Cornelia de Lange syndrome with NIBPL mutation and mosaic Turner syndrome in the same individual

Background: Cornelia de Lange syndrome (CdLS) is a dominantly inherited disorder characterized by facial dysmorphism, growth and cognitive impairment, limb malformations and multiple organ involvement. Mutations in NIPBL gene account for about 60% of patients with CdLS. This gene encodes a key regulator of the Cohesin complex, which controls sister chromatid segregation during both mitosis and meiosis. Turner syndrome (TS) results from the partial or complete absence of one of the X chromosomes, usually associated with congenital lymphedema, short stature, and gonadal dysgenesis. Case presentation: Here we report a four-year-old female with CdLS due to a frameshift mutation in the NIPBL gene (c.1445_1448delGAGA), who also had a tissue-specific mosaic 45,X/46,XX karyotype. The patient showed a severe form of CdLS with craniofacial dysmorphism, pre- and post-natal growth delay, cardiovascular abnormalities, hirsutism and severe psychomotor retardation with behavioural problems. She also presented with minor clinical features consistent with TS, including peripheral lymphedema and webbed neck. The NIPBL mutation was present in the two tissues analysed from different embryonic origins (peripheral blood lymphocytes and oral mucosa epithelial cells). However, the percentage of cells with monosomy X was low and variable in tissues. These findings indicate that, ontogenically, the NIPBL mutation may have appeared before the mosaic monosomy X. Conclusions: The coexistence in several patients of these two rare disorders raises the issue of whether there is indeed a cause-effect association. The detailed clinical descriptions indicate predominant CdLS phenotype, although additional TS manifestations may appear in adolescence

Best Practice Guide for Positive Parenting. A resource for practitioners working with families

[spa] El modo en que se concibe el ejercicio de la parentalidad ha cambiado sustancialmente en nuestra sociedad. Ello no sólo se debe a la gran variedad de formas familiares y diversidad de culturas que conviven actualmente en su seno, sino también a un cambio conceptual que afecta al núcleo básico de la tarea parental. Nos referimos a la necesidad de sustituir el concepto de autoridad parental, centrado únicamente en la necesidad de lograr metas de obediencia y disciplina en los hijos e hijas, por otro más complejo y demandante como es el concepto de responsabilidad parental. Según este concepto, la cuestión clave no es si las figuras parentales deben ejercer la autoridad para que sus hijos/as les obedezcan, sino cómo ejercerla de modo responsable para que se preserven los derechos de los mismos, sin menoscabar los de padres y madres, y se fomenten sus capacidades críticas y de participación en el proceso de socialización, al mismo tiempo que se promueve progresivamente su autonomía y contribución a la vida comunitaria. Ante este cambio cualitativo en la manera de entender las responsabilidades parentales, se alzan muchas voces de desánimo entre los propios padres y madres, quienes en ocasiones se ven impotentes en su tarea al no saber cómo actuar para lograr metas educativas tan complejas y sentir, al mismo tiempo, que están perdiendo capacidades de control sobre sus hijos e hijas. En otras ocasiones, el desánimo y el estrés ante la tarea parental no surge por no saber llevarla a cabo sino por no poder hacerlo adecuadamente debido a la situación de la persona que educa en solitario o en pareja sin contar con redes de apoyo apropiadas. Esto crea situaciones límite que repercuten negativamente en todos y cada uno de los miembros de la familia, especialmente en los más vulnerables.[eng] Our conception of what parenting should look like has changed considerably in our society. This is due not only to the large variety of family structures and the diversity of cultures that currently co-exist in our society, but also to a shift in mindset that touches the very heart of the parenting task. This can be expressed as the need to replace the concept of parental authority, which focuses solely on meeting aims related to the child’s obedience and discipline, with the much more complex and demanding concept of parental responsibility. Here, the key question is not whether the parent figure should exert the necessary authority to ensure a child’s obedience. Rather, it is about how this authority can be exerted responsibly in a way that protects the child’s rights - without of course neglecting the mother’s and father’s rights - and that fosters the child’s skills in critical thinking and participation in the socialisation process, while at the same time progressively fostering the child’s autonomy and contribution to community life. There has been much concern expressed in response to this qualitative shift in how a parent’s responsibilities are viewed, including amongst mothers and fathers themselves. Parents often feel powerless to act, as they do not know how to achieve such complex parenting goals, and feel like they are losing control over their children. Other times, feelings of discouragement and stress arise not because parents do not how to go about the task of parenting, but rather because they find themselves unable to do so, as may be the case for single parents or couples raising children without the necessary support networks. This can lead to extreme situations which can have a negative impact on the entire family, and especially its most vulnerable members

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p < 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

mRNA Quantification of NIPBL Isoforms A and B in Adult and Fetal Human Tissues, and a Potentially Pathological Variant Affecting Only Isoform A in Two Patients with Cornelia de Lange Syndrome

Cornelia de Lange syndrome (CdLS) is a congenital developmental disorder characterized by craniofacial dysmorphia, growth retardation, limb malformations, and intellectual disability. Approximately 60% of patients with CdLS carry a recognizable pathological variant in the NIPBL gene, of which two isoforms, A and B, have been identified, and which only differ in the C-terminal segment. In this work, we describe the distribution pattern of the isoforms A and B mRNAs in tissues of adult and fetal origin, by qPCR (quantitative polymerase chain reaction). Our results show a higher gene expression of the isoform A, even though both seem to have the same tissue distribution. Interestingly, the expression in fetal tissues is higher than that of adults, especially in brain and skeletal muscle. Curiously, the study of fibroblasts of two siblings with a mild CdLS phenotype and a pathological variant specific of the isoform A of NIPBL (c.8387A > G; P.Tyr2796Cys), showed a similar reduction in both isoforms, and a normal sensitivity to DNA damage. Overall, these results suggest that the position of the pathological variant at the 3´ end of the NIPBL gene affecting only isoform A, is likely to be the cause of the atypical mild phenotype of the two brothers.We sincerely thank the patients’ family for participating in this study. This work was supported by: The Spanish Ministry of Health—Fondo de Investigación Sanitaria (FIS) (Ref: PI15/00707); the Diputación General de Aragón (Grupo Consolidado B20), European Social Fund (“Construyendo Europa desde Aragón”) CHROMATIN-Net funded by the German Federal Ministry of Education and Research (BMBF) to Frank J. Kaiser. The Spanish Ministry of Economy (Refs: IPT2011-0964-900000 and SAF2011-13156-E) to Paulino Gómez-Puertas. Swedish Research Council to Lena Ström and the Norwegian Research Council (205217) to Torkild Visnes Beatriz Puisac, María Hernández-Marcos, María-Esperanza Teresa-Rodrigo, María-Concepción Gil-Rodríguez, Feliciano J. Ramos and Juan Pié are members of CIBERER-GCV02 and ISS-Aragon at the School of Medicine, University of Zaragoza and the Hospital Clínico Universitario “Lozano Blesa”.We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI)

Analysis of aberrant splicing and nonsense-mediated decay of the stop codon mutations c.109G>T and c.504_505delCT in 7 patients with HMG-CoA lyase deficiency

Eukaryotic cells can be protected against mutations that generate stop codons by nonsense-mediated mRNA decay (NMD) and/or nonsense-associated altered splicing (NAS). However, the processes are only partially understood and do not always occur. In this work, we study these phenomena in the stop codon mutations c.109G>T (p.Glu37*) and c.504_505delCT; the second and third most frequent mutations in HMG-CoA lyase deficiency (MIM #246450). The deficiency affects the synthesis of ketone bodies and produces severe disorders during early childhood. We used a minigene approach, real-time quantitative PCR and the inhibition of NMD by puromycin treatment, to study the effect of stop codons on splicing (NAS) and NMD in seven patients. Surprisingly, none of the stop codons studied appears to be the direct cause of aberrant splicing. In the mutation c.109G>T, the splicing is due to the base change G>T at position 109, which is critical and cannot be explained by disruption of exonic splicing enhancer (ESE) elements, by the appearance of exonic splicing silencer (ESS) elements which were predicted by bioinformatic tools or by the stop codons. Moreover, the mutation c.504_505delCT produces two mRNA transcripts both with stop codons that generate simultaneous NMD phenomena. The effects of the mutations studied on splicing seemed to be similar in all the patients. Furthermore, we report a Spanish patient with 3-hydroxy-3-methylglutaric aciduria and a novel missense mutation: c.825C>G (p.Asn275Lys).Diputación General de Aragón; European Social Fund; the University of Zaragoza (UZ2007-BIO-13, PIF-UZ-2009-BIO-02)Peer Reviewe

New case of mitochondrial HMG-CoA synthase deficiency: Functional analysis of eight mutations

Mitochondrial HMG-CoA synthase deficiency is a rare inherited metabolic disorder that affects ketone-body synthesis. Acute episodes include vomiting, lethargy, hepatomegaly, hypoglycaemia, dicarboxylic aciduria, and in severe cases, coma. This deficiency may have been under-diagnosed owing to the absence of specific clinical and biochemical markers, limitations in liver biopsy and the lack of an effective method of expression and enzyme assay for verifying the mutations found. To date, eight patients have been reported with nine allelic variants of the HMGCS2 gene. We present a new method of enzyme expression and a modification of the activity assay that allows, for first time, the functional study of missense mutations found in patients with this deficiency. Four of the missense mutations (p.V54M, p.R188H, p.G212R and p.G388R) did not produce proteins that could have been detected in soluble form by western blot; three produced a total loss of activity (p.Y167C, p.M307T and p.R500H) and one, variant p.F174L, gave an enzyme with a catalytic efficiency of 11.5%. This indicates that the deficiency may occur with partial loss of activity of enzyme. In addition, we describe a new patient with this deficiency, in which we detected the missense allelic variant, c.1162G>A (p.G388R) and the nonsense variant c.1270C>T (p.R424X). © 2013 Elsevier Masson SAS.Diputación General de Aragón (DGA) (Grupo Consolidado B20); European Social Fund (“Construyendo Europa desde Aragón”); Spanish Ministry of Education and Science (SAF2004-06843-C03); Spanish Ministerio de Ciencia and Ministerio de Economía y Competitividad (SAF2007-61926, IPT2011-0964-900000, SAF2011-13156-E); Spanish Instituto de Salud Carlos III (CIBER Fisiopatología de la Obesidad y Nutrición); European Commission (FP7 HEALTH-F3-2009-223431, EU project “Divinocell”, FP7 HEALTH-2011-278603; EU project “Dorian”); European Social FundPeer Reviewe

New case of mitochondrial HMG-CoA synthase deficiency. Functional analysis of eight mutations

Mitochondrial HMG-CoA synthase deficiency is a rare inherited metabolic disorder that affects ketone-body synthesis. Acute episodes include vomiting, lethargy, hepatomegaly, hypoglycaemia, dicarboxylic aciduria, and in severe cases, coma. This deficiency may have been under-diagnosed owing to the absence of specific clinical and biochemical markers, limitations in liver biopsy and the lack of an effective method of expression and enzyme assay for verifying the mutations found. To date, eight patients have been reported with nine allelic variants of the HMGCS2 gene. We present a new method of enzyme expression and a modification of the activity assay that allows, for first time, the functional study of missense mutations found in patients with this deficiency. Four of the missense mutations (p.V54M, p.R188H, p.G212R and p.G388R) did not produce proteins that could have been detected in soluble form by western blot; three produced a total loss of activity (p.Y167C, p.M307T and p.R500H) and one, variant p.F174L, gave an enzyme with a catalytic efficiency of 11.5%. This indicates that the deficiency may occur with partial loss of activity of enzyme. In addition, we describe a new patient with this deficiency, in which we detected the missense allelic variant, c.1162G>A (p.G388R) and the nonsense variant c.1270C>T (p.R424X).Fil: Ramos, Mónica. Universidad de Zaragoza; EspañaFil: Menao, Sebastián. Universidad de Zaragoza; EspañaFil: Arnedo, María. Universidad de Zaragoza; EspañaFil: Puisac, Beatriz. Universidad de Zaragoza; EspañaFil: Gil Rodríguez, María Concepción. Universidad de Zaragoza; EspañaFil: Teresa Rodrigo, María Esperanza. Universidad de Zaragoza; EspañaFil: Hernández Marcos, María. Universidad de Zaragoza; EspañaFil: Pierre, Germaine. Birmingham Children’s Hospital; Reino UnidoFil: Ramaswami, Uma. Central Manchester University Hospitals; Reino UnidoFil: Baquero Montoya, Carolina. Universidad de Zaragoza; EspañaFil: Bueno, Gloria. Universidad de Zaragoza; EspañaFil: Casale, Cesar Horacio. Universidad de Zaragoza; España. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Hegardt, Fausto G.. Universidad de Barcelona; EspañaFil: Gómez Puertas, Paulino. Consejo Superior de Investigaciones Científicas; España. Universidad Autónoma de Madrid; EspañaFil: Pié, Juan. Universidad de Zaragoza; Españ

Faculty of Social Communication. Volume 5 No. 8

La revista de la Facultad de Comunicación Social de la UNAB, incluye en sus artículos análisis literario, historia, lingüística, Antropología, sociología.... variedad que refleja el amplio campo de las realidades que deben enfrentarse en una facultad de comunicación social.Presentación. - 5 Ética y responsabilidad social del comunicador social. - 7 Proyecto general para la creación de un periódico en la facultad de comunicación social. - 21 Nuevas tecnologías de información. - 35 Extensión universitaria. - 44 Proyecto de formación docente. - 60 Los medios de comunicación y la metamorfosis de la sociedad civil. - 65 Imagen corporativa. - 76 Palabras y gritos a un ser en exilio. - 84 Apología del inconformismo. - 89 Estadísticas. - 89 Colaboradores. - 97The magazine of the Faculty of Social Communication of the UNAB, includes in its articles literary analysis, history, linguistics, Anthropology, sociology.... a variety that reflects the wide field of realities that must be faced in a faculty of social communication