Molecular genetics and metabolism最新文献

{"title":"Interim analysis of post-marketing surveillance study of intracerebroventricular idursulfase therapy for neuronopathic mucopolysaccharidosis type II: Safety and effectiveness in clinical practice in Japan","authors":"Motomichi Kosuga,&nbsp;Tetsumin So,&nbsp;Yasutsugu Chinen,&nbsp;Shungo Okamoto,&nbsp;Tokiko Fukuda,&nbsp;Eiichi Yamamoto,&nbsp;Azuma Ikari,&nbsp;Tadayuki Kumagai,&nbsp;Ikuma Musha,&nbsp;Yasunori Wada,&nbsp;Toshihiko Kakiuchi,&nbsp;Yuki Ueda,&nbsp;Kiyoshi Egawa,&nbsp;Yuki Yamada,&nbsp;Mahoko Furujo,&nbsp;Sumito Dateki,&nbsp;Yoko Nakajima,&nbsp;Naoko Ozawa,&nbsp;Torayuki Okuyama","doi":"10.1016/j.ymgme.2026.110243","DOIUrl":"10.1016/j.ymgme.2026.110243","url":null,"abstract":"<div><div>Mucopolysaccharidosis type II (MPS II) results from iduronate-2-sulfatase (IDS) enzyme deficiency due to <em>IDS</em> gene mutations. Most patients with neuronopathic MPS II experience progressive neurological decline; however, effectiveness of standard treatment, intravenous idursulfase, is limited by blood-brain barrier transfer. Intracerebroventricular (ICV) idursulfase beta, approved in Japan in 2021, directly delivers idursulfase beta into cerebral ventricles. This post-marketing surveillance reports long-term effectiveness and safety of ICV idursulfase beta (30 mg every 4 weeks) in all treated patients from April 2021 through August 2024. Outcomes included cerebrospinal fluid (CSF) heparan sulfate (HS) levels (quarterly), developmental age (DA; Kyoto Scale of Psychological Development, annually), and safety. Thirty-seven Japanese male patients across 21 sites were enrolled (safety population <em>n</em> = 36; effectiveness population <em>n</em> = 35). Mean CSF HS concentrations decreased from 7.36 to 3.19 μg/mL from baseline to week 24, with reduction sustained through week 100. Patients who initiated treatment within 3 years of age had DA progression aligned with healthy cohorts, regardless of mutation type; however, those starting later had no comparable benefit. Adverse events (AEs) occurred in 20 patients (55.6%). Procedure-related serious AEs (SAEs) occurred in 2 patients (bacterial meningitis, device-related infection, pyrexia). Treatment-related AEs affected 14 patients (38.9%), mainly pyrexia (27.8%, including one SAE). One SAE (membranous glomerulonephritis) was not intervention related. No deaths, anaphylaxis, or anti-IDS antibodies in CSF were detected. ICV idursulfase beta demonstrated sustained CSF HS reduction with no new safety signals. Earlier treatment initiation (≤3 years) was associated with improved neurodevelopmental outcomes, regardless of mutation type.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"149 1","pages":"Article 110243"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early detection in action: developing and refining newborn screening for Pompe disease in North Carolina","authors":"Molly M. Crenshaw,&nbsp;Erica B. Nading,&nbsp;Jamie Mills,&nbsp;Erin Huggins,&nbsp;Natalie Krohl,&nbsp;Deeksha Bali,&nbsp;Sarah P. Young,&nbsp;Ashlee R. Stiles,&nbsp;Kimberly Blake,&nbsp;Lara Percenti,&nbsp;Dee Pettit,&nbsp;Sam Freeman,&nbsp;Scott Shone,&nbsp;Edwin C. Ferren,&nbsp;Katherine J. Dempsey,&nbsp;Kayleigh Bright,&nbsp;Catherine Rehder,&nbsp;Priya S. Kishnani,&nbsp;Jennifer L. Cohen","doi":"10.1016/j.ymgme.2026.110252","DOIUrl":"10.1016/j.ymgme.2026.110252","url":null,"abstract":"<div><div>Pompe disease, a lysosomal disease, was added to the Recommended Uniform Screening Panel in 2015, and it has been included in the newborn screening (NBS) panel in North Carolina (NC) since February 2023. Across the world, the approach to NBS for Pompe disease varies. This study adds to the literature 20 months of population level health data from NC regarding infants who screened positive for Pompe disease via NBS. Fifty-two of 228,474 (0.02%) infants screened positive for Pompe disease, and after diagnostic testing, 18 (35%) were diagnosed with presumed late-onset Pompe disease (LOPD), resulting in a higher than previously reported incidence of 1 in 12,693. No infants with the infantile onset form of disease were identified at the time of data closure. While seasonal variations existed in the absolute value of dried blood spot (DBS) acid α-glucosidase (GAA) enzyme activity, this was successfully controlled for using cutoffs defined by the percent of the daily median of enzyme activity. None of the following parameters correlated with the final clinical designation in a statistically significant manner: percent of the daily median DBS GAA enzyme activity, creatine/creatinine/GAA ratio, nor birthweight. The use of the creatine/creatinine/GAA ratio has been eliminated in NC because of these data. The GAA/α-L-iduronidase ratio was statistically significant in its association to final clinical designations of Pompe disease, and thus provides an opportunity to further refine NBS for Pompe disease in NC. The mean GAA enzyme activity was also statistically significantly different based on the age of NBS sample collection. We propose two algorithms that outline 1) an approach to enable timely treatment of the infantile onset form of Pompe disease; and 2) a more detailed approach for reaching a clinical designation after a positive NBS for Pompe disease. Opportunities for growth, remaining questions, and responsible stewardship of our public health resources are discussed.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"149 1","pages":"Article 110252"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148888076","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 brief history of gene therapy for ornithine transcarbamylase deficiency","authors":"Margo Sheck Breilyn,&nbsp;Laura L. Konczal,&nbsp;Cary O. Harding","doi":"10.1016/j.ymgme.2026.110257","DOIUrl":"10.1016/j.ymgme.2026.110257","url":null,"abstract":"<div><div>Gene therapy encompasses the use of nucleic acids, including DNA and RNA, as therapeutic agents. This broad category includes approaches that permanently modify the genome to correct pathogenic variants, as well as strategies that restore gene expression without altering genomic DNA. In ornithine transcarbamylase (OTC) deficiency, the most common urea cycle disorder, the goal of somatic gene therapy is to restore hepatic expression of functional OTC enzyme and thereby reestablish urea cycle activity. Both viral and non-viral delivery platforms have been investigated in preclinical models and clinical studies to achieve therapeutic OTC expression. Despite contemporary medical therapy, individuals with OTC deficiency (OTCD) remain at risk for recurrent hyperammonemia which may result in neurocognitive impairment and reduced quality of life. Novel therapy that restores liver OTC expression and lessens chronic disease burden is highly desired. In this manuscript, we summarize the history of gene therapy development for OTC deficiency, spanning early preclinical investigations to contemporary clinical trials. Although a definitive cure through gene therapy has not yet been achieved, substantial progress has been made toward the development of safe and effective liver-directed nucleic acid therapeutics for this disorder.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"149 1","pages":"Article 110257"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955744","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":"Corrigendum to “Early detection in action: developing and refining newborn screening for Pompe disease in North Carolina” [Mol. Genet. Med. 149 (1–2) (2026) 110252]","authors":"Molly M. Crenshaw,&nbsp;Erica B. Nading,&nbsp;Jamie Mills,&nbsp;Erin Huggins,&nbsp;Natalie Krohl,&nbsp;Deeksha Bali,&nbsp;Sarah P. Young,&nbsp;Ashlee R. Stiles,&nbsp;Kimberly Blake,&nbsp;Lara Percenti,&nbsp;Dee Pettit,&nbsp;Sam Freeman,&nbsp;Scott Shone,&nbsp;Edwin C. Ferren,&nbsp;Katherine J. Dempsey,&nbsp;Kayleigh Bright,&nbsp;Catherine Rehder,&nbsp;Priya S. Kishnani,&nbsp;Jennifer L. Cohen","doi":"10.1016/j.ymgme.2026.110259","DOIUrl":"10.1016/j.ymgme.2026.110259","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"149 1","pages":"Article 110259"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148983034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systematic genetic, biochemical, and lipidomic characterization of GSD III fibroblast models reveals mis-annotation and defines a conserved disease lipid signature","authors":"K.A. Becker,&nbsp;C.K. Pathmasiri,&nbsp;E.S. Phillippi,&nbsp;K. Casazza,&nbsp;D.W. Todd,&nbsp;D.A. Weinstein,&nbsp;K.L. Ode,&nbsp;A.R. Calhoun,&nbsp;S.M. Cologna,&nbsp;M.L. Schultz","doi":"10.1016/j.ymgme.2026.110249","DOIUrl":"10.1016/j.ymgme.2026.110249","url":null,"abstract":"<div><div>Glycogen storage disease type III (GSD III) is an autosomal recessive disorder caused by pathogenic variants in <em>AGL</em>, which encodes the glycogen debranching enzyme (GDE). Loss of GDE function impairs glycogen degradation, leading to accumulation of abnormal glycogen in liver and skeletal muscle. Clinical manifestations arise in early childhood and include hypoglycemia, hepatomegaly, and progressive myopathy. Despite significant morbidity, no disease-modifying therapies exist, due in part to a lack of rigorously validated cellular models. Patient-derived fibroblasts provide an accessible and scalable system that preserves each patient's endogenous <em>AGL</em> genotype and broader genetic background, enabling investigation of disease heterogeneity, genotype–phenotype relationships, and potential genetic modifiers. We performed whole-genome sequencing and phenotypic characterization of nine fibroblast lines originating from patients who were diagnosed with GSD III. Eight lines harbored biallelic pathogenic or likely pathogenic <em>AGL</em> variants, while one was reclassified based on absence of <em>AGL</em> variants and the presence of a pathogenic variant in an alternative metabolic gene. Validated GSD III fibroblasts exhibited consistent disease features, including absence of GDE protein, impaired glycogen utilization, and distinct lipidomic signatures. We generated an isogenic immortalized <em>AGL</em>-deficient fibroblast model which recapitulated these phenotypes. Together, these patient-derived and isogenic models provide a robust, genomically defined platform for studying the pathogenesis and phenotypic heterogenity of GSD III. Refined characterization and accessibility of these models will be useful to evaluate candidate GSD III therapeutics.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"149 1","pages":"Article 110249"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel pretreatment of dried blood spot filter paper to improve the preservation of amino acids: a technology to increase access and care","authors":"Kirkland A. Wilson,&nbsp;Yun Zhou,&nbsp;Gary Cunningham,&nbsp;Matthew S. Bramble,&nbsp;Sahana Kumar,&nbsp;Kojo Danso,&nbsp;Braelynn Tomanio,&nbsp;Kimberly Chapman,&nbsp;Marshall Summar,&nbsp;Hilaire Musasa Hanshi-Hatuhu,&nbsp;Desire Tshala-Katumbay,&nbsp;Dieudonne Mumba-Ngoyi,&nbsp;Debra S. Regier","doi":"10.1016/j.ymgme.2026.110254","DOIUrl":"10.1016/j.ymgme.2026.110254","url":null,"abstract":"<div><div>Amino acids are vital biomarkers necessary for many critical metabolic pathways and therefore many disorders result in perturbations in amino acid concentrations. Recurrent measurements of amino acids are often necessary for disease management, especially in the inborn errors of metabolism, however many barriers exist restricting patient access to monitoring, especially for those living in rural and low resource areas. Dried blood spots (DBS) do not require medical expertise to obtain, allowing for an expedient method for the collection of multiple time points useful for diagnosis, monitoring, and research. Amino acids in a DBS, however, are highly susceptible to heat and humidity which are often encountered during the multiple days of transport via mailing-in of the sample. Thus, we sought to improve the stability of amino acids in a DBS when exposed to harsh environmental conditions. We showed that pretreatment of the card with ethylenediaminetetraacetic acid (EDTA), or a combination of phosphoric acid then EDTA (Phosphoric Acid-EDTA), significantly increased the consistency of sample recovery and accuracy, compared to untreated DBS. Sample precision was also significantly improved. EDTA pretreatment significantly reduced the amount of change in analyte concentration at high temperature and humidity, and Phosphoric Acid-EDTA pretreatment showed similar improvements at high heat without high humidity. Lastly, we evaluated EDTA pretreatment in “out-of-the-laboratory” collected samples compared to plasma. We show a significant improvement in the recovery and stability of amino acids exposed to harsh environmental conditions, even for multiple days, and thus allow for greater precision and accuracy of DBS sample analysis.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"149 1","pages":"Article 110254"},"PeriodicalIF":4.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycosylation biomarkers for populational screening of hereditary fructose intolerance and fructose-1,6-bisphosphatase deficiency","authors":"Miao He ,&nbsp;Wenyue Zhang ,&nbsp;Yupeng Liu ,&nbsp;Hind Alsharhan","doi":"10.1016/j.ymgme.2026.109942","DOIUrl":"10.1016/j.ymgme.2026.109942","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"148 1","pages":"Article 109942"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147923012","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 intronic splice site variant in GALT results in a mild galactosemia presentation despite undetectable enzyme activity levels in blood","authors":"Emily Black,&nbsp;Sneha Mokashi,&nbsp;Gavin Arno,&nbsp;Bruno Poplawski,&nbsp;Raymond C. Caylor","doi":"10.1016/j.ymgme.2026.109967","DOIUrl":"10.1016/j.ymgme.2026.109967","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"148 1","pages":"Article 109967"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147923256","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":"An age subgroup analysis of the phase 1/2 study of intravenous tividenofusp alfa for mucopolysaccharidosis type II","authors":"Paul Harmatz ,&nbsp;Joseph Muenzer ,&nbsp;Barbara K. Burton ,&nbsp;Deepa S. Rajan ,&nbsp;Simon A. Jones ,&nbsp;Johanna M.P. van den Hout ,&nbsp;John J. Mitchell ,&nbsp;Matthew D. Troyer ,&nbsp;Natalie J. Engmann ,&nbsp;Fabian Model ,&nbsp;Akhil Bhalla ,&nbsp;Imanol Zubizarreta ,&nbsp;Mostafa Wali ,&nbsp;Peter S. Chin ,&nbsp;Carole Ho","doi":"10.1016/j.ymgme.2026.110002","DOIUrl":"10.1016/j.ymgme.2026.110002","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"148 1","pages":"Article 110002"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147923292","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":"Detection of a mild form of carnitine-acylcarnitine translocase (CACT) deficiency by newborn screening in two siblings","authors":"Megan Harrison,&nbsp;Ayesha Ahmad","doi":"10.1016/j.ymgme.2026.110004","DOIUrl":"10.1016/j.ymgme.2026.110004","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"148 1","pages":"Article 110004"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147923293","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}