Journal of Inherited Metabolic Disease最新文献

{"title":"Creatine Supplementation Reduces Guanidinoacetate via Downregulation of AGAT in a Mouse Model of GAMT Deficiency","authors":"Ilona Tkachyova,&nbsp;Dahai Wang,&nbsp;Alex Lee,&nbsp;Philip Rößler,&nbsp;Joshua Atienza,&nbsp;Jens Feugmann,&nbsp;Niko Guischard,&nbsp;Anson Hui,&nbsp;Chloe Shi,&nbsp;Andreas Schulze","doi":"10.1002/jimd.70234","DOIUrl":"https://doi.org/10.1002/jimd.70234","url":null,"abstract":"<div>\u0000 \u0000 <p>The cornerstone of treatment in creatine synthesis defects is the supplementation of creatine (CT). The treatment leads to partial replenishment of creatine; it also leads to the reduction of guanidinoacetate (GAA). Considering the neurotoxic accumulation of GAA in patients with guanidinoacetate methyltransferase (GAMT) deficiency, understanding the process by which CT reduces GAA is crucial. Ten-week-old GAMT mice were fed with different diets, either CT-free or containing 2% and 4% CT for 10 weeks. Subsequent investigations included the analysis of CT and GAA in urine, blood, and mouse organs, and the analysis of AGAT expression in mouse organs by qPCR, western blotting, and enzymatic activity. CT supplementation in GAMT mutant mice led to a significant reduction of GAA in body fluids and organs, with the exception of the liver. The GAA-lowering effect of CT was mediated through downregulation of AGAT expression. The CT supplementation was sufficient to correct CT deficiency in all organs. Even in wild type mice, CT supplementation demonstrated a consistent reduction of GAA and increased the CT concentration in kidney and liver. CT supplementation in wild type mice did not change the CT concentration in brain, heart, and skeletal muscle. The liver exhibited a peculiar situation characterized by resistance to the GAA-lowering effects of CT. Our mouse study provides new insights in the effects of CT supplementation in wild type and GAMT deficient mice and the mechanism by which CT reduces the GAA accumulation in GAMT deficiency via downregulation of AGAT. This mechanism should be further explored for the treatment of GAMT deficiency.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148617030","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":"Hepatic Glycogen Storage Disease Type IX: Long-Term Outcomes in the UK From 89 Patients","authors":"Rebecca K. Halligan,&nbsp;Michael T. Sanders,&nbsp;Arthavan Selvanathan,&nbsp;Nirubhan Veeraghavan,&nbsp;Isaac Bernhardt,&nbsp;Joanna Gribben,&nbsp;Radha Ramachandran,&nbsp;Fiona J. White,&nbsp;Bernd C. Schwahn,&nbsp;Karolina M. Stepien,&nbsp;Preeya Rehsi,&nbsp;Elaine Murphy,&nbsp;Sarah L. Hulley,&nbsp;Helen R. Mundy","doi":"10.1002/jimd.70228","DOIUrl":"10.1002/jimd.70228","url":null,"abstract":"<div>\u0000 \u0000 <p>Hepatic glycogen storage disease type IX (GSD IX) is due to a deficiency of phosphorylase kinase and is one of the most common types of GSD. We conducted a retrospective, observational cohort study on individuals with GSD IX from across the United Kingdom. We describe the natural history and long-term outcomes for 89 individuals with GSD IX with a median age of 16.4 years (range 4 months to 73 years). This included 60 patients with IXα2, 12 with IXβ and 13 with IXγ2. We report 49 novel alleles in <i>PHKA2, PHKB</i> and <i>PHKG2</i>. The median age at initial presentation was 2.5 years, with 82% (<i>n</i> = 68) presenting with hepatomegaly and 46% (<i>n</i> = 38) presenting with ketotic hypoglycaemia. Steatosis was reported in 71% (<i>n</i> = 12) who had a liver biopsy. The mean Z-score for height at initial presentation was −1.21, and this significantly improved over childhood. A spectrum of severity was seen in all subtypes, with some requiring more intensive dietary management after initial presentation and others requiring no formal dietary treatment at all. No patients developed adenomas or hepatocellular carcinomas, and 75% (<i>n</i> = 33) of adults were on no dietary therapy. Individuals with IXγ2 had a more severe disease course and had significantly worse biochemistry at initial presentation compared to other subtypes. They were diagnosed at a younger age and required more intensive dietary management across the lifespan. We believe that GSD IXγ2 is an ideal target for novel therapies. We recommend regular monitoring and multidisciplinary input in all patients with GSD IX and encourage more formal assessment of protein intake with each review.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148578987","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":"Liver Cancer in Methylmalonic and Propionic Acidemias: A Rare Complication? A Clinico-Pathological Study of 24 Livers","authors":"Léa Zloty,&nbsp;Mouna Aoun,&nbsp;Carmen Capito,&nbsp;Anaïs Brassier,&nbsp;Guillaume Morcrette,&nbsp;Ugo Cucinotta,&nbsp;Laurène Dehoux,&nbsp;Claire Mayer,&nbsp;Jean-Paul Duong Van Huynh,&nbsp;Apolline Imbard,&nbsp;Jean-François Benoist,&nbsp;Christophe Chardot,&nbsp;Manuel Schiff,&nbsp;Pascale de Lonlay,&nbsp;Monique Fabre,&nbsp;Florence Lacaille","doi":"10.1002/jimd.70223","DOIUrl":"https://doi.org/10.1002/jimd.70223","url":null,"abstract":"<p>In methylmalonic (MMA) and propionic acidemias (PA), liver or liver-kidney transplantation (Tx) is indicated for metabolic decompensations, kidney failure (MMA), and to improve quality of life. Liver cancer was reported in five patients with MMA. We characterized the pathology of 23 explanted livers and one cancer to investigate for pre-cancerous changes. We included seven patients with PA, 16 with MMA, and a patient with cancer after kidney Tx for MMA. Liver function tests, alpha-foetoprotein, and liver ultrasound were collected. Routine and special stains were performed. Abnormalities were observed in liver tests or ultrasound in half of the patients. Two had cirrhosis (one MMA, one PA). The maximum alpha-foetoprotein was 28 ng/mL. The key lesion was clusters and nodules of clear cells in 83%: distended hepatocytes with central nuclei, sharply demarcated from the parenchyma, in the periportal area. These cells contained less glycogen than the surrounding liver; macro-vacuolar steatosis was observed in 20%. Fibrosis was present in all but two, mostly stage 1 (67%), and mild lymphocytic inflammation in the portal tracts. Large-cell dysplasia was observed in the three oldest patients (one PA, two MMA). The phenotype of the clusters and nodules highlighted mitochondrial and LFABP loss. Abnormal labelling of glutamine synthetase was seen at distance from the nodules. The liver cancer was a hepatocellular carcinoma. Liver abnormalities were observed in all patients. The clusters and nodules of clear cells likely originate from propionyl-CoA accumulation and mitochondrial dysfunction. This abnormal pathology pleads for early liver Tx. Regular liver monitoring is recommended with alpha-foetoprotein and ultrasound.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70223","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148467540","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":"The Role of Urea Cycle Functional Studies in Preclinical Research","authors":"Nathan Breuillard,&nbsp;Nadia Zürcher,&nbsp;Erica Faccin,&nbsp;Kim L. Stocker,&nbsp;Martin Poms,&nbsp;Johannes Häberle","doi":"10.1002/jimd.70225","DOIUrl":"10.1002/jimd.70225","url":null,"abstract":"<p>Inborn errors of metabolism affecting the urea cycle are rare severe conditions caused by impaired nitrogen detoxification, leading to hyperammonemia and neurological morbidity across a broad clinical spectrum. Current biochemical diagnostics largely rely on quantification of metabolites. While indispensable for diagnosis and acute management, these snapshot readouts are highly dependent on external factors and often fail to reflect urea cycle function in metabolically compensated states, limiting their usefulness for disease stratification, therapeutic monitoring, and preclinical evaluation of treatments. Here, we reflect on the rationale, development, and application of a functional ureagenesis assay based on administration of [¹⁵N]-labeled ammonium chloride, enabling quantitative assessment of total in vivo urea cycle function. This assay development was prompted by discordant biochemical and phenotypic findings in a gene therapy-treated mouse model of ornithine transcarbamylase deficiency where supraphysiological enzyme activity did not translate into clinical improvement. We demonstrate that the [¹⁵N]-isotope based ureagenesis assay is applicable to in vivo models and enables detection of functional correction of the urea cycle. Importantly, we show its applicability in metabolically stable individuals affected by urea cycle disorders, where classical biochemical markers are often normal despite significant enzyme or transporter impairment. Together, these data establish the [¹⁵N]ammonium chloride-based functional ureagenesis assay as a robust and sensitive tool for quantifying urea cycle function. This approach offers clear advantages for preclinical research and translational studies, particularly in the evaluation of novel therapeutic strategies where traditional biomarkers lack discriminatory power.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70225","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148447164","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":"Letter to the Editor in Response to Gondrand Et al. “Real-Life Application of a Point-of-Care Biosensor for Phenylalanine in Patients With Phenylketonuria”","authors":"Rachel S. Carling,&nbsp;Emily Whyte,&nbsp;Stuart J. Moat","doi":"10.1002/jimd.70224","DOIUrl":"10.1002/jimd.70224","url":null,"abstract":"&lt;p&gt;We read with great interest the paper by Gondrand et al. describing the real-life application of a point-of-care biosensor for phenylalanine (PHE) monitoring in phenylketonuria (PKU) [&lt;span&gt;1&lt;/span&gt;]. The clinical value of home-based PHE monitoring is well established, and the burden of frequent laboratory testing on patients and families is substantial. Patients themselves have expressed a clear preference for devices that enable home-based monitoring solutions [&lt;span&gt;2&lt;/span&gt;]. The authors are therefore to be commended for evaluating this promising technology in a real-life setting. Precisely because of its clinical importance, several analytical and standardisation aspects may benefit from further clarification to ensure the device can fulfil its potential, safely and reliably.&lt;/p&gt;&lt;p&gt;The flow injection analysis tandem mass spectrometry (FIA-MS/MS) method is described as the “gold standard” throughout; however, this may warrant further qualification. As outlined in reference 7 [&lt;span&gt;3&lt;/span&gt;], the method employed represents a semi-quantitative determination of free PHE in dried blood spots (DBS) commonly used in newborn screening. The limitations of this approach, including imprecision and inaccuracy, have been previously documented [&lt;span&gt;4&lt;/span&gt;] and likely contribute to the increasing scatter observed at higher concentrations in Figure 3. We would also welcome clarification as to whether the FIA-MS/MS DBS results were adjusted to plasma-equivalent values using the 19% adjustment from reference 7. If so, this represents a comparison between plasma-adjusted DBS measurements and capillary blood sensor measurements. Such differences in matrix are clinically relevant and should be explicitly acknowledged, as they may introduce systematic bias.&lt;/p&gt;&lt;p&gt;The reported mean positive bias of 84.8 μmol/L is described as ‘small’, yet for children under 12 years the therapeutic target range (120–360 μmol/L) spans just 240 μmol/L. A systematic bias of this magnitude may therefore be clinically relevant and could influence clinical decision-making, particularly in paediatric management, maternal PKU and determining responsiveness to sapropterin. There are also potential implications for trials with new treatment options. Reagent stability also appears to have a substantial impact on measurement performance. Differences exceeding 400 μmol/L were observed in association with increasing batch age, yet data from batches exceeding the stated shelf life were included in the analysis. Measurements obtained using expired reagents are of uncertain validity and risk obscuring the true analytical performance of the device.&lt;/p&gt;&lt;p&gt;The manuscript states that reagent batches were calibrated using spiked and PKU patient whole blood samples; however, the traceability of these spiked materials and the process used for value-assignment are not clearly described. For a device intended to support clinical management, calibration should ideally be traceable to a higher-order ","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70224","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148430602","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":"NAXD Deficiency: Heterogeneous Phenotypes and Positive Response to Niacin Treatment","authors":"Najmesadat Seyedkatouli,&nbsp;Liana N. Semcesen,&nbsp;Lucia Gallucci,&nbsp;Tim Sikora,&nbsp;Jean-François Conrotte,&nbsp;Mei R. M. Du,&nbsp;Marat Kasakin,&nbsp;Gezime Seferi,&nbsp;Licia Corona,&nbsp;Martin Jakubec,&nbsp;Brunda Nijagal,&nbsp;Sajel Lala,&nbsp;Rebecca D. Ganetzky,&nbsp;Ana Maria Rodriguez Barreto,&nbsp;Marina Szlago,&nbsp;Melanie Wong,&nbsp;Margit Shah,&nbsp;James Nurse,&nbsp;Nicola Foulds,&nbsp;Shankar Sadagopan,&nbsp;Ha Nguyen Thu,&nbsp;Dung Vu Chi,&nbsp;Khanh Nguyen Ngoc,&nbsp;Michelle G. de Silva,&nbsp;Mirana Ramialison,&nbsp;Fernando Rossello,&nbsp;MitoMDT Diagnostic Network for Genomics and Omics,&nbsp;David R. Thorburn,&nbsp;Matthew Lynch,&nbsp;Pauline McGrath,&nbsp;David A. Stroud,&nbsp;John Christodoulou,&nbsp;Carole L. Linster,&nbsp;Nicole J. Van Bergen","doi":"10.1002/jimd.70217","DOIUrl":"10.1002/jimd.70217","url":null,"abstract":"<p>Early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-2 (PEBEL2) is a rare autosomal recessive neurometabolic disorder caused by pathogenic variants in <i>NAXD</i>, in which febrile illness or infection triggers rapid clinical deterioration. We describe nine new cases that expand the clinical and molecular spectrum. Four children showed the typical presentation of severe neurological decline following fever or illness and carried variants affecting the enzyme domain. Four cases presented with illness-triggered cardiac dysfunction associated with variants in the mitochondrial targeting sequence. One case showed severe prenatal neurodegeneration resulting in stillbirth. In two patients, disease onset followed COVID-19 infection. Functional analysis of five missense variants demonstrated impaired NAXD protein solubility, reduced NADHX dehydratase activity and/or decreased thermostability. Patient fibroblasts confirmed accumulation of damaged cofactors (S-, R- and cyclic NADHX) and reduced NAXD protein levels. Comparative proteomic analysis revealed distinct molecular profiles in atypical cardiac and prenatal cases compared with typical neurological presentations. Four patients received high-dose niacin (vitamin B3) and survived repeated febrile episodes. These findings support early recognition and suggest that niacin therapy may improve outcomes across the clinical spectrum of PEBEL2.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70217","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148430590","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":"Biallelic Loss-Of-Function Variant in ATP5ME Is Associated With Severe and Early Onset Oxidative Phosphorylation Deficiency","authors":"Pranavi Hegde,&nbsp;Aakanksha Anand,&nbsp;Rita Rani,&nbsp;Namanpreet Kaur,&nbsp;Ami Shah,&nbsp;Shilpa Kulkarni,&nbsp;Janani Supraja Mallavaram,&nbsp;Raghavender Medishetti,&nbsp;Amoolya Kandettu,&nbsp;Huzail Shaikh,&nbsp;Shahyan Siddiqui,&nbsp;Purvi Majethia,&nbsp;Vivekananda Bhat,&nbsp;Periyasamy Radhakrishnan,&nbsp;Aarti Sevilimedu,&nbsp;Sanjiban Chakrabarty,&nbsp;Anju Shukla","doi":"10.1002/jimd.70222","DOIUrl":"10.1002/jimd.70222","url":null,"abstract":"<p>ATP synthase (complex V) catalyzes ATP synthesis and is composed of the F₁ catalytic sector and the F₀ proton-conducting sector. The e subunit of the F₀ sector, encoded by <i>ATP5ME</i>, is essential for complex V dimerization and cristae organization; however, genetic variants in <i>ATP5ME</i> have not yet been implicated in human disease. We ascertained a 4-year-old male, born of a consanguineous marriage, who presented with neuroregression, feeding difficulty, spasticity, encephalopathy, bilateral sensorineural hearing loss and optic atrophy. Exome sequencing identified a biallelic 62 bp deletion, c.-48_14del in <i>ATP5ME</i> (NM_007100.4; NC_000004.12: g.674234_674295del), spanning the upstream sequence, the 5′ untranslated region, and part of exon 1. Patient-derived fibroblasts exhibited markedly decreased <i>ATP5ME</i> transcript and protein levels, accompanied by a reduction in the expression of complex I, IV, and V subunits. In vitro assays demonstrated reduced activities of complexes I, IV, and V, impaired mitochondrial respiration, reduced reactive oxygen species levels, decreased mitochondrial membrane potential, and reduced ATP levels. Additionally, <i>atp5me</i> knockout zebrafish demonstrated a severe developmental phenotype characterized by craniofacial defects, reduced locomotion, and decreased ATP levels. This was accompanied by reduced protein levels of complex II and IV subunits, mild decrease in mtDNA, and upregulation of genes associated with glycolysis and oxidative stress. All observed phenotypes were rescued by human <i>ATP5ME</i> mRNA complementation, thereby validating the pathogenicity of <i>ATP5ME</i> deficiency in vivo.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70222","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148391081","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":"Correction to \"Long-Term Follow-Up of Patients With Transaldolase Deficiency\".","authors":"","doi":"10.1002/jimd.70227","DOIUrl":"10.1002/jimd.70227","url":null,"abstract":"","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 4","pages":"e70227"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13389089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549325","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":"Immune Dysregulation in Branched Chain Organic Acidemias","authors":"Abdul L. Shakerdi,&nbsp;Jack Drda,&nbsp;Justin A. Dutta,&nbsp;Jerry Vockley","doi":"10.1002/jimd.70203","DOIUrl":"10.1002/jimd.70203","url":null,"abstract":"<p>Organic acidemias (OAs) are a group of inherited disorders, most commonly caused by defects in mitochondrial enzymes involved in amino acid and fatty acid metabolism. While they characteristically present with metabolic and neurological crises, growing evidence reveals a significant burden of chronic immune dysregulation in some disorders and patients. This review provides a synthesis of clinical and mechanistic evidence discussing immune dysregulation in OAs. Cytopenia can occur in OAs and predispose patients to recurrent and severe infections. Adaptive immune deficits, such as hypogammaglobulinemia, reduced B and T cell populations, and impaired vaccine-specific antibody responses, including to diphtheria and tetanus in MSUD and to the inactivated COVID-19 vaccine in propionic acidemia, have also been reported. Additionally, some case series note hyperinflammatory conditions, such as hemophagocytic lymphohistiocytosis. Mechanistic studies indicate that accumulated metabolites disrupt innate and adaptive hematopoietic progenitor function, mitochondrial homeostasis, and inflammatory signaling. Emerging therapeutic avenues, such as gene and mRNA-based therapies, hold the potential to improve or normalize the biochemical phenotype in OAs. While their impact on immune abnormalities remains largely unexplored, future clinical trials offer an opportunity to systematically assess potential effects on immune parameters. OAs are increasingly recognized as disorders with intrinsic immune dysregulation, extending beyond their well-characterized metabolic and neurological manifestations. Future clinical trials will benefit from including immunological endpoints to evaluate immunological recovery for novel therapies.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70203","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148360782","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":"Beyond Upper Airway Involvement: Evidence of Intrinsic Lung Disease in a Mouse Model of Mucopolysaccharidosis I","authors":"Martin Donnelley,&nbsp;Ronan Smith,&nbsp;Patricia Cmielewski,&nbsp;Nicole Reyne,&nbsp;Piraveen Pirakalathanan,&nbsp;Nina Eikelis,&nbsp;Kris Nilsen,&nbsp;Jennie Louise,&nbsp;Kate Barratt,&nbsp;Jessica Logan,&nbsp;Ben Ung,&nbsp;David Parsons,&nbsp;Doug Brooks,&nbsp;Sandra Orgeig,&nbsp;Emma Parkinson-Lawrence","doi":"10.1002/jimd.70219","DOIUrl":"10.1002/jimd.70219","url":null,"abstract":"<p>Almost all patients with mucopolysaccharidosis (MPS) develop respiratory dysfunction of varying severity during disease progression. While respiratory disease in MPS has traditionally been attributed to upper airway obstruction caused by glycosaminoglycan (GAG) accumulation in the trachea and bronchi, involvement of the intrapulmonary conducting airways and lung parenchyma remains poorly defined. Here, we characterised lung disease in a mouse model of MPS I using a combination of non-invasive X-ray Velocimetry (XV) functional lung imaging and gold-standard flexiVent respiratory mechanics testing, complemented by lung volume measurements and histological analysis. XV provides regional ventilation information across the entire lung during tidal breathing. MPS I mice demonstrated reduced mean specific ventilation (the average regional expansion of lung tissue across the respiratory cycle), driven predominantly by reduced ventilation in the inner (mediastinal-adjacent) lung regions, with evidence of spatially heterogeneous ventilation distribution. Lung mechanics testing showed increased conducting airway resistance, increased respiratory system compliance and reduced tissue elastance, consistent with impaired elastic recoil and expiratory flow limitation. Lung volume analysis revealed reduced opening pressure following degassing together with increased residual volume, functional residual capacity and vital capacity. Histological analysis demonstrated heterogeneous parenchymal architecture with regions of enlarged airspaces. Together, these findings demonstrate that respiratory dysfunction in MPS I is not limited to upper airway obstruction but also involves intrinsic abnormalities of the intrapulmonary conducting airways and lung parenchyma. This intrinsic pulmonary pathology likely contributes to obstructive lung disease and may underlie the susceptibility to respiratory failure observed in patients with MPS I.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70219","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148360771","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}