Journal of Inherited Metabolic Disease最新文献

{"title":"Correction to “Outcome of Haemopoietic Stem Cell Transplantation in 21 Patients With Alpha-Mannosidosis”","authors":"","doi":"10.1002/jimd.70068","DOIUrl":"https://doi.org/10.1002/jimd.70068","url":null,"abstract":"<p>R. Šáhó, R. Formánková, J. B. Eisengart, et al., “Outcome of Haemopoietic Stem Cell Transplantation in 21 Patients With Alpha-Mannosidosis,” <i>Journal of Inherited Metabolic Disease</i> 48, no. 4 (2025): e70047, https://doi.org/10.1002/jimd.70047.</p><p>The authors have added Dr. Chiara Monachesi as a co-author to the paper.</p><p>Chiara Monachesi</p><p>Division of Pediatrics, Department of Clinical Sciences, Azienda Ospedaliero Universitaria delle Marche, Presidio Salesi, Ancona, Italy</p><p>Dr. Monachesi has no conflict of interest.</p><p>Dr. Monachesi's contribution: As the majority of co-authors, she was the treating physician and transplant physician performing the HSCT, examinations, and follow-up in the patients.</p><p>There are no other changes in the author list or affiliations.</p><p>We apologize for this error.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70068","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144646844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Induced Pluripotent Stem Cells for the Treatment of Lysosomal Storage Disorders","authors":"Maryann Lorino,&nbsp;Bei Qiu,&nbsp;Brian Bigger","doi":"10.1002/jimd.70064","DOIUrl":"https://doi.org/10.1002/jimd.70064","url":null,"abstract":"<p>Lysosomal disorders (LSDs) are a group of rare metabolic disorders, with an overall incidence of 1:4800 to 1:8000 live births. LSDs are primarily caused by dysfunctional lysosomal enzymes, which typically lead to the progressive accumulation of substrates within cellular lysosomes. As a result, patients experience a wide array of somatic symptoms such as visceromegaly, cardiopulmonary abnormalities, and respiratory and urinary infections. Additionally, over two-thirds of LSD subtypes have a neurological component, and without treatment, patients experience neurodegeneration, cognitive decline, and life expectancies spanning infancy to adulthood. At present, there is no therapy that rescues the degenerative neuropathology of LSDs, and current developments, such as brain-targeted enzyme replacement therapy, hematopoietic stem cell transplantation, and even gene therapy, can only prevent further neurodegeneration. However, recent advancements involving induced pluripotent stem cells (iPSCs) have demonstrated that stem cells may harbor the potential to both recapitulate the phenotype of neuropathic LSDs in vitro, as well as serve as a vector for regeneration in vivo, by replacing cells and neurons damaged by disease progression. This review reports the current state of iPSC technology in LSD research, and the pathway by which iPSCs are translated from disease modeling to serving as a regenerative therapeutic for neuropathic LSDs in the clinic.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70064","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effectiveness and Safety of Personalized Cholic Acid Treatment in Patients With Bile Acid Synthesis Defects","authors":"Yasmin Polak,&nbsp;Elles Marleen Kemper,&nbsp;Marc Engelen,&nbsp;Femke C. C. Klouwer,&nbsp;Kevin Berendse,&nbsp;Frédéric M. Vaz,&nbsp;Bart G. P. Koot,&nbsp;Eleonora (Noortje) L. Swart,&nbsp;Carla E. M. Hollak","doi":"10.1002/jimd.70062","DOIUrl":"https://doi.org/10.1002/jimd.70062","url":null,"abstract":"<p>Bile acid synthesis defects (BASDs) comprise a group of rare, often severe, metabolic disorders. Bile acid replacement therapy decreases toxic bile acid intermediates production and improves biochemical profiles, potentially delaying or stabilizing disease progression. An open label, non-randomized trial with cholic acid (CA) supplementation included six patients with α-methylacyl-CoA racemase (AMACR) deficiency and one patient with 3β-hydroxy-Δ⁵-C₂₇-steroid oxidoreductase deficiency. Patients received up to 20 mg/kg/day CA for 3.5 years, adjusted for biochemical response, side effects, and clinical evaluation. Bile acid metabolites, liver enzymes, liver stiffness, and neurological symptoms were evaluated at baseline and during follow-up. CA was well tolerated in children (<i>n</i> = 3), allowing for higher doses. Adults (<i>n</i> = 4) experienced more side effects, primarily diarrhea and other gastrointestinal symptoms. Children's transaminase levels normalized during treatment, while adults' levels remained normal throughout. Elevated C₂₇-bile acid intermediates, C₂₉-dicarboxylic acid, and pristanic acid were observed in all AMACR patients. C₂₇-bile acids and C₂₉-dicarboxylic acid decreased with treatment, while pristanic acid fluctuated and remained elevated. No clinically relevant changes were observed in liver elasticity, fat-soluble vitamin levels, neurological assessment, or growth (in children). One adult developed hepatocellular carcinoma during treatment. CA treatment is generally safe, with acceptable tolerance and a marked biochemical response observed in children, although biomarker levels remained markedly elevated. In adults, however, the balance shifts negatively, with side effects outweighing the (biochemical) benefits. A longer study is necessary to evaluate the impact of CA treatment on the clinical relevance of the observed biochemical response.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intramolecular Epistatic Interactions in Genetic Diseases","authors":"Tomás Oliveira-Madureira,&nbsp;Mariana Santos-Pereira,&nbsp;Luísa Azevedo","doi":"10.1002/jimd.70059","DOIUrl":"https://doi.org/10.1002/jimd.70059","url":null,"abstract":"<div>\u0000 \u0000 <p>A key factor influencing the structural and functional impact of amino acid substitutions in disease-associated genes involves the background genetic variation. Epistatic interactions between co-evolving positions in the same gene result in the interdependence of each site with its interacting partners. Evidence supporting the role of these interactions is exemplified in the occurrence of human disease-associated alleles in the genome of non-human species. Although several explanations can contribute to this phenomenon, one possibility is the occurrence of compensatory interacting sites that can fully, or partially, restore the pathogenic effect, contributing to the maintenance of protein structure and proper function. These interactions create genetic contexts that are revisited here through the analysis of literature data for specific proteins, with a particular focus on proteins involved in inborn errors of metabolism.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma Metabolomics, Lipidomics, and Acylcarnitines Are Associated With Vision and Genotype but Not With Dietary Intake in Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD)","authors":"Hak Chung,&nbsp;Dongseok Choi,&nbsp;Ashley Gregor,&nbsp;Elaine Sim,&nbsp;Alison Lau,&nbsp;Danielle Black,&nbsp;Hannah L. Scanga,&nbsp;Angela Linshinski,&nbsp;Mark E. Pennesi,&nbsp;Jose-Alain Sahel,&nbsp;Ken K. Nischal,&nbsp;Paul Yang,&nbsp;Lesley Everett,&nbsp;Jerry Vockley,&nbsp;Dietrich Matern,&nbsp;Cary O. Harding,&nbsp;Melanie B. Gillingham","doi":"10.1002/jimd.70060","DOIUrl":"https://doi.org/10.1002/jimd.70060","url":null,"abstract":"<div>\u0000 \u0000 <p>3-hydroxy acylcarnitines (3-OH-ACs) are key biomarkers for screening of long-chain 3-hydroxyacyl-CoA dehydrogenase and trifunctional protein deficiencies (LCHADD/TFPD). The utility of this biomarker for disease monitoring in identified patients remains debated, and recent suggestions have highlighted the potential use of lipidomics for diagnosis, monitoring, prognosis, and/or identification of new biomarkers. We evaluated the use of omics in LCHADD/TFPD patients by analyzing plasma acylcarnitine profiles, metabolomics, and lipidomics, combined with genotype, visual assessments, and dietary records. Fasting plasma from 39 participants with LCHADD/TFPD and 32 control subjects were analyzed through untargeted metabolomic and lipidomic analyses. In LCHADD/TFPD participants, acylcarnitine profiling, visual and retinal function assessments were performed, and 3-day diet records were collected. Relationships between acylcarnitines, metabolomics, lipidomics, along with visual outcomes and dietary intake were investigated. Plasma of LCHADD/TFPD participants exhibited elevated 3-OH-ACs, which correlated with genotype and visual outcomes. Metabolomics successfully distinguished LCHADD/TFPD from controls, and the biggest divergence was observed in lipid pathways. Metabolomic profiles tightly correlated with 3-OH-ACs, genotype, and visual outcomes. Lower concentrations of total lipids and some individual lipid species such as phosphoethanolamines (PE) were detected in LCHADD/TFPD, except for elevations in several certain triglycerides. LCHADD/TFPD participants followed a diet low in long-chain fat (LCFA) as recommended. LCFA intake did not correlate with either plasma 3-OH-ACs or metabolomics. 3-OH-ACs are strong consistent biomarkers of LCHADD/TFPD that are associated with clinical parameters of vision and genotype. We did not observe a relationship between dietary LCFA intake and 3-OH-ACs.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene Dosage Sensitivity and Human Genetic Diseases","authors":"Reiner A. Veitia,&nbsp;Johannes Zschocke,&nbsp;James A. Birchler","doi":"10.1002/jimd.70058","DOIUrl":"https://doi.org/10.1002/jimd.70058","url":null,"abstract":"<p>Here we review the historical background and contemporary insights into genetic dominance, focusing on haploinsufficiency (HI), that is, when the function of only one allele of a gene is not enough to ensure a normal phenotype in a diploid organism. A related phenomenon is triplosensitivity, that is, pathogenic effects when there are three instead of two copies of some 'genes'. The importance of gene dosage issues was realized in humans when whole chromosomal abnormalities (aneuploidy) could be linked to clinical phenotypes such as Down, Edwards, and Patau syndromes. Subsequently, subtler chromosomal deletions and duplications have been shown to be responsible for many developmental syndromes. In several cases, a dosage-sensitive gene mapping to the relevant regions has been implicated as causal. We delve into the mechanisms of HI, especially due to direct protein insufficiency and subunit imbalances in the context of multi-subunit complexes. We show how the nonlinearity inherent to the relationship between genotype and phenotype is responsible for the dominance of the underlying genetic variants. We also explore why increased gene dosage can lead to abnormal phenotypes. Examples include trisomy or segmental genomic duplications in humans and oncogene amplification in cancers. Finally, we examine a few cases of genetic synergy, where the combined effect of two or more variants amplifies their individual effects, underlying a distinguishable phenotype. Further research is required to elucidate the dynamics of multicomponent interactions to unravel the mechanistic complexities of genetic dominance, inter-gene interactions, and their implications for disease.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70058","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression Profiles of Exosomal miRNAs in Gaucher Patients and Their Association With Severity of Bone Involvement","authors":"Irene Serrano-Gonzalo,&nbsp;Laura López de Frutos,&nbsp;Maria Sancho-Albero,&nbsp;Mercedes Roca-Espiau,&nbsp;Ralf Köhler,&nbsp;Pilar Giraldo","doi":"10.1002/jimd.70061","DOIUrl":"https://doi.org/10.1002/jimd.70061","url":null,"abstract":"<p>Bone manifestations are one of the most prevalent complications in patients with Gaucher disease (GD). Bone involvement is evaluated by using imaging methods, and there are different scores to assess its severity. However, there are no biomarkers that allow us to predict these manifestations. In recent years, several miRNAs have been associated with bone involvement and postulated as excellent bioavailable biomarkers. This study aims to identify a miRNA expression profile from plasma exosomes and to associate it with the severity of bone involvement in patients with GD. This study included 60 untreated patients with GD with bone involvement, who were classified according to the S-MRI score into three groups: mild disease (MiBD; S-MRI &lt; 5), moderate disease (MoBD; S-MRI: 5–11), or severe disease (SBD; S-MRI &gt; 11). Plasma exosomes were purified, and miRNAs were extracted and identified by next-generation sequencing (NGS) technology. Differentially expressed miRNAs were validated by droplet digital PCR (ddPCR). In the patients' groups classified by S-MRI, the median ages (Q1–Q3) were: MiBD 19.0 (4.00–40.00), MoBD 40.5 (28.25–56.00), and SBD 37.5 (31.25–47.00) years. When comparing groups, we found 12 differentially expressed exosomal miRNAs. After validation, four miRNAs were identified as differentially expressed: hsa-miR-127-3p, hsa-miR-184, hsa-miR-197-3p, and hsa-miR-660-5p. Notably, hsa-miR-127-3p, hsa-miR-660-5p, and hsa-miR-184 were correlated with the presence of infarcts, necrosis, and the degree of infiltration into the spine, pelvis, and femur. These three miRNAs could serve as bioavailable biomarkers to assess bone disease in GD, and further revalidation with a higher number of patients.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70061","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144573483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Screening for Life: Perspectives From Adult Metabolic Specialists on Newborn Screening for Inherited Metabolic Diseases","authors":"Mirjam Langeveld,&nbsp;Sandra Sirrs,&nbsp;Daphne H. Schoenmakers,&nbsp;Timothy Fazio,&nbsp;Melanie M. van der Klauw,&nbsp;Francois Maillot,&nbsp;Reena Sharma,&nbsp;Christel Tran,&nbsp;Athanasia Ziagaki,&nbsp;Fanny Mochel","doi":"10.1002/jimd.70057","DOIUrl":"https://doi.org/10.1002/jimd.70057","url":null,"abstract":"<p>The number of inherited metabolic diseases (IMDs) in newborn screening (NBS) programs has increased significantly in the past decades. For some of the IMDs included in NBS (e.g., tyrosinemia type I), there are clear and substantial health benefits of NBS, while for others (e.g., very long chain acyl CoA dehydrogenase deficiency and 3-methylcrotonyl CoA carboxylase 1 deficiency), this is less clear as NBS identifies individuals who are asymptomatic or have milder forms of the disease. Therefore, knowledge of the full disease spectrum (including later onset forms) is needed when setting diagnostic metabolite cut-offs for NBS. Insights into the clinical, genetic and biochemical characteristics of different patient subsets can be used to redefine NBS protocols to identify patients with more severe forms of the disease who are most likely to benefit from identification in the newborn period. These insights require life-long monitoring of individuals identified based on symptoms versus those identified by NBS to determine long-term health outcomes and quantify the benefits of NBS. Adult metabolic specialists should be included in the development of NBS programs to provide data from this long-term monitoring and to contribute specific knowledge about later onset phenotypes of the IMDs included in NBS programs. The goal should be to develop NBS programs that identify newborns that benefit from early disease detection and treatment, without increasing psychological, social and management burden for individuals who may develop disease in adulthood with milder phenotype or potentially even not at all.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70057","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144550826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correlation of Plasma and Urine 2,8-Dihydroxyadenine and Adenine and Clinical Characteristics in Individuals With Adenine Phosphoribosyltransferase Deficiency","authors":"Unnur A. Thorsteinsdottir,&nbsp;Hrafnhildur L. Runolfsdottir,&nbsp;Vidar O. Edvardsson,&nbsp;Margret Thorsteinsdottir,&nbsp;Runolfur Palsson","doi":"10.1002/jimd.70054","DOIUrl":"https://doi.org/10.1002/jimd.70054","url":null,"abstract":"<div>\u0000 \u0000 <p>Adenine phosphoribosyltransferase (APRT) deficiency is a rare, autosomal recessive disorder characterized by urinary excretion of the poorly soluble 2,8-dihydroxyadenine (DHA), leading to kidney stones and chronic kidney disease. Treatment with the xanthine oxidoreductase (XOR) inhibitors allopurinol and febuxostat reduces DHA production. DHA and adenine were measured in 122 paired plasma and urine samples from 26 individuals with confirmed APRT deficiency, using ultra-performance liquid chromatography–tandem mass spectrometry assays. The relationship between plasma DHA and adenine concentrations, urine DHA-to-creatinine (DHA/Cr) and adenine-to-creatinine (adenine/Cr) ratios, and age and estimated glomerular filtration rate (eGFR) was evaluated in a subset of 87 paired plasma and urine samples from 23 individuals using Spearman's rank correlation. Allopurinol and febuxostat treatment reduced plasma DHA, with the median (range) concentration decreasing from 249 (123–1315) ng/mL in untreated individuals to below the limit of detection in those receiving higher doses. Plasma adenine increased during XOR inhibitor treatment. In untreated individuals, a strong negative correlation was observed between plasma DHA and eGFR (<i>r</i>_s = −0.74, <i>p</i> &lt; 0.0001). Plasma DHA correlated with urine DHA/Cr ratio in individuals treated with allopurinol or febuxostat (<i>r</i>_s = 0.65, <i>p</i> &lt; 0.0001), while no significant correlation was observed in untreated individuals (<i>r</i>_s = −0.26, <i>p</i> = 0.14). Treatment with XOR inhibitors effectively reduces the plasma concentration and urinary excretion of DHA. The strong correlation between plasma DHA and eGFR, combined with the lack of correlation between plasma DHA and urine DHA/Cr ratio in untreated individuals, suggests that plasma DHA may be a more reliable marker of systemic DHA burden.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144550827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Variants in VARS2 Demonstrate the Phenotypic Variability of a Rare Mitochondriopathy That Responds to Valine Supplementation","authors":"Jonathan Marquez,&nbsp;Stephen Viviano,&nbsp;Fahmid Rahman,&nbsp;Samuel D. Strohbehn,&nbsp;Aimee Allworth,&nbsp;Norma Perez,&nbsp;University of Washington Center for Rare Disease Research,&nbsp;Undiagnosed Diseases Network,&nbsp;Russell P. Saneto,&nbsp;Scott Anna I,&nbsp;Mónica Penón Portmann,&nbsp;Elizabeth E. Blue,&nbsp;Ian A. Glass,&nbsp;Engin Deniz,&nbsp;Emily Shelkowitz","doi":"10.1002/jimd.70053","DOIUrl":"https://doi.org/10.1002/jimd.70053","url":null,"abstract":"<div>\u0000 \u0000 <p>Mitochondriopathies are a diverse group of disorders caused by disruption of typical mitochondrial function. Heterogenous in nature, many of these disorders arise due to variants in genes encoding key mitochondrial proteins involved in transcription and translation of mitochondrial machinery. One such gene, <i>VARS2</i>, encodes a mitochondrial aminoacyl-tRNA synthetase that catalyzes the attachment of valine to its cognate tRNA molecule. Bi-allelic variants in <i>VARS2</i> have been linked to several forms of mitochondrial encephalopathies or cardiomyoencephalopathies. While associated clinical phenotypes vary, they can include developmental delays, axial hypotonia, limb spasticity, and epilepsy. Here, we describe three additional clinical cases of <i>VARS2</i>-related mitochondriopathy with sequencing-confirmed variants in <i>VARS2</i> that illustrate the phenotypic variability of this disorder. These include three novel variants: Lys225Glu, Cys281Tyr, and Leu732Cysfs*29. We further assess the pathogenicity and severity of the effects of the variants underlying these cases in a <i>Xenopus</i> model of disease through assaying both cardiac function and brain size. In addition, we use this model of <i>VARS2</i> loss of function to assess the therapeutic potential of previously proposed amino acid supplementation. Through this approach, we demonstrate that the beneficial effects of valine supplementation in <i>VARS2</i> mitochondriopathy may be dependent on residual enzyme activity.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}