Journal of Inherited Metabolic Disease最新文献

{"title":"A Dutch translational knowledge agenda for inherited metabolic diseases","authors":"Hans R. Waterham, Ronald J. A. Wanders, Ron A. Wevers, Clara D. van Karnebeek","doi":"10.1002/jimd.12812","DOIUrl":"10.1002/jimd.12812","url":null,"abstract":"<p>The advancement of innovative diagnostics, such as newborn screening and -omics strategies targeting DNA, RNA and metabolites, has led to the identification of a rapidly growing number of patients with an inherited metabolic disorder (IMD) as well as new IMDs, currently encompassing more than 1500 distinct diseases (www.icimd.org). Concurrently, significant therapeutic milestones have been achieved and are being developed for a number of IMDs, including the creation of specific diets, enzyme replacement therapy and DNA/RNA targeting therapies. A recent review of ICIMD identified 287 IMDs amenable to one or more of these treatments (www.iembase.org).</p><p>Despite these advancements, or perhaps partly because of them, numerous clinical, scientific and societal challenges continue to impede the delivery of optimal care to the majority of IMD patients. To identify current knowledge gaps and areas for improvement (i.e. research questions), and to set priorities for the IMD field for the next 4–8 years with an emphasis on achieving improved care and outcomes for IMD patients, the “United for Metabolic Diseases” (UMD) consortium (www.umd.nl) in the Netherlands initiated the development of a Translational Knowledge Agenda for Inherited Metabolic Diseases. The process and outcomes, detailed in a publication in JIMD Reports<span><sup>1</sup></span> involved equal participation of professionals with diverse expertise as well as patient representatives. A multidisciplinary steering committee, comprising 12 metabolic experts—including laboratory specialists, metabolic researchers, metabolic pediatricians, internists, pediatric neurologists, dieticians, nurse specialists, and patient organizations- collected research questions from the field via an online survey using the snowball sampling method. A total of 158 participants completed the survey, with a balanced composition of 54% patient representatives and 46% healthcare professionals and researchers. The 462 proposed research questions were subsequently discussed, categorized and prioritized during a meeting attended by 22 representatives of the aforementioned stakeholder groups, using as main criteria: patient-centeredness, implications for the development of the entire field, unmet needs, feasibility of research and relevance for other stakeholders. The resulting top 10 research questions cover multiple themes, including prediction of disease progression, development of novel tools, mechanistic insights, improved diagnostics, therapeutic integration of multi-omics techniques, assessment of impact on daily life, expansion of treatment avenues, optimal study designs, effects of lifestyle interventions and data utilization following FAIR principles.</p><p>An essential aspect in the development of the knowledge agenda was the consistent incorporation of patients' input and perspectives at each development stage. This active patient engagement ensured the inclusion of lifestyle-related questions and psycho","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12812","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current global vitamin and cofactor prescribing practices for primary mitochondrial diseases: Results of a European reference network survey","authors":"Julia Neugebauer,&nbsp;Karit Reinson,&nbsp;Marcello Bellusci,&nbsp;Julien H. Park,&nbsp;Omar Hikmat,&nbsp;Enrico Bertini,&nbsp;Manuel Schiff,&nbsp;MetabERN PM-MD Consortium authors,&nbsp;Shamima Rahman","doi":"10.1002/jimd.12805","DOIUrl":"10.1002/jimd.12805","url":null,"abstract":"<p>Primary mitochondrial diseases (PMD) account for a group of approximately 400 different genetic disorders with diverse clinical presentations and pathomechanisms. Although each individual disorder is rare, collectively they represent one of the largest groups in the field of inherited metabolic disorders. The complexity of PMD results in a continued lack of therapeutic options, necessitating a predominantly symptomatic treatment approach for affected patients. While a subset of diseases responds exceptionally well to treatment with specific vitamins or cofactors, for most PMD systematic reviews were not able to show significant benefit. This is in discrepancy to their continued frequent use among specialists. To gain further insight into the current clinical practice of vitamin and cofactor supplementation among clinicians treating children and adults affected by PMD, we conducted a worldwide cross-sectional questionnaire study exploring the choice of substances and the specific diseases where they are applied. To our knowledge, this is the first global study exploring this topic and featuring a high response rate from paediatricians. The vast majority (95%, 106/112) of responding specialists recommended the use of vitamins and cofactors, either in an agnostic approach irrespective of the specific PMD or directed to the treatment of specific diseases or phenotypes. Our study highlights significant regional and specialty-specific differences in supplementation practices. We provide some preliminary insights into specialist-based opinions regarding the use of vitamins and cofactors in PMD and highlight the need for more rigorous clinical and preclinical investigations and/or clear consensus statements.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"News from Valencia: JIMD themed issue on ureagenesis defects and allied disorders","authors":"Vicente Rubio,&nbsp;Johannes Häberle","doi":"10.1002/jimd.12811","DOIUrl":"10.1002/jimd.12811","url":null,"abstract":"&lt;p&gt;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.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; 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.&lt;/p&gt;&lt;p&gt;The viewpoint review paper of Häberle, Siri and Dionisi-Vici&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; 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).&lt;/p&gt;&lt;p&gt;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&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;; and the other paper (which appeared in JIMD volume 6, 2023),&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; 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).&lt;/p&gt;&lt;p&gt;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.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; 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","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"47 6","pages":"1117-1119"},"PeriodicalIF":4.2,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12811","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The relation between dietary polysaccharide intake and urinary excretion of tetraglucoside","authors":"Candelas Gross-Valle,&nbsp;Tessa C. Jacobs,&nbsp;Janneke D. A. Dijck-Brouwer,&nbsp;Janniek Lubberts,&nbsp;Barbara M. Bakker,&nbsp;Stephan J. L. Bakker,&nbsp;Yvonne van der Veen,&nbsp;Andrea B. Schreuder,&nbsp;Terry G. J. Derks,&nbsp;Jennifer van der Krogt,&nbsp;Joost Groen,&nbsp;M. Rebecca Heiner-Fokkema","doi":"10.1002/jimd.12801","DOIUrl":"10.1002/jimd.12801","url":null,"abstract":"<p>The urinary metabolite tetraglucoside (Glc4) is a potential biomarker for hepatic glycogen storage diseases (GSDs). Glc4 is believed to reflect body glycogen content and/or turnover. However, dietary polysaccharide intake may influence Glc4 excretion, potentially limiting the utility of Glc4 as a monitoring biomarker in hepatic GSDs. We aimed to investigate the association of dietary polysaccharide intake with Glc4 excretion. Urinary Glc4 excretion (mmol/mmol creatinine and mmol/24 h) was analyzed using a validated LC–MS/MS method. Data was analyzed from 65 kidney transplant recipients and 58 healthy kidney donors in the TransplantLines cohort study. Spearman's correlation and multivariable linear regression analyses were performed. In the multivariable analysis, dry lean body mass (DLBM), dietary polysaccharide intake, transplantation status, age, sex, and glycated hemoglobin (HbA1c) served as independent variables. Daily variation was examined in 21 healthy individuals of urinary Glc4 excretion in 2-h collections over a 24-h period. Mixed generalized additive models were built to study the association of prior polysaccharide intake with Glc4 excretion. No (univariate) associations were found between polysaccharide intake and Glc4 excretion. However, a significant interaction between DLBM and polysaccharide on 24 h Glc4 excretion was observed in the multivariate analysis. Glc4 excretion throughout the day exhibited no relationship to prior polysaccharide intake. Our findings suggest an indirect effect of polysaccharide intake on Glc4 excretion, potentially due to changes in muscle glycogen content and/or turnover. We have found no evidence that dietary polysaccharides under normal intakes increase urinary Glc4 directly.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11668232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nontargeted urine metabolomic analysis of acute intermittent porphyria reveals novel interactions between bile acids and heme metabolism: New promising biomarkers for the long-term management of patients","authors":"Thibaud Lefebvre,&nbsp;Thibaut Eguether,&nbsp;Etienne Thévenot,&nbsp;Antoine Poli,&nbsp;Emeline Chu-Van,&nbsp;Pranvera Krasniqi,&nbsp;Caroline Schmitt,&nbsp;Neila Talbi,&nbsp;Gaël Nicolas,&nbsp;Hervé Puy,&nbsp;Christophe Junot,&nbsp;Antonin Lamazière,&nbsp;Florence Castelli,&nbsp;Laurent Gouya,&nbsp;François Fenaille","doi":"10.1002/jimd.12809","DOIUrl":"10.1002/jimd.12809","url":null,"abstract":"<p>Acute intermittent porphyria is an inherited error of heme synthesis. The underlying pathophysiology, involving mainly hepatic heme synthesis, is poorly understood despite its occurrence, and the severity of acute porphyria attack is still difficult to control. A better understanding of the interactions between heme synthesis and global metabolism would improve the management of AIP patients. An untargeted metabolomic analysis was performed on the urine of 114 patients with overt AIP and asymptomatic carriers using liquid chromatography coupled to high-resolution mass spectrometry. The collected data were analyzed by combining univariate and multivariate analyses. A total of 239 metabolites were annotated in urine samples by matching chromatographic and mass spectral characteristics with those from our chemical library. Twenty-six metabolites, including porphyrin precursors, intermediates of tryptophan or glycine metabolism and, unexpectedly, bile acids, showed significant concentration differences between the phenotypic groups. Dysregulation of bile acid metabolism was confirmed by targeted quantitative analysis, which revealed an imbalance in favor of hydrophobic bile acids associated with changes in conjugation, which was more pronounced in the severe phenotype. Using a random forest model, the cholic acid/chenodeoxycholic acid ratio enables the differential classification of severe patients from other patients with a diagnostic accuracy of 84%. The analysis of urine samples revealed significant modifications in the metabolome of AIP patients. Alteration in bile acids provides new insights into the pathophysiology of chronic complications, such as primary liver cancer, while also providing new biomarker candidates for predicting the most severe phenotypes.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic liver cell transplantation to treat murine PKU","authors":"Melanie Willimann,&nbsp;Hiu Man Grisch-Chan,&nbsp;Nicole Rimann,&nbsp;Tanja Rothgangl,&nbsp;Martina Hruzova,&nbsp;Gerald Schwank,&nbsp;Beat Thöny","doi":"10.1002/jimd.12802","DOIUrl":"10.1002/jimd.12802","url":null,"abstract":"<p>For gene therapy of the liver, in vivo applications based on adeno-associated virus are the most advanced vectors despite limitations, including low efficacy and episomal loss, potential integration and safety issues, and high production costs. Alternative vectors and/or delivery routes are of high interest. The regenerative ability of the liver bears the potential for ex vivo therapy using liver cell transplantation for disease correction if provided with a selective advantage to expand and replace the existing cell mass. Here we present such treatment of a mouse model of human phenylketonuria (PKU). Primary hepatocytes from wild-type mice were gene modified in vitro (with a lentiviral vector) that carries a gene editing system (CRISPR) to inhibit <i>Cypor</i>. <i>Cypor</i> inactivation confers paracetamol (or acetaminophen) resistance to hepatocytes and thus a growth advantage to eliminate the pre-existing liver cells upon grafting (via the spleen) and exposure to repeated treatment with paracetamol. Grafting <i>Cypor</i>-inactivated wild-type hepatocytes into inbred young adult <i>enu2</i> (PKU) mice, followed by selective expansion by paracetamol dosing, resulted in replacing up to 5% of cell mass, normalization of blood phenylalanine, and permanent correction of PKU. Hepatocyte transplantation offers thus an armamentarium of novel therapy options for genetic liver defects.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"47 6","pages":"1322-1335"},"PeriodicalIF":4.2,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12802","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring RNA therapeutics for urea cycle disorders","authors":"Eva Richard,&nbsp;Ainhoa Martínez-Pizarro,&nbsp;Lourdes R. Desviat","doi":"10.1002/jimd.12807","DOIUrl":"10.1002/jimd.12807","url":null,"abstract":"<p>RNA has triggered a significant shift in modern medicine, providing a promising way to revolutionize disease treatment methods. Different therapeutic RNA modalities have shown promise to replace, supplement, correct, suppress, or eliminate the expression of a targeted gene. Currently, there are 22 RNA-based drugs approved for clinical use, including the COVID-19 mRNA vaccines, whose unprecedented worldwide success has meant a definitive boost in the RNA research field. Urea cycle disorders (UCD), liver diseases with high mortality and morbidity, may benefit from the progress achieved, as different genetic payloads have been successfully targeted to liver using viral vectors, N-acetylgalactosamine (GalNAc) conjugations or lipid nanoparticles (LNP). This review explores the potential of RNA-based medicines for UCD and the ongoing development of applications targeting specific gene defects, enzymes, or transporters taking part in the urea cycle. Notably, LNP-formulated mRNA therapy has been assayed preclinically for citrullinemia type I (CTLN1), adolescent and adult citrin deficiency, argininosuccinic aciduria, arginase deficiency and ornithine transcarbamylase deficiency, in the latter case has progressed to the clinical trials phase.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"47 6","pages":"1269-1277"},"PeriodicalIF":4.2,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12807","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural history of valve disease in patients with mucopolysaccharidosis II and the impact of enzyme replacement therapy","authors":"Christoph Kampmann,&nbsp;Christina Lampe,&nbsp;Christiane M. Wiethoff,&nbsp;Laila Arash-Kaps,&nbsp;Eugen Mengel,&nbsp;Joerg Reinke,&nbsp;Michael Beck,&nbsp;Julia B. Hennermann,&nbsp;Tariq Abu-Tair","doi":"10.1002/jimd.12808","DOIUrl":"10.1002/jimd.12808","url":null,"abstract":"<p>Mucopolysaccharidosis II (MPS II, Hunter syndrome) is a rare, X-linked lysosomal storage disease caused by reduced activity of iduronate-2-sulfatase (I2S), with subsequent cellular accumulation of the glycosaminoglycans (GAGs), heparan sulfate, and dermatan sulfate (DS). DS is a major component of the extracellular matrix of heart valves, which can be affected in MPS II. We investigated the natural history of valve disease in MPS II and the impact of long-term intravenous enzyme replacement therapy (ERT) with recombinant I2S (idursulfase). In total, 604 cardiac examinations were assessed from serial follow-up of 80 male patients (49 neuronopathic). Valve disease was classified according to standard practice from hemodynamic features evident from echocardiography. The natural history group comprised 48 patients (up to 14.8 years of follow-up; median, 2.6 years; 24 patients started ERT during the study); 56 patients were treated (up to 14.2 years of follow-up; median, 6.2 years). Lifetime GAG burden (calculated from urinary GAG measurements) correlated significantly with the degree of valve disease. Onset of moderate-to-severe valve disease was significantly delayed in treated (median age at onset, 29.1 ± 2 [95% CI: 25.2–32.9] years; Kaplan–Meier estimation) versus untreated patients (17.6 ± 1 [95% Cl: 15.8–19.4] years; <i>p</i> &lt; 0.0001). Cox regression modeling found that long-term ERT reduced the probability of developing severe valve disease (<i>χ</i>², 32.736; significant after 5 years of ERT). Overall, this study found that valve disease severity in MPS II correlates with GAG burden and that progression is delayed by long-term ERT.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670151/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An update on autophagy disorders","authors":"Hormos Salimi Dafsari,&nbsp;Diego Martinelli,&nbsp;Afshin Saffari,&nbsp;Darius Ebrahimi-Fakhari,&nbsp;Manolis Fanto,&nbsp;Carlo Dionisi-Vici,&nbsp;Heinz Jungbluth","doi":"10.1002/jimd.12798","DOIUrl":"10.1002/jimd.12798","url":null,"abstract":"<p>Macroautophagy is a highly conserved cellular pathway for the degradation and recycling of defective cargo including proteins, organelles, and macromolecular complexes. As autophagy is particularly relevant for cellular homeostasis in post-mitotic tissues, congenital disorders of autophagy, due to monogenic defects in key autophagy genes, share a common “clinical signature” including neurodevelopmental, neurodegenerative, and neuromuscular features, as well as variable abnormalities of the eyes, skin, heart, bones, immune cells, and other organ systems, depending on the expression pattern and the specific function of the defective proteins. Since the clinical and genetic resolution of <i>EPG5</i>-related Vici syndrome, the paradigmatic congenital disorder of autophagy, the widespread use of massively parallel sequencing has resulted in the identification of a growing number of autophagy-associated disease genes, encoding members of the core autophagy machinery as well as related proteins. Recently identified monogenic disorders linking selective autophagy, vesicular trafficking, and other pathways have further expanded the molecular and phenotypical spectrum of congenital disorders of autophagy as a clinical disease spectrum. Moreover, significant advances in basic research have enhanced the understanding of the underlying pathophysiology as a basis for therapy development. Here, we review (i) autophagy in the context of other intracellular trafficking pathways; (ii) the main congenital disorders of autophagy and their typical clinico-pathological signatures; and (iii) the recommended primary health surveillance in monogenic disorders of autophagy based on available evidence. We further discuss recently identified molecular mechanisms that inform the current understanding of autophagy in health and disease, as well as perspectives on future therapeutic approaches.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11669743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein requirements in adults with phenylketonuria and bioavailability of glycomacropeptide compared to an l-amino acid-based product","authors":"Abrar Turki,&nbsp;Sylvia Stockler-Ipsiroglu,&nbsp;Sandra Sirrs,&nbsp;Jennifer Branov,&nbsp;Taryn Bosdet,&nbsp;Rajavel Elango","doi":"10.1002/jimd.12806","DOIUrl":"10.1002/jimd.12806","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Phenylketonuria (PKU) is caused by phenylalanine hydroxylase deficiency. Treatment is primarily a low-Phe diet combined with <span>l</span>-amino acid-based products (<span>l</span>-AA). Protein requirements in adults with PKU have not been directly determined. A formula with glycomacropeptide (GMP) and low phenylalanine is available, yet untested for optimal protein synthesis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>To determine the protein requirements in adults with PKU and the bioavailability of GMP-AA in the same patients using the indicator amino acid oxidation (IAAO) technique.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Each participant was allocated to 7 separate <span>l</span>-AA intakes (range: 0.1–1.8 g/kg/day) in Experiment 1. In Experiment 2, the same patients participated in 4 GMP-AA intakes (range: 0.1–0.9 g/kg/day). The IAAO method with <span>l</span>-[1-¹³C]-lysine as the indicator amino acid and its oxidation to ¹³CO₂ was used as the primary indicator of protein synthesis. Protein requirements were identified with a breakpoint, and bioavailability was determined by comparing ¹³CO₂ slope from GMP-AA versus <span>l</span>-AA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Six adults with PKU (4 M: 2F) completed a total of 54 study days over the 2 experiments. The estimated average requirement (EAR) for protein was determined to be 1.11 g/kg/day (<i>R</i>² = 0.20). The bioavailability of protein from GMP-AA was determined to be 99.98%, which was high and near to 100% comparable to <span>l</span>-AA; although, the results apply only to the tested GMP-AA blend.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>To our knowledge, this is the first study to directly define a quantitative protein requirement and indicates that current PKU protein recommendations for adults with PKU may be underestimated. The bioavailability of protein in the GMP-AA blend was high and optimal for protein synthesis in adults with PKU.</p>\u0000 </section>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}