Journal of Inherited Metabolic Disease最新文献

{"title":"Neurocognitive Impairment in Inherited Metabolic Disorders due to Intoxication and Energy Defects: A Systematic Review","authors":"Marta Gil-González,&nbsp;Carolina Arias,&nbsp;Jean-Marie Saudubray,&nbsp;Roser Colomé-Roura,&nbsp;Ángeles García-Cazorla","doi":"10.1002/jimd.70084","DOIUrl":"https://doi.org/10.1002/jimd.70084","url":null,"abstract":"<p>Inherited metabolic disorders (IMD) can disrupt brain development and functioning, leading to cognitive and behavioral abnormalities. This systematic review aims to provide a comprehensive synthesis of the evidence regarding neurocognitive impairments in intoxication IMD due to the accumulation of small molecule disorders and energy-related IMD. A search was conducted in the PubMed database until August 2024, using the term “cognition” and up to 421 energy-related IMD and 196 intoxication IMD. Reviews, animal models, studies with non-standardized measures, and studies that focused on complex molecule disorders, small molecule deficiencies, and phenylketonuria were excluded. In total, 163 studies were included in the final analysis. The cognitive domains assessed were executive functions, attention, processing speed, language, speech, visual performance, fine motor dexterity, memory, behavioral and emotional regulation, and social cognition. Most available evidence focused on intoxication IMD (83%), which exhibited better global cognitive functioning than energy defects. The cognitive domains most frequently reported as impaired were fine motor dexterity (80.9%), behavioral and emotional regulation (80%), executive functions (73.3%), attention (72.4%), and social cognition (65.6%). After applying the chi-square test with a 95% confidence level, no statistically significant differences were found between intoxication and energy-related IMD. However, language impairments were slightly more pronounced in intoxication disorders, while visuospatial deficits were more common in energy disorders. Individuals with IMD are at a higher risk of neurodevelopmental disorders, which can persist despite early detection and treatment. Although the number of cognitive studies has increased in recent years, further research with standardized measures is necessary to understand the underlying pathophysiology of neurocognitive impairments.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70084","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144905577","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":"In Memoriam Douglas S. Kerr","authors":"Suzanne D. DeBrosse,&nbsp;Jirair K. Bedoyan","doi":"10.1002/jimd.70082","DOIUrl":"https://doi.org/10.1002/jimd.70082","url":null,"abstract":"","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70082","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144891566","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":"Treatment of Inborn Errors by Product Replacement: The Example of Inborn Errors of Bile Acid Synthesis","authors":"Peter T. Clayton,&nbsp;Rohit Hirachan,&nbsp;Elaine Murphy","doi":"10.1002/jimd.70081","DOIUrl":"https://doi.org/10.1002/jimd.70081","url":null,"abstract":"<p>Many inborn errors of metabolism affect pathways involved in the synthesis of a metabolite that has an important biochemical or physiological function, and adverse effects of the disorder can be attributed to the lack of this metabolite. Thus, there is the opportunity for treatment by ‘product replacement’. One of the disorders in the pathways for the synthesis of bile acids from cholesterol, 3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency, causes cholestatic liver disease in infancy that can be treated very effectively with chenodeoxycholic acid (CDCA) and/or cholic acid (CA). There are several other enzyme deficiencies that can cause liver disease in infancy that improve with CDCA or CA or both (alongside a reduction of abnormal bile acids or alcohols); however, individuals with the same gene variant(s) may remain asymptomatic or have transient liver dysfunction that resolves spontaneously. In some disorders, the more usual presentation is with neurological disease later in childhood or in adolescence or adult life, for example, cerebrotendinous xanthomatosis (CTX), α-methylacyl-CoA racemase deficiency, and oxysterol 7α-hydroxylase deficiency. Treatment with CDCA has been dramatically effective in the neurological disease of CTX. In the disorders of peroxisome biogenesis, liver disease is a part of the clinical picture although neurological symptoms tend to be predominant. Treatment with CDCA and CA (or CA alone) leads to a reduction in the levels of C27 bile acids. Some trials suggest this treatment leads to significant improvement in clinical status and liver function tests; others do not. Defects in individual peroxisomal enzymes and transporters vary in their clinical presentations. Treatment of acyl-CoA oxidase 2 deficiency with ursodeoxycholic acid is discussed.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70081","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144891565","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":"Delivering the Message: Translating mRNA Therapy for Liver Inherited Metabolic Diseases","authors":"Sonam Gurung,&nbsp;Dany Perocheau,&nbsp;Roopkatha Ghosh,&nbsp;Stephen L. Hart,&nbsp;Julien Baruteau","doi":"10.1002/jimd.70078","DOIUrl":"https://doi.org/10.1002/jimd.70078","url":null,"abstract":"<p>mRNA encapsulated in lipid nanoparticles (LNPs) provides a dual revolution in the field of gene therapy. mRNA brings fleeting efficacy and the possibility to adjust the therapy to clinical needs. LNP, as a non-viral vehicle with flexible organ-targeting, overcomes most immune complications of viral gene therapy. mRNA-LNP has rapidly progressed from preventive medicine and vaccine applications to therapeutic use, especially in inherited metabolic diseases (IMDs). Given their natural tropism for liver uptake, this platform has been utilised successfully in numerous preclinical programmes. Early phase clinical trials are recruiting to assess safety and efficacy in liver IMDs. Here, we provide the latest update on mRNA and LNP technologies, preclinical studies and clinical trials targeting IMDs, safety considerations with a spotlight on infusion-related reactions and safety modelling. We discuss the future directions of therapeutic mRNA-LNP in IMDs and the right clinical use of this adjustable therapy, still to be defined. The versatility of this technology is appealing, with multiple clinical applications as bridge, long-term cure, rescue, or adjuvant therapy. mRNA-LNP for gene editing/insertion is an alternative approach for one-off cure. Translating various successful preclinical programmes in patients remains an unsolved limitation. mRNA-LNP can be tuned according to the patient's needs and is the next step in personalised medicine and individualised gene therapy.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70078","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144869384","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":"Biomarker Validation in NPC1: Foundations for Clinical Trials and Regulatory Alignment","authors":"Krista Casazza,&nbsp;Stephanie M. Cologna,&nbsp;Elizabeth Berry-Kravis,&nbsp;Jeanine Jarnes,&nbsp;Forbes D. Porter","doi":"10.1002/jimd.70075","DOIUrl":"https://doi.org/10.1002/jimd.70075","url":null,"abstract":"<div>\u0000 \u0000 <p>Niemann–Pick Type C1 (NPC1) disease is a rare, autosomal recessive, neurovisceral lysosomal storage disorder caused by mutations in the <i>NPC1</i>. This condition leads to defective intracellular cholesterol and lipid trafficking, resulting in the accumulation of unesterified cholesterol and glycosphingolipids in late endosomes and lysosomes. Clinically, NPC1 manifests with a heterogeneous spectrum of progressive neurological symptoms, including ataxia, vertical supranuclear gaze palsy, dysarthria, cognitive decline, and dystonia, often accompanied by systemic signs such as hepatosplenomegaly and neonatal cholestasis. The age of neurological symptom onset, rather than age at diagnosis, better reflects disease severity and progression, as delays in diagnosis are common due to phenotypic variability and lack of awareness. Therapeutic development for NPC1 has been historically limited, with miglustat approved in some regions for off-label use and 2-hydroxypropyl-β-cyclodextrin currently under clinical investigation. Recent advances in disease understanding have prompted the development of pharmacodynamic, diagnostic, and prognostic biomarkers to support earlier diagnosis and monitor therapeutic efficacy. Dysregulation of cholesterol homeostasis, neuroinflammation, and neuronal loss have guided biomarker discovery, with promising candidates including 24(<i>S</i>)-hydroxycholesterol, neurofilament light chain, and bile acid derivatives such as 3β,5α,6β-trihydroxycholanic acid. Novel lipid biomarkers including <i>N</i>-palmitoyl-<i>O</i>-phosphocholine-serine and oxysterols such as 7-ketocholesterol and cholestane-3β,5α,6β-triol also show diagnostic value. Despite growing mechanistic insight and a robust pipeline of candidate biomarkers and therapies, NPC1 remains a life-limiting disease with significant diagnostic and therapeutic gaps. Ongoing clinical trials and translational research are essential to accelerate biomarker qualification and regulatory approval of disease-modifying treatments. A comprehensive, mechanistically driven approach that integrates molecular, biochemical, and clinical endpoints is key to advancing precision medicine for NPC1.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144843467","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":"Personalized Genome-Scale Modeling Reveals Metabolic Perturbations in Fibroblasts of Methylmalonic Aciduria Patients","authors":"Almut Heinken,&nbsp;Hussein Awada,&nbsp;Vito R. T. Zanotelli,&nbsp;D. Sean Froese,&nbsp;Rosa-Maria Guéant-Rodriguez,&nbsp;Jean-Louis Guéant","doi":"10.1002/jimd.70077","DOIUrl":"https://doi.org/10.1002/jimd.70077","url":null,"abstract":"<p>Cobalamin (vitamin B12) is an essential cofactor for two human enzymes, methionine synthase and methylmalonyl-CoA mutase. Inborn errors of cobalamin metabolism (IECMs) are inherited genetic defects resulting in improper transport, modification, or utilization of cobalamin and include inherited methylmalonic acidurias, a group of IECMs most frequently caused by a defect in the methylmalonyl-CoA mutase enzyme. Here, we performed genome-scale modeling of IECMs to gain insight into their metabolic perturbations. First, we simulated deficiencies in 11 IECM-related genes and demonstrated that they cluster based on impaired metabolic pathways. Next, we leveraged RNA sequencing data from fibroblasts of 202 individuals with methylmalonic aciduria and 19 unaffected controls to construct and interrogate personalized metabolic models. Finally, we analyzed fluxes differing between patients depending on reported symptom presentation. Our findings reveal that (i) metabolic pathways including fatty acid metabolism and heme biosynthesis have reduced flux in IECMs, (ii) in personalized simulations, succinate and fumarate production and heme biosynthesis are impaired, especially in methylmalonyl-CoA mutase deficiency, (iii) one-carbon metabolism reactions such as serine hydroxymethyltransferase and folylglutamate synthase have reduced flux in all individuals with methylmalonic aciduria, and (iv) specific metabolic pathways are up- or down-regulated according to symptoms, including failure to thrive and hematological abnormalities, and treatments, such as antibiotics and protein restriction. Overall, our study delineates metabolic pathways perturbed in IECMs. In future applications, our modeling framework could be applied to other rare genetic diseases or used to predict personalized therapeutic or dietary interventions.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70077","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144814659","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":"Real-World Migalastat Use in Fabry Disease: Comparative Insights From the Pisani and Hughes Studies","authors":"Eleonora Riccio,&nbsp;Antonio Pisani","doi":"10.1002/jimd.70080","DOIUrl":"https://doi.org/10.1002/jimd.70080","url":null,"abstract":"&lt;p&gt;Since its EU approval in 2016, the oral pharmacological chaperone migalastat has been available as a treatment option for Fabry disease (FD) patients with amenable GLA mutations; real-world data are crucial for better defining its effectiveness and its role in clinical practice.&lt;/p&gt;&lt;p&gt;Two recent studies published in the &lt;i&gt;Journal of Inherited Metabolic Disease&lt;/i&gt;—by Hughes et al. [&lt;span&gt;1&lt;/span&gt;] and Pisani et al. [&lt;span&gt;2&lt;/span&gt;] offer contrasting insights into the effects of migalastat in a real-world setting. Notably, the study by Hughes et al. [&lt;span&gt;1&lt;/span&gt;] was funded by Amicus Therapeutics, while the study by Pisani et al. [&lt;span&gt;2&lt;/span&gt;] was supported by Sanofi.&lt;/p&gt;&lt;p&gt;Hughes et al. [&lt;span&gt;1&lt;/span&gt;] analyzed 125 patients from the followME Pathfinder Registry (age at enrolment ≥ 12 years; median 58 years), ~75% of whom were treatment-naïve and ~25% had received ERT for ≤ 2 years. Only patients receiving ≥ 3 years of uninterrupted migalastat therapy were included. The reported annualized eGFR change was −0.9 mL/min/1.73 m&lt;sup&gt;2&lt;/sup&gt;/year (95% confidence interval [CI]: −10.8, 9.9), with a low incidence of Fabry-associated clinical events (FACEs) (20.0%: 19.2% cardiac, 0.8% renal), suggesting favorable long-term outcomes. However, the broad CI and exclusion of patients treated for &lt; 3 years may reflect a survivorship bias, potentially overestimating treatment benefit.&lt;/p&gt;&lt;p&gt;In contrast, Pisani et al. [&lt;span&gt;2&lt;/span&gt;] evaluated 83 patients (median age at ERT initiation: 44 years; at switch to migalastat: 50 years) who switched from ≥ 1 year of agalsidase beta to migalastat for ≥ 6 months. The authors observed a mean eGFR decline of −1.96 mL/min/1.73 m&lt;sup&gt;2&lt;/sup&gt;/year after the switch, with increasing lyso-Gb&lt;sub&gt;3&lt;/sub&gt; levels, particularly in patients with the classic phenotype. Classic males experienced notable worsening in proteinuria and cardiac biomarkers.&lt;/p&gt;&lt;p&gt;Key differences in patient selection, baseline characteristics, and methodology are critical to interpreting these findings.&lt;/p&gt;&lt;p&gt;First, Hughes included predominantly treatment-naïve subjects with a median age of 58 years at treatment initiation, likely reflecting a milder disease course. In addition, patients treated with migalastat for ≤ 3 years were excluded, potentially overestimating effectiveness by excluding those who discontinued before 3 years due to inefficacy or intolerance. Conversely, Pisani's cohort comprised exclusively previously treated patients, with a median age of 50 years at switch to migalastat (and 44 years at first FD-treatment), and a higher proportion of classic males (38.6% vs. 6.7% in Hughes), a group known to have more severe manifestations. Moreover, Pisani analyzed a broader, more representative population, including both patients who successfully responded to migalastat and those who required to switch back to ERT. Again, variant amenability in Hughes may be overestimated, as some included mutations had high residual enzyme activity or u","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70080","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144814658","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":"Dietary Shift Leads to Venous Thrombosis-Induced Congestive Liver Failure in CBS-Deficient Mice","authors":"Hyung-Ok Lee,&nbsp;Cathy Q. Qai,&nbsp;Michael J. Slifker,&nbsp;Warren D. Kruger","doi":"10.1002/jimd.70076","DOIUrl":"https://doi.org/10.1002/jimd.70076","url":null,"abstract":"<div>\u0000 \u0000 <p>Cystathionine beta-synthase (CBS) deficiency is an inborn error of metabolism that results in a large increase in plasma total homocysteine (tHcy) and a significant risk of venous thrombosis. Although a mouse model of CBS deficiency (<i>Tg-I278T Cbs</i>^−/−) has several phenotypes in common with human patients, it has not been shown to have elevated thrombosis risk. Here, we describe a novel phenotype in which 40% of <i>Tg-I278T Cbs</i>^−/− mice die of liver failure due to hepatic vein thrombosis shortly after being shifted from a low methionine diet (LMD) to a regular diet (RD). Importantly, no deaths or thromboses occur if the mice are continuously maintained on RD or LMD for extended periods of time. RNAseq analysis of the livers of <i>Tg-I278T Cbs</i>^{<i>−/−</i>} mice that were shifted to RD for 3 days after spending 1 week on LMD (RD3D) shows significant differences in many transcripts involved in coagulation and fibrinolysis, key processes involved in thrombosis. Interestingly, the liver gene expression profile and serum amino acid profiles of both <i>Tg-I278T</i> Cbs^−/− and <i>Tg-I278T Cbs</i>^<i>+/−</i> mice maintained continuously on RD are also significantly different from RD3D mice. Since the only difference between RD and RD3D mice is their previous exposure to an LMD diet, this shows that the liver transcriptional profile is affected not only by the current diet but also by the animals' previous dietary history. Overall, our findings indicate that there is a strong gene-diet interaction between the <i>Cbs</i> genotype and dietary methionine and that this interaction may help explain the thrombosis phenotype in human CBS deficient patients.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144782530","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":"Effectiveness of Pyridoxal-5′-Phosphate in PNPO Deficiency: A Systematic Review","authors":"Nina N. Stolwijk,&nbsp;Laura van Dussen,&nbsp;Niels D. Reijnhout,&nbsp;Marion M. M. G. Brands,&nbsp;Bregje Jaeger,&nbsp;Peter T. Clayton,&nbsp;Carla E. M. Hollak,&nbsp;Annet M. Bosch","doi":"10.1002/jimd.70074","DOIUrl":"https://doi.org/10.1002/jimd.70074","url":null,"abstract":"<p>Pyridox(am)ine 5′-phosphate oxidase (PNPO) deficiency is an ultrarare inherited neurometabolic disease, characterized by primarily neonatal-onset B6-responsive epileptic encephalopathies. Treatment often requires sustainable access to high-quality pyridoxal-5′-phosphate (PLP, i.e., active vitamin B6), although some patients (also) respond to pyridoxine (PN). While PN is authorized as a medicinal product, PLP is not, and this forces reliance on lesser-regulated food supplements, which risks dosing inaccuracies. This systematic review evaluates the effectiveness and safety of PLP in PNPO deficiency (PROSPERO, CRD42024542199). A systematic search was conducted in PubMed, Embase, and ClinicalTrials.gov, with risk of bias assessed and observational evidence summarized using a narrative synthesis approach. A total of 30 studies were included reporting on 49 patients treated with PLP. Clinical seizure responsiveness following PLP therapy was observed in the majority of patients (<i>n</i> = 38, 77.6%) and PLP treatment significantly improved survival (<i>p</i> &lt; 0.001) compared with untreated siblings with a similar phenotype. The majority of PLP-responsive patients responded exclusively to PLP, with PN being attempted but ineffective in most of them (<i>n</i> = 30/33, 90.9%) Liver toxicity was the most frequently observed adverse event (<i>n</i> = 10, 20.4%) and although the underlying pathophysiological mechanism remains unclear, it may be associated with high-dose PLP. Therefore, regular liver disease screening is recommended during PLP therapy. This means that PLP remains the only effective therapy for achieving and maintaining seizure control in the majority of PNPO deficient patients, but the therapeutic window for optimal management is narrow. Thus, it is essential to ensure patient access to high-quality and appropriate forms of PLP.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70074","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144758487","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":"ARSA Variants Associated With Cognitive Decline and Long-Term Preservation of Motor Function in Metachromatic Leukodystrophy","authors":"Shanice Beerepoot,&nbsp;Daphne H. Schoenmakers,&nbsp;Francesca Fumagalli,&nbsp;Samuel Groeschel,&nbsp;Ludger Schöls,&nbsp;Raphael Schiffmann,&nbsp;Sheila Wong,&nbsp;Odile Boespflug-Tanguy,&nbsp;Caroline Sevin,&nbsp;Yann Nadjar,&nbsp;Annette Bley,&nbsp;Fanny Mochel,&nbsp;Morten A. Horn,&nbsp;Cristina Baldoli,&nbsp;Sara Locatelli,&nbsp;Holger Hengel,&nbsp;Lucia Laugwitz,&nbsp;Carla E. M. Hollak,&nbsp;Volkmar Gieselmann,&nbsp;Marjo S. van der Knaap,&nbsp;Nicole I. Wolf","doi":"10.1002/jimd.70072","DOIUrl":"https://doi.org/10.1002/jimd.70072","url":null,"abstract":"<p>Patients with metachromatic leukodystrophy (MLD) show variable motor and cognitive decline. The <i>ARSA</i> variants c.256C&gt;T, p.(Arg86Trp), c.257G&gt;A, p.(Arg86Gln) and c.542T&gt;G, p.(Ile181Ser) are associated with predominantly cognitive decline. This multinational study analyzed MLD onset type, presenting signs/symptoms, cognitive function, gross motor function, central motor tract involvement, MRI severity score, peripheral neuropathy, and survival of 47 patients (three homozygous for c.256C&gt;T and five, twelve and 27 compound heterozygous for c.256C&gt;T, c.257G&gt;A, or c.542T&gt;G and another <i>ARSA</i> variant, respectively). Eleven underwent hematopoietic stem cell transplantation (HSCT). Onset was late-juvenile (46.8%) or adult (44.7%) with predominantly cognitive decline (<i>n</i> = 40/41 symptomatic patients). At diagnosis, untreated patients typically retained independent walking (100%), sparing of central motor tracts (87.5%), and absence of demyelinating neuropathy (95.5%), which persisted in follow-up for most (76.5%, 71.4%, and 64.7%, respectively). Early-juvenile onset and rapid motor decline occurred only in patients compound heterozygous for c.256C&gt;T and a severe second variant (<i>n</i> = 4), showing central motor tract involvement at diagnosis. One untreated and one treated patient died of disease progression, and another from HSCT complications. All other treated patients retained independent walking, and four of five tested normal cognitive function. Median MRI severity score remained lower in treated (13) than untreated patients (25). The phenotype of c.256C&gt;T carriers depends on the severity of the second <i>ARSA</i> variant. Patients harboring c.257G&gt;A or c.542T&gt;G show late-juvenile or adult onset with cognitive decline and preserved motor function, usually associated with sparing of central motor tracts. In these patients, cognitive function and MRI severity score should be preferred treatment outcomes.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70072","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144758488","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}