Molecular genetics and metabolism最新文献

{"title":"WORLDSymposium™ 2026 Preliminary Program^⁎.","authors":"","doi":"10.1016/j.ymgme.2025.109297","DOIUrl":"https://doi.org/10.1016/j.ymgme.2025.109297","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"147 2","pages":"109297"},"PeriodicalIF":3.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WORLDSymposium™ 2026 Introduction.","authors":"","doi":"10.1016/j.ymgme.2025.109296","DOIUrl":"https://doi.org/10.1016/j.ymgme.2025.109296","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"147 2","pages":"109296"},"PeriodicalIF":3.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WORLDSymposium™ 2026.","authors":"","doi":"10.1016/j.ymgme.2025.109295","DOIUrl":"https://doi.org/10.1016/j.ymgme.2025.109295","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"147 2","pages":"109295"},"PeriodicalIF":3.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vascular complications and imaging-based cardiovascular risk assessment in Mucopolysaccharidoses: A systematic review.","authors":"Eamon P McCarron, Victoria Burgess, Steven K Rogers, Peter Woolfson, Petra Jenkins, Simon A Jones, Raymond Wang, Karolina M Stepien","doi":"10.1016/j.ymgme.2025.109687","DOIUrl":"10.1016/j.ymgme.2025.109687","url":null,"abstract":"<p><strong>Background: </strong>Mucopolysaccharidoses (MPS) are lysosomal storage disorders characterised by glycosaminoglycan (GAG) accumulation, leading to progressive multisystem disease. Cardiovascular complications, including arterial wall stiffness, and valvular dysfunction, are major causes of morbidity and mortality. Conventional cardiovascular risk tools are unreliable in MPS, and the role of vascular imaging remains underdefined.</p><p><strong>Aim: </strong>This systematic review evaluated vascular complications in paediatric and adult MPS patients, focusing on carotid intimal-media thickness (CIMT) and functional vascular parameters (e.g. carotid cross-sectional compliance (cCSC), carotid incremental elastic modulus (cIEM), carotid cross-sectional distensibility (cCSD)), to assess their utility for cardiovascular risk stratification.</p><p><strong>Methods: </strong>A systematic search of MEDLINE, EMBASE, and Cochrane Library was conducted (inception-July 2025). Eligible studies reported vascular outcomes in MPS types I, II, III, IV, VI, or VII using imaging or functional measures. Risk of bias was assessed using ROBINS-I for observational studies and RoB 2.0 for the single randomised trial.</p><p><strong>Results: </strong>Eight studies comprising 224 patients were included. CIMT was consistently increased across subtypes, with adult values frequently observed in childhood, indicating accelerated vascular pathology. Patients demonstrated reduced arterial compliance, increased arterial stiffness, and a high prevalence of mitral and aortic valvular disease. Enzyme replacement therapy (ERT) and haematopoietic stem cell transplantation (HSCT) showed partial attenuation of vascular pathology.</p><p><strong>Conclusion: </strong>CIMT and vascular stiffness are sensitive markers of subclinical vasculopathy in MPS where conventional cardiovascular risk tools may remain unreliable. Standardised vascular imaging and biomarker development are needed to improve risk stratification and long-term outcomes (particularly in adults).</p>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":" ","pages":"109687"},"PeriodicalIF":3.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145648918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomarking MELAS with neurofilament light chain and circulating cell free mitochondrial DNA.","authors":"Alessandra Maresca, Monica Moresco, Giulia Amore, Chiara La Morgia, Maria Lucia Valentino, Giada Capirossi, Giulia Sacchetti, Valerio Carelli, Christian Vedeler, Laurence A Bindoff, Kristin N Varhaug","doi":"10.1016/j.ymgme.2026.109753","DOIUrl":"https://doi.org/10.1016/j.ymgme.2026.109753","url":null,"abstract":"<p><p>Mitochondrial diseases are genetic disorders caused either by nuclear or mitochondrial DNA (mtDNA) alterations and characterized by high genetic and phenotypic variability. The common mtDNA m.3243 A > G variant in the MT-TL1 gene leads to clinical manifestations ranging from the classical MELAS (myopathy, encephalopathy, lactic acidosis and stroke-like episodes) syndrome to milder phenotypes such as MIDD (maternally inherited diabetes and deafness) or a spectrum of clinical features of intermediate severity defined as MELAS-Spectrum. The heterogeneous disease course makes the identification of biomarkers for monitoring disease progression challenging, particularly if we consider the occurrence of stroke-like episodes (SLEs), which remain unpredictable events. Here, we assessed two biomarkers, neurofilament light chain (NF-L) and circulating cell free-mtDNA (ccf-mtDNA), in a cross-sectional study in MELAS patients, including both patients in the interictal period and during SLEs, and MELAS-Spectrum patients. Both biomarkers were significantly elevated in MELAS patients during SLEs, compared to the other patients. In addition, we found significant correlation between NF-L and m.3243 A > G blood heteroplasmy in MELAS patients, as well as between NF-L and clinical severity in the whole patients cohort. Despite the limitations derived from the small sample size and the cross-sectional sample collection, our study confirms the value of NF-L and ccf-mtDNA as biomarkers efficiently hallmarking SLEs, highlighting their potential use to monitor the progression of MELAS.</p>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"147 3","pages":"109753"},"PeriodicalIF":3.5,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Primary mitochondrial diseases: A rare disease virtual workshop","authors":"Catherine Pilgrim-Grayson ,&nbsp;Anna Choe ,&nbsp;Naomi Knoble ,&nbsp;Yan Wang ,&nbsp;Kerry Jo Lee ,&nbsp;Lea Ann Browning-McNee ,&nbsp;Cartier Esham ,&nbsp;Amel Karaa","doi":"10.1016/j.ymgme.2025.109707","DOIUrl":"10.1016/j.ymgme.2025.109707","url":null,"abstract":"<div><div>The Reagan-Udall Foundation for the FDA (Foundation) in collaboration with the Food and Drug Administration (FDA) hosted a workshop titled “Primary Mitochondrial Diseases: A Rare Disease Virtual Workshop” on 22 May 2025, to explore opportunities to optimize therapeutic development for primary mitochondrial diseases (PMD). The event brought together a diverse group of experts including FDA regulators, regulated industries, health care professionals, scientists, patients and their families and caregivers, and patient organizations. The presentations and panels discussed existing challenges and proposed strategies to improve enrollment and optimize clinical trial design elements (<em>e.g.,</em> outcome measures, endpoint and patient population selection, and statistical analysis) that may support clinical trial innovations for PMD therapeutics in alignment with regulatory standards.</div></div><div><h3>Meeting purpose</h3><div>Primary mitochondrial diseases (PMDs) are rare, often debilitating genetic disorders caused by variants in nuclear or mitochondrial DNA. There are approximately 70,000 PMD patients in the U.S. and 1 in 200 carry a pathogenic mtDNA variant.([<span><span>1</span></span>,<span><span>2</span></span>]) The multisystemic and heterogenous clinical presentations of PMDs present unique challenges for the development of targeted therapies.</div><div>There have been ongoing collaborations between the PMD community and FDA to discuss the challenges and align on solutions for successful PMD drug development. For example, in 2019 the FDA hosted a scientific symposium titled <em>Developing Therapies for Primary Mitochondrial Diseases: Bridging the Gap</em>, where multiple stakeholders discussed ways to integrate mitochondrial biology into drug development, the value of registries, the refinement of patient-focused outcomes, and additional regulatory and scientific considerations for clinical trial designs in PMD [<span><span>3</span></span>]. Building on the foundation laid, FDA and the PMD community continued to engage on approaches to clinical trial design and endpoint selection for PMD treatments and most recently, these discussions culminated in the 2025 “Primary Mitochondrial Diseases: A Rare Disease Virtual Workshop” [<span><span>4</span></span>]. This workshop focused on specific clinical development and design approaches, engagement with patients and other disease experts, analytic strategies for managing heterogeneity, and leveraging lessons learned for future success. PMD patients, families, advocates, academic clinical experts, FDA representatives, and others from the PMD community participated in the workshop.</div><div>This paper provides summaries of the presentations and reactor panels included in the workshop and concludes with key learnings and future directions for drug development for PMD identified during this meeting.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"147 3","pages":"Article 109707"},"PeriodicalIF":3.5,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A rare GCH1 p.Arg170Gly variant shows impaired enzymatic activity and co-occurs with a novel NEXMIF p.Asp155GlnfsTer2 leading to a complex neurological phenotype: functional studies and clinical aspects","authors":"Klaudia Ślusarczyk ,&nbsp;Julia Zuzanna Kamińska ,&nbsp;Katarzyna Kuśmierska ,&nbsp;Elżbieta Czyżyk ,&nbsp;Magdalena Łazicka ,&nbsp;Kacper Domżał ,&nbsp;Sylwia Rzońca-Niewczas ,&nbsp;Aleksandra Landowska ,&nbsp;Krzysztof Szczałuba ,&nbsp;Katarzyna Wertheim-Tysarowska ,&nbsp;Jolanta Sykut-Cegielska ,&nbsp;Krystyna Szymańska ,&nbsp;Jakub Drożak ,&nbsp;Agnieszka Magdalena Rygiel","doi":"10.1016/j.ymgme.2026.109736","DOIUrl":"10.1016/j.ymgme.2026.109736","url":null,"abstract":"<div><div>GTP cyclohydrolase I deficiency is a rare inherited disorder of biogenic amine metabolism due to pathogenic <em>GCH1</em> variants, manifesting as DOPA-responsive dystonia or severe encephalopathy. Pathogenic variants in the <em>NEXMIF</em> gene cause X-linked intellectual disability and epilepsy. Here, using trio-WES approach, we identified a rare, previously uncharacterized <em>GCH1</em> p.Arg170Gly variant and a novel <em>NEXMIF</em> p.Asp155GlnfsTer2 variant in a female patient. This study aimed to confirm the pathogenicity of these variants and elucidate their underlying molecular pathomechanisms by molecular <em>in vitro</em> studies. First, we confirmed that the <em>NEXMIF</em> variant introduces a premature stop codon at the cDNA level, implying loss of NEXMIF protein function. To explore the functional consequences of the <em>GCH1</em> variant, we expressed and purified wild-type (WT) and p.Arg170Gly homodecameric GCH1, as well as a mixed population of heterodecameric GCH1 proteins, and performed biochemical characterization. Kinetic studies revealed that the catalytic efficiency of the mutant homo- and heterodecameric GCH1 was reduced by 37- and 9-fold, respectively, compared to the WT enzyme, confirming a significant loss of activity. Furthermore, the presence of mutant GCH1 monomers negatively affected catalytic cooperativity in the decameric enzyme. Circular dichroism indicated that p.Arg170Gly slightly impacts the structure of the protein, as shown by reduced α-helical content in the mutant homodecamer. In summary, we provide the first functional evidence that the <em>GCH1</em> p.Arg170Gly variant is pathogenic mainly due to reduced enzyme activity, and that its combination with a novel <em>NEXMIF</em> loss-of-function variant manifests as a complex neurological phenotype arising from two distinct disorders.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"147 3","pages":"Article 109736"},"PeriodicalIF":3.5,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics analysis reveals ER stress as a main feature in two endothelial cell models of N-linked congenital disorders of glycosylation","authors":"Karen Driesen ,&nbsp;Veronika Holubová ,&nbsp;Pedro Magalhães ,&nbsp;Shauni Loopmans ,&nbsp;Mainak Guharoy ,&nbsp;Isabelle Meyts ,&nbsp;Eva Morava ,&nbsp;Bart Ghesquière ,&nbsp;Peter Witters","doi":"10.1016/j.ymgme.2026.109737","DOIUrl":"10.1016/j.ymgme.2026.109737","url":null,"abstract":"<div><div>Glycosylation is one of the most important posttranslational modifications. When the glycosylation machinery is affected, this leads to a congenital disorder of glycosylation (CDG). CDG are a class of rare multisystemic diseases that often affect the endoplasmic reticulum (ER). Although vascular complications have been reported in CDG, the contribution of endothelial dysfunction to these phenotypes remains incompletely understood. Here, we evaluated the effect of glycosylation deficiency on endothelial dysfunction by generating two endothelial cell models using pharmacological inhibitors: tunicamycin (a well-known glycosylation inhibitor at the level of DPAGT1), and 2-deoxy-2-fluoro-D-mannose (FMan). This is a novel inhibitor that inhibits mannose and related sugar-phosphate metabolism. These cell models were subjected to transcriptomics, proteomics, and tracer metabolomics to pinpoint the pathways that are most affected across these different levels. Both transcriptomics and proteomics revealed ER stress as the top upregulated feature. This was functionally characterized by decreased cell growth, induced apoptosis, decreased cell migration, and induced an immune response. The barrier function of the cells was not affected. Here, we demonstrate that N-glycosylation deficiency triggers an ER stress response, contributing to endothelial dysfunction, and investigated ER stress mitigation as a potential therapeutic strategy for CDG.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"147 3","pages":"Article 109737"},"PeriodicalIF":3.5,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enzyme replacement therapy for CLN1 batten disease that crosses the blood-brain-barrier","authors":"Renuka Raman ,&nbsp;Ben Horst ,&nbsp;Zahra Shahrokh ,&nbsp;Nader Hatambeygi ,&nbsp;Maryam Zare ,&nbsp;Magdalena Leszczyniecka ,&nbsp;Joshua S. Harris ,&nbsp;William A. Banks ,&nbsp;Kim M. Hansen ,&nbsp;Michelle A. Erickson ,&nbsp;Sean Ekins","doi":"10.1016/j.ymgme.2026.109733","DOIUrl":"10.1016/j.ymgme.2026.109733","url":null,"abstract":"<div><div>CLN1 Batten disease is caused by mutations in the CLN1 gene which codes for the lysosomal enzyme palmitoyl-protein thioesterase-1 (PPT1). Disease progression is marked by intellectual and motor deterioration, seizures, vision loss, and early mortality. There are no approved treatments for this severe pediatric condition. We describe the development and characterization of recombinant human PPT1 (rhPPT1) suitable for use as a clinical enzyme replacement therapy in CLN1 Batten patients. rhPPT1 displays similar mannose-6-phosphate receptor (M6PR)-dependent uptake kinetics in neuronal cell lines from human, rat and non-human primate but not in mouse cells. rhPPT1 crosses the blood-brain-barrier (BBB) in adult mice which is uncommon for unmodified lysosomal enzymes, and is independent of the M6PR and sialic acid receptors even though analytical characterization of rhPPT1 shows complex M6P and sialic acid containing glycans. Our findings suggest for the first time that intravenous dosing of rhPPT1 may be complementary to other dosing strategies in CLN1 patients and may expand its use for other applications.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"147 3","pages":"Article 109733"},"PeriodicalIF":3.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory news: Velmanase alfa-tycv (Lamzede) for the treatment of non-CNS manifestations alpha mannosidosis: Approval summary","authors":"Sarah Fuchs,&nbsp;Therri Usher","doi":"10.1016/j.ymgme.2026.109732","DOIUrl":"10.1016/j.ymgme.2026.109732","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"147 3","pages":"Article 109732"},"PeriodicalIF":3.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145979709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}