Journal of Inherited Metabolic Disease最新文献

{"title":"Never-Treated, Non Splenectomised Patients With Gaucher Disease (The French GANT Study): The Prospective Follow-Up","authors":"Alberto Nasce,&nbsp;Yann Nguyen,&nbsp;Nadia Belmatoug,&nbsp;Karima Yousfi,&nbsp;Fabrice Camou,&nbsp;Magali Pettazzoni,&nbsp;Florence Dalbies,&nbsp;Bérengère Cador,&nbsp;Anaïs Brassier,&nbsp;Samia Pichard,&nbsp;Bénédicte Hivert,&nbsp;Laure Swiader,&nbsp;Ivan Bertchansky,&nbsp;Vanessa Leguy Seguin,&nbsp;Wladimir Mauhin,&nbsp;Leonardo Astudillo,&nbsp;Isabelle Hau Rainsard,&nbsp;Sébastien Humbert,&nbsp;Celia Hoebeke,&nbsp;Dalil Hamroun,&nbsp;Agathe Masseau,&nbsp;Marc G. Berger,&nbsp;Jérôme Stirnemann,&nbsp;Christine Serratrice,&nbsp;Comité d'Evaluation et de Traitement de la maladie de Gaucher (CETG)","doi":"10.1002/jimd.70026","DOIUrl":"10.1002/jimd.70026","url":null,"abstract":"<div>\u0000 \u0000 <p>Treatment options for Type 1 Gaucher Disease (GD1) include enzyme replacement therapy and oral substrate reduction therapy. The criteria for treatment initiation vary across regions. Recent retrospective studies have highlighted the natural progression of never-treated GD1, suggesting that some patients remain asymptomatic or stable for extended periods. However, there is no data on long-term prospective follow-up. We conducted a prospective study following a cross-sectional analysis of 36 never-treated, non-splenectomised GD1 patients from the French Gaucher Disease Registry (FGDR). The objective was to describe the natural disease progression, tracking clinical, radiological, and biological characteristics over time. Thirty-six non-splenectomised and never-treated patients (19 women and 17 men) diagnosed with Gaucher Disease were prospectively followed for an additional median duration of 6.5 (5–8.3) years. Of the cohort, 17 remained untreated, 10 initiated treatment, and 7 were lost to follow-up. Although never-treated patients tended to be older at the time of first symptoms, diagnosis, and last follow-up compared to those who received treatment, the difference was not significant in this small cohort. At last follow-up, never-treated patients had no worsening of most of their symptoms. No significant changes were observed in platelets, chitotriosidase, and lyso-Gb1. In this prospective cohort, we highlight that patients with mild GD can remain untreated with no disease progression, offering insights into cost-effective management strategies. Identifying such patients is still challenging.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663656","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":"Glycerophospholipids: Roles in Cell Trafficking and Associated Inborn Errors","authors":"Foudil Lamari,&nbsp;Francis Rossignol,&nbsp;Grant A. Mitchell","doi":"10.1002/jimd.70019","DOIUrl":"https://doi.org/10.1002/jimd.70019","url":null,"abstract":"<p>Glycerophospholipids (GPLs) are the main lipid components of cellular membranes. They are implicated in membrane structure, vesicle trafficking, neurotransmission, and cell signalling. GPL molecules are amphiphilic, organized around the three carbons of glycerol. Positions <i>sn-1</i> and <i>sn-2</i> are each esterified to a fatty acid (FA). At position <i>sn-3</i>, a phosphate group is linked, which in turn can bind a polar head group, the most prevalent classes being phosphatidic acid (PA, phosphate alone as head group), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), and cardiolipin (CL). Pathways of GPL biosynthesis span several cell compartments (endoplasmic reticulum (ER), Golgi mitochondria). Particularly important are mitochondria-associated membranes (MAMs), where the ER and mitochondrial outer membrane are in proximity. After synthesis, GPLs continuously undergo remodelling by FA hydrolysis and re-esterification. Esterification with different FAs alters membrane properties. Many steps in GPL synthesis and remodelling can be mediated by more than one enzyme, suggesting complexity that requires further exploration. The 38 known GPL-related inborn errors are clinically diverse. 23 (61%) have neurologic features, sometimes progressive and severe, particularly developmental delay/encephalopathy in 16 (42%) and spastic paraplegia in 12 (32%). Photoreceptor/neuroretinal disease occurs in 14 (37%). Three present skeletal dysplasias (8%). Most GPL inborn errors have been diagnosed by broad molecular testing. Lipidomics holds promise for diagnostic testing and for the discovery of functionally relevant metabolite profiles for monitoring natural history and treatment response.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70019","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143645778","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":"Correction to “Comparative Analysis of Gene and Disease Selection in Genomic Newborn Screening Studies”","authors":"","doi":"10.1002/jimd.70022","DOIUrl":"https://doi.org/10.1002/jimd.70022","url":null,"abstract":"<p>I. R. Betzler, M. Hempel, U. Mütze, et al., “Comparative Analysis of Gene and Disease Selection in Genomic Newborn Screening Studies,” <i>Journal of Inherited Metabolic Disease</i> 47, no. 5 (2024): 945–970, https://doi.org/10.1002/jimd.12750.</p><p>It has come to our attention that our original article contained errors in the mapping of ClinGen's Gene-Disease Validity data to gene lists from genomic newborn screening studies. Specifically, Table 2 mistakenly included the genes <i>MAGT1</i>, <i>CACNA1C</i>, <i>GJA1</i>, <i>KCNJ5</i>, <i>NOTCH3</i>, and <i>RASA1</i>, which were assigned to phenotypes primarily listed in ClinGen rather than those considered in the gNBS panels.</p><p>These corrections do not alter the overall conclusions of our study but clarify the challenges involved in defining target diseases for gNBS. We sincerely appreciate the constructive feedback from our colleagues and apologize for this error. We remain committed to transparency and accuracy in genomic newborn screening research.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70022","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143645779","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":"Performance of Relative Exchangeable Copper for the Diagnosis of Wilson Disease in Acute Liver Failure","authors":"Daniela Spirea,&nbsp;Claire Vanlemmens,&nbsp;François Parant,&nbsp;Teresa Antonini,&nbsp;Muriel Bost,&nbsp;Alain Lachaux,&nbsp;Abdelouahed Belmalih,&nbsp;Olivier Guillaud,&nbsp;Jerome Dumortier,&nbsp;Eduardo Couchonnal","doi":"10.1002/jimd.70024","DOIUrl":"https://doi.org/10.1002/jimd.70024","url":null,"abstract":"<p>Acute liver failure (ALF) can be one of the manifestations of Wilson disease (WD), and due to its severity, prompt diagnosis is essential. A ratio &gt; 15% of the exchangeable copper to total serum copper, known as relative exchangeable copper (REC), has been shown to have a 100% sensitivity and specificity for the diagnosis of WD but this has not yet been studied in an ALF setting. Patients diagnosed with ALF from 1 November 2011 to 31 December 2023, with available REC determination during the acute event, were included. Thirty-three patients were included (11 with WD and 22 without WD). The median age [IQR] at ALF was 12.9 [8.9–20.2] years, range: 0.6–71.0 years. Serum ceruloplasmin (Cp) &lt; 0.20 g/L and 24 h urinary copper excretion &gt; 1.6 μmol/L had both a sensitivity (Se) and specificity (Sp) for the diagnosis of WD of 100% and 72.7%, respectively. A ROC analysis of REC determined that the best cut-off point was 14.4% (AUC 1, <i>p</i> &lt; 0.01). All the WD patients had REC values &gt; 14.4%, yielding a sensitivity and specificity of 100. Relative exchangeable copper has 100% sensitivity and specificity for diagnosing Wilson disease in acute liver failure. Relative exchangeable copper has excellent performance in diagnosing Wilson disease in acute liver failure.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70024","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639064","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":"Safety and Efficacy of DTX401, an AAV8-Mediated Liver-Directed Gene Therapy, in Adults With Glycogen Storage Disease Type I a (GSDIa)","authors":"David A. Weinstein,&nbsp;Terry G. Derks,&nbsp;David F. Rodriguez-Buritica,&nbsp;Ayesha Ahmad,&nbsp;María-Luz Couce,&nbsp;John J. Mitchell,&nbsp;Rebecca Riba-Wolman,&nbsp;Malaya Mount,&nbsp;Julieta Bonvin Sallago,&nbsp;Katalin M. Ross,&nbsp;Melanie M. van der Klauw,&nbsp;Foekje de Boer,&nbsp;Caroline van der Schaaf,&nbsp;Heather Saavedra,&nbsp;Miguel Martínez-Olmos,&nbsp;Elvis Atanga,&nbsp;Asad Hosseini,&nbsp;Deepali Mitragotri,&nbsp;Eric Crombez","doi":"10.1002/jimd.70014","DOIUrl":"https://doi.org/10.1002/jimd.70014","url":null,"abstract":"<p>Glycogen storage disease type Ia (GSDIa) is a rare, life-threatening, inherited carbohydrate metabolism disorder caused by glucose-6-phosphatase (G6Pase) deficiency, which is essential for glycogenolysis and gluconeogenesis. GSDIa management includes a strict medically prescribed diet that typically includes daily uncooked cornstarch doses, including overnight, to maintain euglycemia. DTX401 is an investigational adeno-associated virus serotype 8 vector expressing the human <i>G6PC1</i> gene that encodes G6Pase. This open-label, phase 1/2, dose-escalation, 52-week gene therapy trial evaluated the safety and efficacy of a single DTX401 infusion in 12 adults with GSDIa (ClinicalTrials.gov Identifier: NCT03517085). Three participants in Cohort 1 received DTX401 2.0 × 10¹² genome copies (GC)/kg, and three participants each in Cohorts 2, 3, and 4 received 6.0 × 10¹² GC/kg. Corticosteroids were administered to mitigate vector‑induced inflammatory response. All participants experienced a treatment-emergent adverse event (TEAE) and a related TEAE. No participant experienced a dose-limiting toxicity, TEAE leading to study discontinuation, TEAE leading to death, or serious treatment-related TEAE. Mean (SD) time to hypoglycemia in minutes/gram of carbohydrate during a controlled fasting challenge was 5.0 (1.6) at baseline and 6.9 (2.7) at Week 52, a mean (SD) increase of 46% (72%). Mean total daily cornstarch intake was 284 g at baseline and 85 g at Week 52 in the 10 participants with available values at both time points, a mean (SD) total daily cornstarch intake reduction of 68% (20%); <i>p</i> &lt; 0.001. DTX401 showed a favorable safety and efficacy profile at Week 52. Participants in all cohorts showed significant cornstarch need reductions from baseline to Week 52.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595247","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":"Elevated Cerebrospinal Fluid Total Tau in Niemann-Pick Disease Type C1: Correlation With Clinical Severity and Response to Therapeutic Interventions","authors":"Niamh X. Cawley,&nbsp;Ruyu Zhou,&nbsp;Nicole M. Farhat,&nbsp;James Iben,&nbsp;Derek M. Alexander,&nbsp;Rachel A. Luke,&nbsp;Cameron J. Padilla,&nbsp;Hibaaq O. Mohamed,&nbsp;Orsolya K. Albert,&nbsp;Kendall P. Robbins,&nbsp;Samar Rahhal,&nbsp;An Dang Do,&nbsp;Elizabeth Berry-Kravis,&nbsp;Stephanie M. Cologna,&nbsp;Fang Liu,&nbsp;Forbes D. Porter","doi":"10.1002/jimd.70016","DOIUrl":"https://doi.org/10.1002/jimd.70016","url":null,"abstract":"<p>Niemann-Pick disease, type C1 (NPC1) is an inborn error of intracellular cholesterol transport. Impaired function of NPC1 leads to endolysosomal accumulation of unesterified cholesterol, which results in progressive neurodegeneration. Although the age of onset is variable, classical NPC1 is a pediatric disease. Identification of biomarkers that correlate with clinical phenotype and respond to therapeutic interventions will be essential for developing effective therapeutic interventions. Aβ peptides and Tau protein are primary components of amyloid plaques and neurofibrillary tangles, respectively, which are major pathological features in neurodegenerative disorders. Cerebrospinal fluid (CSF) levels of total Tau, a biomarker of axonal damage, were elevated ~3-fold (<i>p</i> &lt; 0.0001) in 106 individuals with Niemann-Pick disease, type C1, relative to age-appropriate comparison samples. Baseline CSF total Tau levels correlated with clinical measures of disease severity. Specifically, CSF total Tau levels decreased with increased age of neurological onset (<i>r</i>_<i>s</i> = −0.42, FDR adj. <i>p</i> &lt; 0.0001) and increased with increased Annual Severity Increment Score (<i>r</i>_<i>s</i> = 0.52, FDR adj. <i>p</i> &lt; 0.0001). Baseline CSF total Tau levels were decreased 40% (<i>p</i> = 0.0066) in individuals being treated with miglustat, and longitudinal analysis substantiated this observation with a 40% decrease (<i>p</i> &lt; 0.0001, 95% CI 32%–47.4%). Longitudinal analysis also showed a significant (<i>p</i> = 0.004) decrease of 19% (95% CI 7%–30%) in total Tau levels associated with intrathecal 2-hydroxypropyl-β-cyclodextrin therapy. These data show that CSF total Tau levels are significantly increased in individuals with NPC1, positively correlated with increased disease severity, and respond to therapeutic interventions.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595055","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 Therapeutic Future for Congenital Disorders of Glycosylation","authors":"I. J. J. Muffels,&nbsp;T. Kozicz,&nbsp;E. O. Perlstein,&nbsp;E. Morava","doi":"10.1002/jimd.70011","DOIUrl":"https://doi.org/10.1002/jimd.70011","url":null,"abstract":"<div>\u0000 \u0000 <p>The past decade, novel treatment options for congenital disorders of glycosylation (CDG) have advanced rapidly. Innovative therapies, targeting both the root cause, the affected metabolic pathways, and resulting manifestations, have transitioned from the research stage to practical applications. However, with novel therapeutic abilities, novel challenges await, specifically when it concerns the large number of clinical trials that need to be performed in order to treat all 190 genetic defects that cause CDG known to date. The present paper aims to provide an overview of how the CDG field can keep advancing its therapeutic strategies over the coming years with these challenges in mind. We focus on three important pillars that may shape the future of CDG: the use of disease models, clinical trial readiness, and the possibility to make individualized treatments scalable to the entire CDG cohort.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595053","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":"Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects","authors":"Eva M. M. Hoytema van Konijnenburg,&nbsp;Joline Rohof,&nbsp;Gautam Kok,&nbsp;Peter M. van Hasselt,&nbsp;Clara D. van Karnebeek,&nbsp;Irena J. J. Muffels,&nbsp;Sabine A. Fuchs","doi":"10.1002/jimd.70017","DOIUrl":"https://doi.org/10.1002/jimd.70017","url":null,"abstract":"<p>Aminoacyl-transfer RNA (tRNA) synthetases (ARSs) are key enzymes for protein translation. The number of identified patients with recessive ARS1 deficiencies is rapidly increasing. Initially, only supportive care was available, but in recent years beneficial effects of targeted amino acid supplementation have been described. To allow early treatment and prevention of symptoms, rapid recognition is necessary, as well as insight into the natural history to evaluate treatment effects. We performed a scoping literature search for clinical characteristics and treatment effects of patients with ARS1 deficiencies. Symptoms were matched to Human Phenotype Ontology terms. We identified 438 patients with 20 different ARS1 deficiencies. Overall mortality was 22%. Neurological symptoms were most prevalent across all ARS1 deficiencies (in 87% of patients), including neurodevelopmental disorder (79%), microcephaly (50%) and seizures (46%). Growth issues and ophthalmological symptoms were also prevalent in many ARS1 deficiencies. Two distinct phenotypical clusters were seen: one with multisystemic disease including liver- and lung disease and another with a predominantly neurological phenotype. Supplementation with cognate amino acids was described in 21 patients, with beneficial effects (e.g., improvements in growth, development, liver and lung disease) in the majority. Treatment did not alleviate the most severe phenotypes. Specific symptoms relate to (a cluster of) specific ARS1 deficiencies; the mechanism is not yet understood. Multi-organ involvement should trigger inclusion of ARS1 genes in the diagnostic work-up. Treatment with cognate amino acids is promising, but it remains challenging to distinguish treatment effects from natural history. Synopsis: Treatment with cognate amino acids in ARS1 deficiencies is promising, but it remains challenging to distinguish treatment effects from natural history.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70017","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554717","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":"Normothermic Machine Perfusion of Explanted Human Metabolic Livers: A Proof of Concept for Studying Inborn Errors of Metabolism","authors":"Samira Safarikia,&nbsp;Riccardo Cirelli,&nbsp;Gionata Spagnoletti,&nbsp;Diego Martinelli,&nbsp;Giulia Bravetti,&nbsp;Paola Francalanci,&nbsp;Annamaria D'Alessandro,&nbsp;Giovina Di Felice,&nbsp;Marta Maistri,&nbsp;Elena Baldissone,&nbsp;Alberto M. Fratti,&nbsp;Raffaele Simeoli,&nbsp;Elisa Sacchetti,&nbsp;Sara Cairoli,&nbsp;Cristiano Rizzo,&nbsp;Rosanna Pariante,&nbsp;Michele Vacca,&nbsp;Andrea Cappoli,&nbsp;Christian Albano,&nbsp;Andrea Pietrobattista,&nbsp;Marco Spada,&nbsp;Carlo Dionisi Vici","doi":"10.1002/jimd.70010","DOIUrl":"https://doi.org/10.1002/jimd.70010","url":null,"abstract":"<p>The human liver plays a central metabolic role; however, its physiology may become imbalanced in inborn errors of metabolism (IEM), a broad category of monogenic disorders. Liver transplantation has been increasingly used to improve patient metabolic control, especially in diseases related to amino acid metabolism, such as urea cycle disorders and organic acidurias, to provide enzyme replacement. Ex vivo liver normothermic machine perfusion (NMP) techniques have recently been developed to increase the number of transplantable grafts and improve transplantation outcomes. This study used seven NMP of explanted livers from patients with IEM undergoing transplantation as models to investigate disease-related liver metabolism and function. The perfused livers demonstrated positive viability indicators and disease-specific targeted metabolomics providing the proof-of-principle that our ex vivo model expresses the biochemical disease characteristics and responds to therapeutical intervention in a unique “physiological” milieu, offering an ideal tool to study novel treatments, in a setting closely mirroring human disease.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530222","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":"Altered Fibroblast Glutamine Metabolism Is Linked to the Severity of Cardiac Dysfunction in DCMA, a Mitochondrial Cardiomyopathy","authors":"Melissa A. King,&nbsp;Katherine C. Heger,&nbsp;Marija Drikic,&nbsp;Ayush Mandwal,&nbsp;Aneal Khan,&nbsp;David S. Sinasac,&nbsp;Keir Pittman,&nbsp;Edward L. Huttlin,&nbsp;Steven C. Greenway,&nbsp;Ian A. Lewis","doi":"10.1002/jimd.70018","DOIUrl":"https://doi.org/10.1002/jimd.70018","url":null,"abstract":"<p>The dilated cardiomyopathy with ataxia (DCMA) syndrome is a rare mitochondrial disorder caused by mutations in the poorly understood <i>DNAJC19</i> gene. Cardiac involvement in DCMA ranges from mild conduction abnormalities to early severe myocardial dysfunction. Although evidence suggests that DCMA is linked to abnormalities in mitochondrial function, the molecular underpinnings of this condition are unclear, and there is no way to predict which patients will develop life-threatening disease. To address this, we developed a metabolic flux assay for assessing the metabolic function of mitochondria in fibroblasts derived from DCMA patients. Using this approach, we discovered that DCMA fibroblasts have elevated glutamine uptake, increased glutamate and ammonium secretion, and elevated lactate production. Moreover, we observed that these cellular perturbations were closely correlated with cardiac dysfunction in a blinded cohort of patient cell lines. These findings suggest that glutamine catabolism is abnormal in DCMA and may serve as a predictor of clinical progression.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143533556","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}