Molecular genetics and metabolism最新文献

{"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":"Novel method for detection of UBE3A protein in CSF from individuals with Angelman syndrome","authors":"Omar S. Mabrouk ,&nbsp;Nicole T. Comfort Harris ,&nbsp;Robert W. Komorowski ,&nbsp;Kyle Fraser ,&nbsp;Elizabeth Berry-Kravis ,&nbsp;Mark D. Shen ,&nbsp;Lynne M. Bird ,&nbsp;Wen-Hann Tan ,&nbsp;Robert P. Carson ,&nbsp;Gali Heimer ,&nbsp;Brenda Amaral ,&nbsp;Rebecca Crean ,&nbsp;Gregory M. Dillon ,&nbsp;James P. Gilbert ,&nbsp;Kristina H. Holmberg ,&nbsp;Hang Zhang ,&nbsp;Sarah Hubbard ,&nbsp;Alan A. Shomo ,&nbsp;Unnati Kapadnis ,&nbsp;Andrew Traube-Childs ,&nbsp;Viet Nguyen","doi":"10.1016/j.ymgme.2025.109132","DOIUrl":"10.1016/j.ymgme.2025.109132","url":null,"abstract":"<div><div>Loss of production of ubiquitin protein ligase E3A (UBE3A) in neurons leads to Angelman Syndrome (AS). There are limited methods to reliably measure UBE3A in cerebrospinal fluid (CSF), which negatively impacts therapeutic development. To overcome this gap, we developed and analytically validated a novel method for CSF UBE3A quantitation, which includes an immunoprecipitation protein capture step followed by tryptic digestion and high-resolution mass spectrometry detection of a unique UBE3A peptide. Our data suggest that we can reliably detect UBE3A at concentrations as low as 2.5 pg/mL. The assay was used to show that UBE3A could be detected in CSF samples of both healthy adults and patients with AS. As expected, CSF UBE3A levels in healthy adults (24.76 ± 6.75 pg/mL, <em>N</em> = 14) were significantly higher (<em>p</em> &lt; 0.01) than the CSF UBE3A levels measured in two AS cohorts (5.30 ± 0.42 pg/mL, <em>N</em> <em>=</em> 19 and 5.59 ± 0.40 pg/mL, <em>N</em> = 10), with no significant difference in UBE3A levels observed between the two AS cohorts. There was also no significant difference in CSF UBE3A levels when comparing AS patients carrying either a mutation or chromosomal deletion in either cohort. Overall, these data demonstrate the utility of this novel CSF UBE3A assay for UBE3A quantitation in studies of AS.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 3","pages":"Article 109132"},"PeriodicalIF":3.7,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123836","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}

{"title":"The use and performance of lyso-Gb3 for the diagnosis and monitoring of Fabry disease: A systematic literature review","authors":"Uma Ramaswami ,&nbsp;Michael L. West ,&nbsp;Karen Tylee ,&nbsp;Genaro Castillon ,&nbsp;Andreas Braun ,&nbsp;Megan Ren ,&nbsp;Indraraj Umesh Doobaree ,&nbsp;Heena Howitt ,&nbsp;Albina Nowak","doi":"10.1016/j.ymgme.2025.109110","DOIUrl":"10.1016/j.ymgme.2025.109110","url":null,"abstract":"<div><h3>Background</h3><div>Fabry disease (FD) is a rare, X-linked lysosomal storage disorder in which a lack of alpha-galactosidase (α-Gal A) enzyme activity leads to intracellular accumulation of deacylated globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), and their analogs. Lyso-Gb3, present in the blood and urine of affected patients, has been extensively investigated as a biomarker for FD. This systematic literature review (SLR) aimed to comprehensively assess the use of lyso-Gb3 as a biomarker for screening, monitoring, and diagnosis of FD in both real-world and clinical trial settings.</div></div><div><h3>Methods</h3><div>An SLR was performed to identify the following outcomes in adult and pediatric patients with FD: lyso-Gb3 testing patterns, lyso-Gb3 levels in subpopulations, performance and accuracy of lyso-Gb3 testing for diagnosis, and lyso-Gb3 testing for monitoring of disease progression or treatment efficacy/effectiveness. Interventional and non-interventional studies published between 1 January 2017 and 3 November 2022 were included. Searches were primarily conducted in MEDLINE and Embase; pragmatic or hand searches were also performed. The methodological quality of included full-text studies was assessed using validated appraisal tools. Extracted data were synthesized qualitatively.</div></div><div><h3>Results</h3><div>The SLR included 83 eligible publications, comprising 71 observational studies and 12 clinical trials. Differences in lyso-Gb3 levels were identified across subpopulations, with several studies reporting higher levels in males versus females. Lyso-Gb3 demonstrated good diagnostic performance in newborns and high-risk patients when used in combination with other markers (α-Gal A activity or <em>GLA</em> variants) but failed to diagnose females with late-onset FD. Reliability and stability across different methods used to measure lyso-Gb3 was high, with a coefficient of variation &lt;10 % for inter- and intra-assay measurements. Several studies identified moderate to strong correlation between plasma lyso-Gb3 levels and cardiac measures, but association with renal measures needs further investigation.</div></div><div><h3>Conclusions</h3><div>Lyso-Gb3 testing demonstrated accuracy in screening, diagnosis, and monitoring of FD in certain subpopulations, particularly males, but considering its lower sensitivity in late-onset female patients, it should be used in conjunction with other tools. Given the reliability of the test, it can be considered a feasible method for monitoring disease progression in FD in individual patients. Several gaps in the literature were identified, warranting further investigation.</div><div><strong>Registration:</strong> PROSPERO (CRD42022375141).</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 2","pages":"Article 109110"},"PeriodicalIF":3.7,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143904591","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":"Substrate reduction using a glucosamine analogue in Drosophila melanogaster and mouse models of Sanfilippo syndrome","authors":"Sher Li Tan ,&nbsp;Daniel Neumann ,&nbsp;Paul J. Trim ,&nbsp;Laura J. Hewson ,&nbsp;Nooramirah Farhana Mustaffar ,&nbsp;Qi Qi He ,&nbsp;Norbert Wimmer ,&nbsp;Marten F. Snel ,&nbsp;Vito Ferro ,&nbsp;Louise V. O'Keefe ,&nbsp;Kim M. Hemsley ,&nbsp;Adeline A. Lau","doi":"10.1016/j.ymgme.2025.109112","DOIUrl":"10.1016/j.ymgme.2025.109112","url":null,"abstract":"<div><div>Mucopolysaccharidosis (MPS) types III A and C are inherited neurodegenerative disorders resulting from the lack of a specific enzyme involved in heparan sulfate (HS) catabolism, leading to the accumulation of partially-degraded HS fragments. At present, there are no approved treatments and death is commonly in the second decade of life. Several therapies have undergone pre-clinical evaluation for these conditions, including substrate reduction therapy, with the most studied compound of this class being the isoflavone genistein. However, findings from a Phase III clinical trial demonstrated that high dose oral genistein did not significantly improve neurodevelopmental outcomes in patients with MPS III (Sanfilippo syndrome). Here, we have tested an <em>N</em>-acetylglucosamine analogue, 4-deoxy-<em>N</em>-acetylglucosamine peracetate, as a novel substrate reduction therapy for HS-storing lysosomal storage disorders such as MPS III. Treatment with this compound significantly reduced HS levels in cultured MPS IIIA patient and mouse fibroblasts in a time- and dose-dependent manner. MPS IIIC <em>Drosophila</em> fed 4-deoxy-<em>N</em>-acetylglucosamine peracetate contained significantly less HS relative to those raised on control diets. Likewise, improvements in HS load within the MPS IIIA mouse brain suggests that the compound crossed the blood-brain barrier after oral administration. Although long-term studies are needed, these findings indicate that 4-deoxy-GlcNAc peracetate may be beneficial in slowing the accumulation of HS and may represent a novel substrate reduction therapeutic for MPS III and potentially other HS-storing disorders.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 2","pages":"Article 109112"},"PeriodicalIF":3.7,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143873434","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}