Journal of Inherited Metabolic Disease最新文献

{"title":"Long Term Follow-Up After Transplantation in Propionic Acidemia: A Retrospective French Pediatric and Adult Cohort Study","authors":"Tristan Mekdade,&nbsp;Claire-Marine Bérat,&nbsp;Manuel Schiff,&nbsp;Margaux Gaschignard,&nbsp;Juliette Bouchereau,&nbsp;Jean-Baptiste Arnoux,&nbsp;Claire Francoz,&nbsp;Aude Servais,&nbsp;Myriam Dao,&nbsp;Vickie Lacroix,&nbsp;Julien Maquet,&nbsp;Apolline Imbard,&nbsp;Edouard Le Guillou,&nbsp;Clément Pontoizeau,&nbsp;Jean-François Benoist,&nbsp;Mehdi Oualha,&nbsp;Marion Grimaud,&nbsp;Charles de Marcellus,&nbsp;Laurent Sabbah,&nbsp;Claire Mayer,&nbsp;Christophe Chardot,&nbsp;Carmen Capito,&nbsp;Diala Khraiche,&nbsp;Florence Lacaille,&nbsp;Pascale de Lonlay,&nbsp;Anaïs Brassier","doi":"10.1002/jimd.70216","DOIUrl":"https://doi.org/10.1002/jimd.70216","url":null,"abstract":"<p>Propionic acidemia (PA) is a rare inherited metabolic disorder associated with recurrent metabolic decompensations and chronic multisystemic complications. Liver transplantation (LT) may improve metabolic stability, but its long-term impact on organ involvement remains debated. We retrospectively studied 20 patients with PA transplanted between 1993 and 2024 in three French reference centers. Clinical, biochemical, and organ-specific data were collected before and after transplantation. Eighteen isolated LT and two combined liver–kidney transplantations were performed. Median age at transplantation was 13.6 years; median follow-up was 4.5 years. Indications included frequent metabolic decompensation (70%) and cardiomyopathy (35%). Four patients died perioperatively, three from cardiac causes; crude survival was 75%. Transplantation markedly improved metabolic stability and allowed significant dietary liberalization, with reduced need for enteral feeding. Cardiac involvement, present in 15 patients pre-transplant, showed variable evolution: 10 improved initially, but three deteriorated later, and one required heart transplantation. New neurological manifestations occurred in eight patients, with acute episodes including CNI-related encephalopathy. Psychiatric disorders progressed from 40% to 59% of patients, requiring treatment in seven. Renal impairment worsened post-LT to 70%, with mean measured glomerular filtration rate declining from 72 to 60 mL/min/1.73 m². LT improves metabolic and nutritional outcomes but does not consistently prevent chronic organ complications. In conclusion, early LT, before the onset of cardiac, neurologic, and psychiatric manifestations, should be considered on a case-by-case basis, as we could not demonstrate correlation between age at transplantation and organ involvement.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70216","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148324648","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":"Tri-Parametric Assessment of α-Galactosidase A Activity, lysoGb3 and X-Inactivation Aids Genotype-Phenotype Categorization of Fabry Disease Female Patients","authors":"Ladislav Kuchar,&nbsp;Lenka Dvorakova,&nbsp;Linda Berna,&nbsp;Martin Reboun,&nbsp;Petra Slavikova,&nbsp;Radovan Bakalar,&nbsp;Jana Ledvinova,&nbsp;Helena Poupetova,&nbsp;Petr Ruzicka,&nbsp;Asfaw Befekadu,&nbsp;Gabriela Dostalova,&nbsp;Stella Reichmannova,&nbsp;Ales Linhart,&nbsp;Jakub Sikora","doi":"10.1002/jimd.70218","DOIUrl":"10.1002/jimd.70218","url":null,"abstract":"<p>Fabry disease (FD, OMIM 301500) is an X-linked lysosomal storage disorder caused by deficient activity of lysosomal alpha-galactosidase A (AGAL, E.C. 3.2.1.22) due to pathogenic variants in the <i>GLA</i> gene (HGNC:4296, Xq22.1). Plasmatic deacylated globotriaosylceramide (lysoGb3) is elevated in FD patients as a reflection of lysosomal accumulation of Gb3. Specific (AGALopathic) <i>GLA</i> variants have been recently shown to accumulate within the secretory pathway and trigger endoplasmic reticulum stress and unfolded protein response rather than result in profound enzymatic deficiency. In part due to lack of integrative measures of clinical severity and biochemical/molecular parameters, specific impacts and consequences of X-chromosomal inactivation (XCI) on clinical manifestation in FD female heterozygotes still remain to be fully understood. Our study aimed at evaluation of XCI (% of inactive wt GLA allele) in untreated female FD heterozygotes with classic FD (<i>n</i> = 17), late-onset FD (<i>n</i> = 19) and individuals carrying <i>GLA</i> variants (p.(L394P) (<i>n</i> = 7), p.(A143T) (<i>n</i> = 4), and p.(D313Y) (<i>n</i> = 4)) with predominant AGALopathic effects. XCI was correlated with age of the patients, clinical phenotype, (residual) AGAL activity, and lysoGb3. AGAL activity corresponded to XCI independently of the type of the <i>GLA</i> mutation. The best separation of the clinical phenotypes (classic FD, late-onset FD and AGALopathy) was achieved by correlating XCI to the ratio of AGAL activity to lysoGb3. This three parametric calculated marker was then confronted with the Mainz Severity Score Index (MSSI) to generate an Integrative Clinical-Laboratory quotient (ICLq). ICLq discriminated the three female patient groups and demonstrated group-dependent differences in its average age-related increase.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70218","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148295439","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":"Obituary","authors":"Peter Burgard,&nbsp;Georg F. Hoffmann,&nbsp;Ertan Mayatepek,&nbsp;Hildegard Przyrembel,&nbsp;Udo Wendel","doi":"10.1002/jimd.70213","DOIUrl":"https://doi.org/10.1002/jimd.70213","url":null,"abstract":"","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70213","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148324187","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":"Integrating Functional Consequence Annotation With PAH Allelic Phenotype Values Refines Prediction of Tetrahydrobiopterin Responsiveness","authors":"Nastassja Himmelreich,&nbsp;Nenad Blau","doi":"10.1002/jimd.70220","DOIUrl":"10.1002/jimd.70220","url":null,"abstract":"<p>Tetrahydrobiopterin (BH4; sapropterin) responsiveness in phenylalanine hydroxylase (PAH) deficiency is genotype dependent, yet many patients remain untested. Allelic phenotype values (APV) summarize allele severity, but responsiveness can be heterogeneous within APV strata. We assessed whether integrating functional consequence annotation from Ensembl variant effect predictor (VEP) improves genotype-based prediction of BH4 response. We analyzed 23 640 individuals with biallelic <i>PAH</i> genotypes and BH4 status (RESP, S-RESP, N-RESP, or not tested). Tested individuals were used for model development (responders defined as RESP+S-RESP; nonresponders as N-RESP). APV values were assigned from published APV resources and merged at the variant level. Functional consequence predictors were derived from VEP output and included strict predicted loss-of-function (pLoF) flags, splice-impact scores (SpliceAI maximum delta score), and missense pathogenicity predictions (SIFT and PolyPhen). Genotype predictors were constructed using a milder-versus-severer allele framework, with the milder allele defined as the allele with the higher APV. Models were evaluated using genotype-held-out cross-validation (GroupKFold by genotype). Among 4640 tested individuals, 2044 (44.1%) were BH4 responders. Responder rates were enriched in milder phenotypes and increased monotonically across milder-allele APV bins. In genotype-held-out evaluation, integrating functional consequence predictors with APV improved discrimination modestly overall and more clearly in intermediate APV genotypes. Genotype predicts BH4 responsiveness with high performance under stringent genotype-held-out validation, and VEP-derived functional consequence annotation provides modest complementary value beyond APV, particularly for intermediate-severity genotypes.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70220","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148295444","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":"Mapping the Severity of Phenylalanine Hydroxylase Deficiency","authors":"S. Haitjema,&nbsp;E. M. van Steenis,&nbsp;C. M. A. Lubout,&nbsp;M. R. Heiner-Fokkema,&nbsp;J. Zschocke,&nbsp;F. J. van Spronsen","doi":"10.1002/jimd.70215","DOIUrl":"10.1002/jimd.70215","url":null,"abstract":"<p>Since the 1960s, phenylalanine hydroxylase (PAH) deficiency can be detected via newborn screening, allowing early start of treatment to prevent severe intellectual disability. Precise determination of PAH deficiency severity continues to be hampered by several factors. Nevertheless, as therapeutic options broaden, precise determination of PAH deficiency severity becomes critical to inform individualized treatment selection. Although various methods (hepatic PAH activity, pretreatment phenylalanine (Phe) levels, Phe loading test, Phe tolerance, in vitro expression analysis, tracer studies, prediction models) have been used to assess and/or classify PAH deficiency, all of them still report inconsistencies in the correlation between genotype and biochemical phenotype. Establishing the genotype–phenotype correlation for different genotypes is complicated by the enormous genetic heterogeneity within the <i>PAH</i> gene. Furthermore, variability in the terminology applied to different phenotype strata further complicates interpretation. Here, we aim to summarize the methods that have been described in the literature to assess the classification of PAH deficiency and propose terminology to describe phenotype levels as a crucial step to overcome these issues.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70215","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148295425","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":"Gaucher Disease Treated With Lentiviral-Mediated Gene Therapy: First Case","authors":"Mona Shafey,&nbsp;Nicole Prokopishyn,&nbsp;Aneal Khan","doi":"10.1002/jimd.70221","DOIUrl":"10.1002/jimd.70221","url":null,"abstract":"<div>\u0000 \u0000 <p>Gaucher disease is a rare, autosomal recessive disease, with decreased activity of lysosomal glucocerebrosidase (GCase) due to changes in the <i>GBA1</i> gene. There is no cure for Gaucher disease, and standard treatment involves the use of enzyme replacement therapy or substrate reduction therapy. We describe the first case of Gaucher disease that was treated with an autologous transplant of lentivirus-transduced CD34⁺ cells. Enzyme therapy was stopped 4 weeks prior to Day 0 of transplant. At 5 years of follow-up, dried blood spot GCase enzyme levels have remained in the normal range; there has been a consistent and sustained reduction of lyso-GB1 and liver volume, and hematological indices such as leukocyte count, hemoglobin, and platelet count have remained in the normal range despite no additional therapy for the Gaucher disease. This case shows a sustained response to a single dose of lentiviral gene therapy for Gaucher disease.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148295399","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":"A Rapamycin Pharmacogenomic Approach for the Childhood Dementia Niemann-Pick C","authors":"Benjamín Szenfeld,&nbsp;Macarena Las Heras,&nbsp;Juan Carlos Rubilar,&nbsp;Pablo Villarreal,&nbsp;Valeria Olguín,&nbsp;Francisco A. Cubillos,&nbsp;Andrés D. Klein","doi":"10.1002/jimd.70214","DOIUrl":"10.1002/jimd.70214","url":null,"abstract":"<div>\u0000 \u0000 <p>Niemann-Pick type C (NPC) is a childhood dementia characterized by lysosomal lipid accumulation. In <i>Npc1</i>^{<i>−/−</i>} mice, Rapamycin, an autophagy inductor, yielded opposite results depending on genetic background, suggesting the presence of pharmacogenomic modifiers. To identify them, we used a genotyped yeast panel designed for gene mapping and the NPC-mimetic U18666A (U18-drug) in the presence and absence of rapamycin. We evaluated cell growth, vacuolar fragmentation, and transcriptomics across diverse strains. Linkage analysis based on cell growth identified a significant locus, leading to the prioritization of nine genes. Notably, <i>ccs1</i> (copper chaperone for superoxide dismutase) and <i>avo2</i> (TORC2 subunit) deletions decreased cell growth compared to U18-Rapa in WT cells, while <i>irc21</i> (DNA damage and ceramide metabolism) increased it. Our results suggest that genomic variants within these genes should be assessed before using rapamycin for NPC. This study represents a crucial step towards personalized rapamycin therapeutics.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148271969","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":"Methionine Synthase Interacts With the Methionine Adenosyl-Transferase MATα2 and the DNA Methyltransferase DNMT3b in the Nucleus","authors":"Manon Jeandel,&nbsp;Jean-Marc Alberto,&nbsp;Okan Baspinar,&nbsp;Aurélie Robert,&nbsp;Natacha Dreumont,&nbsp;Zeinab Alsahly,&nbsp;David Meyre,&nbsp;Jean-Louis Guéant,&nbsp;David Coelho","doi":"10.1002/jimd.70211","DOIUrl":"10.1002/jimd.70211","url":null,"abstract":"<p>Transmethylation reactions, which are crucial for regulating gene expression, require S-adenosyl-L-methionine (SAM) as methyl donor. The substrate for SAM synthesis is methionine, which can be produced by methionine synthase (MS) whose dysfunctions are associated with SAM synthesis alterations despite the presence of methionine in the milieu, suggesting a preferential use of the methionine produced de novo. This highlights the crucial role of MS activity and would imply nuclear import of SAM or MS nuclear localization, allowing protein–protein interactions with the methionine adenosyl-transferases (MAT) responsible for SAM production. Using subcellular fractions of human cells, biochemical and cellular approaches, including incorporation of ¹⁴C-methyltetrahydrofolate, here we provide the experimental evidence of MS localization and activity in the nucleus where it interacts with MATα2, the catalytic subunit of MATII, and the methyltransferase DNMT3b. These results support the idea that spatial compartmentalization of one-carbon metabolism could play a major role in regulating the epigenome.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70211","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148271991","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":"Validating a Human Cell Model of Null Galactosylceramidase (GALC) Enzyme Activity That Recapitulates Krabbe Disease","authors":"Rodrigo T. Starosta,&nbsp;Nazia Khatoon,&nbsp;Marie S. Roberts,&nbsp;Steven Q. Le,&nbsp;Grant Austin,&nbsp;Xiaoxia Cui,&nbsp;Gregory Strout,&nbsp;Robert E. Schmidt,&nbsp;Xuntian Jiang,&nbsp;Mark S. Sands,&nbsp;Patricia I. Dickson","doi":"10.1002/jimd.70212","DOIUrl":"10.1002/jimd.70212","url":null,"abstract":"<div>\u0000 \u0000 <p>Krabbe Disease (KD) is a lysosomal leukodystrophy characterized by the production of psychosine in oligodendrocytes, leading to neurodegeneration and ultimately death. The only treatment modality currently available for this disease is hematopoietic stem cell transplantation (HSCT), a procedure with high morbidity, highlighting the need for further therapies to be developed. In this study, we established and characterized <i>GALC</i> knockout MO3.13 cells, a cell line derived from human oligodendrocytes, as a model for KD. Clonal MO3.13 cells with <i>GALC</i> KO were obtained via CRISPR/Cas9-mediated gene editing. GALC activity was measured by a 4-methylumbellyferyl (4-MU)-based assay, and morphology analyses were performed using light microscopy and transmission electron microscopy. Psychosine was measured by liquid chromatography–tandem mass spectrometry (LC–MS/MS). The <i>GALC</i> KO cells have elevated levels of psychosine and an increased number of autophagosomes, autolysosomes, and cytoplasmic granules on transmission electron microscopy. Glycogen abundance was decreased in <i>GALC</i> KO cells compared to controls. After administration of BMN-S202, a ceramide galactosyltransferase inhibitor, psychosine levels in <i>GALC</i> KO cells were reduced back to WT levels. In conclusion, we demonstrated that the <i>GALC</i> KO MO3.13 cell line recapitulates the KD phenotype and biochemical response to SRT and may be a useful KD model for mechanistic studies and therapeutic development for KD.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148217751","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":"Prevalence, Disease Onset and Clinical Outcome in Arginase 1 Deficiency: Cross-Border Surveillance in Germany, Austria, and Switzerland","authors":"Svenja Scharre,&nbsp;Annette L. Hess,&nbsp;Florian Gleich,&nbsp;Sven F. Garbade,&nbsp;Patrik Feyh,&nbsp;Daniela Karall,&nbsp;Anna Baghdasaryan,&nbsp;Martina Huemer,&nbsp;Julia B. Hennermann,&nbsp;Andreas Hahn,&nbsp;Martin Lindner,&nbsp;Gwendolyn Gramer,&nbsp;Thomas Luecke,&nbsp;Nils Kleinelanghorst,&nbsp;Johannes Haeberle,&nbsp;Amelie S. Lotz-Havla,&nbsp;Georg F. Hoffmann,&nbsp;Juergen G. Okun,&nbsp;Ulrike Muetze,&nbsp;Stefan Kölker","doi":"10.1002/jimd.70210","DOIUrl":"10.1002/jimd.70210","url":null,"abstract":"<p>Arginase 1 deficiency (ARG1-D) is an ultra-rare urea cycle disorder characterized by progressive spastic paraplegia, developmental delay, epilepsy, and episodic hyperammonemia. Evidence on prevalence and clinical presentation is scarce. Therefore, epidemiology and the phenotypical spectrum were assessed in Germany, Austria, and Switzerland (DACH region). We conducted a questionnaire-based, cross-sectional study of confirmed ARG1-D patients in the DACH region. Patients were stratified into early-diagnosed (newborn screening [NBS] or high-risk family screening [HR]) and diagnosed after symptom onset. We evaluated clinical, biochemical, and therapeutic characteristics of individuals with confirmed ARG1-D. Epidemiological prevalence estimates were derived using national population data. A total of 20 patients were identified (Germany: 12, Austria: 7, Switzerland: 1). Eight were diagnosed early (NBS: 4, HR: 4) and 12 after symptom onset. Symptomatically diagnosed patients (median age 11 years) presented with a broad range of clinical manifestations, specifically progressive spastic paraplegia (67%), epilepsy (58%), dystonia (46%), developmental delay (58%), and hepatopathy (50%). Median age at diagnosis was 35 months in symptomatic patients versus 1 month in early-diagnosed patients (<i>p</i> = 0.03). Estimated pediatric prevalence was 1:1042080 in the DACH region, with high regional differences. Hyperammonemia was reported in 72%. Enzyme therapy had been initiated in 21%; 2 patients underwent liver transplantation. ARG1-D is a rare disease with a prevalence of approximately 1:1000000 individuals, and a complex and progressive clinical phenotype. Detection via NBS or HR allows early diagnosis and treatment initiation, potentially altering the clinical outcome.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70210","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148199279","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}