{"title":"News from Valencia: JIMD themed issue on ureagenesis defects and allied disorders","authors":"Vicente Rubio, Johannes Häberle","doi":"10.1002/jimd.12811","DOIUrl":null,"url":null,"abstract":"<p>Valencia (Spain) was the birthplace of the urea cycle (UC) pioneer Santiago Grisolia. After 30 years in the United States, he returned in 1978 to live and work in Valencia, passing away just 3 months before the celebration there (16–20 October 2022) of the second “International Conference on Ureagenesis Defects (UCDs) and Allied Conditions 2022. Novel models and treatment options.” The first was held in Pontresina (Switzerland) in March 2018.<span><sup>1</sup></span> The present JIMD themed issue contains presentations from the 70+ participants in the Valencia Conference (Appendix A). We dedicate this Editorial and entire JIMD issue to the memory of Dr. Grisolia.</p><p>The viewpoint review paper of Häberle, Siri and Dionisi-Vici<span><sup>2</sup></span> reflects the concept of UCDs “allied conditions” due to derangements of components ancillary to the UC. This materialized in our Conference on presentations on carbonic anhydrase 5A (CA5A) deficiency (poor bicarbonate supply to carbamoyl phosphate synthetase 1, CPS1), pyrroline-5-carboxylate synthetase deficiency (poor supply of de novo made ornithine), ornithine aminotransferase deficiency (potential cause of neonatal or early infantile hyperammonemia) and lysinuric protein intolerance (amino acid transport defect; it can also cause hyperammonemia). To take advantage of molecular analogies for propelling advances, the meeting also considered presentations on CAD and aralar deficiencies (MIM Nos. 612949 and 616457, respectively). CAD catalyzes the initial three steps of pyrimidine biosynthesis, encompassing paralogs of CPS1 and ornithine transcarbamylase (CPS2 and aspartate transcarbamylase). Aralar is the extrahepatic nearly-twin brother of citrin (UC transporter).</p><p>These “Allied Disorders” presentations have translated into two papers linked to this issue, one in JIMD Reports, led by Fathiya Al-Murshedi, highlighting the clinical variability for an 18-member cohort of patients of CA5A deficiency sharing the same mutation and living in the Arabic peninsula<span><sup>3</sup></span>; and the other paper (which appeared in JIMD volume 6, 2023),<span><sup>4</sup></span> from Santiago Ramón-Maiques's laboratory, which furthers the understanding of CAD and its deficiency and uses a fast experimental pathogenicity-testing cellular assay for CAD variants (including variants from Saskia Wortmann and Paula Sánchez-Pintos presentations).</p><p>Another novelty for a meeting held in a Western country was the devoting of an afternoon/evening to citrin deficiency. The time was ripe for this, as shown in Johannes Häberle solo paper in this issue.<span><sup>5</sup></span> The Citrin Foundation was our partner, funding this Spotlight session and being scientifically very well represented, with its Scientific Supervisory Board's Chairman, the Nobel Laureate (Chemistry, 1997) Sir John Walker, attending the meeting and delivering the keynote lecture that will translate into a paper on citrin deficiency (which will appear in JIMD now or somewhat later). Three additional contributions reflect the emphasis on citrin deficiency: newborn screening, led by the Kumamoto group, reflecting the Japanese experience<span><sup>6</sup></span> the clinical landscape, incorporating East Asian, US and European (Saikat Santra) patient cohorts, and calling for worldwide awareness<span><sup>7</sup></span>; and the therapeutic landscape, recapitulating present therapies, with key participation of the Citrin Foundation (Li Eon Kuek and Barbara Yu) not only in the science but also in reflecting patients' voices.<span><sup>8</sup></span></p><p>Classical UCDs were also represented. Morizono and Caldovic's group (Washington DC)<span><sup>9</sup></span> largely investigated why <i>N</i>-acetyl-<span>l</span>-glutamate synthase (NAGS) deficiency is rare, and searched for novel potential gene regulatory features for classical UC enzymes. Also, on NAGS deficiency, Vicente Rubio's group in Valencia<span><sup>10</sup></span> reports human NAGS stabilization by chimerism, enabling the testing at ease of the effects of patient-found mutations, illustrating this approach's value for any UCD. Julian Baruteau group's paper<span><sup>11</sup></span> explores the pathophysiology and neuroimaging of neurodegenerative traits (particularly movement disorders) in argininosuccinate lyase (ASL) deficiency, using a unique combination of patients' data, state-of-the art neuroimaging and a rodent model of ASL deficiency corrected metabolically by administrations of <i>ASL</i> mRNA. Of methodological importance for classical UCDs, Makris's paper (from Zürich)<span><sup>12</sup></span> compares the value of several cell-based models for investigating the UC and its disorders, studying expression and functionality (stable-isotope assays) of the UC in each of them.</p><p>On the management/therapy side, Karolina M. Stepien (Salford, UK) leads a breakthrough paper,<span><sup>13</sup></span> which conveys a reassuring message on the outcomes of pregnancies of female UCDs patients based on retrospective surveys of published and in-house information from 18 centers (United Kingdom, continental Europe, Australia, New Zealand and Canada), highlighting the importance for good outcome of multidisciplinary management by an experienced team, and of application of a prospective plan. A solo therapy paper by Marshall Summar (Maryland)<span><sup>14</sup></span> highlights the value of citrulline (outside the field of UCDs) for treating nitric oxide deficiency, endothelial dysfunction and oxidative stress, reviewing the conditions that benefit or are candidates for citrulline therapy. There were in the Conference several presentations on gene therapy, but because of the closeness of the publication in JIMD (January 2024) of a review of gene-therapy approaches for UCDs,<span><sup>15</sup></span> only one paper in our issue was on that topic, an update of RNA therapeutics of UCDs<span><sup>16</sup></span> led by a recognized expert (Lourdes R Desviat, Madrid).</p><p>A final characteristic of this conference was the reliance for financial help on non-profit funders/sponsors (SSIEM, Citrin Foundation, Ramón Areces Foundation, Valencian Government, CIBER for Rare Diseases, University Católica of Valencia), so we can claim on firm grounds that the conclusions from this conference are not influenced by the industry.</p><p>In summary, this JIMD issue is highly representative of the meeting contents, transmitting major unpublished novelties, possibly making of this issue a long-lasting reference (notwithstanding the fact that the next conference of this series is fast approaching: 22–24 April 2026, organized by Nicola Brunetti-Pierri in Pozzuoli, Italy) .</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"47 6","pages":"1117-1119"},"PeriodicalIF":4.2000,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12811","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Inherited Metabolic Disease","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jimd.12811","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0
Abstract
Valencia (Spain) was the birthplace of the urea cycle (UC) pioneer Santiago Grisolia. After 30 years in the United States, he returned in 1978 to live and work in Valencia, passing away just 3 months before the celebration there (16–20 October 2022) of the second “International Conference on Ureagenesis Defects (UCDs) and Allied Conditions 2022. Novel models and treatment options.” The first was held in Pontresina (Switzerland) in March 2018.1 The present JIMD themed issue contains presentations from the 70+ participants in the Valencia Conference (Appendix A). We dedicate this Editorial and entire JIMD issue to the memory of Dr. Grisolia.
The viewpoint review paper of Häberle, Siri and Dionisi-Vici2 reflects the concept of UCDs “allied conditions” due to derangements of components ancillary to the UC. This materialized in our Conference on presentations on carbonic anhydrase 5A (CA5A) deficiency (poor bicarbonate supply to carbamoyl phosphate synthetase 1, CPS1), pyrroline-5-carboxylate synthetase deficiency (poor supply of de novo made ornithine), ornithine aminotransferase deficiency (potential cause of neonatal or early infantile hyperammonemia) and lysinuric protein intolerance (amino acid transport defect; it can also cause hyperammonemia). To take advantage of molecular analogies for propelling advances, the meeting also considered presentations on CAD and aralar deficiencies (MIM Nos. 612949 and 616457, respectively). CAD catalyzes the initial three steps of pyrimidine biosynthesis, encompassing paralogs of CPS1 and ornithine transcarbamylase (CPS2 and aspartate transcarbamylase). Aralar is the extrahepatic nearly-twin brother of citrin (UC transporter).
These “Allied Disorders” presentations have translated into two papers linked to this issue, one in JIMD Reports, led by Fathiya Al-Murshedi, highlighting the clinical variability for an 18-member cohort of patients of CA5A deficiency sharing the same mutation and living in the Arabic peninsula3; and the other paper (which appeared in JIMD volume 6, 2023),4 from Santiago Ramón-Maiques's laboratory, which furthers the understanding of CAD and its deficiency and uses a fast experimental pathogenicity-testing cellular assay for CAD variants (including variants from Saskia Wortmann and Paula Sánchez-Pintos presentations).
Another novelty for a meeting held in a Western country was the devoting of an afternoon/evening to citrin deficiency. The time was ripe for this, as shown in Johannes Häberle solo paper in this issue.5 The Citrin Foundation was our partner, funding this Spotlight session and being scientifically very well represented, with its Scientific Supervisory Board's Chairman, the Nobel Laureate (Chemistry, 1997) Sir John Walker, attending the meeting and delivering the keynote lecture that will translate into a paper on citrin deficiency (which will appear in JIMD now or somewhat later). Three additional contributions reflect the emphasis on citrin deficiency: newborn screening, led by the Kumamoto group, reflecting the Japanese experience6 the clinical landscape, incorporating East Asian, US and European (Saikat Santra) patient cohorts, and calling for worldwide awareness7; and the therapeutic landscape, recapitulating present therapies, with key participation of the Citrin Foundation (Li Eon Kuek and Barbara Yu) not only in the science but also in reflecting patients' voices.8
Classical UCDs were also represented. Morizono and Caldovic's group (Washington DC)9 largely investigated why N-acetyl-l-glutamate synthase (NAGS) deficiency is rare, and searched for novel potential gene regulatory features for classical UC enzymes. Also, on NAGS deficiency, Vicente Rubio's group in Valencia10 reports human NAGS stabilization by chimerism, enabling the testing at ease of the effects of patient-found mutations, illustrating this approach's value for any UCD. Julian Baruteau group's paper11 explores the pathophysiology and neuroimaging of neurodegenerative traits (particularly movement disorders) in argininosuccinate lyase (ASL) deficiency, using a unique combination of patients' data, state-of-the art neuroimaging and a rodent model of ASL deficiency corrected metabolically by administrations of ASL mRNA. Of methodological importance for classical UCDs, Makris's paper (from Zürich)12 compares the value of several cell-based models for investigating the UC and its disorders, studying expression and functionality (stable-isotope assays) of the UC in each of them.
On the management/therapy side, Karolina M. Stepien (Salford, UK) leads a breakthrough paper,13 which conveys a reassuring message on the outcomes of pregnancies of female UCDs patients based on retrospective surveys of published and in-house information from 18 centers (United Kingdom, continental Europe, Australia, New Zealand and Canada), highlighting the importance for good outcome of multidisciplinary management by an experienced team, and of application of a prospective plan. A solo therapy paper by Marshall Summar (Maryland)14 highlights the value of citrulline (outside the field of UCDs) for treating nitric oxide deficiency, endothelial dysfunction and oxidative stress, reviewing the conditions that benefit or are candidates for citrulline therapy. There were in the Conference several presentations on gene therapy, but because of the closeness of the publication in JIMD (January 2024) of a review of gene-therapy approaches for UCDs,15 only one paper in our issue was on that topic, an update of RNA therapeutics of UCDs16 led by a recognized expert (Lourdes R Desviat, Madrid).
A final characteristic of this conference was the reliance for financial help on non-profit funders/sponsors (SSIEM, Citrin Foundation, Ramón Areces Foundation, Valencian Government, CIBER for Rare Diseases, University Católica of Valencia), so we can claim on firm grounds that the conclusions from this conference are not influenced by the industry.
In summary, this JIMD issue is highly representative of the meeting contents, transmitting major unpublished novelties, possibly making of this issue a long-lasting reference (notwithstanding the fact that the next conference of this series is fast approaching: 22–24 April 2026, organized by Nicola Brunetti-Pierri in Pozzuoli, Italy) .
期刊介绍:
The Journal of Inherited Metabolic Disease (JIMD) is the official journal of the Society for the Study of Inborn Errors of Metabolism (SSIEM). By enhancing communication between workers in the field throughout the world, the JIMD aims to improve the management and understanding of inherited metabolic disorders. It publishes results of original research and new or important observations pertaining to any aspect of inherited metabolic disease in humans and higher animals. This includes clinical (medical, dental and veterinary), biochemical, genetic (including cytogenetic, molecular and population genetic), experimental (including cell biological), methodological, theoretical, epidemiological, ethical and counselling aspects. The JIMD also reviews important new developments or controversial issues relating to metabolic disorders and publishes reviews and short reports arising from the Society''s annual symposia. A distinction is made between peer-reviewed scientific material that is selected because of its significance for other professionals in the field and non-peer- reviewed material that aims to be important, controversial, interesting or entertaining (“Extras”).