Journal of Inherited Metabolic Disease最新文献

{"title":"A Contemporary Pathomechanistic Nosology of Inherited Lysosomal Disorders","authors":"Eamon P. McCarron,&nbsp;Nenad Blau,&nbsp;Emily R. Eden,&nbsp;Frances M. Platt,&nbsp;Johannes M. Aerts,&nbsp;Simon A. Jones,&nbsp;Carlos R. Ferreira,&nbsp;Karolina M. Stepien","doi":"10.1002/jimd.70245","DOIUrl":"10.1002/jimd.70245","url":null,"abstract":"<div>\u0000 \u0000 <p>Lysosomal disorders (LDs) have traditionally been defined by intra-lysosomal substrate accumulation resulting from deficiencies of lysosomal enzymes or associated proteins. Advances in lysosomal biology have demonstrated that lysosomes function as central regulators of cellular signalling, membrane trafficking, autophagy, nutrient sensing, organelle communication and cellular homeostasis, expanding the spectrum of inherited disorders associated with lysosomal dysfunction beyond classical storage phenotypes. We developed a contemporary pathomechanistic nosology of inherited LDs through expert curation and targeted review of databases and published literature. Disorders were included when pathogenic variants resulted in lysosomal dysfunction as a major disease mechanism through defects affecting lysosomal degradation, membrane function, intracellular trafficking, biogenesis, autophagy–lysosome pathways or lysosome-related organelles. A total of 108 inherited lysosomal disorders caused by defects in 102 genes were identified and organised into 11 major disease categories. Neurologic and eye involvement were the most frequently affected organ–system categories, occurring in 80.6% and 68.5% of disorders, respectively. Digestive (including hepatosplenomegaly), dysmorphic, skeletal and haematological involvement occurred in 48.1%, 45.4%, 40.7% and 38.9% of disorders, respectively. Distinct phenotypic signatures were observed across disease categories despite substantial mechanistic overlap involving impaired autophagy, vesicular trafficking, lysosomal stress and altered organelle homeostasis. This proposed nosology extends disease classification beyond substrate accumulation alone and provides a biologically informed framework for disease classification, genomic interpretation, biomarker development, patient stratification and the development of mechanism-based therapies.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148818662","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":"Patient Perspective—Where Does the Value for Money of a Treatment Really Lie?","authors":"Toni A. Mathieson,&nbsp;William R. H. Evans,&nbsp;Justin L. Hopkin,&nbsp;Sandra L. Cowie","doi":"10.1002/jimd.70231","DOIUrl":"10.1002/jimd.70231","url":null,"abstract":"","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808672","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":"From Single Cells to Diagnosis: Proteomics Technologies in the Multi-Omics Landscape of Rare and Mitochondrial Diseases","authors":"Simon Wetzel,&nbsp;Sebastian Porsdam Mann,&nbsp;Florian A. Rosenberger","doi":"10.1002/jimd.70236","DOIUrl":"10.1002/jimd.70236","url":null,"abstract":"<p>Proteomics by mass spectrometry has rapidly matured from a niche method into a standard tool. The recent 10-year trajectory of single-cell proteomics has opened a new biological dimension for studying disease. Mitochondrial diseases, with their pronounced cell-to-cell heterogeneity, are particularly, well-suited to these methods. Here, we discuss how this approach can serve as an orthogonal functional layer for rare disease diagnostics. We trace the evolution of rare disease diagnostics from biochemical enzyme assays through genomics, transcriptomics, proteomics and metabolomics, highlighting incremental gains in diagnostic yield from individual omics layers and their integration. We discuss the limitations of bulk approaches in capturing the functional consequences of genetic perturbations, the new opportunities opened up by single-cell measurements and how spatial single-cell proteomics can further enrich the biological signal of affected cells in diagnostic tissues. We observe that the persisting diagnostic gap reflects not only technological limitations but, increasingly, challenges in data sharing and infrastructure as well as interpretive frameworks for functional molecular evidence. In this context, we consider opportunities for artificial intelligence and the ethical dimensions of single-cell proteomics in rare disease diagnostics. Finally, we propose a single-cell deep visual proteomics (scDVP) framework for clinical diagnostics of rare diseases with cell-to-cell variability, arguing that mitochondrial diseases are an ideal proof-of-concept.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13504187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148812764","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":"An Optimized Diagnostic Approach for Adults With Suspected Inherited Metabolic Disorders","authors":"Machteld M. Oud,&nbsp;Elise A. Ferreira,&nbsp;Clara D. M. van Karnebeek,&nbsp;Robin Wijngaard,&nbsp;Nicole I. Wolf,&nbsp;Marc Engelen,&nbsp;Mareen Datema,&nbsp;Sacha Ferdinandusse,&nbsp;André B. P. van Kuilenburg,&nbsp;Laura Steinbusch,&nbsp;Saskia N. van der Crabben,&nbsp;Mirjam Langeveld,&nbsp;the ZOEMBA Study Group","doi":"10.1002/jimd.70238","DOIUrl":"https://doi.org/10.1002/jimd.70238","url":null,"abstract":"<p>Inherited metabolic disorders (IMDs) arise from defects in metabolic pathways essential for normal biochemical function. Although the pathogenic genetic variants are present at birth, clinical manifestations may not emerge until adolescence or adulthood. Symptoms may be more subtle compared to those of childhood onset IMDs and may have overlap with signs and symptoms of acquired disorders. This makes diagnosing IMDs in adulthood challenging. To identify how routine diagnostic care for adults suspected of having an IMD could be improved, we conducted a reanalysis study in a cohort of 31 adult participants. The participants, who remained undiagnosed after standard diagnostic care, were seen by a clinical geneticist, adult metabolic specialist and neurologist for deep phenotyping and data collection. Subsequently, exome sequencing data were reanalyzed and possible disease-causing variants were prioritized for further evaluation by a multidisciplinary team including both clinicians and geneticists (biochemical and molecular). This approach led to a (partial) diagnosis for nine participants from six families, giving a 25% diagnostic yield. We could distinguish four possible reasons why the identified disease-associated variants were not detected during routine diagnostic care. Beyond the expected impact of technical advancements and emerging knowledge of disease genes, we found that the most impactful factor was of organizational nature. Our findings underscore the value of reviewing all strong genetic variants within a multidisciplinary team setting, facilitating a bidirectional exchange of expertise. This approach enhances diagnostic accuracy, particularly when the underlying cause of the disease is not immediately apparent.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70238","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784008","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":"Occurrence of Infusion Associated Reactions and Antidrug Antibodies in Enzyme Replacement Therapy for Fabry Disease and the Effect of Preventive Measures","authors":"Maud Janssens,&nbsp;Sanne J. van der Veen,&nbsp;Laura van Dussen,&nbsp;André B. P. van Kuilenburg,&nbsp;Marion M. M. G. Brands,&nbsp;Mirjam Langeveld","doi":"10.1002/jimd.70235","DOIUrl":"https://doi.org/10.1002/jimd.70235","url":null,"abstract":"<p>Male patients with the classical phenotype of Fabry disease (FD) are at risk of developing inhibiting antidrug antibodies (iADAs) against recombinant α-galactosidase-A, administered in the form of enzyme replacement therapy (ERT). The presence of ADAs is linked to infusion-associated reactions (IARs) and reduced ERT effectiveness. This study evaluates the incidence of iADAs and IARs in ERT treated classical male FD patients, their interrelatedness and the effect of an adjusted ERT initiation protocol, aimed at inducing immune tolerance. In this monocenter cohort study, a retrospective analysis was performed to evaluate the occurrence of iADAs and IARs. Prospectively, a stepwise dose escalation ERT initiation protocol was evaluated in classical male FD patients with a calculated high risk of iADA formation and compared to the standard initiation protocol. Retrospectively (<i>n</i> = 52), the proportion of patients experiencing IARs was higher in patients that developed iADAs (20/27 seropositive patients, 0/19 seronegative, <i>p</i> &lt; 0.001). Higher iADA titers were associated with persisting iADA titers (<i>p</i> = 0.004). Prospectively (<i>n</i> = 17), none of the patients in the intervention group (stepwise dose escalation) experienced IARs (0/8), compared to half of the patients in the control group (5/9, <i>p</i> = 0.029). The proportion of patients developing iADAs was not different between the two groups (respectively, 4/8 and 6/9, <i>p</i> = 0.52). To conclude, iADA development is associated with the occurrence of IARs. The stepwise dose escalation at ERT initiation used in the current study in a single cohort seems to prevent IARs in male patients with classical FD, but does not seem to prevent iADA development.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70235","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784009","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":"From Common Pathway to Divergent Diseases: Metabolic Aspects of Inborn Errors of CoA Biosynthesis","authors":"Ivano Di Meo,&nbsp;Yair Anikster,&nbsp;Valeria Tiranti,&nbsp;Arcangela Iuso","doi":"10.1002/jimd.70239","DOIUrl":"https://doi.org/10.1002/jimd.70239","url":null,"abstract":"<p>Coenzyme A (CoA) biosynthesis is a conserved, dynamically regulated pathway essential for mitochondrial energy production, fatty acid oxidation, lipid biosynthesis and protein acylation. Biallelic variants in <i>PANK2</i>, <i>PPCS</i>, <i>PPCDC</i>, and <i>COASY</i> cause rare inborn errors of CoA biosynthesis, associated with markedly different clinical phenotypes: <i>PANK2</i> and <i>COASY</i> defects predominantly cause neurological disorders within or adjacent to the neurodegeneration with brain iron accumulation (NBIA) spectrum, whereas <i>PPCS</i> and <i>PPCDC</i> deficiencies present mainly as severe early-onset dilated cardiomyopathy. However, <i>COASY</i> variants can also cause pontocerebellar hypoplasia and riboflavin-responsive lipid storage myopathy. This review examines these four disorders from a metabolic perspective, integrating clinical features, experimental models, biochemical data and emerging therapeutic approaches. Current evidence indicates that disease pathogenesis cannot be explained only by global CoA depletion. Total CoA levels may be reduced in <i>PPCS</i> and <i>PPCDC</i> deficiency, but are often preserved under basal conditions in PKAN and COASY-related models. Instead, impaired compartment-specific CoA handling and failure to sustain CoA-dependent flux under increased metabolic demand are emerging as central pathogenic concepts. Perturbation of fatty acid handling, acyl-CoA/acylcarnitine balance, mitochondrial function, iron homeostasis, protein acylation and 4′-phosphopantetheinylation may contribute to tissue-selective vulnerability. Therapeutic strategies are therefore likely to require disease-specific approaches, including precursor bypass or PANK activation where pathway flux can be restored, early pantethine supplementation in cardiomyopathic forms, and downstream or gene-directed strategies for COASY-related disorders. Understanding CoA as a regulator of metabolic adaptability provides a unifying framework for interpreting both shared mechanisms and disease divergence.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70239","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148753957","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":"Proteo-Metabolomic Profiling of PMM2-CDG Reveals Dysregulation of Retinoic Acid Synthesis, Myo-Inositol, and the Hexosamine Pathway","authors":"Diana Gallego,&nbsp;Giuseppina Andreotti,&nbsp;Maria Monticelli,&nbsp;Debora Paris,&nbsp;Arturo Martín-Martínez,&nbsp;Alejandra Gámez,&nbsp;Mercedes Serrano,&nbsp;José Córdoba-Caballero,&nbsp;Pedro Seoane,&nbsp;Juan A. G. Ranea,&nbsp;Belén Pérez","doi":"10.1002/jimd.70233","DOIUrl":"10.1002/jimd.70233","url":null,"abstract":"<p>Phosphomannomutase deficiency (PMM2-CDG), the most common congenital disorder of glycosylation (CDG), is characterized by multisystem involvement and a lack of disease-modifying therapies. While previous transcriptomic studies have uncovered disrupted cellular pathways, the functional consequences of these alterations remain poorly understood. To further investigate PMM2-CDG pathophysiology, we integrated proteomic and metabolomic profiling of patient-derived fibroblasts with previously published transcriptomic data. Proteomic analysis was performed using Tandem Mass Tag-based mass spectrometry, while metabolomics was conducted via Nuclear Magnetic Resonance spectroscopy. Multi-omics integration was performed using principal component analysis–based dimensionality reduction, incorporating clinical metadata as supplementary variables. Proteomic analysis identified 43 significantly altered proteins, with enrichment in the retinoic acid synthesis pathway, wound healing, and cytoskeletal organization. Metabolomic profiling revealed altered amino acid levels and elevated concentrations of UDP-GlcNAc, consistent with perturbation of the hexosamine biosynthesis pathway, and increased levels of <i>my</i><i>o</i>-inositol. Notably, <i>myo</i>-inositol levels showed a strong association with disease severity in the integrated analysis. RT-qPCR confirmed the upregulation of <i>GFPT2</i>. This integrative multi-omics study identifies consistent alterations in the retinoic acid synthesis pathway and hexosamine biosynthesis in PMM2-CDG patient-derived fibroblasts and reveals an association between intracellular <i>myo</i>-inositol levels and disease severity. These findings provide new insights into PMM2-CDG–associated molecular alterations and illustrate the value of multi-omics integration for hypothesis generation in rare diseases.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70233","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148722657","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":"High-Protein Diet Ameliorates Cardiomyopathy in a Cardiac-Specific AGL Knockout Mouse Model: Association With Upregulated Hepatic Gluconeogenesis","authors":"Caiqi Du,&nbsp;Hao Fu,&nbsp;Tingting Yu,&nbsp;Sisi Cao,&nbsp;Haotian Zhang,&nbsp;Boda Wei,&nbsp;Cai Zhang,&nbsp;Juan Ye,&nbsp;Wenjun Long,&nbsp;Xiaoping Luo,&nbsp;Yan Liang","doi":"10.1002/jimd.70237","DOIUrl":"10.1002/jimd.70237","url":null,"abstract":"<p>Glycogen storage disease type IIIa (GSDIIIa) causes progressive cardiomyopathy, and current high-fat dietary strategies lack consensus regarding long-term cardiovascular safety. We evaluated the efficacy and safety of high-protein versus high-fat diets in a novel cardiac-specific <i>AGL</i> knockout (CKO; <i>AGL</i>^{<i>flox/flox</i>}/<i>MHC-Cre</i>) mouse model to specifically assess isolated cardiac responses. CKO mice were randomized at weaning to High-Protein (HPD), High-Protein High-Fat (HPHFD), or Low-Protein (LPD) diets, with approximate protein/fat/carbohydrate distributions of 40%/4%/50%, 40%/50%/10%, and 10%/4%/80%, respectively; CKO mice on normal diet (ND) and <i>AGL</i>^{<i>flox/flox</i>} mice served as controls. Cardiac phenotypes and hepatic gluconeogenic enzymes were evaluated longitudinally up to 24 weeks. CKO-ND mice developed progressive cardiomyopathy with elevated myocardial glycogen at 24 weeks (32.01 ± 3.22 vs. 5.90 ± 2.21 mg/g in controls, <i>p</i> &lt; 0.001), reduced left ventricular ejection fraction, and elevated serum creatine kinase. Both HPD and HPHFD significantly reduced myocardial glycogen burden (12.82 ± 3.58 and 15.07 ± 4.40 mg/g, <i>p</i> &lt; 0.001), restored systolic function, and normalized hypertrophy. However, HPHFD induced distinct hyperlipidemia, whereas HPD maintained a stable lipid profile. Furthermore, therapeutic benefits in high-protein groups were associated with upregulated hepatic rate-limiting gluconeogenic enzymes (FBP2, PCK1). In this cardiac-specific <i>AGL</i> knockout model, a high-protein, non-high-fat diet attenuated cardiac glycogen accumulation and systolic dysfunction without the hyperlipidemia observed with the high-fat regimen. These preclinical findings support further evaluation of high-protein dietary strategies for GSDIIIa cardiomyopathy and suggest a possible liver-heart metabolic axis involving hepatic gluconeogenesis.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70237","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148706800","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":"Behavioral Phenotyping of the Pahenu2 Mouse Model for Phenylketonuria—A Scoping Review and Future Perspectives","authors":"Junfei Cao,&nbsp;Lennart Kruizinga,&nbsp;Iris B. Hovens,&nbsp;Els van der Goot,&nbsp;Robbert Havekes,&nbsp;Eddy A. van der Zee","doi":"10.1002/jimd.70229","DOIUrl":"10.1002/jimd.70229","url":null,"abstract":"<p>Phenylketonuria (PKU) is a rare metabolic disorder resulting from a mutation in the gene encoding the enzyme phenylalanine hydroxylase (PAH), resulting in very high phenylalanine (Phe) levels in blood and brain. A PKU mutant mouse model was developed via N-ethyl-N-nitrosourea (ENU) mutagenesis, mimicking the high brain Phe content seen in classic PKU patients. A large variety of behavioral tasks have been employed to explore the behavioral phenotype of the Pah^enu2 mouse. The purpose of this scoping review is to provide an overview of the behavioral performance of PKU mutant mice. We addressed three aims: (1) provide an overview of the behavioral tasks that have been performed with these mice, (2) summarize the reported findings across behavioral domains, (3) identify gaps and future perspectives for behavioral testing in the field of preclinical PKU. Peer-reviewed studies published in English up to May 2026 were identified through structured searches in PubMed and Web of Science, supplemented by free-text searches. Studies were eligible if they used adult untreated Pah^enu2 mice and included a comparison with wild-type controls. Twenty-two studies were included. Nest-building behavior and balance beam performance always reveal deficits in PKU mutant mice, whereas most studies found no significant anxiety-like phenotypes. A striking variation in cognitive test performance was found across studies, despite high Phe levels. In conclusion, balance beam and nest-building tests reliably demonstrate deficits in Pah^enu2 mice, while other cognitive findings remain variable. The Pah^enu2 model retains value for future behavioral research and benchmarking of novel PKU models.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13443032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148678730","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":"Baat-Deficient Mice Recapitulate Elevated 7α-Hydroxy-3-Oxo-4-Cholestenoic Acid Observed in a Japanese Patient With BAAT Deficiency","authors":"Soma Koga,&nbsp;Hajime Takei,&nbsp;Ryutaro Tamura,&nbsp;Yugo Takaki,&nbsp;Hiroyuki Kusuhara,&nbsp;Hiroshi Nittono,&nbsp;Hisamitsu Hayashi","doi":"10.1002/jimd.70232","DOIUrl":"10.1002/jimd.70232","url":null,"abstract":"<p>Bile acid Coenzyme A: amino acid N-acyltransferase (<i>BAAT</i>) catalyzes the conjugation of bile acids with taurine or glycine, a process essential for bile acid solubility and intestinal lipid absorption. Mutations in <i>BAAT</i> cause an inborn error of bile acid metabolism, typically characterized by reduced conjugated bile acids and fat-soluble vitamin deficiency. However, several clinical features of <i>BAAT</i> deficiency cannot be fully explained by impaired conjugation alone, suggesting the presence of broader metabolic disturbances. In this study, we analyzed serum bile acid and intermediate profiles in a Japanese patient with genetically confirmed <i>BAAT</i> deficiency and identified a marked elevation of 7α-hydroxy-3-oxo-4-cholestenoic acid (7-HOCA), a key intermediate in bile acid synthesis. To investigate the metabolic consequences of <i>BAAT</i> loss, we generated a hepatic <i>Baat</i> knockdown mouse model using adeno-associated virus serotype 8–mediated delivery of Nme2Cas9 and <i>Baat</i>-targeting sgRNA. This model faithfully recapitulated the accumulation of 7-HOCA observed in the patient, together with a significant reduction in amino acid–conjugated bile acids. Integrated analyses combining bile acid profiling, quantitative PCR, and stable-isotope tracing of cholesterol demonstrated enhanced cholesterol flux toward bile acid biosynthetic pathways and upregulation of bile acid synthetic enzymes in <i>Baat</i>-deficient livers. These findings indicate that <i>BAAT</i> deficiency leads to dysregulated bile acid synthesis in addition to defective conjugation. Together, our results reveal a previously unrecognized metabolic phenotype of <i>BAAT</i> deficiency and provide mechanistic insight into its pathophysiology, establishing a novel in vivo model for studying bile acid metabolism beyond simple conjugation defects.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13439729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148673758","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}