CI: 0.13–0.99; p = 0.048). In silico analysis of the potential functional SNP suggested significant difference in the affinity of the Glucocorticoid Receptor binding site between alternative allelic variants, confirmed by chromatin immunoprecipitation analysis displaying stronger affinity for the risk allele (C). Furthermore, our findings indicate that the rs2868371 influences (mRNA) HSPB1 expression, offering insight into the regulation of HSPB1 transcription. Conclusion The functional HSPB1 rs2868371 promoter variant may affect lung cancer survival by regulation of HSPB1 expression levels through glucocorticoid receptor interaction.

More than forty years after the first baby's birth through in vitro fertilization, innovations in the field of human reproduction have experienced a significant growth increase. Those first techniques have led evolved to others that push the biological limits of reproduction. Recent developments in genomic editing -particularly, CRISPR/Cas9 technology- had leaded an intense ethical, social and legal discussion about the boundaries limits of the new models of human reproduction, and their consequences in recent years. The number of conflicting legal interests suggests that the application of these techniques must combine the respect for the law, the defense of the human rights of all the agents involved in the process, and the freedom of scientific research. The present paper tries to deal with the diverse ethical implications and legal limits of three of those techniques, recently developed or to be developed in the near future: surrogacy, uterus transplantation and artificial uterus.

[Background] Small cell lung cancer (SCLC) is one of the greatest therapeutic challenges of oncology. Potential associations between single nucleotide polymorphisms in heat shock protein β1 (HSPB1) and transforming growth factor β1 (TGFβ1) and survival have been investigated., [Methods] A prospective multicenter study of 94 patients with SCLC treated between 2013 and 2016 was conducted. Clinical, tumour-related, therapeutic, and genetic (9 SNPs of TGFβ1 gene and 5 of HSPB1 gene) variables were analyzed., [Results] The cohort included 77 men and 17 women with a median age of 61 years. Eighty percent presented with limited stage at diagnosis and received thoracic radiation with a median dose of 45 Gy (twice-daily radiation in 42%). Forty-seven percent received concurrent platinum-based chemotherapy and 57% received prophylactic cranial irradiation (PCI). Overall survival (OS) was 34% at 2 years and 16% at 3 years. In multivariate analysis, the rs4803455:CA genotype of the TGFβ1 gene showed a statistically significant association with lower disease-free survival (DFS; hazard ratio [HR] 3.13; confidence interval [CI] 1.19–8.17; p = 0.020) and higher local recurrence (HR 3.80; CI 1.37–10.5; p = 0.048), and a marginal association with lower OS (HR 1.94; CI 0.98–3.83; p = 0.057). A combined analysis showed that patients receiving PCI and carrying the rs4803455:CA genotype had statistically significant lower OS (p < 0.001) and DFS (p < 0.001) than patients receiving PCI and carrying the rs4803455:AA genotype., [Conclusions] Genetic analysis showed the CA genotype of TGFβ1 SNP rs4803455 was associated with worse prognosis in patients with SCLC and could be considered as a potential biomarker.

© 2020 The Author(s)., [Objectives]: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters., [Methods]: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs)., [Results]: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22–0.47; p < 0.001) for tocilizumab, 0.82 (0.71–1.30; p 0.82) for IHDC, 0.61 (0.43–0.86; p 0.006) for PDC, and 1.17 (0.86–1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02–0.17; p < 0.001)., [Conclusions]: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situation., IJ has received honoraria for participating in an advisory board from Gilead Sciences, and for educational activities from ViiV. JB has received research grants from AbbVie, Gilead Sciences, Merck, and ViiV, and honoraria for being a speaker or advisory board participation from AbbVie, Gilead Sciences, Janssen, Merck, and ViiV. JRA received fees for participating in an advisory board, being a speaker, and research grant support from Viiv, Janssen, Gilead, MSD, Teva, Alexa and Serono. PR is involved as speaker or advisory board participant for Gilead Sciences, AbbVie and ViiV. JR-B, JP, JC and MY have no conflicts of interest to declare. SAM-COVID was funded by Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (COV20/01031) co-funded by European Union (ERDF/ESF, “Investing in your future”) and Fundación SEIMC/GeSIDA. In addition, Juan Berenguer, Jesús Rodríguez-Baño, Inmaculada Jarrín, Jordi Carratalá, Jerónimo Pachón, and José R Arribas received funding for research from Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades – co- financed by European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 2014–2020 through the networks: Spanish AIDS Research Network (RIS) [RD16/0025/0017 (JB), RD16/0025/0018 (JRA), RD16/0025/00XX (IJ)] and Spanish Network for Research in Infectious Diseases (REIPI)[RD16/0016/0001 (JRB), RD16/0016/0005 (JC), and RD16/0016/0009 (JP).

[Background and purpose] Radiochemotherapy (RCT) success in lung cancer (LC) can be limited due to the onset of adverse effects in the adjacent normal tissue such as radiation-induced esophageal toxicity (RIET). Therefore, specific biomarkers to customize the RCT dose administration and esophageal toxicity prediction are necessary to improve treatment effectiveness., [Materials and methods] 47 LC patients prospectively recruited between 2012 and 2016 from 3 institutions were genotyped for 7 SNPs along TGFB1 and HSPB1 genes seeking an association with RIET risk development. Kaplan–Meier cumulative probability and Cox proportional hazards analyses were used to evaluate the effect of TGFB1 and HSPB1 genotypes on such risk., [Results] Multivariate analyses showed that patients carrying the HSPB1 rs7459185 CC genotype were associated with a significantly higher risk of acute grade 3 RIET than those carrying the GG/GC genotypes (HR = 17.73; 95% CI = 2.896–108.49; p = 0.002). LC patients who received higher (>median) volume of esophagus exposed to 30 Gy and harboring the rs7459185 GG/GC genotypes showed a significantly lower RIET incidence (p 60 Gy) radiation dose who presented the rs11466353 GG genotype had a significantly lower RIET incidence (p = 0.025)., [Conclusion] The presence of different rs7459185/rs11466353 genotypes in LC patients associated with RIET risk and may be useful biomarkers along with other risk factors for guiding therapy intensity in an individualized therapy., This work was supported by grants from Instituto de Salud Carlos III (PI13/01155, PI16/02104) and Consejeria de Salud of the Junta de Andalucia (PI-0096-2012), Spain.

The purpose of this study is to find out whether telephone referral from Primary Health Care to Internal Medicine Consult manages to reduce waiting days as compared to traditional referral. This study also aims to know how acceptable is the telephone referral to general practitioners and their patients. No blind randomized controlled clinical trial. Northern Huelva Health District. 154 patients. Patients referrals from intervention clinicians were sent via telephone consultation, whereas patients referrals from control clinicians were sent by traditional via. Number of days from referral request to Internal Medicine Consult. Number of telephone and traditional referrals. Number of doctors and patients denied. Denial reasons. A statistically significant difference was found between groups, with an average of 27 (21-34) days. Among General Practitioners, 8 of the first 58 total doctors after randomization and, subsequently, 6 of the 20 doctors of the test group refused to engage in the trial because they considered "excessive time and effort consuming". 50% of patients referred by the 14 General Practitioners finally randomized to the intervention group were denied referral by telephone due to patient's complexity. Telephone referral significantly reduces waiting days for Internal Medicine consult. This type of referral did not mean an "excessive time and effort consuming" to General Practitioners and was not all that beneficial to complex patients.

Background and study aims: To assess the cost-effectiveness of introducing endoscopic treatment based on radiofrequency ablation plus endoscopic mucosal resection in selected patients into the standard of care of Barrett's esophagus patients with high-grade dysplasia or low-grade dysplasia in Spain. Methods: The disease evolution was modeled via a semi-Markov model. The treatment strategies compared included endoscopic treatment based on radiofrequency ablation plus endoscopic mucosal resection and the Standard of Care (esophagectomy or palliative chemoradiotherapy according to disease status for high-grade dysplasia and endoscopic surveillance for low-grade dysplasia). Efficacy rates, transition probabilities and utility values were obtained from the literature. Clinical management patterns and resource use were modeled according to Spanish clinical expert opinion. Costs were expressed in euros (€) from 2016 reflecting the Spanish National Health System perspective. Sensitivity analyses were performed to assess the robustness of the model. Results: With respect to the Spanish Standard of Care, endoscopic treatment based on radiofrequency ablation plus endoscopic mucosal resection was a dominant strategy for high-grade dysplasia patients. When a willingness-to-pay threshold of €30,000 per quality-adjusted life-years gained was considered, this was cost-effective for low-grade dysplasia patients (€12,865 per quality-adjusted life-years gained). The sensitivity analyses supported the base case analysis results and pointed towards the main drivers of uncertainty in the model. Conclusions: From a health care decision-maker, endoscopic treatment based on radiofrequency ablation plus endoscopic mucosal resection is the intervention of choice for dysplasic Barrett's esophagus patients in Spain.

Resumen Objetivo Averiguar si la derivación telefónica desde Atención Primaria a consultas externas de Medicina Interna (CCEE de MI) reduce días de espera, con respecto a la derivación presencial. Averiguar la aceptación de la consulta telefónica por parte de los médicos de familia (MF) de Atención Primaria y de sus pacientes. Diseño Ensayo clínico controlado aleatorizado sin enmascaramiento. Emplazamiento Área de Gestión Sanitaria Norte de Huelva. Participantes Ciento cincuenta y cuatro pacientes. Intervenciones Los pacientes de los MF del grupo experimental fueron derivados vía telefónica (salvo cumplimiento criterios exclusión) y los del grupo control vía presencial. Mediciones Número de días desde la solicitud de derivación hasta la consulta en MI. Número de derivaciones telefónicas y presenciales. Número de médicos y de pacientes rechazados. Causas de los rechazos. Resultados Diferencia estadísticamente significativa, estimándose en 27 (21-34) días entre ambos grupos. De los 58 MF, 8 prealeatorización, y 6 de los 20 asignados al grupo experimental rechazaron participar por «suponer consumo excesivo de tiempo y esfuerzo». Para un 50% de los pacientes derivados por los 14 MF que quedaron finalmente en el grupo experimental se rechazó la vía telefónica, siendo la complejidad de los pacientes la principal causa. Conclusiones La derivación telefónica reduce considerablemente los días de espera para CCEE de MI, elimina las principales barreras de la consulta telefónica a tiempo real, no supuso un mayor gasto de tiempo ni de esfuerzo para los médicos y no se consideró tan beneficiosa en pacientes complejos.

Hirschsprung disease (HSCR) is attributed to a failure of neural crest derived cells to migrate, proliferate, differentiate or survive in the bowel wall during embryonic Enteric Nervous System (ENS) development. This process requires a wide and complex variety of molecules and signaling pathways which are activated by transcription factors. In an effort to better understand the etiology of HSCR, we have designed a study to identify new transcription factors participating in different stages of the colonization process. A differential expression study has been performed on a set of transcription factors using Neurosphere-like bodies from both HSCR and control patients. Differential expression levels were found for CDYL, MEIS1, STAT3 and PAX6. A significantly lower expression level for PAX6 in HSCR patients, would suit with the finding of an over-representation of the larger tandem (AC)m(AG)n repeats within the PAX6 promoter in HSCR patients, with the subsequent loss of protein P300 binding. Alternatively, PAX6 is a target for DNMT3B-dependant methylation, a process already proposed as a mechanism with a role in HSCR. Such decrease in PAX6 expression may influence in the proper function of signaling pathways involved in ENS with the confluence of additional genetic factors to the manifestation of HSCR phenotype., This work was supported by the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness, Spain (PI1301560) and Regional Ministry of Innovation, Science and Enterprise of the Autonomous Government of Andalucia (CTS-7447). MVE-R is supported by fellowship PI11/00533 from ISCIII.

Hirschsprung disease (HSCR; OMIM 142623) is a developmental disorder characterized by aganglionosis along variable lengths of the distal gastrointestinal tract, which results in intestinal obstruction. Interactions among known HSCR genes and/or unknown disease susceptibility loci lead to variable severity of phenotype. Neither linkage nor genome-wide association studies have efficiently contributed to completely dissect the genetic pathways underlying this complex genetic disorder. We have performed whole exome sequencing of 16 HSCR patients from 8 unrelated families with SOLID platform. Variants shared by affected relatives were validated by Sanger sequencing. We searched for genes recurrently mutated across families. Only variations in the FAT3 gene were significantly enriched in five families. Within-family analysis identified compound heterozygotes for AHNAK and several genes (N = 23) with heterozygous variants that co-segregated with the phenotype. Network and pathway analyses facilitated the discovery of polygenic inheritance involving FAT3, HSCR known genes and their gene partners. Altogether, our approach has facilitated the detection of more than one damaging variant in biologically plausible genes that could jointly contribute to the phenotype. Our data may contribute to the understanding of the complex interactions that occur during enteric nervous system development and the etiopathology of familial HSCR.

Hirschsprung disease (HSCR, OMIM 142623) is a developmental disorder characterized by the absence of ganglion cells along variable lengths of the distal gastrointestinal tract, which results in tonic contraction of the aganglionic gut segment and functional intestinal obstruction. The RET proto-oncogene is the major gene for HSCR with differential contributions of its rare and common, coding and noncoding mutations to the multifactorial nature of this pathology. Many other genes have been described to be associated with the pathology, as NRG1 gene (8p12), encoding neuregulin 1, which is implicated in the development of the enteric nervous system (ENS), and seems to contribute by both common and rare variants. Here we present the results of a comprehensive analysis of the NRG1 gene in the context of the disease in a series of 207 Spanish HSCR patients, by both mutational screening of its coding sequence and evaluation of 3 common tag SNPs as low penetrance susceptibility factors, finding some potentially damaging variants which we have functionally characterized. All of them were found to be associated with a significant reduction of the normal NRG1 protein levels. The fact that those mutations analyzed alter NRG1 protein would suggest that they would be related with HSCR disease not only in Chinese but also in a Caucasian population, which reinforces the implication of NRG1 gene in this pathology. © 2012 Luzón-Toro et al., This study was funded by the Instituto de Salud Carlos III, Spain (PI1001290) and Consejeria de Innovación Ciencia y Empresa de la Junta de Andalucia (CTS-2590 and CTS-7447). The CIBER de Enfermedades Raras is an initiative of the ISCIII, Spanish Ministry of Science and Innovation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

[Background] RET is the major gene associated to Hirschsprung disease (HSCR) with differential contributions of its rare and common, coding and noncoding mutations to the multifactorial nature of this pathology. In the present study, we have performed a comprehensive study of our HSCR series evaluating the involvement of both RET rare variants (RVs) and common variants (CVs) in the context of the disease., [Methods] RET mutational screening was performed by dHPLC and direct sequencing for the identification of RVs. In addition Taqman technology was applied for the genotyping of 3 RET CVs previously associated to HSCR, including a variant lying in an enhancer domain within RET intron 1 (rs2435357). Statistical analyses were performed using the SPSS v.17.0 to analyze the distribution of the variants., [Results] Our results confirm the strongest association to HSCR for the "enhancer" variant, and demonstrate a significantly higher impact of it in male versus female patients. Integration of the RET RVs and CVs analysis showed that in 91.66% of cases with both kinds of mutational events, the enhancer allele is in trans with the allele bearing the RET RV., [Conclusions] A gender effect exists on both the transmission and distribution of rare coding and common HSCR causing mutations. In addition, these RET CVs and RVs seem to act in a synergistic way leading to HSCR phenotype., This study was funded by Fondo de Investigación Sanitaria, Spain (PI070080, PI1001290, and PI071315 for the E-Rare Project), Consejeria de Innovación Ciencia y Empresa de la Junta de Andalucia (CTS-2590), and Consejeria de Salud de la Junta de Andalucia (PI0249-2008). The CIBER de Enfermedades Raras is an initiative of the ISCIII.

There is scant information on the use of endoscopic retrograde cholangiopancreatography (ERCP) in patients under 18.To analyze our experience in all patients under 18 who underwent ERCP.We performed a retrospective study of all ERCP conducted in patients under 18 between 1993 and 2006. We analyzed indications, endoscopic and radiologic findings, diagnostic and therapeutic success, and complications.We included 31 patients who underwent 36 ERCP in total. The mean age was 9.89 +/- 5 years old. We used general anesthesia in 58.3% (21 patients), with a mean age of 8 +/- 5 years. The most frequent indications were complications after liver transplantation in 33.3% (12 patients), suspicion of biliary obstruction in 27.7% (10 patients), and pancreatitis in 22.2% (8 patients). We achieved cannulation and repletion in the selected duct in 94.4%. The most frequent pathologic findings were changes in the biliary tract after liver transplantation in 25% (9 patients). The results of ERCP were normal in 10 patients (27.7%). Therapeutic maneuvers were indicated in 17 out of the 34 (50%) examinations considered, achieving therapeutic success in 76.47% (13/17). Complications consisted of hemorrhage after simple sphincterotomy in one patient (2.8%) and mild pancreatitis in two patients (5.6%).We found ERCP to be a safe procedure with a high diagnostic and therapeutic success rate, and a low rate of early complications.

Placement of nasoenteral feeding tubes can require endoscopic support.To analyze the usefulness of transnasal ultrathin endoscopy in the placement of nasoenteral feeding tubes.We performed an ambispective study of all patients who underwent nasoenteral feeding (4.9 mm) in 2007.Twenty-six procedures were performed. The mean age of the patients was 69.3+/-13 years. Nasal anesthesia was used in 23 patients (88.4%), and midazolam in 8 (30.8%). No anesthesia was used in 4 patients (15.3%).stenotic esophageal lesions (42.3%), distal placement to the pathological alteration (46.1%), and failure of placement through the normal route (11.5%). We placed 13 (50%) nasoduodenal, 7 (29.6%) nasogastric and 6 (23.1%) nasojejunal tubes. The success rate was 100%. The most frequently used calibre was 12 F. There were no complications.The use of transnasal ultrathin endoscopy in the placement of nasoenteral feeding tubes in our patients was safe, effective and relatively easy.

espanolAntecedentes: la realizacion de una colonoscopia puede originar ansiedad en los pacientes. Esta situacion ha sido poco estudiada en nuestro medio. Objetivos: determinar la frecuencia, el grado y los factores relacionados con la ansiedad previa a la realizacion de una colonoscopia. Metodos: estudio prospectivo descriptivo de los pacientes sometidos a colonoscopia ambulatoria en nuestro hospital. Se valoro la ansiedad mediante una escala visual analogica de 0 a 100. Se pondero la gravedad de la ansiedad en leve, moderada e intensa segun los valores de la escala entre 1-29, 30-79 y 80-100, respectivamente. Resultados: completaron el estudio 327 pacientes, 154 (47,1%) hombres con una edad mediana de 54 anos (p25-75: 45-65). En 309 (94,5%) pacientes existia algun grado de ansiedad. La mediana del valor de la escala visual analogica fue de 31 (p25-75: 10-53). La ansiedad fue leve en 136 (44%), moderada en 141 (45,6%) e intensa en 32 (10,4%) pacientes. Se asocio una mayor ansiedad con el sexo femenino (media 40,38 vs. 31,99, p = 0,01) a una colonoscopia previa mal tolerada (media 50,67 vs. 28,44, p = 0,01) y se correlaciono de manera inversa con la edad (r = -0,170, p = 0,02). Conclusiones: la realizacion de una colonoscopia provoca algun grado de ansiedad en la mayoria de los pacientes. El sexo femenino, una edad menor y una tolerancia mala en una exploracion previa se asocian con un mayor grado de ansiedad. Esta circunstancia debe ser tenida en cuenta para implementar medidas para mejorar la calidad y la tolerancia de la colonoscopia. EnglishBackground: Undergoing a colonoscopy can cause anxiety in patients and this is something which has not been closely studied. Objective: To determine the frequency and intensity of anxiety prior to a colonoscopy and the factors which are related to the procedure. Methods: This is a prospective study of patients undergoing outpatient colonoscopy in our hospital. Anxiety was assessed using a visual analogue scale of 0 to 100. The severity of anxiety was rated as mild (1-29), moderate (30-79) or severe (80-100). Results: Three hundred and twenty-seven patients completed the study, of whom 154 (47.1%) were men with a median age of 54 years (p25-75: 45-65). Three hundred and nine (94.5%) patients were found to suffer a certain degree of anxiety. The median value on the visual analogue scale was 31 (p25-75: 10-53). Anxiety levels were mild in 136 patients (44%), moderate in 141 (45.6%) and severe in 32 (10.4%). Greater anxiety was associated with female patients (mean 40.38 vs 31.99, p = 0.01) and a poorly tolerated previous colonoscopy (mean 50.67 vs 28.44, p = 0.01) and correlated inversely with age (r = -0.170, p = 0.02). Conclusions: Colonoscopy causes some degree of anxiety in most patients. Being female, younger and having experienced poor tolerance to a previous scan are associated with greater degrees of anxiety. These findings should be taken into account in the implementation of measures to improve the quality and tolerance of colonoscopy.

Finding gene associations in rare diseases is frequently hampered by the reduced numbers of patients accessible. Conventional gene-based association tests rely on the availability of large cohorts, which constitutes a serious limitation for its application in this scenario. To overcome this problem we have used here a combined strategy in which a pathway-based analysis (PBA) has been initially conducted to prioritize candidate genes in a Spanish cohort of 53 trios of short-segment Hirschsprung’s disease. Candidate genes have been further validated in an independent population of 106 trios. The study revealed a strong association of 11 gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other HSCR-related processes. Among the preselected candidates, a total of 4 loci, RASGEF1A, IQGAP2, DLC1 and CHRNA7, related to signal transduction and migration processes, were found to be significantly associated to HSCR. Network analysis also confirms their involvement in the network of already known disease genes. This approach, based on the study of functionally-related gene sets, requires of lower sample sizes and opens new opportunities for the study of rare diseases., This work was supported by the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness, Spain (PI1001290); Spanish Ministry of Economy and Competitiveness (BIO2008-04212), GVA-FEDER (PROMETEO/2010/001) and Consejeria de Innovación Ciencia y Empresa de la Junta de Andalucia (CTS-7447). The CIBER de Enfermedades Raras is an initiative of the ISCIII, Spanish Ministry of Economy and Competitiveness. LG-A and MVE-R are supported by fellowships PFIS FI10/00020 and FI11/00533 from ISCIII respectively.