Journal of Inherited Metabolic Disease最新文献

{"title":"Disease Burden and Pharmacological Treatment Patterns in Children and Adults With Phenylketonuria: A Real-World Matched Cohort Study.","authors":"Nicola Longo, Barbara K Burton, Shailja Vaghela, Fan Mu, Aolin Wang, Jess Smith, Emily Reichert, Ryan B Simpson, Vanja Sikirica, Sue Perera","doi":"10.1002/jimd.70194","DOIUrl":"10.1002/jimd.70194","url":null,"abstract":"<p><p>Phenylketonuria (PKU) is caused by defective catabolism of phenylalanine (Phe), resulting in Phe accumulation and subsequent neurocognitive impairment. This retrospective study used a large United States claims database linked to laboratory records (6/2018-05/2023) to compare comorbidities, healthcare resource utilization, and healthcare costs between individuals with PKU and matched controls, stratified by age and Phe level, as well as describe pharmacological treatment patterns among individuals with PKU. The study included 5729 and 2648 matched pairs aged ≥ 12 and < 12 years, respectively (mean age: 31 and 3 years; 60% and 47% female). Individuals aged ≥ 12 years with PKU had significantly higher prevalence of neuropsychiatric and cognitive comorbidities than controls, including intellectual or developmental disabilities (prevalence difference: 5.2%), fatigue and malaise (4.9%), and anxiety (4.2%; all p < 0.05), along with other comorbidities across multiple organ systems. Individuals aged ≥ 12 years with PKU also accessed the healthcare system more than controls (39% more hospitalizations, 18% more emergency room visits, and 25% more outpatient visits) and incurred higher medical and pharmacy costs ($2869 and $9075, respectively; p < 0.05). Individuals aged < 12 years similarly had higher burden than controls, but only for certain outcomes and at smaller magnitudes. Individuals with Phe ≥ 600 μmol/L showed a greater incremental burden for certain comorbidities, such as intellectual or developmental disabilities, compared to individuals with Phe < 600 μmol/L. These findings demonstrate the substantial burden of PKU across age and Phe level strata, notably in those aged ≥ 12 years, highlighting the need for improved treatments.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70194"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13112333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773825","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":"2025 Consensus Clinical Management Guidelines for Niemann-Pick Disease Type C.","authors":"Tarekegn Hiwot, Forbes D Porter, Tatiana Bremova-Ertl, Uma Ramaswami, Caroline Hastings, Bénédicte Héron, Justin Hopkin, Joella Melville, Hernan Amartino, Mireia Del Toro, Federica Deodato, Fatih Ezgü, Paul Gissen, James B Gibson, Can Ficicioglu, Roberto Giugliani, Orna Staretz-Chacham, Frances Platt, Nathalie Guffon, Kristina Julich, Nikola Kresojević, Anna Lehman, Yann Nadjar, Susanne A Schneider, Simon Jones, Eugen Mengel, Michel Tchan, Mark Walterfang, Ozlem Goker-Alpan, Charlotte Dawson, Sandra Cowie, Toni Mathieson, Elizabeth Berry-Kravis, Marc C Patterson","doi":"10.1002/jimd.70185","DOIUrl":"10.1002/jimd.70185","url":null,"abstract":"<p><p>In 2018, the International Niemann-Pick Disease Alliance (INPDA) and the International Niemann-Pick Disease Registry (INPDR) developed and published comprehensive clinical management guidelines to support inclusive and standardized care pathways in Niemann-Pick disease type C (NPC)-an ultra-rare, autosomal recessive, neurovisceral lysosomal disorder. Since then, advances in diagnostics, care, and the approval of two novel disease-modifying agents have underscored the need to revise these guidelines to ensure safe, consistent, and high-quality care for those affected by NPC. In response, the INPDA and INPDR convened a multidisciplinary Guidelines Development Group (GDG) comprising individuals with NPC expertise from 14 countries across five continents, representing a broad range of specialties, as well as patients and families involved in NPC care. Informed by a comprehensive literature review and two meetings, the GDG systematically reviewed, revised, and updated the 2018 guideline statements, re-evaluating the level of evidence, strength of recommendations, and expert agreement for each. The resulting 2025 consensus clinical management guidelines constitute a timely, up-to-date, and internationally applicable resource for the diagnosis, treatment, and holistic management of individuals with NPC. These guidelines serve as a critical resource for specialist centers, hospital-based medical teams, staff involved in NPC patient care, family physicians and other primary caregivers, and, importantly, patients and their families.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70185"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13110917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to \"Multimodal Noninvasive Biomarker Characterization of Structural and Functional Alterations in ADSS1-Deficient Myopathy\".","authors":"","doi":"10.1002/jimd.70200","DOIUrl":"10.1002/jimd.70200","url":null,"abstract":"","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70200"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147874420","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 Clinical Progression to Brain Atrophy in CLN2 Patients Under Cerliponase Alfa Treatment: A Prospective Neuroimaging Study.","authors":"Marvin Petersen, Lena Marie Westermann, Luca Hagenah, Miriam Nickel, Christoph Schwering, Eva Wibbeler, Felix L Naegele, Nils-Ole Gloyer, Fabian Flottmann, Jens Fiehler, Götz Thomalla, Bastian Cheng, Angela Schulz","doi":"10.1002/jimd.70202","DOIUrl":"10.1002/jimd.70202","url":null,"abstract":"<p><p>Neuronal ceroid lipofuscinosis type 2 (CLN2) disease, a lysosomal storage disorder, causes early childhood psychomotor regression, vision loss, seizures, and rapid progressive gray matter loss. However, the link between neurodegenerative processes induced by lysosomal pathophysiology and the clinical phenotype remains unclear. This study investigated the longitudinal association of gray matter atrophy on MRI with in-depth clinical phenotyping in 27 patients receiving intraventricular enzyme therapy (n_timepoints = 170; biannual clinical assessments and MRIs). Longitudinal changes in cortical thickness and subcortical volumes were modeled via linear mixed effects regression. We used linear regression to correlate 24-week (Δ24) changes in clinical assessments with global cortical thickness and applied multivariate data-driven statistics to model how specific brain regions are associated with clinical domains. Our analysis revealed a significant reduction in the mean cortical thickness over time (β = -0.002, p = 0.021), corresponding to an annual loss of 4.2%, compared to natural history controls with 12.5%, respectively. Regional analysis revealed a widespread pattern of cortical and subcortical gray matter atrophy. Global cortical thickness reductions over 24 weeks (Δ24) were significantly associated with changes in the Hamburg motor and language scale Δ24, Weill Cornell scale Δ24, and Movement Disorder Inventory Δ24. Multivariate statistics identified a significant latent dimension relating regional morphometric abnormalities to worse clinical outcomes, accounting for 82% of the shared variance. Leveraging connectome data, we demonstrated that atrophy was linked to brain network architecture. Given their strong associations with clinical outcomes, MRI-based brain morphometric measures are promising CLN2 disease biomarkers to aid diagnosis, monitor disease progression, and guide therapy.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70202"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148005492","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":"Optical Coherence Tomography Reflectivity as a Diagnostic Tool and Neurological Biomarker in Sialidosis Type I.","authors":"Teck Boon Tew, Chin-Hsien Lin, Hsueh-Wen Hsueh, Sung-Pin Fan, Ni-Chung Lee, Yin-Hsiu Chien, Wuh-Liang Hwu, Chao-Wen Lin","doi":"10.1002/jimd.70191","DOIUrl":"10.1002/jimd.70191","url":null,"abstract":"<p><p>Sialidosis type I (ST-1) is a rare lysosomal storage disease (LSD) caused by NEU1 gene mutations, leading to progressive neurological and visual dysfunction. The classical macular cherry-red spot (CRS) is considered a hallmark ocular sign, but its diagnostic value, particularly in older patients, remains unclear. This study aimed to characterize ocular manifestations and evaluate optical coherence tomography (OCT) reflectivity as a potential structural biomarker of neurological function. In this 2-year prospective cohort study, 15 genetically confirmed ST-1 patients underwent neurological evaluations every 6 months and annual ophthalmic assessments including best-corrected visual acuity (BCVA), fundus photography, OCT, and visual evoked potential (VEP). OCT reflectivity of the inner retina (R_in) and ellipsoid zone at the foveola (R_ez) was quantified using greyscale analysis. Fifteen age-matched healthy controls were included for comparison. CRS was present in 46.7% of patients, predominantly in younger individuals. OCT revealed significantly elevated R_in and R_ez in ST-1 patients compared to controls (p < 0.0001), including in those without clinically visible CRS. OCT reflectivity was strongly associated with neurological severity but not with BCVA. Conversely, BCVA correlated with parafoveal and ganglion cell complex thinning and with delayed VEP latency. Age-related declines in reflectivity, retinal thickness, and BCVA were observed in ST-1 but not in controls. These findings highlight OCT reflectivity is a more sensitive biomarker than the CRS for diagnosing ST-1 and reflects neurological severity even in patients without visible CRS. Importantly, the structure-function relationship between OCT parameters and neurological outcomes suggests broader applicability in LSD and other neurodegenerative conditions.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70191"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147729351","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 and Metabolic Management of Adult Refsum Disease: Guidance From the Medical and Scientific Committee of Global DARE (Defeat Adult Refsum Everywhere).","authors":"Radha Ramachandran, Raphael Buttigieg, Florian Eichler, Bart P Leroy, Omar Mahroo, Rachel M Huckfeldt, Sarah Firman, Eleanor Baldwin, Kristie DeMarco, Susan Kuranoff, Amena Fine, Reinhard Klingel, Sacha Ferdinandusse, Joseph G Hacia, Ronald J Wanders, Anthony S Wierzbicki","doi":"10.1002/jimd.70201","DOIUrl":"10.1002/jimd.70201","url":null,"abstract":"<p><p>Adult Refsum disease (ARD; OMIM 266510) is a degenerative autosomal recessive condition typically diagnosed in adulthood. It affects visual, auditory and nervous system function. It is characterised by plasma, neuro-ophthalmological and adipose tissue accumulation of the dietary-derived phytanic acid (PA). This guidance reviews the clinical aspects of ARD and discusses interventions to address various co-morbidities of the disease. This GRADE-aligned guidance is based on a review of the literature and a consensus statement reflecting the conclusions of professionals with experience in the diagnosis and management of ARD. This statement reviews clinical aspects of ARD and discusses current and potential interventions to address various symptoms of the disease. It provides an overview of the clinical phenotype, reviews the clinical, biochemical, and genetic findings in ARD, and the neurological and ophthalmological investigations needed at diagnosis and during follow-up. It highlights the importance of dietary management and its role in situations such as acute hospital admissions for inter-current illness. Furthermore, it provides guidance on the acute management of decompensation in ARD and outlines when therapeutic plasma exchange/lipoprotein plasmapheresis should be considered. Greater clinician and patient awareness will lead to early diagnosis and improved outcomes. Implementation of a low PA diet before further end organ involvement offers the best prognosis. Life-long dietary therapy, along with therapeutic plasma exchange/lipoprotein apheresis during acute decompensations, remains the mainstay of management. Patients should have access to a multidisciplinary team to ensure specialist dietary input and supportive management of comorbidities.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70201"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147982019","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":"Multimodal Noninvasive Biomarker Characterization of Structural and Functional Alterations in ADSS1-Deficient Myopathy.","authors":"Merve Koç Yekedüz, Raquel van Gool, Hanne van der Heijden, Buket Sonbas Cobb, Nehal Shah, Georgina Johnson, Cara A Timpani, Julie Shulman, Vanessa Rameh, Evan E Hsu, Courtney LeSon, Pui Y Lee, Adam P Vogel, Walla Al-Hertani, Hyung Jun Park, Emma Rybalka, Seward B Rutkove, Jaymin Upadhyay","doi":"10.1002/jimd.70193","DOIUrl":"10.1002/jimd.70193","url":null,"abstract":"<p><p>Adenylosuccinate synthase 1 (ADSS1)-deficient myopathy is an ultra-rare disease characterized by progressive muscle dysfunction. The objective of this investigation was to employ a noninvasive biomarker approach to phenotype (fine-)motor skills, communication and cognition in adults with ADSS1-deficient myopathy. Five individuals with ADSS1-deficient myopathy and five age-sex-matched healthy controls (HCs) underwent a multimodal evaluation. Assessments included, (i) evaluation of motor performance, (ii) speech and voice production and cognitive test batteries, (iii) patient-reported outcomes, (iv) electrical impedance myography (EIM), (v) musculoskeletal magnetic resonance imaging (MRI), and (vi) plasma proteomics. ADSS1-deficient myopathy participants vs. HCs demonstrated reduced performance on the 9-Hole Peg and grip strength tests as well as lower self-reported mobility. Analysis of speech and voice performance revealed asthenia (vocal weakness) (p = 0.02), lower intelligibility (p = 0.008), and worse voice quality during the sustained vowel task (p = 0.03) in the ADSS1-deficient myopathy cohort. Cognitive functioning remained unaffected in patients with ADSS1-deficient myopathy. On EIM, ADSS1-deficient myopathy participants vs. HCs, demonstrated a pattern of higher resistance and lower reactance and phase across upper- and lower-extremity measurements, indicative of poorer muscle health, with large effect sizes (Cliff's δ = 0.5-0.9). MRI revealed intramuscular fat infiltration, particularly in posterior compartments of the upper leg (e.g., biceps femoris). Proteomics indicated reduced (p = 0.04) Neurotrophin-3 (NTF3; implicated in neuronal development, survival, and differentiation) levels in the ADSS1-deficient myopathy cohort relative to HCs. Lower NTF3 levels associated with poorer performance on hand-motor tasks as well as higher resistance and lower reactance and phase on EIM. This study highlighted the value of multimodal phenotyping for quantifying disease expression and advancing monitoring strategies in ADSS1-deficient myopathy. This multimodal investigation demonstrates that integrating electrical impedance myography with quantitative motor, speech, musculoskeletal imaging, and proteomic assessments provides a sensitive and noninvasive research framework for capturing neuromuscular dysfunction and functional disease burden in patients with ADSS1-deficient myopathy, thereby supporting the current biomarker strategy for refined phenotyping and longitudinal disease monitoring in this ultra-rare condition.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70193"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773914","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":"Shifting Towards Empagliflozin First-Line Therapy in Glycogen Storage Disease Type Ib: A Nationwide Real-World Study.","authors":"Sema Kalkan Uçar, Neslihan Önenli Mungan, Gülden Fatma Gökçay, Ayşe Çiğdem Aktuğlu Zeybek, Sebile Kılavuz, Seda Güneş, Fatih Kardaş, Pelin Teke Kısa, Kısmet Çıkı, Aynur Küçükçongar Yavaş, Ayça Burcu Kahraman, Merve Yoldaş Çelik, Ebru Canda, Deniz Kor, Meryem Karaca, Tanyel Zübarioğlu, Emine Genç, Havva Yazıcı, Fatma Derya Bulut, Şebnem Kılıç, Hanım Aghakıshılı, Fehime Erdem Karapınar, Ezgi Burgaç, Ertuğrul Kıykım, Alperen Elek, Nihal Kardaş, Ekrem Ünal, Tuba Hilkay Karapınar, Meryem Albayrak, Canan Albayrak, Ayşegül Ünüvar, Saskia B Wortmann, Deniz Yılmaz Karapınar","doi":"10.1002/jimd.70198","DOIUrl":"10.1002/jimd.70198","url":null,"abstract":"<p><p>Neutrophil dysfunction and neutropenia are burdensome findings in glycogen storage disease type Ib (GSDIb). Treatment with granulocyte-colony stimulating factor (G-CSF) often corrects neutropenia but fails to improve clinical symptoms like inflammatory bowel disease (IBD). Recently, empagliflozin (EMPA) was shown to correct the neutrophil dysfunction and its clinical consequences. It is increasingly used as first-line monotherapy, but long-term, real-world data are lacking. This nation-wide retrospective study investigated 42 GSD1b patients (36 children) treated with EMPA as first-line monotherapy and compared them with those receiving combination therapy with G-CSF and treatment-naïve patients (I:EMPA first-line monotherapy [n = 9]; II:G-CSF monotherapy [n = 7]; III:EMPA plus G-CSF [n = 16]; and IV: neither EMPA nor GCSF [n = 10]). Pediatric (P) patients were evaluated separately. In pediatric patients receiving EMPA as first-line monotherapy (P-I) and those with EMPA plus G-CSF (P-III), the frequency of infections, hospital admissions, and IBD was significantly lower than in patients receiving GCSF-monotherapy (P-II) or no treatment (P-IV). Additionally, significantly improved weight gain was observed in P-I. While clinical improvement related to correction of neutrophil dysfunction was seen with EMPA first-line monotherapy (P-I), significant improvement in absolute neutrophil count (ANC) and hemoglobin levels was only seen in P-III with additional G-CSF treatment. In three cases, EMPA was safely paused and subsequently resumed, for example, during pregnancy or liver transplantation. First-line EMPA monotherapy effectively corrects clinical symptoms of neutrophil dysfunction in GSD Ib patients, even in the absence of a statistically significant increase in ANC.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70198"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147815443","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":"Differential Trafficking Phenotypes of NPC1 Mutant Proteins Reveal Distinct Cholesterol Accumulation Profiles.","authors":"Sanaa Abdelmalek Mahmoud, AhmedElmontaser Mergani, Maren von Köckritz-Blickwede, Hassan Y Naim","doi":"10.1002/jimd.70186","DOIUrl":"10.1002/jimd.70186","url":null,"abstract":"<p><p>Niemann-Pick disease type C (NPC) is a rare autosomal recessive lysosomal storage disorder that affects approximately 1 in 100 000 live births. It is primarily caused by mutations in the NPC1 gene, which disrupts intracellular cholesterol transport and leads to lipid accumulation in late endosomes and lysosomes. This results in visceral dysfunction and progressive neurological deterioration. This study investigated the effects of three NPC1 disease-causing mutations (p.I1061T, p.D874V, and p.P1007A) on NPC1 biosynthesis, trafficking of NPC1, and cellular cholesterol levels. By expressing NPC1 mutants and wild-type NPC1 in NPC1 knockout Chinese hamster ovary cells (CHO-CT43), we analysed the trafficking patterns using Western blot based on endoglycosidase H sensitivity. We also examined lipid raft distribution and unesterified cholesterol accumulation using flotillin 2, filipin staining, and high-performance liquid chromatography (HPLC). Our findings revealed significant differences in NPC1 mutant expression levels and trafficking patterns, categorizing them into three distinct phenotypes: intracellularly retained, slow-trafficking, and finally wild-type-like mutants. Notably, the variations in NPC1 mutant expression and trafficking patterns in CHO-CT43 cells correlated with alterations in lipid rafts distribution and cellular cholesterol levels. The study demonstrated a clear association between cholesterol accumulation and NPC1 mutant trafficking phenotypes, with the p.I1061T variant exhibiting the most severe biochemical profile and highest cellular cholesterol levels. In conclusion, this study highlights a promising framework for elucidating the genotype-phenotype relationships in NPC and assessing their potential pathogenicity. These findings have significant implications for understanding the molecular mechanisms underlying NPC, and they propose personalized, targeted therapeutic strategies for this devastating disease.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70186"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13080411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147690592","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":"Survival and Clinical Progression in Barth Syndrome: Insights From the Barth Syndrome Foundation's Database of 502 Affected Individuals.","authors":"Kexin Fu, Yonglin Huang, Valerie Bowen, Katherine McCurdy, Reina B Tan, Colin K L Phoon, Lindsay Marjoram, Alex Dahlen","doi":"10.1002/jimd.70189","DOIUrl":"10.1002/jimd.70189","url":null,"abstract":"<p><p>Barth syndrome (BTHS; OMIM 302060) is an ultra-rare, life-limiting genetic disorder characterized by cardiomyopathy, skeletal muscle myopathy, neutropenia, gastrointestinal issues, and fatigue. Formal analyses of survival and clinical progression remain limited. Barth Syndrome Foundation has maintained an intake database (n = 502), representing > 80% of the known global population, as well as a patient-inputted registry for a subset of individuals (n = 162) with up to 11 years of longitudinal outcome data. We estimate the survival curve, identify factors associated with mortality, characterize clinical manifestations over time, and evaluate causes of death. Death disproportionately affected young children, with a 59% transplant-free survival rate for those age < 5. The risk of death plateaued between ages 5-25 before rising again. Heart transplantation (HR = 0.316, 95% CI: 0.162-0.619, p < 0.001) and living in a developed country (HR = 0.109, 95% CI: 0.018-0.659, p < 0.05) were associated with reduced risk of death. Clinical manifestations increased with age, with musculoskeletal/fatigue (66%) being most frequent. Top causes of death were cardiac-related complications, with cardiomyopathy/heart failure (51.3%), mostly in young children < 5, and arrhythmia/cardiac arrest (15%). This is the most comprehensive longitudinal assessment of BTHS survival, mortality risk, and clinical manifestation progression. Early childhood is a period of high mortality risk, driven in large part by heart failure. Although risk of death and hospitalizations plateaued between ages 5-25, the clinical burden of BTHS increases throughout the lifespan. Our results may guide clinical care, identify time windows for optimal intervention, and help clinicians better recognize BTHS clinical features.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"49 3","pages":"e70189"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816029","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}