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1. Genome and RNA sequencing were essential to reveal cryptic intronic variants associated to defective ATP6AP1 mRNA processing

Author

Morales-Romero, Blai, Muñoz-Pujol, Gerard, Artuch, Rafael, García-Cazorla, Angels, O'Callaghan, Mar, Sykut-Cegielska, Jolanta, Campistol, Jaume, Moreno-Lozano, Pedro Juan, Oud, Machteld M., Wevers, Ron A., Lefeber, Dirk J., Esteve-Codina, Anna, Yepez, Vicente A., Gagneur, Julien, Wortmann, Saskia B., Prokisch, Holger, Ribes, Antonia, García-Villoria, Judit, and Tort, Frederic

Published
2024
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3. Consensus guidelines for the diagnosis and management of succinic semialdehyde dehydrogenase deficiency

Author

Tokatly Latzer, Itay, Bertoldi, Mariarita, Blau, Nenad, DiBacco, Melissa L., Elsea, Sarah H., García-Cazorla, Àngels, Gibson, K. Michael, Gropman, Andrea L., Hanson, Ellen, Hoffman, Carolyn, Jeltsch, Kathrin, Juliá-Palacios, Natalia, Knerr, Ina, Lee, Henry H.C., Malaspina, Patrizia, McConnell, Alice, Opladen, Thomas, Oppebøen, Mari, Rotenberg, Alexander, Walterfang, Mark, Wang-Tso, Lee, Wevers, Ron A., Roullet, Jean-Baptiste, and Pearl, Phillip L.

Published
2024
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4. Impact of supplementation with L-citrulline/arginine after liver transplantation in individuals with Urea Cycle Disorders

Author

Schulze, Andreas, García-Cazorla, Angeles, Ficicioglu, Can, Harding, Cary O., Lam, Christina, Coughlin, Curtis R., 2<ce:sup loc='post">nd</ce:sup>, Le Mons, Cynthia, Wong, Derek, Dobbelaere, Dries, Diaz, George A., Berry, Gerard T., Enns, Gregory M., Wilkening, Greta, Lawrence Merritt, J., 2<ce:sup loc='post">nd</ce:sup>, Seminara, Jennifer, Konczal, Laura, Burrage, Lindsay C., Breilyn, Margo, Lindner, Martin, Baumgartner, Matthias R., Mew, Nicholas Ah., Gallagher, Renata C., McCandless, Shawn E., Berry, Susan A., Stricker, Tamar, Posset, Roland, Garbade, Sven F., Gleich, Florian, Nagamani, Sandesh C.S., Gropman, Andrea L., Epp, Friederike, Ramdhouni, Nesrine, Druck, Ann-Catrin, Hoffmann, Georg F., Kölker, Stefan, and Zielonka, Matthias

Published
2024
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5. Disorders of Cellular Trafficking

Author

García-Cazorla, Ángeles, Dionisi-Vici, Carlo, Saudubray, Jean-Marie, Saudubray, Jean-Marie, editor, Baumgartner, Matthias R., editor, García-Cazorla, Ángeles, editor, and Walter, John, editor

Published
2022
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8. Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes

Author

Himmelreich, Nastassja, Bertoldi, Mariarita, Alfadhel, Majid, Alghamdi, Malak Ali, Anikster, Yair, Bao, Xinhua, Bashiri, Fahad A., Zeev, Bruria Ben, Bisello, Giovanni, Ceylan, Ahmet Cevdet, Chien, Yin-Hsiu, Choy, Yew Sing, Elsea, Sarah H., Flint, Lisa, García-Cazorla, Àngels, Gijavanekar, Charul, Gümüş, Emel Yılmaz, Hamad, Muddathir H., Hişmi, Burcu, Honzik, Tomas, Hübschmann, Oya Kuseyri, Hwu, Wuh-Liang, Ibáñez-Micó, Salvador, Jeltsch, Kathrin, Juliá-Palacios, Natalia, Kasapkara, Çiğdem Seher, Kurian, Manju A., Kusmierska, Katarzyna, Liu, Ning, Ngu, Lock Hock, Odom, John D., Ong, Winnie Peitee, Opladen, Thomas, Oppeboen, Mari, Pearl, Phillip L., Pérez, Belén, Pons, Roser, Rygiel, Agnieszka Magdalena, Shien, Tan Ee, Spaull, Robert, Sykut-Cegielska, Jolanta, Tabarki, Brahim, Tangeraas, Trine, Thöny, Beat, Wassenberg, Tessa, Wen, Yongxin, Yakob, Yusnita, Yin, Jasmine Goh Chew, Zeman, Jiri, and Blau, Nenad

Published
2023
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9. Volumetric study of brain MRI in a cohort of patients with neurotransmitter disorders

Author

Alfonsi, Chiara, Stephan-Otto, Christian, Cortès-Saladelafont, Elisenda, Palacios, Natalia Juliá, Podzamczer-Valls, Inés, Cruz, Nuria Gutiérrez, Jiménez, María Rosario Domingo, Micó, Salvador Ibáñez, Vila, Miguel Tomás, Jeltsch, Kathrin, Hübschmann, Oya Kuseyri, Opladen, Thomas, Fragua, Ramón Velázquez, Gómez, Teresa, Fortuny, Oscar Alcoverro, Jiménez, Inmaculada García, Laso, Eduardo López, Martínez, Ana Roche, López, Jordi Muchart, and Garcia-Cazorla, Àngels

Published
2022
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10. Long-term effects of medical management on growth and weight in individuals with urea cycle disorders.

Author

Posset, Roland, Garbade, Sven F, Gleich, Florian, Gropman, Andrea L, de Lonlay, Pascale, Hoffmann, Georg F, Garcia-Cazorla, Angeles, Nagamani, Sandesh CS, Baumgartner, Matthias R, Schulze, Andreas, Dobbelaere, Dries, Yudkoff, Marc, Kölker, Stefan, Zielonka, Matthias, Urea Cycle Disorders Consortium (UCDC), and European registry and network for Intoxication type Metabolic Diseases (E-IMD)

Subjects
Urea Cycle Disorders Consortium, European registry and network for Intoxication type Metabolic Diseases
Abstract

Low protein diet and sodium or glycerol phenylbutyrate, two pillars of recommended long-term therapy of individuals with urea cycle disorders (UCDs), involve the risk of iatrogenic growth failure. Limited evidence-based studies hamper our knowledge on the long-term effects of the proposed medical management in individuals with UCDs. We studied the impact of medical management on growth and weight development in 307 individuals longitudinally followed by the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD). Intrauterine growth of all investigated UCDs and postnatal linear growth of asymptomatic individuals remained unaffected. Symptomatic individuals were at risk of progressive growth retardation independent from the underlying disease and the degree of natural protein restriction. Growth impairment was determined by disease severity and associated with reduced or borderline plasma branched-chain amino acid (BCAA) concentrations. Liver transplantation appeared to have a beneficial effect on growth. Weight development remained unaffected both in asymptomatic and symptomatic individuals. Progressive growth impairment depends on disease severity and plasma BCAA concentrations, but cannot be predicted by the amount of natural protein intake alone. Future clinical trials are necessary to evaluate whether supplementation with BCAAs might improve growth in UCDs.

Published
2020

11. Postoperative Complications in Emergency Surgeries at a Referral Hospital in Eastern Venezuela

Author

Castañeda-Marquez, Victor, primary, Rivero-Moreno, Yeisson, additional, Avila-Liendo, Enrique, additional, Gonzalez-Quinde, Gabriel, additional, Garcia-Cazorla, Wilson, additional, Mendez-Meneses, Georcimar, additional, Salcedo, Yoalkris E, additional, Rodriguez-Rugel, Tamara, additional, Antigua-Herrera, Jackner, additional, Rivas-Perez, Miguel, additional, Agudelo-Mendoza, Silvia, additional, and Estrella-Gaibor, Cesar, additional

Published
2024
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12. Thoracic Ultrasound Utility in Pulmonary Pathologies Following Blunt Chest Trauma: A Cross-Sectional Study From Barcelona, Venezuela

Author

Uzcategui-Gutierrez, Jennifer, primary, Rivero-Moreno, Yeisson, additional, Mendez-Meneses, Georcimar, additional, Salcedo, Yoalkris E, additional, Garcia-Cazorla, Wilson, additional, Tarabey-Yunis, Laila, additional, Garcia-Sánchez, Emiliana, additional, Machado-Paled, Debbye, additional, Estrella-Gaibor, Cesar, additional, Rodriguez-Rugel, Tamara, additional, and Mejías-Caraballo, Luis, additional

Published
2024
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13. Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders—A successful strategy for clinical research of rare diseases

Author

Posset, Roland, Garbade, Sven F, Boy, Nikolas, Burlina, Alberto B, Dionisi‐Vici, Carlo, Dobbelaere, Dries, Garcia‐Cazorla, Angeles, de Lonlay, Pascale, Teles, Elisa Leão, Vara, Roshni, Mew, Nicholas Ah, Batshaw, Mark L, Baumgartner, Matthias R, McCandless, Shawn E, Seminara, Jennifer, Summar, Marshall, Hoffmann, Georg F, Kölker, Stefan, Burgard, Peter, Berry, Susan A, Burrage, Lindsay, Coughlin, Curtis, Diaz, George A, Gallagher, Renata C, Gropman, Andrea, Harding, Cary O, Lee, Brendan, Le Mons, Cynthia, Lawrence Merritt, J, Nagamani, Sandesh CS, Schulze, Andreas, Stricker, Tamar, Tuchman, Mendel, Waisbren, Susan, WeisfeldAdams, James, Wong, Derek, Yudkoff, Marc, Arnoux, JeanBaptiste, Bari&cacute;, Ivo, Bosch, Annet M, Chabrol, Brigitte, Chakrapani, Anupam, CortèsSaladefont, Elisenda, Couce, Maria L, Eyskens, Francois, Laet, Corine, Meirleir, Linda, Freisinger, Peter, Gleich, Florian, Grünewald, Stephanie, Häberle, Johannes, Hwu, WuhLiang, Jalan, Anil, Karall, Daniela, Lindner, Martin, Lund, Allan M, Martinelli, Diego, Murphy, Elaine, Mühlhausen, Chris, Olivieri, Giorgia, Ottolenghi, Chris, Rodrigues, Esmeralda, Rubert, Laura, Sarajlija, Adrijan, Schiff, Manuel, Sokal, Etienne, SykutCegielska, Jolanta, Walter, John H, Williams, Monique, and Zeman, Jiri

Subjects
Clinical Research, Pediatric, Digestive Diseases, Neurodegenerative, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Good Health and Well Being, Cohort Studies, Data Analysis, Delayed Diagnosis, Europe, Female, Humans, Infant, Newborn, Male, Neonatal Screening, North America, Ornithine Carbamoyltransferase Deficiency Disease, Rare Diseases, Urea, Urea Cycle Disorders, Inborn, Urea cycle Disorders, international registry and database, diagnostic methods, Additional individual contributors of the UCDC and the E-IMD consortium, Clinical Sciences, Genetics & Heredity
Abstract

BACKGROUND:To improve our understanding of urea cycle disorders (UCDs) prospectively followed by two North American (NA) and European (EU) patient cohorts. AIMS:Description of the NA and EU patient samples and investigation of the prospects of combined and comparative analyses for individuals with UCDs. METHODS:Retrieval and comparison of the data from 1095 individuals (NA: 620, EU: 475) from two electronic databases. RESULTS:The proportion of females with ornithine transcarbamylase deficiency (fOTC-D), particularly those being asymptomatic (asfOTC-D), was higher in the NA than in the EU sample. Exclusion of asfOTC-D resulted in similar distributions in both samples. The mean age at first symptoms was higher in NA than in EU patients with late onset (LO), but similar for those with early (≤ 28 days) onset (EO) of symptoms. Also, the mean age at diagnosis and diagnostic delay for EO and LO patients were similar in the NA and EU cohorts. In most patients (including fOTC-D), diagnosis was made after the onset of symptoms (59.9%) or by high-risk family screening (24.7%), and less often by newborn screening (8.9%) and prenatal testing (3.7%). Analysis of clinical phenotypes revealed that EO patients presented with more symptoms than LO individuals, but that numbers of symptoms correlated with plasma ammonium concentrations in EO patients only. Liver transplantation was reported for 90 NA and 25 EU patients. CONCLUSIONS:Combined analysis of databases drawn from distinct populations opens the possibility to increase sample sizes for natural history questions, while comparative analysis utilizing differences in approach to treatment can evaluate therapeutic options and enhance long-term outcome studies.

Published
2019

14. Genetic landscape of Segawa disease in Spain. Long-term treatment outcomes

Author

Ochoa Sepúlveda, J.J., Serrano Cárdenas, J., Sobrido Gómez, M.J., Mora, M.D., Moreno-Medinilla, E., Ramos, J., Llorente, M., Teva, M.D., Castaño-de la Mota, C., Martínez-Ruiz, J., González Gutierrez-Solana, L., Martí, M.J., Gómez-Esteban, J.C., Hernandez-Vara, J., García Cazorla, Á., Artuch, R., Adarmes, A., Mir, P., Fernández-Ramos, Joaquín A., De la Torre-Aguilar, María José, Quintáns, Beatriz, Pérez-Navero, Juan Luis, Beyer, Katrin, and López-Laso, Eduardo

Published
2022
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15. Sphingolipid desaturase DEGS1 is essential for mitochondria-associated membrane integrity

Author

Planas-Serra, Laura, Launay, Nathalie, Goicoechea, Leire, Heron, Benedicte, Jou, Cristina, Julia-Palacios, Natalia, Ruiz, Montserrat, Fourcade, Stephane, Casasnovas, Carlos, De La Torre, Carolina, Gelot, Antoinette, Marsal, Maria, Loza- Alvarez, Pablo, Garcia-Cazorla, Angels, Fatemi, Ali, Ferrer, Isidre, Portero-Otin, Manel, Area-Gomez, Estela, and Pujol, Aurora

Subjects
Sphingolipids -- Health aspects -- Physiological aspects, Mitochondrial membranes -- Physiological aspects -- Health aspects, Endoplasmic reticulum -- Health aspects -- Physiological aspects, Enzymes -- Health aspects -- Physiological aspects, Metabolism, Inborn errors of -- Causes of -- Genetic aspects, Lipid metabolism -- Health aspects -- Genetic aspects, Health care industry
Abstract

Sphingolipids function as membrane constituents and signaling molecules, with crucial roles in human diseases, from neurodevelopmental disorders to cancer, best exemplified in the inborn errors of sphingolipid metabolism in lysosomes. The dihydroceramide desaturase A4-dihydroceramide desaturase 1 (DEGS1) acts in the last step of a sector of the sphingolipid pathway, de novo ceramide biosynthesis. Defects in DEGS1 cause the recently described hypomyelinating leukodystrophy-18 (HLD18) (OMIM #618404). Here, we reveal that DEGS1 is a mitochondria-associated endoplasmic reticulum membrane-resident (MAM-resident) enzyme, refining previous reports locating DEGS1 at the endoplasmic reticulum only. Using patient fibroblasts, multiomics, and enzymatic assays, we show that DEGS1 deficiency disrupts the main core functions of the MAM: (a) mitochondrial dynamics, with a hyperfused mitochondrial network associated with decreased activation of dynamin-related protein 1; (b) cholesterol metabolism, with impaired sterol O- acyltransferase activity and decreased cholesteryl esters; (c) phospholipid metabolism, with increased phosphatidic acid and phosphatidylserine and decreased phosphatidylethanolamine; and (d) biogenesis of lipid droplets, with increased size and numbers. Moreover, we detected increased mitochondrial superoxide species production in fibroblasts and mitochondrial respiration impairment in patient muscle biopsy tissues. Our findings shed light on the pathophysiology of HLD18 and broaden our understanding of the role of sphingolipid metabolism in MAM function., Introduction Sphingolipids (SLs) are fundamental components of cellular membranes and bioactive signaling molecules that are constituted by a sphingoid base backbone coupled to a fatty acyl chain. Ceramide (Cer) serves [...]

Published
2023
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16. Effect of Obesity on Surgical Outcomes and Complication Rates in Pediatric Patients: A Comprehensive Systematic Review and Meta-Analysis

Author

Rivero-Moreno, Yeisson, primary, Garcia, Andrea, additional, Rivas-Perez, Miguel, additional, Coa-Bracho, Jesus, additional, Salcedo, Yoalkris, additional, Gonzalez-Quinde, Gabriel, additional, Montero-Palma, Erinor, additional, Valdivia-Sepulveda, Denisse, additional, Paz-Castillo, Marialejandra, additional, Machado-Paled, Debbye, additional, Garcia-Cazorla, Wilson, additional, Acero-Alvarracín, Katheryn, additional, Tarabey-Yunis, Laila, additional, and Estrella-Gaibor, Cesar, additional

Published
2024
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17. Effect of blood contamination of cerebrospinal fluid on amino acids, biogenic amines, pterins and vitamins

Author

Marta Batllori, Mercedes Casado, Cristina Sierra, Maria del Carmen Salgado, Laura Marti-Sanchez, Joan Maynou, Guerau Fernandez, Angels Garcia-Cazorla, Aida Ormazabal, Marta Molero-Luis, and Rafael Artuch

Subjects
Cerebrospinal fluid, Amino acids, Biogenic amines, Pterins, Vitamins, Blood contamination, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Cerebrospinal fluid (CSF) metabolomic investigations are a powerful tool for studying neurometabolic diseases. We aimed to assess the effect of CSF contamination with blood on the concentrations of selected biomarkers. Methods CSF samples were spiked in duplicate with increasing volumes of whole blood under two conditions: (A) pooled CSF spiked with fresh whole blood and frozen to cause red blood cell (RBC) lysis; (B) pooled CSF spiked with fresh blood and centrifuged (the supernatant with no RBCs was frozen until the moment of analysis). CSF concentrations of amino acids, biogenic amines, pterins, and vitamins were analysed by HPLC coupled with tandem mass spectrometry, electrochemical and fluorescence detection. Results Aspartate, glutamate, taurine, ornithine, glycine, citrulline, pyridoxal 5´-phosphate, 5-methyltetrahydrofolate, and thiamine showed higher values when RBCs were lysed when compared with those of CSF with no RBC, while arginine, 5-hydroxyindoleacetic and homovanillic acids showed lower values. When RBCs were removed from CSF, only some amino acids, thiamine and pyridoxal 5´-phosphate showed moderately higher values when compared with the non-spiked CSF sample. Conclusions CSF-targeted metabolomic analysis is feasible even when substantial RBC contamination of CSF has occurred since CSF centrifugation to remove RBC prior to freezing eliminated most of the interferences observed.

Published
2019
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18. The most recurrent monogenic disorders that overlap with the phenotype of Rett syndrome

Author

Maria del Mar, O'Callaghan, Garcia-Cazorla, Àngels, del Carmen Serrano Munuera, Maria, García, Silvia Cuso, Troncoso, Monica, Fariña, Guillermo, García Peñas, Juan José, Fournier, Belen Gil, León, Soraya Ramiro, Guitart, Miriam, Baena, Neus, de Nanclares, Guiomar Perez, Oci, Intzane Ocio, Gutiérrez-Delicado, Eva, Abarrategui, Belén, Barroso, Eva, Santos-Simarro, Fernando, Lapunzina, Pablo, García, Francisco J., Acedo, Juan M., García, Asunción, Martinez, Miguel A., Martínez-Bermejo, Antonio, Vidal, S., Brandi, N., Pacheco, P., Maynou, J., Fernandez, G., Xiol, C., Pascual-Alonso, A., Pineda, M., and Armstrong, J.

Published
2019
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19. Neurological Disease

Author

García-Cazorla, Angels, Wolf, Nicole I., Mochel, Fanny, Hoffmann, Georg F., Hoffmann, Georg F., editor, Zschocke, Johannes, editor, and Nyhan, William L., editor

Published
2017
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20. Cerebrospinal fluid neopterin as a biomarker of neuroinflammatory diseases

Author

Molero-Luis, Marta, Casas-Alba, Didac, Orellana, Gabriela, Ormazabal, Aida, Sierra, Cristina, Oliva, Clara, Valls, Anna, Velasco, Jesus, Launes, Cristian, Cuadras, Daniel, Pérez-Dueñas, Belén, Jordan, Iolanda, Cambra, Francisco J., Ortigoza-Escobar, Juan D., Muñoz-Almagro, Carmen, Garcia-Cazorla, Angels, Armangué, Thais, and Artuch, Rafael

Published
2020
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21. Predicting the disease severity in male individuals with ornithine transcarbamylase deficiency

Author

Scharre, Svenja, Posset, Roland, Garbade, Sven F., Gleich, Florian, Seidl, Marie J., Druck, Ann‐Catrin, Okun, Jürgen G., Gropman, Andrea L., Nagamani, Sandesh C. S., Hoffmann, Georg F., Kölker, Stefan, Zielonka, Matthias, Ah Mew, Nicholas, Baumgartner, Matthias R., Berry, Gerard T., Berry, Susan A., Burrage, Lindsay, Diaz, George A., Ficicioglu, Can, Kisin, Genya, Konczal, Laura, Lam, Christina, McCandless, Shawn E., Merritt, J. Lawrence, Schulze, Andreas, Walter, Magdalena E., Wilson, Ashley, Wong, Derek, Arnaudo, Florence, Augoustides‐ Savvopoulou, Persephone, Barić, Ivo, Bosch, Annet M., Cano, Aline, Chien, Yin‐Hsiu, Dionisi‐Vici, Carlo, Dobbelaere, Dries, Eyskens, Francois, Freisinger, Peter, Garcia‐Cazorla, Angeles, Honzik, Tomas, Karall, Daniela, Lund, Allan M., Murphy, Elaine, Santer, René, Schiff, Manuel, Skouma, Anastasia, Sykut‐Cegielska, Jolanta, Wijburg, Frits A., Zeman, Jiri, for the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E‐IMD) Consortia Study Group, VU University medical center, Paediatric Metabolic Diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and ARD - Amsterdam Reproduction and Development

Subjects
Male, Phenotype, ornithine transcarbamylase deficiency, disease severity, prediction, General Neuroscience, Humans, Hyperammonemia, Neurology (clinical), Severity of Illness Index, Ornithine Carbamoyltransferase Deficiency Disease
Abstract

Objective: Ornithine transcarbamylase deficiency (OTC-D) is an X-linked metabolic disease and the most common urea cycle disorder. Due to high phenotypic heterogeneity, ranging from lethal neonatal hyperammonemic events to moderate symptoms and even asymptomatic individuals, the prediction of the disease course at an early disease stage is very important to individually adjust therapies such as medical treatment or liver transplantation. In this translational study, we developed a severity-adjusted classification system based on in vitro residual enzymatic OTC activity. Methods: Applying a cell-based expression system, residual enzymatic OTC activities of 71 pathogenic OTC variants were spectrophotometrically determined and subsequently correlated with clinical and biochemical outcome parameters of 119 male individuals with OTC-D (mOTC-D) as reported in the UCDC and E-IMD registries. Results: Integration of multiple data sources enabled the establishment of a robust disease prediction model for mOTC-D. Residual enzymatic OTC activity not only correlates with age at first symptoms, initial peak plasma ammonium concentration and frequency of metabolic decompensations but also predicts mortality. The critical threshold of 4.3% residual enzymatic activity distinguishes a severe from an attenuated phenotype. Interpretation: Residual enzymatic OTC activity reliably predicts the disease severity in mOTC-D and could thus serve as a tool for severity- adjusted evaluation of therapeutic strategies and counselling patients and parents.

Published
2022

22. Encephalopathies with intracranial calcification in children: clinical and genetic characterization

Author

Davide Tonduti, Celeste Panteghini, Anna Pichiecchio, Alice Decio, Miryam Carecchio, Chiara Reale, Isabella Moroni, Nardo Nardocci, Jaume Campistol, Angela Garcia-Cazorla, Belen Perez Duenas, Cerebral Calcification International Study Group, Luisa Chiapparini, Barbara Garavaglia, and Simona Orcesi

Subjects
Cerebral calcification, Leukodystrophy, Aicardi-Goutières syndrome, Next generation sequencing, Medicine
Abstract

Abstract Background We present a group of patients affected by a paediatric onset genetic encephalopathy with cerebral calcification of unknown aetiology studied with Next Generation Sequencing (NGS) genetic analyses. Methods We collected all clinical and radiological data. DNA samples were tested by means of a customized gene panel including fifty-nine genes associated with known genetic diseases with cerebral calcification. Results We collected a series of fifty patients. All patients displayed complex and heterogeneous phenotypes mostly including developmental delay and pyramidal signs and less frequently movement disorder and epilepsy. Signs of cerebellar and peripheral nervous system involvement were occasionally present. The most frequent MRI abnormality, beside calcification, was the presence of white matter alterations; calcification was localized in basal ganglia and cerebral white matter in the majority of cases. Sixteen out of fifty patients tested positive for mutations in one of the fifty-nine genes analyzed. In fourteen cases the analyses led to a definite genetic diagnosis while results were controversial in the remaining two. Conclusions Genetic encephalopathies with cerebral calcification are usually associated to complex phenotypes. In our series, a molecular diagnosis was achieved in 32% of cases, suggesting that the molecular bases of a large number of disorders are still to be elucidated. Our results confirm that cerebral calcification is a good criterion to collect homogeneous groups of patients to be studied by exome or whole genome sequencing; only a very close collaboration between clinicians, neuroradiologists and geneticists can provide better results from these new generation molecular techniques.

Published
2018
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24. Disorders of Neurotransmission

Author

Garcia-Cazorla, Angels, Artuch, Rafael, Gibson, K. Michael, Saudubray, Jean-Marie, editor, Baumgartner, Matthias R., editor, and Walter, John, editor

Published
2016
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32. Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders—a successful strategy for clinical research of rare diseases

Author

Posset, Roland, Garbade, Sven F., Boy, Nikolas, Burlina, Alberto B., Dionisi-Vici, Carlo, Dobbelaere, Dries, Garcia-Cazorla, Angeles, de Lonlay, Pascale, Teles, Elisa Leão, Vara, Roshni, Ah Mew, Nicholas, Batshaw, Mark L., Baumgartner, Matthias R., McCandless, Shawn, Seminara, Jennifer, Summar, Marshall, Hoffmann, Georg F., Kölker, Stefan, Burgard, Peter, and Additional individual contributors of the UCDC and the E-IMD consortium

Published
2018
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33. A randomized, double‐blind trial of triheptanoin for drug‐resistant epilepsy in glucose transporter 1 deficiency syndrome

Author

Pasquale Striano, Stéphane Auvin, Abigail Collins, Rita Horvath, Ingrid E. Scheffer, Michal Tzadok, Ian Miller, Mary Kay Koenig, Adrian Lacy, Ronald Davis, Angela Garcia‐Cazorla, Russell P. Saneto, Melanie Brandabur, Susan Blair, Tony Koutsoukos, and Darryl De Vivo

Subjects
Adult, Drug Resistant Epilepsy, Glucose Transporter Type 1, Adolescent, Monosaccharide Transport Proteins, Treatment Outcome, Double-Blind Method, Epilepsy, Absence, Neurology, Seizures, Humans, Anticonvulsants, Drug Therapy, Combination, Neurology (clinical), Child, Triglycerides, Carbohydrate Metabolism, Inborn Errors
Abstract

This study was undertaken to evaluate efficacy and long-term safety of triheptanoin in patients1 year old, not on a ketogenic diet, with drug-resistant seizures associated with glucose transporter 1 deficiency syndrome (Glut1DS).UX007G-CL201 was a randomized, double-blind, placebo-controlled trial. Following a 6-week baseline period, eligible patients were randomized 3:1 to triheptanoin or placebo. Dosing was titrated to 35% of total daily calories over 2 weeks. After an 8-week placebo-controlled period, all patients received open-label triheptanoin through Week 52.The study included 36 patients (15 children, 13 adolescents, eight adults). A median 12.6% reduction in overall seizure frequency was observed in the triheptanoin arm relative to baseline, and a 13.5% difference was observed relative to placebo (p = .58). In patients with absence seizures only (n = 9), a median 62.2% reduction in seizure frequency was observed in the triheptanoin arm relative to baseline. Only one patient with absence seizures only was present in the control group, preventing comparison. No statistically significant differences in seizure frequency were observed. Common treatment-emergent adverse events included diarrhea, vomiting, abdominal pain, and nausea, mostly mild or moderate in severity. No serious adverse events were considered to be treatment related. One patient discontinued due to status epilepticus.Triheptanoin did not significantly reduce seizure frequency in patients with Glut1DS not on the ketogenic diet. Treatment was associated with mild to moderate gastrointestinal treatment-related events; most resolved following dose reduction or interruption and/or medication for treatment. Triheptanoin was not associated with any long-term safety concerns when administered at dose levels up to 35% of total daily caloric intake for up to 1 year.

Published
2022

36. Discovery of Biomarker Panels for Neural Dysfunction in Inborn Errors of Amino Acid Metabolism

Author

Castells, Alba-Aina, Gueraldi, Daniela, Balada, Rafel, Tristán-Noguero, Alba, Cortès-Saladelafont, Elisenda, Ramos, Federico, Meavilla, Silvia, De Los Santos, Mariela, Garcia-Volpe, Camila, Colomé, Roser, Couce, Maria Luz, Sierra, Cristina, Ormazábal, Aida, Batllori, Marta, Artuch, Rafael, Armstrong, Judith, Alcántara, Soledad, and Garcia-Cazorla, Àngels

Published
2019
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38. Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

Author

Huemer, Martina, Diodato, Daria, Schwahn, Bernd, Schiff, Manuel, Bandeira, Anabela, Benoist, Jean-Francois, Burlina, Alberto, Cerone, Roberto, Couce, Maria L., Garcia-Cazorla, Angeles, la Marca, Giancarlo, Pasquini, Elisabetta, Vilarinho, Laura, Weisfeld-Adams, James D., Kožich, Viktor, Blom, Henk, Baumgartner, Matthias R., and Dionisi-Vici, Carlo

Published
2017
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41. Disorders of Neurotransmission

Author

García-Cazorla, Àngels, Gibson, K. Michael, Clayton, Peter T., Saudubray, Jean-Marie, editor, van den Berghe, Georges, editor, and Walter, John H., editor

Published
2012
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43. A randomized, double-blind trial of triheptanoin for drug-resistant epilepsy in glucose transporter 1 deficiency syndrome

Author

Striano, Pasquale, Auvin, Stéphane, Collins, Abigail, Horvath, Rita, Scheffer, Ingrid E, Tzadok, Michal, Miller, Ian, Kay Koenig, Mary, Lacy, Adrian, Davis, Ronald, Garcia-Cazorla, Angela, Saneto, Russell P, Brandabur, Melanie, Blair, Susan, Koutsoukos, Tony, De Vivo, Darryl, Striano, Pasquale [0000-0002-6065-1476], Auvin, Stéphane [0000-0003-3874-9749], Scheffer, Ingrid E [0000-0002-2311-2174], Miller, Ian [0000-0003-0416-1015], and Apollo - University of Cambridge Repository

Subjects
Adult, Drug Resistant Epilepsy, Glucose Transporter Type 1, drug resistance, Adolescent, Monosaccharide Transport Proteins, diet treatment, triheptanoin, glucose transporter 1 deficiency syndrome, Treatment Outcome, Double-Blind Method, Epilepsy, Absence, Seizures, epilepsy, Humans, Anticonvulsants, Drug Therapy, Combination, Child, Triglycerides, Carbohydrate Metabolism, Inborn Errors
Abstract

Funder: Ultragenyx Pharmaceutical Inc.; Id: http://dx.doi.org/10.13039/100013220, OBJECTIVE: This study was undertaken to evaluate efficacy and long-term safety of triheptanoin in patients >1 year old, not on a ketogenic diet, with drug-resistant seizures associated with glucose transporter 1 deficiency syndrome (Glut1DS). METHODS: UX007G-CL201 was a randomized, double-blind, placebo-controlled trial. Following a 6-week baseline period, eligible patients were randomized 3:1 to triheptanoin or placebo. Dosing was titrated to 35% of total daily calories over 2 weeks. After an 8-week placebo-controlled period, all patients received open-label triheptanoin through Week 52. RESULTS: The study included 36 patients (15 children, 13 adolescents, eight adults). A median 12.6% reduction in overall seizure frequency was observed in the triheptanoin arm relative to baseline, and a 13.5% difference was observed relative to placebo (p = .58). In patients with absence seizures only (n = 9), a median 62.2% reduction in seizure frequency was observed in the triheptanoin arm relative to baseline. Only one patient with absence seizures only was present in the control group, preventing comparison. No statistically significant differences in seizure frequency were observed. Common treatment-emergent adverse events included diarrhea, vomiting, abdominal pain, and nausea, mostly mild or moderate in severity. No serious adverse events were considered to be treatment related. One patient discontinued due to status epilepticus. SIGNIFICANCE: Triheptanoin did not significantly reduce seizure frequency in patients with Glut1DS not on the ketogenic diet. Treatment was associated with mild to moderate gastrointestinal treatment-related events; most resolved following dose reduction or interruption and/or medication for treatment. Triheptanoin was not associated with any long-term safety concerns when administered at dose levels up to 35% of total daily caloric intake for up to 1 year.

Published
2022

44. Neurological Disease

Author

García-Cazorla, Angels, Wolf, Nicole I., Hoffmann, Georg F., Hoffmann, Georg F., editor, Zschocke, Johannes, editor, and Nyhan, William L., editor

Published
2010
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45. List of Contributors

Author

Artuch, R., primary, Bennett, M.J., additional, Couser, N., additional, Dasouki, M., additional, DeArmond, P.D., additional, Dietzen, D.J., additional, Ferguson, A.M., additional, Ganetzky, R., additional, Garcia-Cazorla, A., additional, Garg, U., additional, Gucsavas-Calikoglu, M., additional, He, M., additional, Hubert, L., additional, Jones, P.M., additional, Lo, S.F., additional, Molero-Luis, M., additional, Morrissey, M.A., additional, Ormazabal, A., additional, Pyle-Eilola, A.L., additional, Reynoso, F.J., additional, Smith, L.D., additional, Sun, Q., additional, Sutton, V.R., additional, and Yu, C., additional

Published
2017
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48. Age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders

Author

Posset, Roland, Garcia-Cazorla, Angeles, Valayannopoulos, Vassili, Teles, Elisa Leão, Dionisi-Vici, Carlo, Brassier, Anaïs, Burlina, Alberto B., Burgard, Peter, Cortès-Saladelafont, Elisenda, Dobbelaere, Dries, Couce, Maria L., Sykut-Cegielska, Jolanta, Häberle, Johannes, Lund, Allan M., Chakrapani, Anupam, Schiff, Manuel, Walter, John H., Zeman, Jiri, Vara, Roshni, Kölker, Stefan, and Additional individual contributors of the E-IMD consortium

Published
2016
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