43 results on '"Jorge J. Cebolla"'
Search Results
2. A novel mutation in two Spanish children with Niemann Pick disease: description of genotype, sphingomyelinase activity, phenotype and review
- Author
-
Pablo del Villar-Guerra, Celia Reig, Pilar Irún, Blanca Moreno, Pilar Giraldo, and Jorge J. Cebolla
- Subjects
Pediatrics ,RJ1-570 - Published
- 2021
- Full Text
- View/download PDF
Catalog
3. Identification of risk features for complication in Gaucher’s disease patients: a machine learning analysis of the Spanish registry of Gaucher disease
- Author
-
Marcio M. Andrade-Campos, Laura López de Frutos, Jorge J. Cebolla, Irene Serrano-Gonzalo, Blanca Medrano-Engay, Mercedes Roca-Espiau, Beatriz Gomez-Barrera, Jorge Pérez-Heredia, David Iniguez, and Pilar Giraldo more...
- Subjects
Gaucher disease ,Machine learning ,Bone crisis ,Neoplasia ,ERT ,Medicine - Abstract
Abstract Background Since enzyme replacement therapy for Gaucher disease (MIM#230800) has become available, both awareness of and the natural history of the disease have changed. However, there remain unmet needs such as the identification of patients at risk of developing bone crisis during therapy and late complications such as cancer or parkinsonism. The Spanish Gaucher Disease Registry has worked since 1993 to compile demographic, clinical, genetic, analytical, imaging and follow-up data from more than 400 patients. The aims of this study were to discover correlations between patients’ characteristics at diagnosis and to identify risk features for the development of late complications; for this a machine learning approach involving correlation networks and decision trees analyses was applied. Results A total of 358 patients, 340 type 1 Gaucher disease and 18 type 3 cases were selected. 18% were splenectomyzed and 39% had advanced bone disease. 81% of cases carried heterozygous genotype. 47% of them were diagnosed before the year 2000. Mean age at diagnosis and therapy were 28 and 31.5 years old (y.o.) respectively. 4% developed monoclonal gammopathy undetermined significance or Parkinson Disease, 6% cancer, and 10% died before this study. Previous splenectomy correlates with the development of skeletal complications and severe bone disease (p = 0.005); serum levels of IgA, delayed age at start therapy (> 9.5 y.o. since diagnosis) also correlates with severe bone disease at diagnosis and with the incidence of bone crisis during therapy. High IgG (> 1750 mg/dL) levels and age over 60 y.o. at diagnosis were found to be related with the development of cancer. When modelling the decision tree, patients with a delayed diagnosis and therapy were the most severe and with higher risk of complications. Conclusions Our work confirms previous observations, highlights the importance of early diagnosis and therapy and identifies new risk features such as high IgA and IgG levels for long-term complications. more...
- Published
- 2020
- Full Text
- View/download PDF
4. Muscle-tendon weakness contributes to chronic fatigue syndrome in Gaucher’s disease
- Author
-
Mercedes Roca-Espiau, Marcio Andrade-Campos, Jorge J. Cebolla, Laura López de Frutos, Blanca Medrano-Engay, Maria-Pilar López-Royo, and Pilar Giraldo
- Subjects
Gaucher disease ,Fatigue ,Strain-elastography ,Achilles tendon stiffness ,QoL ,Orthopedic surgery ,RD701-811 ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
Abstract Background Chronic fatigue (CFg) is a prevalent symptom in Gaucher disease (GD) at diagnosis (79%) and remains in a quarter of patients after years of therapy. Bone abnormalities are present in over 70% and peripheral neuropathy in about 11% of the patients, which contributes to the disabling and debilitating complications. Our hypothesis is that other factors such as muscle-tendinous weakness could have influence in the development of CFg. Methods We have evaluated the fiber structure and elasticity of muscle-tendinous unit by strain-elastography (S-ELA) and analyzed their influence in the CFg. S-ELA study was performed in Achilles tendon in 25 type 1 and two type 3 GD patients, all of them with fatigue and were on enzymatic replacement therapy for mean 13 years; simultaneously, bone marrow burden by MRI and calcaneus ultrasound densitometry were evaluated. Blood cell counts, plasma biomarkers, GBA1 genotyping, and SF36 quality of life scale (QoL) were also performed. Statistical analysis: descriptive and comparative test. Results All patients showed a normal Achilles tendinous structure. Abnormal stiff grade 2–3 was found in 17/27 (62.9%); in 11/27 (40.7%) of patients, the alteration was bilateral. There were no correlations between the S-ELA results to other variables; nevertheless, a significant correlation between the degree of tendon hardness and the low score on the QoL scales (p = 0.0035) was found. The S-ELA is a sensitive painless, fast, and low cost method to detect muscle-tendinous subclinical dysfunction that could contribute to CFg in GD. The identification of subclinical tendon alteration would be a sign of alarm, focused on the risk of development of bone complications. Conclusion Intratendinous alteration in strain-elastography is an independent variable in GD patients with persistent fatigue. more...
- Published
- 2019
- Full Text
- View/download PDF
5. Mutations identified in a cohort of Mexican patients with lysosomal acid lipase deficiency
- Author
-
Alejandra Consuelo-Sánchez, Rodrigo Vázquez-Frias, Alejandra Reyes-De La Rosa, Carlos P. Acosta-Rodríguez-Bueno, María P. Ortal-Vite, and Jorge J. Cebolla
- Subjects
Lysosomal acid lipase deficiency ,LIPA gene ,Pediatrics ,Lysosomal disease ,Liver ,Specialties of internal medicine ,RC581-951 - Abstract
Introduction and Objectives: Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive disease caused by mutations in the LIPA gene, located on the long arm of chromosome 10 (10q23.31). Up until now, more than 59 mutations have been described and which are the cause of a very wide clinical spectrum. The goal of this study was to identify the mutations present in Mexican pediatric patients with a diagnosis of LAL-D. Materials and methods: A cross-sectional study was carried out which included all the pediatric patients with LAL-D treated in a tertiary hospital in Mexico from January 2000 to June 2017. Results: Sixteen patients with LAL-D were identified with a disease phenotype marked by the accumulation of cholesteryl esters. Eight distinct variants in the LIPA gene sequence were found, four pathogenic variants and four probably pathogenic. In six individuals, the variants were found in the homozygous state and ten were compound heterozygous. The eight variants were inverted, with five found on exon 4 and the others on exons 2, 8 and 10. The variant c.386A>G;p.His129Arg was the most common, being found in six of the 16 individuals (37.5%), making it much more frequent than what had previously been reported in the literature in proportion to the rest of the variants. The mutation known as E8SJM, which has been the mostly frequently found at the international level, was not the most common among this group of Mexican patients.In conclusion, Mexican patients present a different frequency of mutations associated with LAL-D in comparison to European populations. more...
- Published
- 2019
- Full Text
- View/download PDF
6. Recommendations for overcoming challenges in the diagnosis of lysosomal acid lipase deficiency
- Author
-
Pilar Giraldo, Laura López de Frutos, and Jorge J Cebolla
- Subjects
Health Policy ,Pharmacology (medical) ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) - Published
- 2022
- Full Text
- View/download PDF
7. A novel mutation in two Spanish children with Niemann Pick disease: description of genotype, sphingomyelinase activity, phenotype and review
- Author
-
Pilar Irún, Pablo del Villar-Guerra, Pilar Giraldo, Jorge J. Cebolla, Celia Reig, and Blanca Moreno
- Subjects
Genetics ,Management of Technology and Innovation ,Genotype ,medicine ,Biology ,Acid sphingomyelinase ,Niemann–Pick disease ,medicine.disease ,Novel mutation ,Phenotype ,Pediatrics ,RJ1-570 ,medicine.drug - Published
- 2021
8. Nueva mutación asociada con la enfermedad de Niemann-Pick en dos niños españoles: descripción del genotipo, actividad de la esfingomielinasa ácida, fenotipo y revisión
- Author
-
Pilar Giraldo, Jorge J. Cebolla, Pablo del Villar-Guerra, Celia Reig, Pilar Irún, and Blanca Moreno
- Subjects
Pediatrics, Perinatology and Child Health ,Biology ,Pediatrics ,RJ1-570 - Published
- 2021
9. Serum protein profile analysis in lysosomal storage disorders patients
- Author
-
Elena García-González, Yolanda Gonzalez-Irazabal, Carlos Lahoz, Laura López de Frutos, Pilar Irún, Jorge J. Cebolla, Pilar Giraldo, and Beatriz Garcia-Rodriguez
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Clinical Biochemistry ,Population ,Lysosomal acid lipase deficiency ,Biochemistry ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Gammopathy ,medicine ,Humans ,education ,Multiple myeloma ,education.field_of_study ,Gaucher Disease ,medicine.diagnostic_test ,business.industry ,Biochemistry (medical) ,General Medicine ,medicine.disease ,Blood proteins ,Lysosomal Storage Diseases ,030104 developmental biology ,030220 oncology & carcinogenesis ,Serum protein electrophoresis ,Monoclonal ,Immunoglobulin Light Chains ,Lysosomes ,Multiple Myeloma ,business ,Nephelometry - Abstract
Introduction Serum protein electrophoresis (SPE) is a well-established technique to identify alterations in plasma protein profiles, caused by diseases as multiple myeloma (MM). In addition, it could be a cost-effective technique to discover new plasma biomarkers. Relation between MM and lysosomal storage diseases (LSDs) as Gaucher disease has been set out but, it has not been evaluated on other LSDs nor the utility of the SPE as first step on LSDs biomarkers discovery projects. Materials and methods Stored plasma samples at diagnosis from several LSDs patients underwent analysis. Quality control was checked prior to the SPE was analyzed by capillary electrophoresis. The analysis for monoclonal spikes and the differences between each fraction on patients’ samples vs the control data previously published, were evaluated. Furthermore, immunoprotein quantification and free light chains ratio were done by nephelometry and turbidimetry. Results Seventy-five samples of LSD patients at diagnosis, were assessed. The frequency of the MGUS on LSDs patients was not higher than in general population whereas one lysosomal acid lipase deficiency infant showed increased IgA and kappa deviation. Regarding to the usefulness of SPE in biomarkers discovery, statistically significant differences were observed on SPE fractions between LSDs and healthy population. Discussion The evaluation of SPE fractions can be a useful tool to understand pathophysiologic aspects in LDSs and, to simplify new marker discovery projects. In some of them, the MGUS appearance is a risk factor for the MM development despite its frequency is not increased on the studied LSDs at diagnosis. more...
- Published
- 2020
- Full Text
- View/download PDF
10. LC-MS/MS analysis of plasma glucosylsphingosine as a biomarker for diagnosis and follow-up monitoring in Gaucher disease in the Spanish population
- Author
-
Laura López de Frutos, Mercedes Roca-Espiau, Isabel De Castro-Orós, Pilar Giraldo, Jorge J. Cebolla, and Pilar Irún
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Adolescent ,Genotype ,Clinical Biochemistry ,Disease ,Gastroenterology ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Tandem Mass Spectrometry ,Internal medicine ,medicine ,Humans ,Substrate reduction therapy ,Child ,Chromatography, High Pressure Liquid ,Aged ,Retrospective Studies ,Gaucher Disease ,medicine.diagnostic_test ,business.industry ,Biochemistry (medical) ,Psychosine ,CCL18 ,Infant ,Magnetic resonance imaging ,Retrospective cohort study ,General Medicine ,Enzyme replacement therapy ,Middle Aged ,Spanish population ,Hexosaminidases ,030104 developmental biology ,Spain ,Case-Control Studies ,Child, Preschool ,030220 oncology & carcinogenesis ,Biomarker (medicine) ,Female ,Chemokine CCL18 ,business ,Biomarkers - Abstract
Background Gaucher disease (GD), caused by a deficiency in acid β-glucosidase, leads to the accumulation of glucosylsphingosine (GluSph), which has been used as a powerful biomarker for the diagnosis and follow-up of GD. Our aim was to perform the first retrospective study of GluSph in Spanish patients, analyzing its relationship with classical biomarkers and other parameters of disease and its utility regarding treatment monitoring. Methods Classical biomarkers were evaluated retrospectively by standard methods in a total of 145 subjects, including 47 GD patients, carriers, healthy controls and patients suffering from other lysosomal lipidoses. GluSph was also measured using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method developed as part of the present study. Results The optimized method presented intra- and inter-assay variations of 3.1 and 11.5%, respectively, overall recovery higher than 96% and linearity up to plasma concentrations of 1000 ng/mL with 100% specificity and sensitivity. Only GD patients displayed GluSph levels above 5.4 ng/mL at diagnosis and this was significantly correlated with the classical biomarkers chitotriosidase (r = 0.560) and the chemokine CCL18/PARC (CCL18/PARC) (ρ = 0.515), as well as with the Spanish magnetic resonance imaging index (S-MRI, r = 0.364), whereas chitotriosidase correlated with liver volume (r = 0.372) and CCL18/PARC increased in patients with bone manifestations (p = 0.005). GluSph levels decreased with treatment in naïve patients. Conclusions Plasma GluSph is the most disease-specific biomarker for GD with demonstrated diagnostic value and responsiveness to therapy. GluSph in the present series of patients failed to demonstrate better correlations with clinical characteristics at onset than classical biomarkers. more...
- Published
- 2020
- Full Text
- View/download PDF
11. New variants in Spanish Niemann–Pick type c disease patients
- Author
-
Laura López de Frutos, Sinziana Stanescu, Pilar Giraldo, Ángela de la Vega, Carlos Lahoz, Jorge J. Cebolla, Luis Aldámiz-Echevarría, and Pilar Irún
- Subjects
0301 basic medicine ,Genetics ,Sanger sequencing ,Promoter ,General Medicine ,Disease ,Biology ,Compound heterozygosity ,03 medical and health sciences ,symbols.namesake ,Exon ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,symbols ,Biomarker (medicine) ,NPC1 ,Molecular Biology ,Gene - Abstract
Niemann–Pick type C (NPC) disease is a rare inherited disease, with progressive neurodegeneration as the main symptom. It is a lysosomal storage disorder caused by mutations in NPC1 or NPC2 genes, leading to a lysosomal cholesterol trafficking impairment. Disease indicators are the clinical suspicion and biomarker levels. However, a genetic study is mandatory for the diagnosis, which is complicated due to the different variants with unknown significance. The aim of this work was to identify the variants responsible for NPC in our pediatric population. Twenty-two samples from non-related infants believed to have NPC disease were analyzed during the last 3 years. Surrogate biomarkers of the disease were evaluated whenever possible. Sanger sequencing for both genes is reported for all samples. Complementary genetic studies were performed when necessary. NPC disease was confirmed in 31.8% of subjects due to homozygous or compound heterozygous genetic variants in NPC1. The following four novel variants were identified: a gross deletion variant composed of the gene promoter and the first exon, NM_000271.3:c.385delT, NM_000271.3:c.1553+1342_1655-291del, and NM_000271.3:c.1757delA. None had functional activity and all resulted in important structural changes in the protein. more...
- Published
- 2020
- Full Text
- View/download PDF
12. The erythrocyte osmotic resistance test as screening tool for cholesterol-related lysosomal storage diseases
- Author
-
Pilar Giraldo, Ralf Köhler, Pilar Irún, Jorge J. Cebolla, and Laura López de Frutos
- Subjects
Adult ,Male ,0301 basic medicine ,Osmosis ,medicine.medical_specialty ,Erythrocytes ,Screening test ,Sodium ,Clinical Biochemistry ,chemistry.chemical_element ,Lysosomal acid lipase deficiency ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Internal medicine ,medicine ,Humans ,Screening tool ,Chemistry ,Cholesterol ,Cell Membrane ,Biochemistry (medical) ,General Medicine ,Sterol Esterase ,medicine.disease ,Haemolysis ,Lysosomal Storage Diseases ,030104 developmental biology ,Endocrinology ,Tonicity ,Female ,NPC1 ,Biomarkers - Abstract
Background Erythrocyte volume regulation and membrane elasticity are essential for adaptation to osmotic and mechanical stress, and life span. Here, we evaluated whether defective cholesterol trafficking caused by the rare lysosomal storages diseases (LSDs), Niemann-Pick type C (NPC) and Lysosomal acid lipase (LAL) deficiency (LALD) impairs these properties. Moreover, we tested whether measurements of cholesterol membrane content and osmotic resistance serve as a screening test for these LSDs. Methods Patients were genotyped for mutations in NPC1, NPC2, or LIPA genes. We measured LSD plasma biomarkers and LAL activity. Red blood cells (RBC) membrane cholesterol content was evaluated in 73 subjects. Osmotic resistance tests (ORT) were conducted in 121 blood samples from LSD suspected patients and controls. Results We did not find statistically significant differences between RBC cholesterol content between subjects and controls. However, the ORT, particularly at 0.49% (w/v) hypotonic sodium chloride solution, revealed a significant higher osmotic resistance in LSDs patients than in controls. We established a cut-off value of ≤51% of haemolysis with sensibility and specificity values of 80% and 70%, respectively. Conclusions NPC and LALD do not alter cholesterol content in the RBC membrane but increase osmotic resistance. Therefore, ORT serves as screening test for the studied LSDs. more...
- Published
- 2018
- Full Text
- View/download PDF
13. Neonatal cholestasis and Niemann-pick type C disease: A literature review
- Author
-
Pilar Irún, I. De Castro-Orós, Laura López de Frutos, Pilar Giraldo, and Jorge J. Cebolla
- Subjects
medicine.medical_specialty ,Disease ,Gastroenterology ,Organomegaly ,symbols.namesake ,Internal medicine ,otorhinolaryngologic diseases ,Lysosomal storage disease ,Humans ,Mass Screening ,Medicine ,Neonatal cholestasis ,Sanger sequencing ,Cholestasis ,Hepatology ,business.industry ,Incidence (epidemiology) ,Infant, Newborn ,Infant ,Niemann-Pick Disease, Type C ,medicine.disease ,stomatognathic diseases ,Child, Preschool ,symbols ,Biomarker (medicine) ,medicine.symptom ,NPC1 ,business ,Biomarkers - Abstract
Background Neonatal cholestasis (NC) is one of the most serious diseases in newborns and infants and results from metabolic disorders, such as Niemann-Pick type C (NPC), among other causes. Objective We evaluated the incidence of NPC in our NC plus lysosomal storage disease (LSD) suspicious neonates and infants series. Methods The study included children (≤3 years old) with a history of NC together with a suspicion of LSD, referred from Spanish Hospitals during the period 2011−2020. Screening for NPC was done by plasma biomarker assay (chitotriosidase activity and 7-ketocholesterol), and Sanger sequencing for NPC1 and NPC2 genes. Results We screened NPC disease in 17 patients with NC plus organomegaly and that were LSD suspicious, finding 5 NPC patients (29.4%) and 2 carriers. Conclusions Our results emphasize the need to study NPC when NC and visceral enlargement arise in a newborn or infant. more...
- Published
- 2021
- Full Text
- View/download PDF
14. Serum protein electrophoresis pattern alterations on lipidoses patients
- Author
-
Eva Mora-Hernández, Irene Serrano-Gonzalo, Laura López de Frutos, Pilar Irún, Elena García-González, Pilar Giraldo, Beatriz Garcia-Rodriguez, Carlos Lahoz, Jorge J. Cebolla, and Yolanda Gonzalez-Irazabal more...
- Subjects
Endocrinology ,medicine.diagnostic_test ,Chemistry ,Endocrinology, Diabetes and Metabolism ,Serum protein electrophoresis ,Genetics ,medicine ,Molecular Biology ,Biochemistry ,Molecular biology - Published
- 2020
- Full Text
- View/download PDF
15. Impact of immunoparesis on Gaucher disease (GD): Results from a network relationship analysis of data at diagnosis of the patients included in the Spanish registry of GD
- Author
-
Jorge J. Cebolla Sanz, Beatriz Gomez-Barrera, Maria Blanca Medrano Engay, Laura López de Frutos, Mercedes Roca Espiau, David Iñiguez, Marcio Andrade-Campos, and Jorge Perez-Heredia
- Subjects
Pediatrics ,medicine.medical_specialty ,Endocrinology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Relationship analysis ,Genetics ,medicine ,Disease ,business ,Molecular Biology ,Biochemistry - Published
- 2020
- Full Text
- View/download PDF
16. New variants in Spanish Niemann-Pick type c disease patients
- Author
-
Laura, López de Frutos, Jorge J, Cebolla, Luis, Aldámiz-Echevarría, Ángela, de la Vega, Sinziana, Stanescu, Carlos, Lahoz, Pilar, Irún, and Pilar, Giraldo
- Subjects
Male ,DNA Mutational Analysis ,Intracellular Signaling Peptides and Proteins ,Computational Biology ,Genetic Variation ,Infant ,Niemann-Pick Disease, Type C ,Severity of Illness Index ,Niemann-Pick C1 Protein ,Spain ,Child, Preschool ,Databases, Genetic ,Mutation ,Humans ,Female ,Genetic Predisposition to Disease ,Child ,Alleles ,Biomarkers ,Genetic Association Studies - Abstract
Niemann-Pick type C (NPC) disease is a rare inherited disease, with progressive neurodegeneration as the main symptom. It is a lysosomal storage disorder caused by mutations in NPC1 or NPC2 genes, leading to a lysosomal cholesterol trafficking impairment. Disease indicators are the clinical suspicion and biomarker levels. However, a genetic study is mandatory for the diagnosis, which is complicated due to the different variants with unknown significance. The aim of this work was to identify the variants responsible for NPC in our pediatric population. Twenty-two samples from non-related infants believed to have NPC disease were analyzed during the last 3 years. Surrogate biomarkers of the disease were evaluated whenever possible. Sanger sequencing for both genes is reported for all samples. Complementary genetic studies were performed when necessary. NPC disease was confirmed in 31.8% of subjects due to homozygous or compound heterozygous genetic variants in NPC1. The following four novel variants were identified: a gross deletion variant composed of the gene promoter and the first exon, NM_000271.3:c.385delT, NM_000271.3:c.1553+1342_1655-291del, and NM_000271.3:c.1757delA. None had functional activity and all resulted in important structural changes in the protein. more...
- Published
- 2019
17. Web-Based Bioinformatics Predictors: Recommendations to Assess Lysosomal Cholesterol Trafficking Diseases-Related Genes
- Author
-
Laura López de Frutos, Pilar Giraldo, Ralf Köhler, Jorge J. Cebolla, and Pilar Irún
- Subjects
020205 medical informatics ,In silico ,Health Informatics ,02 engineering and technology ,Computational biology ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Unknown Significance ,Health Information Management ,0202 electrical engineering, electronic engineering, information engineering ,Humans ,splice ,Disease ,030212 general & internal medicine ,Frameshift Mutation ,Gene ,Advanced and Specialized Nursing ,Internet ,Genetic variants ,Computational Biology ,Biological Transport ,Exons ,Pathogenicity ,Introns ,Cholesterol ,ROC Curve ,RNA splicing ,Mutation ,NPC1 ,Lysosomes - Abstract
Introduction The growing number of genetic variants of unknown significance (VUS) and availability of several in silico prediction tools make the evaluation of potentially deleterious gene variants challenging. Materials and Methods We evaluated several programs and software to determine the one that can predict the impact of genetic variants found in lysosomal storage disorders (LSDs) caused by defects in cholesterol trafficking best. We evaluated the sensitivity, specificity, accuracy, precision, and Matthew's correlation coefficient of the most common software. Results Our findings showed that for exonic variants, only MutPred1 reached 100% accuracy and generated the best predictions (sensitivity and accuracy = 1.00), whereas intronic variants, SROOGLE or Human Splicing Finder (HSF) generated the best predictions (sensitivity = 1.00, and accuracy = 1.00). Discussion Next-generation sequencing substantially increased the number of detected genetic variants, most of which were considered to be VUS, creating a need for accurate pathogenicity prediction. The focus of the present study is the importance of accurately predicting LSDs, with majority of previously unreported specific mutations. Conclusion We found that the best prediction tool for the NPC1, NPC2, and LIPA variants was MutPred1 for exonic regions and HSF and SROOGLE for intronic regions and splice sites. more...
- Published
- 2019
18. Biomarker combination is necessary for the assessment of Gaucher disease?
- Author
-
Laura López de Frutos, Jorge J. Cebolla, and Pilar Giraldo
- Subjects
0301 basic medicine ,Progranulin ,business.industry ,Drug administration ,General Medicine ,Disease ,Gaucher disease ,Bioinformatics ,03 medical and health sciences ,030104 developmental biology ,Lysosomal storage diseases ,Medicine ,Biomarker (medicine) ,Chitinase-3-like-1 ,business ,Pathological ,Research Paper - Abstract
We recently reported that progranulin (PGRN) is a novel regulator of glucocerebrosidase and its deficiency associates with Gaucher Diseases (GD) (Jian et al., 2016a; Jian et al., 2018). To isolate the relevant downstream molecules, we performed a whole genome microarray and mass spectrometry analysis, which led to the isolation of Chitinase-3-like-1 (CHI3L1) as one of the up-regulated genes in PGRN null mice. Elevated levels of CHI3L1 were confirmed by immunoblotting and immunohistochemistry. In contrast, treatment with recombinant Pcgin, a derivative of PGRN, as well as imigluerase, significantly reduced the expressions of CHI3L1 in both PGRN null GD model and the fibroblasts from GD patients. Serum levels of CHIT1, a clinical biomarker for GD, were significantly higher in GD patients than healthy controls (51.16 ± 2.824 ng/ml vs 35.07 ± 2.099 ng/ml, p, Highlights • CHI3L1 is isolated as a as PGRN downstream molecule associated with Gaucher Diseases (GD). • Expression of CHI3L1 is increased in Gba1 D409V/null GD animal model. • CHI3L1 level is reduced when GD phenotypes is improved following treatments. • Serum levels of CHI3L1 is significantly elevated in GD patients compared with healthy controls. Gaucher disease (GD), common lysosomal storage disease (LSD), is caused by mutations in GBA1 with resultant defective glucocerebrosidase (GCase) activity. PGRN is a novel factor of GD that directly binds to GCase and GD patients have significantly lower levels of PGRN in serum compared with healthy controls (Jian et al., 2016a). Mechanistically, PGRN functions as a chaperone molecule that facilitates GCase lysosomal delivery (Jian et al., 2016b). In this study, CHI3L1 was isolated as a PGRN downstream molecule associated with GD. CHI3L1 expression is up-regulated in Gba1 D409V/null model, and its level is reduced following treatment with PGRN, PGRN deriative Pcgin, or Imiglucerase. In addition, serum levels of CHI3L1 are significantly elevated in GD patients compared with healthy controls. more...
- Published
- 2019
19. TRAZELGA: Preliminary results of the Spanish prospective, multi-center follow-up study and immune activation markers in adult Gaucher disease patients treated with eliglustat
- Author
-
Marcio Andrade-Campos, Lucia Villalon, Daiana Ibarretxe, Irene Serrano, Javier García-Frade, María Soledad Noya Pereira, Jose Maria Hernandez-Rivas, M. Morales-Conejo, Laura López de Frutos, M.A. Fernandez-Galan, Jorge J. Cebolla Sanz, Miguel López-Dupla, and J.A. Perez de Leon more...
- Subjects
Pediatrics ,medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Follow up studies ,Biochemistry ,Endocrinology ,Genetics ,Medicine ,business ,Molecular Biology ,Adult Gaucher disease ,Eliglustat ,Immune activation - Published
- 2020
- Full Text
- View/download PDF
20. Evaluation of two approaches to lysosomal acid lipase deficiency patient identification: An observational retrospective study
- Author
-
Pilar Giraldo, Pilar Irún, P. Mozas, and Jorge J. Cebolla
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Apolipoprotein B ,Adolescent ,030204 cardiovascular system & hematology ,Lysosomal acid lipase deficiency ,Compound heterozygosity ,Gastroenterology ,03 medical and health sciences ,PCSK9 Gene ,Young Adult ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Child ,Aged ,Retrospective Studies ,Aged, 80 and over ,biology ,business.industry ,CCL18 ,Wolman Disease ,Infant ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Lipid Metabolism ,030104 developmental biology ,Hexosaminidases ,Liver ,Chemokines, CC ,Child, Preschool ,LDL receptor ,biology.protein ,Biomarker (medicine) ,Female ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers - Abstract
Background and aims Lysosomal acid lipase deficiency (LALD) leads to the accumulation of cholesteryl esters and/or triglycerides (TG) in lysosomes due to the lack of the enzyme codified by the LIPA gene. The most common symptoms are dyslipidaemia and hypertransaminasemia, together with manifestations common to other lysosomal storage disorders (LSDs), including visceromegalies and elevated plasma biomarkers. Alteration of the lipid-liver profile (LLP) has been widely applied as a criterion for LALD screening, but the usefulness of biomarkers has not yet been explored. Our purpose was to explore the utility of plasma chitotriosidase activity (ChT) and CCL18/PARC concentration in addition to LLP to identify LALD patients in an observational retrospective study of two different sample collections. Methods Biological samples refining: Collection 1 (primary hypercholesterolemia suspected) included unrelated individuals with hyperlipidaemia and without LDLR, APOB and PCSK9 gene mutations (Set 1), and Collection 2 (LSD suspected) included individuals without definitive LSD diagnosis (Set 2). We assessed plasma LLP (total cholesterol and its fractions, TG concentration and transaminases activities), as well as plasma ChT and CCL18/PARC. All subjects with anomalous LLP and/or biomarker levels were LIPA sequenced. Results Twenty-four subjects showed altered LLP and/or biomarkers. We identified two LALD patients (one homozygous and one compound heterozygous) and one carrier of a novel LIPA variant. Conclusions The measurement of plasma ChT and CCL18/PARC combined with LLP will be a useful approach to identifying LALD patients in retrospective LALD patient studies. more...
- Published
- 2018
21. Prospective multi-center national study to standardize the follow-up of type 1 Gaucher disease patients treated with eliglustat under standard of care practice: TRAZELGA project
- Author
-
M.A. Perez Saenz, Marta Morado, Jose Maria Hernandez Rivas, Jorge J. Cebolla, Daiana Ibarretxe, Pilar Giraldo, Marcio Andrade-Campos, Javier García-Frade, Jesús Villarrubia, Abelardo Bárez, S. Nieto, Maria Teresa Molero, Maria Soledad Noya, Lucia Villalon, M.L. Lozano Almela, Laura López de Frutos, N. Hermosin, A.I. Arribas, and Pilar Irún more...
- Subjects
Pediatrics ,medicine.medical_specialty ,Standard of care ,business.industry ,Endocrinology, Diabetes and Metabolism ,Type 1 Gaucher Disease ,Biochemistry ,Endocrinology ,Genetics ,medicine ,National study ,Center (algebra and category theory) ,business ,Molecular Biology ,Eliglustat - Published
- 2019
- Full Text
- View/download PDF
22. Assessment of plasma 7-ketocholesterol concentration, chitotriosidase activity and CCL18/PARC concentration in Spanish patients treated with human recombinant lisosomal acid lipase
- Author
-
Pilar Irún, D. Gil Ortega, Carlos Lahoz, Luis Aldámiz-Echevarría, A. Brea-Hernando, E. Balmaseda-Serrano, Jorge J. Cebolla, Pilar Giraldo, Inmaculada Garcia-Jimenez, Daiana Ibarretxe, J. Quintero Bernabeu, J. de Las Heras, and N. Plana more...
- Subjects
Endocrinology ,Biochemistry ,Chemistry ,law ,Endocrinology, Diabetes and Metabolism ,Genetics ,CCL18 ,Recombinant DNA ,7-ketocholesterol ,Molecular Biology ,Acid lipase ,law.invention - Published
- 2019
- Full Text
- View/download PDF
23. Inhibition of Intermediate-Conductance Calcium-Activated K Channel (KCa3.1) and Fibroblast Mitogenesis by α-Linolenic Acid and Alterations of Channel Expression in the Lysosomal Storage Disorders, Fabry Disease, and Niemann Pick C
- Author
-
Pilar Irún, Laura López de Frutos, Ralf Köhler, Yolanda Gilaberte, Aida Oliván-Viguera, Edgar Abarca-Lachen, Javier Lozano-Gerona, Pilar Giraldo, Jorge J. Cebolla, A. L. García-Otín, and Ana Julia García-Malinis more...
- Subjects
0301 basic medicine ,food.ingredient ,Physiology ,Farmacología ,Cell ,chemistry.chemical_element ,Calcium ,Biology ,Ion channel pharmacology ,03 medical and health sciences ,0302 clinical medicine ,food ,Linseed oil ,linolenic acids ,fibroblasts ,Physiology (medical) ,medicine ,Fibroblast ,Linolenic acids ,Original Research ,chemistry.chemical_classification ,fabry disease ,Fabry disease ,Fatty acid ,Long-term potentiation ,Lipid metabolism ,Fibroblasts ,medicine.disease ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Biochemistry ,KCa3.1/SK4 channel ,ion channel pharmacology ,030217 neurology & neurosurgery - Abstract
The calcium/calmodulin-gated KCa3.1 channel regulates normal and abnormal mitogenesis by controlling K+-efflux, cell volume, and membrane hyperpolarization-driven calcium-entry. Recent studies suggest modulation of KCa3.1 by omega-3 fatty acids as negative modulators and impaired KCa3.1 functions in the inherited lysosomal storage disorder (LSD), Fabry disease (FD). In the first part of present study, we characterize KCa3.1 in murine and human fibroblasts and test the impact of omega-3 fatty acids on fibroblast proliferation. In the second, we study whether KCa3.1 is altered in the LSDs, FD, and Niemann-Pick disease type C (NPC). Our patch-clamp and mRNA-expression studies on murine and human fibroblasts show functional expression of KCa3.1. KCa currents display the typical pharmacological fingerprint of KCa3.1: Ca2+-activation, potentiation by the positive-gating modulators, SKA-31 and SKA-121, and inhibition by TRAM-34, Senicapoc (ICA-17043), and the negative-gating modulator, 13b. Considering modulation by omega-3 fatty acids we found that α-linolenic acid (α-LA) and docosahexanenoic acid (DHA) inhibit KCa3.1 currents and strongly reduce fibroblast growth. The α-LA-rich linseed oil and γ-LA-rich borage oil at 0.5% produce channel inhibition while α-LA/γ-LA-low oils has no anti-proliferative effect. Concerning KCa3.1 in LSD, mRNA expression studies, and patch-clamp on primary fibroblasts from FD and NPC patients reveal lower KCa3.1-gene expression and membrane expression than Oliván-Viguera et al. Regulation of KCa3.1 by α-LA and in LSDs in control fibroblasts. In conclusion, the omega-3 fatty acid, α-LA, and α-LA/γ-LA-rich plant oils, inhibit fibroblast KCa3.1 channels and mitogenesis. Reduced fibroblast KCa3.1 functions are a feature and possible biomarker of cell dysfunction in FD and NPC and supports the concept that biased lipid metabolism is capable of negatively modulating KCa3.1 expression. more...
- Published
- 2017
24. Computational Analysis Model Applied to Spanish Gaucher Registry Data
- Author
-
Blanca Medrano-Engay, Pilar Giraldo, Mercedes Roca-Espiau, Jorge J. Cebolla, Beatriz Gomez-Barrera, Laura López de Frutos, David Iñiguez, and Marcio Andrade-Campos
- Subjects
Computer science ,business.industry ,Immunology ,Cell Biology ,Hematology ,computer.software_genre ,Biochemistry ,Arthroplasty replacement ,LDL Cholesterol Lipoproteins ,Registry data ,Artificial intelligence ,Computational analysis ,Speech reception threshold ,business ,computer ,Natural language processing - Abstract
Introduction Type 1 Gaucher disease (GD)(OMIM # 230800), has a pan-ethnic distribution, in Spain its prevalence is about 1/100,000. Since more than twenty years the impact of therapies in the awareness of the disease is changing the characteristics and expectations of patients. The Spanish Gaucher disease Registry (SGDR) is working since 1993 and compiled demographic, clinical, genetic, analytical and imaging data about 360 type 1 GD Spanish patients. The application of new high computing capacity and powerful network analysis to analyze the registered data could provide a visualization tool and allows to extract knowledge from complex and very numerous relationships. The objective of this analysis is to discover useful ideas and new correlations to predict the risk of developing late complications and to extract knowledge of complex and very numerous relationships. Patients & Methods From 416 patients included in the SGDR we have selected 358 with more than 70% of data and follow-up. GD type 2 patients have been excluded. The variables included in the database at diagnosis: demographic data and the clinical, analytical and imaging information at diagnostic and during the treatment follow-up as well as comorbidities. With Kampal Data Solutions, a spin-off company of the University of Zaragoza dedicated to the development of computer applications and advanced data analytics, this company has experience in the homogenization of information and in the elaboration of classic and advanced statistics projects, as well as in the visualization of said information complex network techniques and the relationship between variables and model designs.Variables:Birthdate, age at diagnosis, gender, death date, severity category of disease (mild, moderate, severe), concomitant diseases, Parkinson disease in relatives, liver volume, spleen volume, spleen removal, bone disease, S-MRI, DEXA, chitotriosidase, CCL18/PARC, lyso Gb1, B12 vitamin level, iron concentration, ferritin, cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, AST, ALT, GGT, acid phosphatase, bilirubin, hemoglobin concentration, Hsc, WBC count, platelets count, serum gammaglobulin fraction, IgG, IgA, IgM, GBA activity, GBAgenotype, CHIT1genotype, age to start therapy, type of therapy (ERT, SRT), new bone crisis or joint replacement, development of malignancies or Parkinson disease. Results: The 358 subjects were mostly GD1 (340 vs 18 GD3), 18% were splenectomized and 39% have advanced bone disease and bone complications. Most of the patients have a complex heterozygous genotype (81% vs 19% homozygous). 47% of patients were diagnosed before 2,000 and 10% die before this study. Most of them are receiving ERT (54%). About comorbidities, 4% of patients developed MGUS or Parkinson disease and 6% malignant neoplasias. The main results have founded a significant correlation between skeletal complications and impaired and spleen removal (p=0.0005); this fact confirm previous reports. In this study a low IgA serum level shows a significant correlation with severe bone disease(p=0.0000), and with the incidence of new bone crisis during long term ERT. A IgG increase was related to the development of neoplasia. There were two more important factors that we have found; the age at diagnosis and the age to start therapy. Comments: Registries are key resources to help increasing timely and accurate diagnosis, improving patient's management, tailoring treatments, facilitating clinical trials, supporting healthcare planning and speeding up research. This is the very first attempt to establish a correlation network among different biomarkers and clinical characteristics in a national base cohort. As has been hypothesized seems that the impairment of immune system has a strong impact in long term complications, in our study the humoral immunity dysfunction pops up as an important factor. Despite of our short cohort, the quality of data is accurate and can reflect the own Spanish Gaucher disease characteristics. Currently we are working in the design of algorithms to help to predict patient outcomes. Disclosures No relevant conflicts of interest to declare. more...
- Published
- 2019
- Full Text
- View/download PDF
25. Twenty-five years diagnosing Gaucher disease in Spain: What we have learned?
- Author
-
Jesus J. Fraile, Izaskun Arenaz, Marcio Andrade-Campos, Laura López de Frutos, Maria Teresa Molero, Jorge J. Cebolla, Horacio Cano, Jose Luis Capablo, Mercedes Roca, Pilar Irún, Jesús Villarrubia, Pilar Giraldo, Abelardo Bárez, and Lucia Villalon more...
- Subjects
Pediatrics ,medicine.medical_specialty ,Endocrinology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Genetics ,medicine ,Disease ,business ,Molecular Biology ,Biochemistry - Published
- 2019
- Full Text
- View/download PDF
26. Update on lysosomal acid lipase deficiency: Diagnosis, treatment and patient management
- Author
-
Carmen, Camarena, Luis J, Aldamiz-Echevarria, Begoña, Polo, Miguel A, Barba Romero, Inmaculada, García, Jorge J, Cebolla, and Emilio, Ros
- Subjects
Diagnosis, Differential ,Disease Progression ,Wolman Disease ,Humans ,Enzyme Replacement Therapy ,Sterol Esterase ,Combined Modality Therapy ,Recombinant Proteins - Abstract
Lysosomal acid lipase deficiency (LALD) is an ultra-rare disease caused by a congenital disorder of the lipid metabolism, characterized by the deposition of cholesterol esters and triglycerides in the organism. In patients with no enzyme function, the disease develops during the perinatal period and is invariably associated with death during the first year of life. In all other cases, the phenotype is heterogeneous, although most patients develop chronic liver diseases and may also develop an early cardiovascular disease. Treatment for LALD has classically included the use of supportive measures that do not prevent the progression of the disease. In 2015, regulatory agencies approved the use of a human recombinant LAL for the treatment of LALD. This long-term enzyme replacement therapy has been associated with significant improvements in the hepatic and lipid profiles of patients with LALD, increasing survival rates in infants with a rapidly progressive disease. Both the severity of LALD and the availability of a specific treatment highlight the need to identify these patients in clinical settings, although its low prevalence and the existing clinical overlap with other more frequent pathologies limit its diagnosis. In this paper we set out practical recommendations to identify and monitor patients with LALD, including a diagnostic algorithm, along with an updated treatment. more...
- Published
- 2016
27. Prospective National-Base Multicenter Study to Standardize the Follow-up of Type 1Gaucher Disease Patients Treated with Eliglustat Under Standard of Care Practice. Trazelga Project
- Author
-
Soledad Noya, Jesús María Hernández-Rivas, Maria Luisa Lozano, Javier García-Frade, Lucia Villalon, Daiana Ibarretxe, Maria Lourdes Hermosin, Santiago Nieto, Laura López de Frutos, Marcio Andrade-Campos, Abelardo Bárez, Maria Angeles Perez-Saenz, Teresa Molero, Jorge J. Cebolla, Ana I Arribas, Jesús Villarrubia, Pilar Giraldo, and Pilar Irún more...
- Subjects
medicine.medical_specialty ,CYP2D6 ,business.industry ,Immunology ,Cell Biology ,Hematology ,Enzyme replacement therapy ,Biochemistry ,Clinical trial ,Quality of life ,Concomitant ,Internal medicine ,Miglustat ,Medicine ,Adverse effect ,business ,Eliglustat ,medicine.drug - Abstract
Type 1 Gaucher disease (GD1) is caused by the deficiency in the lysosomal enzyme glucocerebrosidase and causes the accumulation of glucocerebroside mainly in macrophages, inducing deterioration of the organs in which it is deposited.The new substrate inhibitor Eliglustat (ELI), approved by EMA in 2015 and available in Spain since January 2017, has proved to be an effective therapy that selectively inhibits the enzyme glucosylceramide synthase, decreasing the accumulation of substrate. It is indicated in GD1 extensive, intermediate or poor metabolizers of the cytochrome CYP2D6. The phase 2 and 3 clinical trials have demonstrated improvement and stabilization of the parameters in the naïve patients and in switched from enzyme replacement therapy. In this work we present the design of a prospective follow-up post-authorization study (GEE-ELI-2017-01) to asure the traceability of eliglustat therapy in Spanish GD1patients (TRAZELGA) is exposed. MethodsThe national multi-center study TRAZELGA, designed as a tool to uniformly evaluate the response to ELI therapy during one year, analyzing clinical parameters, biomarkers, changes in medullary infiltration quantified by MRI and DEXA, compliance and side effects. In addition, a quality of life sub-study is included as well as an exploratory study to analyze immune system activation markers (cytokine profile, ferritin, lipocalin, gamma globulins, oxidative stress markers). All the current recommendations previous ELI therapy have been reinforced, including cardiac, hepatic and renal function assessment and suitability according concomitant medications. An electronic tool has been designed to help physicians to easily registry and update the patient information. All the current rules for data protection were taken in account. Results: 40 GD1 patients have started oral treatment with Eliglustat. In this presentation we provide preliminary results of 32 patients whom fulfilled 6 months of follow-up (median age: 43.8 years (23-75), 47% males), genotype c.1226A>G in homozygosity (29.4%), c.1226A>G/c.1448T>C (41.2% ), other double heterozygotes with c.1226A>G (29.4%); metabolism of CYP2D6 (12% poor metabolizers, 64.5% intermediate and 33.5% extensive), no patient received the treatment in first line and its baseline characteristics (table1), are from patients stabilized with ERT (23 cases) or miglustat (9).Two splenectomized patients, 3 patients with palpable splenomegaly at the time of inclusion, 6 patients with multimorbidities and polymedications and 6 patients complained of fatigue as the main symptom before inclusion in the study. The median follow-up is 6 (6-14) months. Conclusions: The acceptance of the project in the medical community has been excellent with a good inclusion page. At the end of the one year follow-up period we will be available to analyze the influence of Eliglustat on biomarkers, markers of inflammation, bone mineral density also to provide information about adherence and adverse events in every day clinical practice. This work has been partially granted by FEETEG Disclosures No relevant conflicts of interest to declare. more...
- Published
- 2018
- Full Text
- View/download PDF
28. Twenty-Five Years Diagnosing Gaucher’s Disease in Spain, What We Have Learned?
- Author
-
Jorge J. Cebolla, Jesús Villarrubia, Jesus J. Fraile, Marcio Andrade-Campos, Pilar Irún, Abelardo Bárez, Horacio Cano, Laura López de Frutos, Mercedes Roca-Espiau, Izaskun Arenaz, Pilar Giraldo, Jose Luis Capablo, Teresa Molero, and Lucia Villalon more...
- Subjects
Pediatrics ,medicine.medical_specialty ,education.field_of_study ,business.industry ,Anemia ,Immunology ,Population ,Cell Biology ,Hematology ,Disease ,medicine.disease ,Biochemistry ,Pancytopenia ,Hemorrhagic disorder ,Gaucher's disease ,Medicine ,Substrate reduction therapy ,medicine.symptom ,business ,Bone pain ,education - Abstract
Gaucher disease (GD), has a pan-ethnic distribution with incidence in non-Ashkenazi Jewish population about 1/70-140 thousand inhabitants. The deficiency in lysosomal acid beta-glucosidase enzyme secondary to variants in the GBA gene with autosomal recessive inheritance gives rise to a variable clinical picture. It appears at any age with symptoms that include anemia, thrombocytopenia, pain and vascular bone lesions, visceral enlargement, persistent fatigue. It was the first EDL to have enzymatic replacement and substrate reduction therapy that impact in the awareness of the disease. In 1993, the Spanish Registry of Gaucher Disease was created (REsEG), within the Spanish Foundation for the Study and Therapeutics of EG (FEETEG), with the aim of providing support to all those involved in the management of patients with EG and summarize experience at the national level. This work review the characteristics at diagnosis of type 1 adult GD (GD1) patients, diagnosed outside active early diagnosis programs, along of twenty five years of REsEG existence focus on leading diagnostic symptoms in order to answer the current challenges in patients suspicions. Aim: To analyze the evolving profile of GD1 patients diagnosed before and after 2000 based on the principal manifestations including visceral, hematological involvement, bone pain, bleeding in order to define the current suspicious characteristics in our population. Methods: Patients 18+ years old included in the REsEG were selected. Demographic, genetic, clinical (hematological, visceral, bone, neurological) data, severity index, biomarkers and other relevant information were included in a database created for this purpose. Platelets Disclosures No relevant conflicts of interest to declare. more...
- Published
- 2018
- Full Text
- View/download PDF
29. Defective function of KCa3.1 channels in lysosomal disorders
- Author
-
Pilar Irún, Ralf Köehler, Laura López de Frutos, Marcio Andrade-Campos, Pilar Giraldo, and Jorge J. Cebolla
- Subjects
Endocrinology ,Chemistry ,Endocrinology, Diabetes and Metabolism ,Genetics ,Molecular Biology ,Biochemistry ,Function (biology) ,Cell biology - Published
- 2018
- Full Text
- View/download PDF
30. Discovery study for new genetic variants related to Niemann-Pick disease type C
- Author
-
Pilar Irún, Jorge J. Cebolla, Laura López de Frutos, and Pilar Giraldo
- Subjects
Genetics ,Endocrinology ,Niemann–Pick disease, type C ,Endocrinology, Diabetes and Metabolism ,medicine ,Genetic variants ,Biology ,medicine.disease ,Molecular Biology ,Biochemistry - Published
- 2018
- Full Text
- View/download PDF
31. Erythrocyte osmotic resistance test as a screening tool for lysosomal diseases
- Author
-
Laura López de Frutos, Pilar Giraldo, Ralf Köhler, Pilar Irún, and Jorge J. Cebolla
- Subjects
Resistance test ,Endocrinology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Genetics ,Medicine ,Screening tool ,Pharmacology ,business ,Molecular Biology ,Biochemistry - Published
- 2018
- Full Text
- View/download PDF
32. Increased glycolipid storage produced by the inheritance of a complex intronic haplotype in the α-galactosidase A (GLA) gene
- Author
-
Pilar Irún, Luis Plaza, José C. Rodríguez-Rey, Javier Gervas-Arruga, Pilar Giraldo, Jose C. Roche, Javier Pérez-López, Miguel Pocovi, Jose Luis Capablo, Jorge J. Cebolla, and Universidad de Cantabria
- Subjects
Adult ,Male ,α-galactosidase A ,Genotype ,medicine.disease_cause ,Cell Line ,Enzyme activator ,Glycolipid ,Genetics ,medicine ,Leukocytes ,Humans ,Genetics(clinical) ,Allele ,Genetics (clinical) ,Alleles ,Genetic Association Studies ,Aged ,Messenger RNA ,Mutation ,Fabry disease ,Alpha-galactosidase ,biology ,Podocytes ,Fibroblasts ,Middle Aged ,Molecular biology ,Introns ,Pedigree ,Enzyme Activation ,Real-time polymerase chain reaction ,Haplotypes ,Cell culture ,alpha-Galactosidase ,biology.protein ,GLA ,lipids (amino acids, peptides, and proteins) ,Female ,Galactosphingolipids ,RNA Splice Sites ,Glycolipids ,Research Article - Abstract
BACKGROUND: Accumulation of galactosphingolipids is a general characteristic of Fabry disease, a lysosomal storage disorder caused by the deficient activity of α-galactosidase A encoded by the GLA gene. Although many polymorphic GLA haplotypes have been described, it is still unclear whether some of these variants are causative of disease symptoms. We report the study of an inheritance of a complex intronic haplotype (CIH) (c.-10C > T, c.369 + 990C > A, c.370-81_370-77delCAGCC, c.640-16A > G, c.1000-22C > T) within the GLA gene associated with Fabry-like symptoms and galactosphingolipid accumulation. We analysed α-Gal A activity in plasma, leukocytes and skin fibroblasts in patients, and measured accumulation of galactosphingolipids by enzymatic methods and immunofluorescence techniques. Additionally, we evaluated GLA expression using quantitative PCR, EMSA, and cDNA cloning. RESULTS: CIH carriers had an altered GLA expression pattern, although most of the carriers had high residual enzyme activity in plasma, leukocytes and in skin fibroblasts. Nonetheless, CIH carriers had significant galactosphingolipid accumulation in fibroblasts in comparison with controls, and also glycolipid deposits in renal tubules and glomeruli. EMSA assays indicated that the c.-10C > T variant in the promoter affected a nuclear protein binding site. CONCLUSIONS: Thus, inheritance of the CIH caused an mRNA deregulation altering the GLA expression pattern, producing a tissue glycolipid storage. Acknowledgements. The authors gratefully thank Cesar Vallejo for technical support; Dr. Erika Fernandez-Vizarra for critical revision of the manuscript and Dr. Gracia Mendoza for immunofluorescence support. This study was supported by grant FIS (PI 09/02556) and by the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), an initiative of the ISCIII. more...
- Published
- 2015
33. Actualización en deficiencia de lipasa ácida lisosomal: diagnóstico, tratamiento y seguimiento de los pacientes
- Author
-
Miguel A. Barba Romero, Luis Aldámiz-Echevarría, Begoña Polo, Emilio Ros, Jorge J. Cebolla, Carmen Camarena, and Inmaculada Plasencia García
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Enzyme function ,Cholesterol ,business.industry ,Lipid metabolism ,General Medicine ,Disease ,Enzyme replacement therapy ,030204 cardiovascular system & hematology ,Lysosomal acid lipase deficiency ,medicine.disease ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,chemistry ,Internal medicine ,medicine ,business ,Progressive disease ,Congenital disorder - Abstract
Lysosomal acid lipase deficiency (LALD) is an ultra-rare disease caused by a congenital disorder of the lipid metabolism, characterized by the deposition of cholesterol esters and triglycerides in the organism. In patients with no enzyme function, the disease develops during the perinatal period and is invariably associated with death during the first year of life. In all other cases, the phenotype is heterogeneous, although most patients develop chronic liver diseases and may also develop an early cardiovascular disease. Treatment for LALD has classically included the use of supportive measures that do not prevent the progression of the disease. In 2015, regulatory agencies approved the use of a human recombinant LAL for the treatment of LALD. This long-term enzyme replacement therapy has been associated with significant improvements in the hepatic and lipid profiles of patients with LALD, increasing survival rates in infants with a rapidly progressive disease. Both the severity of LALD and the availability of a specific treatment highlight the need to identify these patients in clinical settings, although its low prevalence and the existing clinical overlap with other more frequent pathologies limit its diagnosis. In this paper we set out practical recommendations to identify and monitor patients with LALD, including a diagnostic algorithm, along with an updated treatment. more...
- Published
- 2017
- Full Text
- View/download PDF
34. Update on lysosomal acid lipase deficiency: Diagnosis, treatment and patient management
- Author
-
Luis Aldámiz-Echevarría, Jorge J. Cebolla, Inmaculada Plasencia García, Emilio Ros, Carmen Camarena, Miguel A. Barba Romero, and Begoña Polo
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Cholesterol ,business.industry ,Lipid metabolism ,Disease ,Enzyme replacement therapy ,Lysosomal acid lipase deficiency ,medicine.disease ,Phenotype ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,Endocrinology ,chemistry ,Internal medicine ,medicine ,business ,Progressive disease ,Congenital disorder - Abstract
Lysosomal acid lipase deficiency (LALD) is an ultra-rare disease caused by a congenital disorder of the lipid metabolism, characterized by the deposition of cholesterol esters and triglycerides in the organism. In patients with no enzyme function, the disease develops during the perinatal period and is invariably associated with death during the first year of life. In all other cases, the phenotype is heterogeneous, although most patients develop chronic liver diseases and may also develop an early cardiovascular disease. Treatment for LALD has classically included the use of supportive measures that do not prevent the progression of the disease. In 2015, regulatory agencies approved the use of a human recombinant LAL for the treatment of LALD. This long-term enzyme replacement therapy has been associated with significant improvements in the hepatic and lipid profiles of patients with LALD, increasing survival rates in infants with a rapidly progressive disease. Both the severity of LALD and the availability of a specific treatment highlight the need to identify these patients in clinical settings, although its low prevalence and the existing clinical overlap with other more frequent pathologies limit its diagnosis. In this paper we set out practical recommendations to identify and monitor patients with LALD, including a diagnostic algorithm, along with an updated treatment. more...
- Published
- 2017
- Full Text
- View/download PDF
35. New haplotype of Fabry disease among patients screened for left ventricular hypertrophy of unknown cause
- Author
-
Tomás Ripoll, Gonzalo de la Morena, Pablo García-Pavía, Antonio García-Honrubia, Juan R. Gimeno, Miguel Pocovi, Vicente Climent, Amparo Martínez-Monzonis, Jorge J. Cebolla, and Irene Rilo
- Subjects
medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Haplotype ,medicine.disease ,Left ventricular hypertrophy ,Biochemistry ,Fabry disease ,Endocrinology ,Internal medicine ,Genetics ,medicine ,Cardiology ,business ,Molecular Biology - Published
- 2015
- Full Text
- View/download PDF
36. A clinical case with a new damaging variant associated to Niemann-Pick disease type C
- Author
-
Laura López de Frutos, Pilar Irún, Jorge J. Cebolla, María T Sagrario, Jesús Romero, Pilar Giraldo, Adolfo Minguez, and Clementina del Canto
- Subjects
Pathology ,medicine.medical_specialty ,Endocrinology ,Niemann–Pick disease, type C ,business.industry ,Endocrinology, Diabetes and Metabolism ,Genetics ,Medicine ,Clinical case ,business ,medicine.disease ,Molecular Biology ,Biochemistry - Published
- 2017
- Full Text
- View/download PDF
37. Dried blood spot screening of lysosomal acid lipase deficiency and confirmatory studies in Spanish suspected patients
- Author
-
Inmaculada Garcia-Jimenez, Jorge J. Cebolla, Luisa Gonzalez-Dieguez, Pilar Irún, Miguel Angel Barba-Romero, Pablo del Valle Loarte, Ignacio Ros Arnal, and Pilar Giraldo
- Subjects
Pathology ,medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Lysosomal acid lipase deficiency ,medicine.disease ,Biochemistry ,Dried blood spot ,Microbiology ,Endocrinology ,Genetics ,medicine ,business ,Molecular Biology - Published
- 2016
- Full Text
- View/download PDF
38. Evaluation of suspicion index and plasma biomarkers as efficient tool in the diagnosis of Νiemann-Ρick disease type C
- Author
-
Pilar Giraldo, Pilar Alfonso, Jorge J. Cebolla, Pilar Irún, and Laura López de Frutos
- Subjects
medicine.medical_specialty ,Pathology ,Index (economics) ,business.industry ,Endocrinology, Diabetes and Metabolism ,Disease ,Plasma biomarkers ,Biochemistry ,Gastroenterology ,Endocrinology ,Internal medicine ,Genetics ,medicine ,business ,Molecular Biology - Published
- 2016
- Full Text
- View/download PDF
39. Descriptive report of the variant adult visceral form non-neuronopathic of Νiemann-Ρick type C disease in a Spanish series
- Author
-
Jorge J. Cebolla, Pilar Giraldo, Manuel Gaona, Carlos Leiva, Pilar León, Juana Clavel, Carmen Loureiro, Pilar Irún, Abelardo Bárez, Emilio Ojeda, Susana Cantarero, Enrique J. Calderón, Alberto Villarejo, Inmaculada Ballesteros, Nilda Venegas, Pilar Alfonso, Jesús Villarrubia, and Laura López de Frutos more...
- Subjects
Series (stratigraphy) ,Pediatrics ,medicine.medical_specialty ,Pathology ,Endocrinology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Genetics ,Medicine ,Disease ,business ,Molecular Biology ,Biochemistry - Published
- 2016
- Full Text
- View/download PDF
40. Complex intronic haplotype in Fabry disease
- Author
-
Pilar Irún, José C. Rodríguez-Rey, Javier Gervas-Arruga, Javier Pérez-López, Jorge J. Cebolla, Miguel Pocovi, Pilar Giraldo, and Luis Plaza
- Subjects
Genetics ,Endocrinology ,Endocrinology, Diabetes and Metabolism ,Haplotype ,medicine ,Biology ,medicine.disease ,Molecular Biology ,Biochemistry ,Fabry disease - Published
- 2015
- Full Text
- View/download PDF
41. Experience with 7-ketocholesterol and ccl18/parc as surrogated biomarkers in a series of Spanish Niemann–Pick disease type C patients
- Author
-
Pilar Giraldo, Isabel De Castro-Orós, Marcio Andrade-Campos, Miguel Pocovi, Jorge J. Cebolla, Laura López de Frutos, Pilar Irún, and Pilar Alfonso
- Subjects
Pathology ,medicine.medical_specialty ,Niemann–Pick disease, type C ,business.industry ,Endocrinology, Diabetes and Metabolism ,CCL18 ,7-ketocholesterol ,medicine.disease ,Biochemistry ,Endocrinology ,Genetics ,medicine ,business ,Molecular Biology - Published
- 2015
- Full Text
- View/download PDF
42. X-Chromosome tissue inactivation in Fabry disease
- Author
-
Jorge J. Cebolla, Pilar Giraldo, Javier Gervas-Arruga, and Miguel Pocovi
- Subjects
Endocrinology ,Endocrinology, Diabetes and Metabolism ,Genetics ,medicine ,Biology ,medicine.disease ,Molecular Biology ,Biochemistry ,Fabry disease ,Molecular biology ,X chromosome - Published
- 2013
- Full Text
- View/download PDF
43. Influence Of Genetic Variability Related To Bone Remodeling and Cytokine Profile In The Development Of Bone Involvement In Gaucher Disease
- Author
-
Javier Gervas-Arruga, Mercedes Roca, Ignacio de Blas, Jorge J. Cebolla, Pilar Giraldo, and Miguel Pocovi
- Subjects
Endocrinology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Cytokine profile ,Immunology ,Genetics ,Medicine ,Genetic variability ,Disease ,business ,Molecular Biology ,Biochemistry ,Bone remodeling
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.