Molecular genetics and metabolism最新文献

{"title":"An obituary and tribute to Doug Kerr","authors":"Daniel Kerr , Shawn E. McCandless , Stephen Cederbaum","doi":"10.1016/j.ymgme.2025.109137","DOIUrl":"10.1016/j.ymgme.2025.109137","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 3","pages":"Article 109137"},"PeriodicalIF":3.7,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144072700","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":"Letter to the Editors: Concerning “SSR4-CDG, an ultra-rare X-linked congenital disorder of glycosylation affecting the TRAP complex: Review of 22 affected individuals including the first adult patient” by Johnsen et al.","authors":"Alessandra Verde , Maria Rosa Cutri' , Federica Pagani , Alba Pilotta , Lorenzo Pinelli , Alessia Asaro , Luca Cattaneo , Raffaele Badolato , Enza Maria Valente , Jessica Galli","doi":"10.1016/j.ymgme.2025.109136","DOIUrl":"10.1016/j.ymgme.2025.109136","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 2","pages":"Article 109136"},"PeriodicalIF":3.7,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143942373","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":"Long-term enzyme replacement therapy: Findings from the mucopolysaccharidosis VI clinical surveillance program after 15 years follow-up","authors":"Barbara K. Burton ,&nbsp;Paul R. Harmatz ,&nbsp;Veronika Horvathova ,&nbsp;Alice Lail ,&nbsp;Christina Lampe ,&nbsp;Rossella Parini ,&nbsp;Reena Sharma ,&nbsp;Elisa Leão Teles","doi":"10.1016/j.ymgme.2025.109135","DOIUrl":"10.1016/j.ymgme.2025.109135","url":null,"abstract":"<div><h3>Objective</h3><div>To evaluate the long-term real-world efficacy and safety of galsulfase enzyme replacement therapy (ERT) in patients enrolled in the mucopolysaccharidosis (MPS) VI Clinical Surveillance Program (CSP).</div></div><div><h3>Methods</h3><div>The CSP collected long-term observational data of routine clinical and laboratory assessments from 30 June 2005 to 01 May 2020. Outcomes included urinary glycosaminoglycan (uGAG) level, 6-min walk test (6MWT), forced expiratory volume in 1 s (FEV₁), forced vital capacity (FVC), anthropometrics and adverse events.</div></div><div><h3>Results</h3><div>The final analysis population included 221 participants with MPS VI; 212 participants received ERT (median ERT exposure time 11.7 years). In ERT-treated participants with both baseline and follow-up data, uGAG levels decreased by a mean of 59.7 % after a mean follow-up of 8.0 years (<em>P</em> &lt; 0.0001; <em>n</em> = 84), 6MWT distance increased by a mean (SE) of 42.3 (21.81) meters after a mean follow-up of 7.0 years (<em>P</em> = 0.0610, <em>n</em> = 35), FEV₁ increased by 0.36 (0.098) L after 6.5 years (<em>P</em> = 0.0014, <em>n</em> = 24), and FVC increased by 0.52 (0.143) L after 6.3 years (<em>P</em> = 0.0013, <em>n</em> = 25). Improvements were seen across subgroups of participants with high and low baseline uGAG levels (&gt;200 and ≤ 200 μg/mg creatinine). 6MWT and pulmonary function increased primarily in participants younger than 18 years at baseline while older patients showed stabilization. Galsulfase was generally well tolerated with no new safety signals identified. Most adverse events were MPS-related clinical manifestations and considered not related to galsulfase by investigators.</div></div><div><h3>Conclusions</h3><div>Data collected in the CSP over 15 years provide real-world evidence for sustained improvements in endurance and pulmonary function among patients with MPS VI treated with ERT, with no new safety concerns identified. These results further support and confirm observations from the clinical trials and previous findings from the CSP.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 3","pages":"Article 109135"},"PeriodicalIF":3.7,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144072699","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":"Dual pathogenic mechanisms in lysinuric protein intolerance: Interplay between hyperammonemia and cellular metabolic dysregulation in astrocyte injury","authors":"Keisuke Kakisaka ,&nbsp;Takuro Sato ,&nbsp;Yasunori Wada ,&nbsp;Hiroaki Abe ,&nbsp;Shizuka Abe ,&nbsp;Ai Shimodate ,&nbsp;Takuya Watanabe ,&nbsp;Tokio Sasaki ,&nbsp;Yudai Fujiwara ,&nbsp;Tamami Abe ,&nbsp;Akiko Suzuki ,&nbsp;Kei Endo ,&nbsp;Yuichi Yoshida ,&nbsp;Takayoshi Oikawa ,&nbsp;Kei Sawara ,&nbsp;Akio Miyasaka ,&nbsp;Shohei Komaki ,&nbsp;Atsushi Shimizu ,&nbsp;Ken Ishikawa ,&nbsp;Manami Akasaka ,&nbsp;Takayuki Matsumoto","doi":"10.1016/j.ymgme.2025.109134","DOIUrl":"10.1016/j.ymgme.2025.109134","url":null,"abstract":"<div><h3>Background</h3><div>Lysinuric protein intolerance (LPI) is a rare genetic disorder characterized by an inherited defect in cationic amino acid transport caused by pathogenic variants in the <em>SLC7A7</em> gene. While LPI causes systemic complications, the underlying cellular mechanisms remain poorly understood. This study investigated the cellular characteristics of LPI, focusing on intracellular metabolite profiles and astrocyte response to hyperammonemia.</div></div><div><h3>Objectives</h3><div>To examine intracellular metabolite changes in LPI patients and to evaluate the response of patient-derived astrocytes to ammonia exposure.</div></div><div><h3>Methods</h3><div>Peripheral blood mononuclear cells (PBMCs) from three LPI patients and three healthy controls were analyzed for intracellular metabolite profiles using capillary electrophoresis-fourier transform mass spectrometry. Induced pluripotent stem cells were generated from a patient's PBMCs and differentiated into astrocytes. We evaluated LPI-astrocytes and their response to ammonia treatment by RNA sequencing, gene expression profiling, and cell viability assays.</div></div><div><h3>Results</h3><div>Metabolite analysis revealed significant intracellular metabolite imbalances in LPI patients, with increases of 21 metabolites including 11 amino acids. LPI-astrocytes exhibited distinct cellular characteristics regarding altered gene expression and enhanced cell cycle progression. When exposed to ammonia, the astrocytes demonstrated markedly lower cell viability and increased reactive oxygen species (ROS) production compared to control astrocytes. <em>N</em>-acetylcysteine supplementation significantly ameliorated ammonia-induced cytotoxicity.</div></div><div><h3>Conclusions</h3><div>SLC7A7 dysfunction leads to intracellular metabolite disturbances and an increase in vulnerability to ammonia toxicity through ROS production of astrocyte, suggesting hyperammonemia and amino acid deficiencies as potential therapeutic targets in LPI patient care.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 2","pages":"Article 109134"},"PeriodicalIF":3.7,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143931708","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":"Combining clinically benign IDUA variants in cis reduces enzymatic activity of the resulting enzyme within the pathogenic range","authors":"Seok-Ho Yu,&nbsp;Laura Pollard,&nbsp;Heather Flanagan-Steet,&nbsp;Richard Steet","doi":"10.1016/j.ymgme.2025.109131","DOIUrl":"10.1016/j.ymgme.2025.109131","url":null,"abstract":"<div><div>Interpretation of genotypes with multiple variants can be challenging as independent effects of each variant must be determined to predict the overall outcome for biallelic conditions. This is especially difficult when two or more variants exist <em>in cis</em> on a single allele. We used an established functional platform to characterize the impact of different clinically benign <em>IDUA</em> variants alone, or in combination, demonstrating that the relative specific activity of <em>in cis</em> variant combinations is comparable to individual variants associated with attenuated or even severe MPSI. These results reinforce the concept that combinations of otherwise clinically benign variants can produce pathogenic consequences.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 2","pages":"Article 109131"},"PeriodicalIF":3.7,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143934915","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":"Genetic syndromes, eponyms, and toponyms sounding literally Greek to you!","authors":"Alexios-Fotios A. Mentis","doi":"10.1016/j.ymgme.2025.109130","DOIUrl":"10.1016/j.ymgme.2025.109130","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 2","pages":"Article 109130"},"PeriodicalIF":3.7,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143906129","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":"European guidelines on diagnosis and treatment of phenylketonuria: First revision","authors":"A.M.J. van Wegberg ,&nbsp;A. MacDonald ,&nbsp;K. Ahring ,&nbsp;A. Bélanger-Quintana ,&nbsp;S. Beblo ,&nbsp;N. Blau ,&nbsp;A.M. Bosch ,&nbsp;A. Burlina ,&nbsp;J. Campistol ,&nbsp;T. Coşkun ,&nbsp;F. Feillet ,&nbsp;M. Giżewska ,&nbsp;S.C. Huijbregts ,&nbsp;V. Leuzzi ,&nbsp;F. Maillot ,&nbsp;A.C. Muntau ,&nbsp;J.C. Rocha ,&nbsp;C. Romani ,&nbsp;F. Trefz ,&nbsp;F.J. van Spronsen","doi":"10.1016/j.ymgme.2025.109125","DOIUrl":"10.1016/j.ymgme.2025.109125","url":null,"abstract":"<div><div>Phenylketonuria (PKU) is an autosomal recessive inherited disorder of phenylalanine metabolism caused by deficiency of the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. Untreated, PKU results in elevated phenylalanine levels in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems.</div><div>For this first revision of the European PKU Guidelines previous recommendations were re-evaluated and updated according to new research findings. Twenty-one professionals were divided across four working groups and supported by a coordinator and chair.</div><div>In addition to an update of the previous 70 recommendations, 20 new topics were included, resulting in a total of 87 statements in this first revision of the guidelines. Research publications were reviewed up until September 2022. Evidence was graded as high, moderate, low, very low or expert opinion and the recommendations were graded conditional or strong according to GRADE methodology. All recommendations were discussed during 14 plenary online or in person meetings. Recommendations were accepted if more than 75 % of the professionals were in agreement. When recommendations were not amended, the text reported in the European guidelines of 2017 remains valid.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 2","pages":"Article 109125"},"PeriodicalIF":3.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067952","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":"Agreement between the Amsterdam Neuropsychological Tasks and the Cambridge Neuropsychological Test Automated Battery in theassessment of PKU patients and healthy controls","authors":"Ellis M. van Steenis ,&nbsp;Stephan C.J. Huijbregts ,&nbsp;Cristina Romani ,&nbsp;Joëll A. Schoemaker ,&nbsp;Ninke van Vliet ,&nbsp;Allysa M. Kuypers ,&nbsp;M. Estela Rubio-Gozalbo ,&nbsp;Alexander J.M. Rennings ,&nbsp;Maaike de Vries ,&nbsp;M. Rebecca Heiner-Fokkema ,&nbsp;Francjan J. van Spronsen","doi":"10.1016/j.ymgme.2025.109126","DOIUrl":"10.1016/j.ymgme.2025.109126","url":null,"abstract":"<div><h3>Background</h3><div>Several neuropsychological testing batteries have been used to assess and monitor neurocognitive functioning in healthy individuals and patients. Two of these test batteries, the Amsterdam Neuropsychological Tasks (ANT) and the Cambridge Neuropsychological Automated Test Battery (CANTAB), have indicated impairments in early- and continuously treated phenylketonuria (PKU) patients. However, the tasks of these batteries have never been cross-validated. This study aims to establish the comparability of the two test batteries in the assessment and monitoring of PKU patients and healthy controls.</div></div><div><h3>Methods</h3><div>22 PKU patients and 19 controls of various ages (7–67 years old) were tested twice, once using tasks from the ANT and once using tasks from the CANTAB. Tasks of the two batteries were matched based on the neurocognitive functions they (were deemed to) assess, including motor skills, emotion recognition, sustained attention and executive functions (working memory, inhibitory control, and cognitive flexibility). Correlation matrices were used to assess the specificity of the correlations between tasks assigned to similar skills, versus non-related tasks.</div></div><div><h3>Results</h3><div>Correlations between matched tasks from the ANT and CANTAB ranged from moderate to strong (range ρ: 0.50–0.84, <em>P</em> &lt; 0.001), with strong correlations (ρ &gt; 0.70) for emotion recognition, cognitive flexibility and sustained attention. These correlations remained significant after correcting for age. The strongest correlations were generally found between tasks assigned to require similar skills a-priori, validating the matching between tasks.</div></div><div><h3>Conclusion</h3><div>Overall, there was a good level of agreement between ANT and CANTAB tasks, especially in emotion recognition, sustained attention and the broad construct of executive functioning. These results suggest that a number of ANT and CANTAB tasks assessing the same functions may be used and interpreted interchangeably, which would support a better integration of neuropsychological research in PKU.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 2","pages":"Article 109126"},"PeriodicalIF":3.7,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143902076","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":"Cover 2 / Ed. Board","authors":"","doi":"10.1016/S1096-7192(25)00108-8","DOIUrl":"10.1016/S1096-7192(25)00108-8","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 1","pages":"Article 109117"},"PeriodicalIF":3.7,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143873764","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":"250 cases of “type 2 Gaucher disease”: A novel system of clinical categorisation and evidence of genotype: Phenotype correlation","authors":"A. Donald ,&nbsp;S. Brothwell ,&nbsp;B.M. Cabello ,&nbsp;C. Ehrstedt ,&nbsp;J.R. Fernández-Fructuoso ,&nbsp;E. Fernández-Marín ,&nbsp;D. González-Lamuño ,&nbsp;J.M. Lloreda-García ,&nbsp;L. Lykopoulou ,&nbsp;C. Mignot ,&nbsp;J. Nurse ,&nbsp;S. O'Sullivan ,&nbsp;A.N. Persson ,&nbsp;J. Raiman ,&nbsp;D.S. Rajan ,&nbsp;J. Uberos ,&nbsp;S.A. Jones ,&nbsp;H.J. Church","doi":"10.1016/j.ymgme.2025.109124","DOIUrl":"10.1016/j.ymgme.2025.109124","url":null,"abstract":"<div><div>‘Type 2’ Gaucher disease, also referred to as ‘acute neuronopathic’ or ‘infantile’ Gaucher disease is an aggressive subtype of Gaucher disease, resulting from pathogenic variants in <em>GBA1</em>. The spectrum of phenotype ranges from hydropic perinatal presentations to an infantile disease characterised by rapid neurodegeneration. Increasingly, reports are offered of patients who survive into childhood, and it is unclear if these individuals represent a severe form of the type 3 (historically considered ‘juvenile’) disease or have modified outcomes resulting from contemporary medical interventions. Predicting outcome at point of diagnosis is increasingly important to families and clinicians, and while the impact of ‘severe’ or null alleles is appreciated, there remain significant uncertainties surrounding genotype-phenotype correlation.</div><div>In an era of clinical trials and endeavors to find CNS modifying therapeutics, there is a need to be able to categorise and predict clinical outcomes more accurately.</div><div>Here we report a case-series (<em>n</em> = 13) of internationally referred patients to a single centre, highlighting the spectrum of phenotype encompassed by the single nomenclature of ‘type 2 Gaucher’ disease. From this case-series we propose a new pragmatic, <em>clinical</em> classification system which could be applied to any infant at point of presentation. We subsequently applied this classification system to the historical literature and a further series of historical cases contributed by collaborators across the globe. We collated data from 250 cases, and demonstrate that it is feasible to apply this classification system and show that this has the potential to offer future genotype-phenotype correlation if expanded to a larger cohort.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 2","pages":"Article 109124"},"PeriodicalIF":3.7,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143913214","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}