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Background Cornelia de Lange Syndrome (CdLS) is a rare congenital disorder characterized by typical facial features, growth failure, limb abnormalities, and gastroesophageal dysfunction that may be caused by mutations in several genes that disrupt gene regulation early in development. Symptoms in individuals with CdLS suggest that the peripheral nervous system (PNS) is involved, yet there is little direct evidence. Method Somatic nervous system was evaluated by conventional motor and sensory nerve conduction studies and autonomic nervous system by heart rate variability, sympathetic skin response and sudomotor testing. CdLS Clinical Score and genetic studies were also obtained. Results Sympathetic skin response and sudomotor test were pathological in 35% and 34% of the individuals with CdLS, respectively. Nevertheless, normal values in large fiber nerve function studies. Conclusions Autonomic nervous system (ANS) dysfunction is found in many individuals with Cornelia de Lange Syndrome, and could be related to premature aging.

Postzygotic mosaicism (PZM) in NIPBL is a strong source of causality for Cornelia de Lange syndrome (CdLS) that can have major clinical implications. Here, we further delineate the role of somatic mosaicism in CdLS by describing a series of 11 unreported patients with mosaic disease-causing variants in NIPBL and performing a retrospective cohort study from a Spanish CdLS diagnostic center. By reviewing the literature and combining our findings with previously published data, we demonstrate a negative selection against somatic deleterious NIPBL variants in blood. Furthermore, the analysis of all reported cases indicates an unusual high prevalence of mosaicism in CdLS, occurring in 13.1% of patients with a positive molecular diagnosis. It is worth noting that most of the affected individuals with mosaicism have a clinical phenotype at least as severe as those with constitutive pathogenic variants. However, the type of genetic change does not vary between germline and somatic events and, even in the presence of mosaicism, missense substitutions are located preferentially within the HEAT repeat domain of NIPBL. In conclusion, the high prevalence of mosaicism in CdLS as well as the disparity in tissue distribution provide a novel orientation for the clinical management and genetic counselling of families., Spanish Ministry of Health-ISCIII Fondo de Investigación Sanitaria (FIS) [Ref. PI19/01860, to F.J.R. and J.P.]; Diputación General de Aragón-FEDER: European Social Fund [Grupo de Referencia B32_17R / B32_20R, to J.P.]. A.L-P is supported by a “Juan de la Cierva-Incorporación” postdoctoral grant from MICIU (Spanish Ministry of Science and Universities)

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A superexploração do capital natural pela sociedade atual consolida uma crise ambiental global. Diversas abordagens, dentre as quais a dos Serviços Ecossistêmicos, foram formuladas visando frear a degradação e fomentar medidas de conservação ambiental. Nesse contexto, esse trabalho analisa os bens e os serviços ecossistêmicos prestados por elementos da geodiversidade nos locais de interesse geológico (LIG) do Parque Nacional de Ubajara, Ceará, Brasil. A metodologia parte do inventário de LIGs, da avaliação quanti-qualitativa e da proposição de estratégias de valoração em âmbito local. Foram inventariados onze LIGs de relevância nacional que prestam diversos serviços ecossistêmicos. As propostas de valoração têm como alicerce a relação com os agentes econômicos e sociais locais, sendo passíveis de replicação em diferentes unidades de conservação brasileiras.

El campo de la geodiversidad se ha convertido en un nuevo paradigma de las geociencias. Sus estudios de caracter ambiental tienen como objetivo traducir el conocimiento geológico-geomorfológico a un lenguaje cotidiano. El presente estudio discute el papel del potencial didáctico del patrimonio geológico para la realización de este propósito a través del estudio del Geositio Sitio do Bosco, Tianguá, Ceará, Brasil. La metodología parte de la discusión teórica sobre los conceptos principales que integran el tema de Geodiversidad y puesta en marcha de una estrategia de geoconservación. Los análisis señalan que el Geositio Sítio do Bosco tiene un alto potencial educativo, pudiendo ser utilizado en prácticas educativas de diferentes niveles de enseñanza. Se concluye que comprender el patrimonio geológico por su potencial educativo constituye una de las principales y más viables estrategias de geoconservación.

En las últimas décadas, el conocido como “turismo de sol y playa” ha experimentado una reconversión en la modalidad de all-inclusive resorts o grandes villas hoteleras, generalmente situadas en espacios de alta calidad paisajística. Por su rápido crecimiento y su alto poder transformador del territorio, tanto a nivel ambiental como socioeconómico, resulta de especial relevancia evaluar el impacto que estos modelos tienen sobre el paisaje de acogida. En este trabajo se lleva a cabo la delimitación y caracterización de unidades de paisaje de una pequeña isla al norte de Cuba antes y después del desarrollo turístico, obteniéndose nuevas unidades conformadas por las villas hoteleras. Posteriormente se realiza un análisis del paisaje y un diagnóstico de su calidad en las dos etapas definidas, constatándose una disminución general de los valores principalmente asociada a las áreas que han acogido construcciones e infraestructuras. Así mismo, se mantienen entrevistas con representantes de los principales sectores socioeconómicos relacionados con el cayo, con el fin de establecer los objetivos de calidad del paisaje y medidas específicas para alcanzarlos.

There are three human enzymes with HMG-CoA lyase activity that are able to synthesize ketone bodies in different subcellular compartments. The mitochondrial HMG-CoA lyase was the first to be described, and catalyzes the cleavage of 3-hydroxy-3-methylglutaryl CoA to acetoacetate and acetyl-CoA, the common final step in ketogenesis and leucine catabolism. This protein is mainly expressed in the liver and its function is metabolic, since it produces ketone bodies as energetic fuels when glucose levels are low. Another isoform is encoded by the same gene for the mitochondrial HMG-CoA lyase (HMGCL), but it is located in peroxisomes. The last HMG-CoA lyase to be described is encoded by a different gene, HMGCLL1, and is located in the cytosolic side of the endoplasmic reticulum membrane. Some activity assays and tissue distribution of this enzyme have shown the brain and lung as key tissues for studying its function. Although the roles of the peroxisomal and cytosolic HMG-CoA lyases remain unknown, recent studies highlight the role of ketone bodies in metabolic remodeling, homeostasis, and signaling, providing new insights into the molecular and cellular function of these enzymes., This work was supported by: Diputación General de Aragón-FEDER: European Social Fund (Grupo de Referencia B32_17R, to Juan Pié.), as well as grants from the Ministerio de Ciencia, Innovación y Universidades/Agencia Estatal de Investigación RTC-2017-6494-1 and RTI2018-094434-B-I00 (MCIU/AEI/FEDER, UE) to Paulino Gómez-Puertas. Beatriz Puisac and Juan Pié are members of CIBERER-GCV02 and María Arnedo, Ana Latorre-Pellicer, Cristina Lucia-Campos, Marta Gil-Salvador, Rebeca Antoñanzas-Peréz, Beatriz Puisac and Juan Pié are members of ISS-Aragon at the School of Medicine, University of Zaragoza.

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 Fund

La localización del foco endorreico en la orilla izquierda del Duero, aguas abajo de la capital soriana, está relacionado con una serie de factores de tipo litológico, estructural y climático, donde la lenta actividad morfogenética de la red fluvial del río Duero sobre una morfología prácticamente llana desde el Plioceno, ha favorecido la presencia de focos de drenaje dificultoso, que se mantienen funcionales en la actualidad.

En un valle de fondo plano ("val") del sector central de la depresión del Ebro se han estudiado las acumulaciones holocenas, estableciéndose un modelo de evolución partiendo de las dataciones efectuadas mediante c-14 y restos arqueológicos. Los resultados obtenidos muestran la existencia de dos etapas acumulativas, una iniciada en el neolítico y otra a principios de la época ibérica, así como una fase de incisión a lo largo de los últimos 1500 años.

La construcción de una central hidroeléctrica en el barranco de aras afluente de río gallego, provocaría la desaparición de un elemento morfológico singular, como es el de las "señoritas de Arás". El modelado de "dames coiffees" constituye un importante recurso geomorfológico, y por lo tanto paisajístico, de aquí que el conocimiento de su génesis y evolución sirva como un ejercicio educativo para la valoración del entorno natural y la evaluación de los impactos antrópicos.

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)

Diferenciar distintos tipos de cursos de agua en la red fluvial es un proceso clave de la aplicación de la Directiva 2000/60/CE a la determinación de la calidad ecológica de los ríos. Se aporta un sencillo método de tipificación basado en criterios hidromorfológicos y apoyado en los descriptores que propone la Directiva. Se establecen tres grandes grupos de criterios de tipificación: topográficos, hidroclimáticos y geomorfológicos. A continuación se desarrolla un proceso de siinplificación que desemboca en la definición de 13 tipos básicos aplicables a la red fluvial aragonesa.

The mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase deficiency (MIM 600234) is an autosomic recessive inborn error of metabolism, hard to characterize and probably underdiagnosed (Thompson et al., 1997). The enzyme failure is caused by mutations in the gene HMGCS2, located in chromosome 1. The illness was first diagnosed in 1997 (Thompson et al., 1997), in a six-year old boy, who presented a semicomatose state after three days with gastroenteritis and diet (Bouchard et al., 2001). Up to date, only eight patients have been reported with an estimated incidence of

The HMG-CoA lyase (HL) deficiency or 3-hydroxy-3-methylglutaric aciduria (MIM 246450) is an inborn error of intermediary metabolism that was first described in 1976 by Faull et al (Faull et al., 1976). Because its clinical manifestations, it has been included within the Sudden Infant Death Syndrome (Wilson et al., 1984). At present, it is considered a rare disease (

The genes HMGCS2 and HMGCL encode the two main enzymes for ketone-body synthesis, mitochondrial HMG-CoA synthase and HMG-CoA lyase. Here, we identify and describe possible splice variants of these genes in human tissues. We detected an alternative transcript of HMGCS2 carrying a deletion of exon 4, and two alternative transcripts of HMGCL with deletions of exons 5 and 6, and exons 5, 6 and 7, respectively. All splice variants maintained the reading frame. However, Western blot studies and overexpression measurements in eukaryotic or prokaryotic cell models did not reveal HL or mHS protein variants. Both genes showed a similar distribution of the inactive variants in different tissues. Surprisingly, the highest percentages were found in tissues where almost no ketone bodies are synthesized: heart, skeletal muscle and brain. Our results suggest that alternative splicing might coordinately block the two main enzymes of ketogenesis in specific human tissues, Diputación General de Aragón; University of Zaragoza UZ2007-BIO-13); Spanish Ministry of Education and Science ; Instituto de Salud Carlos III (CIBER Fisiopatologıa de la Obesidad y Nutrición); European Union (FP7-223431 ‘‘Divinocell’’ project); Fundación Ramón Areces

Cornelia de Lange syndrome (CdLS) manifests facial dysmorphic features, growth and cognitive impairment, and limb malformations. Mutations in three genes (NIPBL, SMC1A, and SMC3) of the cohesin complex and its regulators have been found in affected patients. Here, we present clinical and molecular characterization of 30 unrelated patients with CdLS. Eleven patients had mutations in NIPBL (37%) and three patients had mutations in SMC1A (10%), giving an overall rate of mutations of 47%. Several patients shared the same mutation in NIPBL (p.R827GfsX2) but had variable phenotypes, indicating the influence of modifiers in CdLS. Patients with NIPBL mutations had a more severe phenotype than those with mutations in SMC1A or those without identified mutations. However, a high incidence of palate defects was noted in patients with SMC1A mutations. In addition, we observed a similar phenotype in both male and female patients with SMC1A mutations. Finally, we report the first patient with an SMC1A mutation and the Sandifer complex.

La dinámica fluvial es la clave no sólo del funcionamiento, sino también del valor ecológico, paisajístico y ambiental de los sistemas fluviales. Si se quiere conservar un río como ecosistema y como corredor ambiental en el territorio se debe proteger ante todo su dinámica hidrogeomorfológica, porque ésta es la que va a garantizar la protección de todos y cada uno de los elementos del sistema y sus relaciones. Por ello, la evaluación del funcionamiento hidrogeomorfológico de los sistemas fluviales es fundamental para determinar su estado ecológico, así como las tendencias previsibles del mismo. Así, se propone un índice de valoración hidrogeomorfológica con el objetivo técnico de la aplicación de la Directiva 2000/60/CE y el no menos importante objetivo científico de la mejora en el conocimiento y diagnóstico de los sistemas fluviales, todo ello en el marco de la urgente y necesaria búsqueda de soluciones a su actual problemática ambiental. El trabajo presentado incluye explicaciones metodológicas para la aplicación del índice, que se estructura en tres parámetros de evaluación: 1) calidad funcional del sistema fluvial, incluyendo a) naturalidad del régimen de caudal, b) disponibilidad y movilidad de sedimentos y c) funcionalidad de la llanura de inundación; 2) calidad del cauce, incluyendo a) naturalidad del trazado y de la morfología en planta, b) continuidad y naturalidad del lecho y de los procesos longitudinales y verticales y c) naturalidad de las márgenes y de la movilidad lateral; y 3) calidad de las riberas, incluyendo a) continuidad longitudinal, b) anchura, estructura y naturalidad y c) interconectividad transversal.

Se analizan los efectos de la orientación de ladera en comunidades arbustivas del sector semiárido central del Valle del Ebro. Los resultados confirman diferencias en parámetros estructurales (biomasa, distribución de frecuencias), y comportamiento hídrico de las dos especies dominantes (Rosmarinas officinalis y Ononis tridentata) que se atribuyen a las diferencias en los factores físicos inducidos por la exposición de ladera (temperatura, ETP, agua en el suelo). Los resultados sugieren la posibilidad de que el efecto de la orientación de ladera sobre el crecimiento vegetal tenga, preferentemente, un carácter selectivo en el tiempo.

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.

Mutations in the cohesin regulators NIPBL and ESCO2 are causative of the Cornelia de Lange syndrome (CdLS) and Roberts or SC phocomelia syndrome, respectively. Recently, mutations in the cohesin complex structural component SMC1A have been identified in two probands with features of CdLS. Here, we report the identification of a mutation in the gene encoding the complementary subunit of the cohesin heterodimer, SMC3, and 14 additional SMC1A mutations. All mutations are predicted to retain an open reading frame, and no truncating mutations were identified. Structural analysis of the mutant SMC3 and SMC1A proteins indicate that all are likely to produce functional cohesin complexes, but we posit that they may alter their chromosome binding dynamics. Our data indicate that SMC3 and SMC1A mutations (1) contribute to approximately 5% of cases of CdLS, (2) result in a consistently mild phenotype with absence of major structural anomalies typically associated with CdLS, and (3) in some instances, result in a phenotype that approaches that of apparently nonsyndromic mental retardation.

3‐Hydroxy‐3‐methylglutaric aciduria is a rare human autosomal recessive disorder caused by deficiency of 3‐hydroxy‐3‐methylglutaryl CoA lyase (HL). This mitochondrial enzyme catalyzes the common final step of leucine degradation and ketogenesis. Acute symptoms include vomiting, seizures and lethargy, accompanied by metabolic acidosis and hypoketotic hypoglycaemia. Such organs as the liver, brain, pancreas, and heart can also be involved. However, the pathophysiology of this disease is only partially understood. We measured mRNA levels, protein expression and enzyme activity of human HMG‐CoA lyase from liver, kidney, pancreas, testis, heart, skeletal muscle, and brain. Surprisingly, the pancreas is, after the liver, the tissue with most HL activity. However, in heart and adult brain, HL activity was not detected in the mitochondrial fraction. These findings contribute to our understanding of the enzyme function and the consequences of its deficiency and suggest the need for assessment of pancreatic damage in these patients. info:eu-repo/semantics/acceptedVersion