Molecular genetics and metabolism最新文献

{"title":"Unmet needs in the treatment and care of somatic manifestations in mucopolysaccharidosis type II: A targeted literature review","authors":"Barbara K. Burton ,&nbsp;Daniel Fertek ,&nbsp;Peter S. Chin ,&nbsp;Carole Ho ,&nbsp;Roberto Giugliani ,&nbsp;Johanna M.P. van den Hout ,&nbsp;Martin Magner ,&nbsp;Fatih Ezgü ,&nbsp;Moeenaldeen AlSayed ,&nbsp;Joseph Muenzer ,&nbsp;Torayuki Okuyama ,&nbsp;Simon A. Jones","doi":"10.1016/j.ymgme.2025.109248","DOIUrl":"10.1016/j.ymgme.2025.109248","url":null,"abstract":"<div><h3>Introduction</h3><div>All people with the rare, inherited, lysosomal disease mucopolysaccharidosis type II (MPS II) experience somatic manifestations, and approximately two-thirds develop neurological and cognitive impairment. There is a well-documented need for novel therapies that target the central nervous system, but it is also clear that, despite enzyme replacement therapy having been available since 2006, somatic manifestations continue to have a substantial impact on quality of life, morbidity, and life expectancy. We conducted a targeted literature review to characterize the unmet needs related to the diagnosis, treatment, and monitoring of the somatic aspects of MPS II.</div></div><div><h3>Methods</h3><div>This review was conducted between July and September 2024. Peer-reviewed publications, abstracts, reports, and posters published between 2006 and 2024 were included. Records were identified from Embase, MEDLINE, and expert sources. Abstracts were screened, and full-text review, citation cross-check, and data extraction were performed.</div></div><div><h3>Results</h3><div>Of 1293 records identified, 365 were included for data extraction. The analysis identified four major unmet needs: (1) a lack of guidelines and recommendations to help enable early diagnosis and treatment initiation, and to advise on monitoring of disease progression and treatment effectiveness; (2) limitations in the ability of current treatments to address somatic manifestations that can lead to premature death, significant morbidity, and impaired quality of life; (3) a lack of strategies and guidelines for the transition from pediatric care to adult care; and (4) significant treatment- and disease-associated burden that affects people with MPS II and their caregivers.</div></div><div><h3>Conclusions</h3><div>Significant unmet needs persist in the management of somatic manifestations of MPS II, despite the availability of approved therapies and irrespective of cognitive status. Consideration of these needs should help guide the development of novel disease management strategies, ultimately improving care for people with MPS II.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 3","pages":"Article 109248"},"PeriodicalIF":3.5,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145270247","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":"Cardiac transplant outcomes in a pediatric patient with novel homozygous variants in TOP3Α causing mitochondrial dysfunction","authors":"J. Ganesh ,&nbsp;C. Donnelly ,&nbsp;A. Ligezka ,&nbsp;G. Preston ,&nbsp;E. Morava ,&nbsp;M. Breilyn ,&nbsp;I. Marin-Valencia ,&nbsp;H. Raynes ,&nbsp;N. Bansal ,&nbsp;J. Lamour ,&nbsp;C. Mintz ,&nbsp;T. Kozicz","doi":"10.1016/j.ymgme.2025.109236","DOIUrl":"10.1016/j.ymgme.2025.109236","url":null,"abstract":"<div><div>Pathogenic variants <em>TOP3A</em> gene have been recently described to cause a multisystem disorder associated with mitochondrial dysfunction in adults (Nicholls et al., 2018 [1]) and with a Bloom syndrome-like disorder in children (Martin et al., 2018 [2]).</div><div>We present the case of an 11-year-old male with homozygosity for a novel variant in <em>TOP3A</em> with myopathy, ataxia, and atrioventricular conduction defect similar to the adult cases described in the literature. He developed dilated cardiomyopathy and presented in acute decompensated heart failure requiring left ventricular assist device support as a bridge to heart transplantation. Clinical and laboratory features showed mitochondrial dysfunction confirming pathogenicity of the <em>TOP3A</em> variants. However, unlike the other pediatric cases of <em>TOP3A</em> related disease reported so far, the features of Bloom syndrome were not evident in this patient.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 3","pages":"Article 109236"},"PeriodicalIF":3.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145270250","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":"Parental psychosocial outcomes after a positive newborn screen for a lysosomal storage disorder","authors":"Courtney Berrios ,&nbsp;Randi Gadea ,&nbsp;Meghan Strenk ,&nbsp;Twisha Nadella ,&nbsp;Jennifer Gannon ,&nbsp;Janelle Noel-MacDonnell","doi":"10.1016/j.ymgme.2025.109235","DOIUrl":"10.1016/j.ymgme.2025.109235","url":null,"abstract":"<div><h3>Purpose</h3><div>This study explores the psychosocial impact of a positive newborn screen (NBS) result for four lysosomal storage disorders (LSDs) (Fabry disease, Krabbe disease, Mucopolysaccharidosis Type I, Pompe disease) across confirmatory results.</div></div><div><h3>Methods</h3><div>Parents whose child who had a positive NBS for one of the included LSDs were recruited for a retrospective cohort (<em>n</em> = 80) or prospective, longitudinal cohorts (<em>n</em> = 50). Surveys assessed uncertainty, anxiety, intrusive or avoidant thoughts, and perceived vulnerability of their child's health. In-depth interviews explored the NBS experience and psychosocial response.</div></div><div><h3>Results</h3><div>Participants experienced uncertainty and anxiety during confirmatory testing that improved as parents received more information. Retrospective cohort surveys showed ongoing levels of anxiety and perceived vulnerability in parents of children with carrier or pseudodeficiency results closer to those with true positive or inconclusive results than to false positives of undetermined cause. Interviews indicated some parents across cohorts and confirmatory results held uncertainty about their child's health, frequent thoughts about NBS, and vulnerable views of their child.</div></div><div><h3>Conclusion</h3><div>This mixed-methods study provides evidence that NBS for LSDs may be associated with extended psychosocial impacts for some families, even if their child does not have an LSD. Lower false positive rates and additional counseling may limit the burden.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 3","pages":"Article 109235"},"PeriodicalIF":3.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134866","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":"Quantitative muscle ultrasound as a window into disease progression in infantile-onset Pompe disease","authors":"Neelam Makhijani ,&nbsp;Myriam Boueri ,&nbsp;Bijan Abar ,&nbsp;Tracy Boggs ,&nbsp;Laura E. Case ,&nbsp;Natalia L. Gonzalez ,&nbsp;Lisa D. Hobson-Webb ,&nbsp;Sarah P. Young ,&nbsp;Priya S. Kishnani","doi":"10.1016/j.ymgme.2025.109237","DOIUrl":"10.1016/j.ymgme.2025.109237","url":null,"abstract":"<div><h3>Background</h3><div>Infantile-onset Pompe disease (IOPD) is caused by a deficiency of the enzyme acid alfa glucosidase, resulting in glycogen accumulation in muscles and other tissues. Without treatment, affected infants typically die within two years. Enzyme replacement therapy (ERT) has significantly improved survival and functional outcomes, especially with early initiation, higher dosing, immune modulation, and newer therapeutic options. However, effective noninvasive tools to monitor disease progression and treatment response are still needed. Quantitative muscle ultrasound (QMUS) may serve as a useful alternative.</div></div><div><h3>Objective</h3><div>To evaluate the effectiveness and feasibility of QMUS for monitoring muscle involvement in IOPD.</div></div><div><h3>Methods</h3><div>This study assessed echo intensity (EI) measurements from QMUS in eight patients with IOPD receiving long-term ERT. EI was recorded annually in seven muscle groups. EI &gt;50 units was considered abnormal, and a composite EI Sum Score was calculated. These values were compared with Gross Motor Function Measure (GMFM) scores using univariable regression.</div></div><div><h3>Results</h3><div>Patients began ERT at a median age of 7 weeks. QMUS assessments were performed, with ages ranging from 7 months to 21 years (median age of 9.5 years) at first evaluation. All patients had at least one muscle group with abnormal EI. Upper extremity EI was significantly lower (mean 47.3) than lower extremity muscle groups (mean 64.1, <em>p</em> = 0.002). Higher EI scores correlated with more severe myopathy and wheelchair use, while lower scores reflected better motor outcomes.</div></div><div><h3>Conclusions</h3><div>QMUS is a promising noninvasive tool for monitoring muscle health in patients with IOPD receiving ERT. It may aid in assessing disease progression and treatment efficacy.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 3","pages":"Article 109237"},"PeriodicalIF":3.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145157142","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":"Defining the clinical spectrum and genotype-phenotype correlations for CCDC115-CDG: A patient report and review of the literature","authors":"Chloé J. Geerts ,&nbsp;Fernando Alvarez ,&nbsp;Brian M. Gilfix ,&nbsp;Matthew J. Schultz ,&nbsp;Philippe M. Campeau","doi":"10.1016/j.ymgme.2025.109234","DOIUrl":"10.1016/j.ymgme.2025.109234","url":null,"abstract":"<div><div>CCDC115-CDG is a recently described combined N- and O-linked congenital disorder of glycosylation affecting Golgi apparatus homeostasis. To date, only thirteen patients have been reported with this condition. The clinical presentation is characterized by hepatosplenomegaly, elevated serum aminotransferases and alkaline phosphatase, often accompanied by psychomotor delay and hypotonia, hypercholesterolemia and copper metabolism anomalies, features that can mimic Wilson disease. Serum transferrin capillary electrophoresis shows a pattern compatible with abnormal Golgi N-glycosylation. We gathered phenotype descriptions and molecular data from all reported patients to better characterize this condition and explore potential genotype-phenotype correlation. Notably, we observed that homozygosity for the p.Leu31Ser variant is associated with higher serum transaminase levels. We also report the natural history of a patient, as clinical narratives are lacking in the literature for this condition. In summary, our report provides new insights into the natural history and genotype-phenotype correlation of CCDC115-CDG, key elements to focus on in ultra-rare conditions.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 3","pages":"Article 109234"},"PeriodicalIF":3.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213266","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":"Practical challenges and ethical considerations in treating early-onset MADD with exogenous ketones","authors":"Mary Kate LoPiccolo ,&nbsp;Johan L.K. Van Hove","doi":"10.1016/j.ymgme.2025.109229","DOIUrl":"10.1016/j.ymgme.2025.109229","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109229"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144925282","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 disorders of dolichol synthesis and utilization","authors":"Eline Pieters ,&nbsp;Jaak Jaeken ,&nbsp;Matthew P. Wilson","doi":"10.1016/j.ymgme.2025.109226","DOIUrl":"10.1016/j.ymgme.2025.109226","url":null,"abstract":"<div><div>The polyisoprenoid lipid dolichol is critical for eukaryotic glycosylation. It is used as the membrane anchor for mono- or oligosaccharides transferred during N-glycosylation, O/C-mannosylation and glycosylphosphatidylinositol anchor biosynthesis. Disorders affecting the synthesis or utilization of dolichol cause defective glycosylation and are therefore classified as Congenital Disorders of Glycosylation (CDG). CDG are a group of approximately 200 mostly autosomal recessive inherited metabolic disorders characterized by defective glycosylation of proteins and lipids. Through recently identified defects, we have gained new insights into dolichol synthesis, important to understand the pathological mechanisms in affected patients. This review provides an overview of dolichol synthesis and utilization and an update on CDG caused by disruption of these processes. Finally, we discuss the existing biomarkers for diagnosis of these disorders and the potential for effective therapies.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109226"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144925283","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":"Defining lung pathogenesis in a murine model of mucopolysaccharidosis Type I by proteomic analysis","authors":"Yuen T. Ngai ,&nbsp;Clifford Young ,&nbsp;Emma J. Parkinson-Lawrence ,&nbsp;Sabine Wimmer-Kleikamp ,&nbsp;Parul Mittal ,&nbsp;Helen Beard ,&nbsp;Matthew T. Briggs ,&nbsp;Manuela Klingler-Hoffmann ,&nbsp;Doug A. Brooks ,&nbsp;Sandra Orgeig ,&nbsp;Peter Hoffmann","doi":"10.1016/j.ymgme.2025.109231","DOIUrl":"10.1016/j.ymgme.2025.109231","url":null,"abstract":"<div><div>Mucopolysaccharidosis type I (MPS I) is a rare lysosomal storage disorder resulting from a deficiency in the lysosomal enzyme alpha-L-iduronidase, which degrades heparan sulfate and dermatan sulfate glycosaminoglycans (GAG) within endosome-lysosome compartments. MPS I patients demonstrate respiratory dysfunction with varying symptoms and severity during disease progression, which has been associated primarily with upper airway involvement and the thoracic cavity. However, the involvement of respiratory complications in patient morbidity and mortality suggests that we know relatively little about the pathogenic process in the lung. Using a proteomics approach, we analyzed lung tissues from a murine model of MPS I to identify proteins and molecular pathways contributing to respiratory pathology. A total of 7604 proteins were identified, of which 144 were significantly upregulated, 93 downregulated, and three proteins (GPNMB, SLC39A1, ABCC10) were uniquely detected in MPS I lung tissue compared to control lung tissue. Gene ontology analysis confirmed significant disruptions to lysosomal biogenesis, GAG degradation pathways, and extracellular matrix remodelling. Immunohistochemistry showed elevated LAMP I expression, which was consistent with the proteomic results and endosome-lysosome dysfunction being a key driver of disease pathogenesis in the MPS I lung. Our findings reveal novel proteomic alterations underlying distal lung pathology in MPS I and identify potential biomarkers that may have clinical utility for monitoring disease progression.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109231"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081128","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":"Identification of a novel RBCK1 splice site donor variant in Basset Hounds with glycogen storage disease myopathy","authors":"Jeanna M. Blake ,&nbsp;Andrew D. Miller ,&nbsp;Jacqueline L. Marr ,&nbsp;Kari J. Ekenstedt","doi":"10.1016/j.ymgme.2025.109232","DOIUrl":"10.1016/j.ymgme.2025.109232","url":null,"abstract":"<div><div>Glycogen storage diseases (GSDs) are rare, typically inherited, disorders caused by various defects in glycogen metabolism enzymes, generally resulting in the accumulation of glycogen in several tissues. Recently, two young adult Basset Hound (BH) littermates were diagnosed with GSD via postmortem histopathology, with excess glycogen manifesting in both cardiac and smooth muscle. Using whole genome sequencing, a homozygous splice site donor variant was identified in exon 8 of <em>RBCK1</em>, a gene which encodes an E3 ubiquitin ligase, in both littermates, suggesting an autosomal recessive mode of inheritance. The presumptive loss of the splice site donor is predicted to result in premature termination in the mid-domain of the protein. Screening for the variant in related (<em>n</em> = 21) and unrelated (<em>n</em> = 124) BHs identified one additional affected littermate and nine familial heterozygous carriers. No variant alleles were present in the unrelated BH population, establishing the novelty of the identified mutation. <em>RBCK1</em> variants have previously been associated with polyglucosan body myopathy type 1 (PGBM1), a type of GSD characterized by skeletal muscle myopathy, cardiomyopathy, and polyglucosan accumulation in humans. To date, no reported variants in <em>RBCK1</em> have been identified in dogs or other large animals associated with GSD, making this the first naturally occurring large animal model of PGBM1 due to an <em>RBCK1</em> defect.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109232"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145044510","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":"Maternal metabolic conditions identified by newborn screening","authors":"Rebecca Sponberg ,&nbsp;Rebekah Barrick ,&nbsp;Kathryn Gasperian ,&nbsp;Jose E. Abdenur","doi":"10.1016/j.ymgme.2025.109228","DOIUrl":"10.1016/j.ymgme.2025.109228","url":null,"abstract":"<div><div>Newborn screening is one of the most successful public health programs that has improved outcomes for children with conditions that can cause long-term disability or even death if not treated quickly. With the introduction of expanded newborn screening (NBS) and the use of tandem mass spectrometry, the number of core and secondary conditions recommended on the United States national NBS guideline called the Recommended Uniform Screening Panel (RUSP), rapidly grew to help screen for inborn errors of metabolism (IEM) [<span><span>1</span></span>]. A few years after this initiation and as more newborns were screened, there were several case reports of mothers who were diagnosed with an IEM condition or vitamin deficiency that was causing their child's abnormal newborn screening results. We conducted a PubMed literature search and identified reports of 14 maternal conditions identified via NBS and provide a comprehensive review of their findings. We define a maternal condition as biochemical or genetic findings that confirm the mother has the condition and the child is unaffected or an obligate carrier. This review could be useful for countries that plan to initiate expanded newborn screening in the future as well as for metabolic providers, who are involved in the confirmatory testing process for newborn screening referrals.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 1","pages":"Article 109228"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987933","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}