Journal of Inherited Metabolic Disease最新文献

{"title":"Aldolase B Deficient Mice Are Characterized by Hepatic Nucleotide Sugar Abnormalities","authors":"Amée M. Buziau,&nbsp;Dirk J. Lefeber,&nbsp;D. Cassiman,&nbsp;M. Estela Rubio-Gozalbo,&nbsp;Hanneke Kwast,&nbsp;Dean R. Tolan,&nbsp;Casper G. Schalkwijk,&nbsp;Martijn C. G. J. Brouwers","doi":"10.1002/jimd.12836","DOIUrl":"10.1002/jimd.12836","url":null,"abstract":"<p>Hereditary fructose intolerance (HFI) is characterized by liver damage and a secondary defect in N-linked glycosylation due to impairment of mannose phosphate isomerase (MPI). Mannose treatment has been shown to be an effective treatment in a primary defect in MPI (i.e., MPI-CDG), which is also characterized by liver damage. Therefore, the aims of this study were to determine: (1) hepatic nucleotide sugar levels, and (2), the effect of mannose supplementation on hepatic nucleotide sugar levels and liver fat, in a mouse model for HFI. Aldolase B deficient mice (<i>Aldob</i>^{<i>−/−</i>}) were treated for four weeks with 5% mannose via the drinking water and compared to <i>Aldob</i>^{<i>−/</i>−} mice and wildtype mice treated with regular drinking water. We found that hepatic GDP-mannose and hepatic GDP-fucose were lower in water-treated <i>Aldob</i>^{<i>−/</i>−} mice when compared to water-treated wildtype mice (<i>p</i> = 0.002 and <i>p</i> = 0.002, respectively), consistent with impaired N-linked glycosylation. Of interest, multiple other hepatic nucleotide sugars not involved in N-linked glycosylation, such as hepatic UDP-glucuronic acid, UDP-xylose, CMP-<i>N</i>-acetyl-beta-neuraminic acid, and CDP-ribitol (<i>p</i> = 0.002, <i>p</i> = 0.003, <i>p</i> = 0.002, <i>p</i> = 0.002), were found to have altered levels as well. However, mannose treatment did not correct the reduction in hepatic GDP-mannose levels, nor was liver fat affected. <i>Aldob</i>^{<i>−/</i>−} mice are characterized by hepatic nucleotide sugar abnormalities, but these were not abrogated by mannose treatment. Future studies are needed to identify the underlying mechanisms responsible for the abnormal hepatic nucleotide sugar pattern and intrahepatic lipid accumulation in HFI.</p><p><b>Trial Registration:</b> PCT ID: PCTE0000340, this animal experiment is registered at (https://preclinicaltrials.eu/).</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11672228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895409","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":"Altered lipid profile and reduced neuronal support in human induced pluripotent stem cell-derived astrocytes from adrenoleukodystrophy patients","authors":"Roberto Montoro Ferrer,&nbsp;Yorrick R. J. Jaspers,&nbsp;Inge M. E. Dijkstra,&nbsp;Nicole Breeuwsma,&nbsp;Jan-Bert van Klinken,&nbsp;Cato Romero,&nbsp;Marc Engelen,&nbsp;Stephan Kemp,&nbsp;Vivi M. Heine","doi":"10.1002/jimd.12832","DOIUrl":"10.1002/jimd.12832","url":null,"abstract":"<p>X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder resulting from pathogenic variants in the <i>ABCD1</i> gene that primarily affects the nervous system and is characterized by progressive axonal degeneration in the spinal cord and peripheral nerves and leukodystrophy. Dysfunction of peroxisomal very long-chain fatty acid (VLCFA) degradation has been implicated in ALD pathology, but the impact on astrocytes, which critically support neuronal function, remains poorly understood. Fibroblasts from four ALD patients were reprogrammed to generate human-induced pluripotent stem cells (hiPSC). hiPSC-derived astrocytes were generated to study the impact of ALD on astrocytic fatty acid homeostasis. Our study reveals significant changes in the lipidome of ALD hiPSC-derived astrocytes, characterized by an enrichment of VLCFAs across multiple lipid classes, including triacylglycerols, cholesteryl esters, and phosphatidylcholines. Importantly, ALD hiPSC-derived astrocytes not only exhibit intrinsic lipid dysregulation but also affect the dendritic tree complexity of neurons in co-culture systems. These findings highlight the cell-autonomous effects of pathogenic variants in the ABCD1 protein on astrocytes and their microenvironment, shed light on potential mechanisms underlying ALD neuropathology, and underscore the critical role of astrocytes in neuronal health.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11660744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864572","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 neuropsychological tests: AI speech analysis in PKU","authors":"Susan E. Waisbren,&nbsp;Raquel Norel,&nbsp;Carla Agurto,&nbsp;Shifali Singh,&nbsp;Zoe A. Connor,&nbsp;Marina G. Ebrahim,&nbsp;Guillermo A. Cecchi","doi":"10.1002/jimd.12831","DOIUrl":"10.1002/jimd.12831","url":null,"abstract":"<p>Phenylketonuria (PKU) is a rare inherited metabolic disorder characterized by toxic phenylalanine (Phe) concentrations in blood and brain. State-of-the-art analyses of speech detected a dimension of verbal discourse providing insights that extend beyond those captured by existing paradigms to measure performance associated with biochemical markers in PKU. The Cookie Theft Picture Task provided a standardized stimulus for eliciting spontaneous speech from 42 adults with PKU and 41 adults without PKU. Subtests measuring language and memory from the Wechsler Adult Intelligence Scale-Fourth Edition showed no differences between the groups and no correlations with biomarkers in PKU. In contrast, AI analyses of responses to the Cookie Theft Task revealed significant differences between the PKU and non-PKU groups on 23 linguistic features. Using multidimensional scaling (MDS), these features were aggregated into a single quantifiable Dimension 1 that significantly correlated with biomarkers. When extreme examples of Dimension 1 were presented to chatGPT, the differences noted reflected attention to detail, clarity in word choice, expression cohesion, contextual awareness and emotion recognition. We subsequently defined Dimension 1 as Proficiency in Verbal Discourse. This novel measure elucidated discourse styles possibly associated with suboptimal achievement and learning disabilities, often reported in PKU. In summary, AI captured a characteristic associated with metabolic status undetectable through traditional neuropsychological measures. Future studies will expand upon this novel paradigm, leveraging speech AI to quantify meaningful aspects of everyday functioning and possibly provide information for management decisions. Once validated, this measure holds promise for extension to other rare diseases and incorporation into clinical trials.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846772","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":"Diagnosis, treatment, management and monitoring of patients with tyrosinaemia type 1: Consensus group recommendations from the German-speaking countries","authors":"Anibh M. Das,&nbsp;Diana Ballhausen,&nbsp;Dorothea Haas,&nbsp;Johannes Häberle,&nbsp;Tobias Hagedorn,&nbsp;Cecilia Janson-Mutsaerts,&nbsp;Nils Janzen,&nbsp;Johannes Sander,&nbsp;Peter Freisinger,&nbsp;Daniela Karall,&nbsp;Uta Meyer,&nbsp;Eberhard Mönch,&nbsp;Susanne Morlot,&nbsp;Stefanie Rosenbaum-Fabian,&nbsp;Sabine Scholl-Bürgi,&nbsp;Stephan vom Dahl,&nbsp;Natalie Weinhold,&nbsp;Jiri Zeman,&nbsp;Karin Lange","doi":"10.1002/jimd.12824","DOIUrl":"10.1002/jimd.12824","url":null,"abstract":"<p>Hepatorenal tyrosinaemia (HT1) is an autosomal recessive disorder of tyrosine degradation resulting in hepatic and renal dysfunction, neurological sequelae may occur in some patients. The use of nitisinone (NTBC) has revolutionised treatment and outcome of this disorder. NTBC has to be combined with a low protein diet. While NTBC modulates the disease course in HT1 patients, several issues are open. Optimal dosage, doses per day, therapeutic range of NTBC concentration, mode of protein restriction and biomarkers are not well defined. HCC and neurocognitive deficits are long-term sequelae. Early diagnosis and treatment are essential to minimise the risk for these complications. Clinical guidance for management of HT1-patients is required. Randomised clinical studies are difficult in the presence of therapeutic options. We discussed these issues in a consensus group of 10 paediatricians, 1 adult hepatologist, 1 geneticist, 2 dieticians, 2 newborn screening specialists with experience in HT1, 1 psychologist and 2 representatives of a patient group from the German-speaking countries (DACH). Recommendations were based on scientific literature and expert opinion, also taking into account recent experience with newborn screening. There was strong consensus that newborn screening using succinylacetone (SA) and early treatment are essential for a good outcome. The dose of NTBC should be as low as possible without losing metabolic control. This has to be accompanied by a low protein diet, in some patients a simplified diet without calculation of protein intake. Specific education and psychosocial support are recommended. Indications for liver transplantation were defined. Monitoring shall include clinical findings, levels of SA, tyrosine, phenylalanine and NTBC in (dried) blood.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828943","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":"Executive and adaptive function impacts long-term outcomes for adults with maple syrup urine disease","authors":"Jessica I. Gold,&nbsp;Alanna Strong,&nbsp;Nina B. Gold,&nbsp;Marc Yudkoff,&nbsp;Dava Szalda,&nbsp;Sophia Jan,&nbsp;Lisa A. Schwartz,&nbsp;Rebecca Ganetzky","doi":"10.1002/jimd.12827","DOIUrl":"10.1002/jimd.12827","url":null,"abstract":"<p>Successful transition to independent adulthood requires intact executive and adaptive function. These neurocognitive domains are frequently impaired in inherited metabolic disorders (IMD), despite optimal management. For many IMDs, the impact of executive and adaptive dysfunction on long-term outcomes remains undefined. Standardized assessments linking neurocognitive status with functional outcomes are needed to improve prognostication and tailor support for affected emerging adults. Maple syrup urine disease (MSUD), a relatively prevalent IMD, is primarily diagnosed in the first week of life through newborn screening. Despite early intervention, executive and adaptive dysfunction persist. We designed a remote, interactive battery of neurocognitive and functional assessments for adults (≥21 years) with MSUD to correlate neurocognition and long-term outcomes. Participants were selectively recruited for racial, ethnic, socio-economic, and geographic diversity. Assessments completed by 28 adults with MSUD (82% diagnosed after symptom onset, 25% from minority communities) show a wide range in educational attainment, employment, and residence. Executive and adaptive function were significantly impaired in adults with MSUD compared to controls. Executive and adaptive deficits correlated negatively with educational attainment, employment, and obtaining skills needed for adult-oriented healthcare or independent living. Clinical history did not predict functional outcomes, but neurocognitive assessments suggest the benefits of pre-symptomatic diagnosis. Independent adulthood is attainable for individuals with MSUD. Routine assessment of neurocognition and interventions targeting executive and adaptive function may improve long-term functional outcomes in IMD.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801136","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":"Integration of multi-omics layers empowers precision diagnosis through unveiling pathogenic mechanisms on maple syrup urine disease","authors":"Juan Ramón Tejedor,&nbsp;Alejandro Soriano-Sexto,&nbsp;Leonardo Beccari,&nbsp;Natalia Castejón-Fernández,&nbsp;Patricia Correcher,&nbsp;Lidia Sainz-Ledo,&nbsp;Juan José Alba-Linares,&nbsp;Rocío G. Urdinguio,&nbsp;Magdalena Ugarte,&nbsp;Agustín F. Fernández,&nbsp;Pilar Rodríguez-Pombo,&nbsp;Mario F. Fraga,&nbsp;Belén Pérez","doi":"10.1002/jimd.12829","DOIUrl":"10.1002/jimd.12829","url":null,"abstract":"<p>Maple syrup urine disease (MSUD) is a rare inherited metabolic disorder characterized by deficient activity of the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex, required to metabolize the amino acids leucine, isoleucine, and valine. Despite its profound metabolic implications, the molecular alterations underlying this metabolic impairment had not yet been completely elucidated. We performed a comprehensive multi-omics integration analysis, including genomic, epigenomic, and transcriptomic data from fibroblasts derived from a cohort of MSUD patients and unaffected controls to genetically characterize an MSUD case and to unravel the MSUD pathophysiology. MSUD patients exhibit a defined episignature that reshapes the global DNA methylation landscape, resulting in the stimulation of HOX cluster genes and the restriction of cell cycle gene-related signatures. Subsequent data integration revealed the impact of AP1-related and CEBPB transcription factors on the observed molecular reorganization, with MEIS1 emerging as a potential downstream candidate affected by robust epigenetic repression in MSUD patients. Furthermore, the integration of multi-omics layers facilitated the identification of a strong epigenetic repression in the <i>DBT</i> promoter in a patient wherein no BCKDH pathogenic variants had been detected. A Circular Chromatin Conformation Capture assay indicated a disturbance of the interactions of <i>DBT</i> promoter, thereby unveiling alternative modes of disease inheritance. Integration of multi-omics data unveiled underlying molecular networks rewired in MSUD patients and represents a powerful approach with diagnostic potential for rare genetic disorders with unknown genetic bases.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807158","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":"Circulatory response to exercise relative to oxygen uptake assessed in the follow-up of patients with fatty acid beta-oxidation disorders","authors":"Apolline Imbard,&nbsp;Hortense de Calbiac,&nbsp;Edouard Le Guillou,&nbsp;Pascal Laforêt,&nbsp;Manuel Schiff,&nbsp;Anaïs Brassier,&nbsp;Elise Thevenet,&nbsp;Clément Pontoizeau,&nbsp;Bertrand Lefrère,&nbsp;Chris Ottolenghi,&nbsp;Elise Lebigot,&nbsp;Pauline Gaignard,&nbsp;Stéphanie Gobin,&nbsp;Cécile Acquaviva-Bourdain,&nbsp;Jean-François Benoist,&nbsp;Caroline Tuchmann-Durand,&nbsp;Antoine Legendre,&nbsp;Pascale de Lonlay","doi":"10.1002/jimd.12819","DOIUrl":"10.1002/jimd.12819","url":null,"abstract":"<p>Patients with fatty acid oxidation disorders (FAODs) experience muscle symptoms due to impaired ATP metabolism and the toxicity of accumulated mitochondrial FAO substrates or intermediates, especially during catabolic states. A major issue is the absence of specific and sensible biomarkers to evaluate metabolic equilibrium. The relationship between cardiac output (Q) and oxygen consumption (VO₂) during incremental exercise (dQ/dVO₂) provides an indirect surrogate of mitochondrial function. A high dQ/dVO₂ slope indicates impaired oxidative phosphorylation in skeletal muscle during exercise. Our study aimed to evaluate dQ/dVO₂ as a potential marker of the severity of FAODs. We retrospectively collected clinical, laboratory parameters and treatment data for FAOD patients over 6 years old, including a disease severity score, plasma acylcarnitines and cardiopulmonary exercise tests with Q measurement via thoracic bioelectrical impedance. FAO flux was measured in whole blood and in myoblasts when available. We included 27 FAOD patients followed from 2015 to 2022, with deficiencies in LCHAD (<i>n</i> = 10), CPT2 (<i>n</i> = 6), VLCAD (<i>n</i> = 7), or MADD (<i>n</i> = 4). CPT2 deficient patients with severe scores had the highest C18:1-, C16-, C18-acylcarnitines, and dQ/dVO₂. In these patients, dQ/dVO₂ was positively correlated with C18:1, C16, and C18 acylcarnitines. In a linear multivariate regression model, dQ/dVO₂ was significantly associated with the severity score (B = 0.831, <i>p =</i> 0.008) and triheptanoin treatment (B = −0.547, <i>p =</i> 0.025). dQ/dVO₂ and plasma long-chain acylcarnitines might be useful to monitor CPT2D, as these parameters associate with our clinical severity score and could reflect altered mitochondrial functions.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794916","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":"Imaging readiness in the gene therapy era-exploring standardized protocols for response assessment","authors":"Asthik Biswas,&nbsp;Audrey K. S. Soo,&nbsp;Manju A. Kurian,&nbsp;Ulrike Löbel,&nbsp;Felice D'Arco,&nbsp;Spyros Batzios,&nbsp;Sniya Sudhakar,&nbsp;Kshitij Mankad,&nbsp;the IMaging Assessment in Gene and Enzyme Replacement therapies (IMAGER) study group","doi":"10.1002/jimd.12828","DOIUrl":"10.1002/jimd.12828","url":null,"abstract":"","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794921","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":"Clinical severity and cardiac phenotype in phosphomannomutase 2-congenital disorders of glycosylation : Insights into genetics and management recommendations","authors":"Veronika Holubova,&nbsp;Rita Barone,&nbsp;Stephanie Grunewald,&nbsp;Markéta Tesařová,&nbsp;Hana Hansíková,&nbsp;Jana Augustínová,&nbsp;Jolanta Sykut-Cegielska,&nbsp;Francesca De Nictolis,&nbsp;Unai Diaz-Moreno,&nbsp;Ramyia Elangovan,&nbsp;Florencia Epifani,&nbsp;Serena Gasperini,&nbsp;Mirian Jansen,&nbsp;Dirk Lefeber,&nbsp;Dorota Maksym-Gasiorek,&nbsp;Martinelli Diego,&nbsp;Katrin Ounap,&nbsp;Fabio Pettinato,&nbsp;Haide Põder,&nbsp;Daisy Rymen,&nbsp;Mari-Anne Vals,&nbsp;Mercedes Serrano,&nbsp;Peter Witters,&nbsp;Tomáš Honzík","doi":"10.1002/jimd.12826","DOIUrl":"10.1002/jimd.12826","url":null,"abstract":"<p>Cardiac involvement (CI) in phosphomannomutase 2-congenital disorders of glycosylation (PMM2-CDG) is part of the multisystemic presentation contributing to high mortality rates. The most common cardiac manifestations are pericardial effusion, cardiomyopathy, and structural heart defects. A genotype–phenotype correlation with organ involvement has not yet been described. We analyzed clinical, biochemical, and molecular genetic data of 222 patients from eight European centers and characterized the natural course of patients with CI. Fifty-seven patients (45 children) presented with CI, of whom 24 died (median age 21 months, standard deviation 49.8). Pericardial effusion was the most frequent manifestation (55.4%), occurring mostly within the first 6 months of life. The most common pathogenic variants in patients with CI were p.(Arg141His) in 74%, followed by p.(Val231Met) in 36%, which is 3.5 times higher than in PMM2-CDG patients without CI (<i>p</i> &lt; 0.0001). Twenty-one out of 36 patients with p.(Val231Met) had CI; among them, 15 died, compared to 33 out of 166 patients without p.(Val231Met) who had CI (<i>p</i> &lt; 0.0001). Nine out of 33 patients died (<i>p</i> = 0.0015), indicating greater clinical severity. Furthermore, the p.(Val231Met) variant is predominant in Eastern Europe, suggesting a founder effect. Cardiac complications in PMM2-CDG patients are common and serious. The variant p.(Val231Met) profoundly influences the extent of CI and mortality rates. Therefore, we recommend cardiac surveillance be included in the follow-up protocols for PMM2-CDG.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780355","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":"Mapping challenges in the accessibility of treatment products for urea cycle disorders: A survey of European healthcare professionals","authors":"Nina N. Stolwijk,&nbsp;Johannes Häberle,&nbsp;Hidde H. Huidekoper,&nbsp;Margreet A. E. M. Wagenmakers,&nbsp;Carla E. M. Hollak,&nbsp;Annet M. Bosch,&nbsp;the E-IMD and MetabERN Working Group on the Real-World Use of products for UCD Management","doi":"10.1002/jimd.12815","DOIUrl":"10.1002/jimd.12815","url":null,"abstract":"<p>Current management guidelines for urea cycle disorders (UCDs) offer clear strategies, incorporating both authorized and non-authorized medicinal products (including intravenous formulations and products regulated as food). These varying product categories are subject to specific accessibility challenges related to availability, reimbursement, and pricing. The aim of this study is to identify potential obstacles to optimal UCD treatment implementation in European clinical practice. A survey aimed at metabolic healthcare professionals (HCPs) managing patients with UCDs in Europe was disseminated through the European Reference Network for Hereditary Metabolic Disorders and the European registry and network for intoxication type metabolic diseases. Forty-eight survey responses were collected from 21 European countries. In 16 of these countries, at least one metabolic HCP reported challenges in accessing UCD products. Reimbursement issues were reported for most products (8/10), including both authorized and non-authorized products. Availability-related challenges were also reported for 8/10 products, although unavailability was limited to non-authorized products. Prices impacted accessibility for all authorized products (3/3) and one non-authorized IV product. The accessibility of UCD treatment products varied across Europe, although no clear regional variations could be discerned. Survey data revealed that metabolic HCPs experience challenges in accessing both authorized and non-authorized products for UCD management in the majority of European countries. This indicates that registering unauthorized products may not resolve all issues. Improved reimbursement policies and fair pricing models, as well as (adjusted) authorization procedures may help address these concerns, thereby optimizing treatment access for UCD patients.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769703","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}