Journal of Internal Medicine最新文献

{"title":"The novel ITPR1 p.Phe2566Ser variant impairs IP3R1-mediated Ca2+ release and is associated with ataxia and miosis","authors":"Josephine Wincent, Songbai Zhang, Andrew Nolan, Shigeaki Kanatani, Frida Nordin, Malin Kvarnung, Per Uhlén, Martin Paucar, Ilse Eidhof","doi":"10.1111/joim.70081","DOIUrl":"10.1111/joim.70081","url":null,"abstract":"<p>Dear Editor,</p><p>Pathogenic variants in the <i>ITPR1</i> gene, which encodes the inositol 1,4,5-trisphosphate receptor type 1 (IP<sub>3</sub>R1) — a critical intracellular calcium (Ca<sup>2+</sup>) release channel — βare known to cause a spectrum of neurological disorders. These include spinocerebellar ataxia types 15 and 29 (SCA15, SCA29), Gillespie syndrome, and pontine/cerebellar hypoplasia. IP<sub>3</sub>R1 is highly expressed in cerebellar Purkinje cells, where it regulates inositol 1,4,5-trisphosphate (IP<sub>3</sub>)-evoked endoplasmic reticulum (ER) Ca<sup>2+</sup> release [<span>1</span>]. Although ataxia is a hallmark of <i>ITPR1</i>-related disease and aniridia or iris hypoplasia is characteristic of Gillespie syndrome, the co-occurrence of ataxia and miosis has been documented only in two cases [<span>2, 3</span>]. The mechanistic basis of this ultrarare presentation is largely elusive. Here, we report a third family with congenital ataxia and miosis, carrying a novel heterozygous <i>ITPR1</i> missense variant.</p><p>The index patient was diagnosed with ataxia and miosis in infancy. There was no follow-up until age 59 when a brain MRI showed mild white matter abnormalities, but no cerebellar atrophy. Upon examination at ages 60 and 62, she displayed mild non-progressive axial ataxia (SARA score 5.5), mirror movements (MM), broken pursuit, and miosis (Fig. 1a) with slow dark adaptation. OCT showed marked thinning of the iris (Fig. 1b). She did not have pyramidal symptoms or areflexia. The patient's mother, two children, and two grandchildren had ataxia, and four of them had miosis (Fig. 1c, Table S1). Unlike previously reported ataxia–miosis cases [<span>2, 3</span>], none exhibited intellectual disability or dysmorphism (Tables S1 and S2). The iris phenotype of the index, however, closely resembled that described by Chesneau et al. [<span>3</span>], with a thin dilator muscle without iris transillumination, distinguishing it from congenital microcoria [<span>4</span>]. Detailed clinical information can be found in the Supporting Information.</p><p>Genetic investigation identified the very rare heterozygous <i>ITPR1</i> variant c.7697T>C (NM_002222.7, p.Phe2566Ser) with a CADD score of 32, which was reported once in the general population (gnomAD v4.1.0), conserved across species, and co-segregated with disease. No pathogenic variants were identified in genes associated with MM.</p><p>The p.Phe2566Ser variant resided within the IP<sub>3</sub>R1 linker (LNK) domain, distinguishing it from the β-TF1 suppressor-domain variants previously associated with ataxia–miosis (Fig. 1d). Using cryo-EM structures of rat IP<sub>3</sub>R1 [<span>5</span>], we found that the homologous residue of Phe2566 (Phe2621) participates in IP<sub>3</sub>R1 state-dependent rearrangements (Figs. S2–S4). In the active IP<sub>3</sub>R1, Phe2621 formed many hydrophobic contacts, particularly with His2631 within a Zn<sup>2+</sup>-binding motif implicated in st","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 5","pages":"643-648"},"PeriodicalIF":9.2,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13061096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147315885","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 cholesterol absorption efficiency interferes with bile acid metabolism and cholesterol elimination from the body","authors":"Piia Simonen,&nbsp;Ingmar Wester,&nbsp;Jyri Lommi,&nbsp;Juha Sinisalo,&nbsp;Helena Gylling","doi":"10.1111/joim.70031","DOIUrl":"10.1111/joim.70031","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Elevated low-density lipoprotein (LDL) cholesterol causes atherosclerotic cardiovascular diseases. Variables of whole-body cholesterol metabolism, for example, high cholesterol absorption efficiency, might also be atherogenic, whereas the role of bile acids is controversial.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>This post hoc study concerns the impact of cholesterol absorption on bile acid metabolism. The hypothesis was that cholesterol absorption efficiency interferes with bile acid metabolism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Cholesterol metabolism was studied using absolute and relative methods. Elimination of cholesterol from the body as bile acids and neutral sterols was assessed from 24-h faecal collections and analysed by gas–liquid chromatography. Cholesterol absorption efficiency was evaluated by a peroral continuous dual-isotope feeding method, and cholesterol synthesis by a sterol-balance technique. The relative methods included analyses of serum biomarkers of cholesterol absorption efficiency and cholesterol synthesis by gas–liquid chromatography.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Faecal bile acids, neutral sterols and cholesterol synthesis were lower in high- versus low-cholesterol absorbers. Elimination of cholesterol from the body as bile acids and neutral sterols was reduced in high- versus low-cholesterol absorbers. Serum and LDL cholesterol levels did not differ in low- versus high-cholesterol absorbers. Absolute and relative methods of cholesterol metabolism correlated with each other, suggesting that the results can be considered valid.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In high-cholesterol absorbers, poor elimination of cholesterol from the body as bile acids and neutral sterols may indicate an increased risk of atherosclerosis. It can be prevented by decreasing cholesterol absorption and increasing reverse cholesterol transport by dietary means combined with ezetimibe and statin treatment, when needed.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 5","pages":"628-638"},"PeriodicalIF":9.2,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13061100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145335963","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":"Collagen and microvascular alterations contribute to neuromuscular degeneration and disease progression in chronic intestinal pseudo-obstruction","authors":"Elisa Boschetti,&nbsp;Irene Neri,&nbsp;Leonardo Caporali,&nbsp;Elena Bonora,&nbsp;Carolina Malagelada,&nbsp;Claudio Fiorini,&nbsp;Danara Ormanbekova,&nbsp;Alessandro Berghella,&nbsp;Roberto D'Angelo,&nbsp;Rita Rinaldi,&nbsp;Cristiana Caliceti,&nbsp;Anna Costanzini,&nbsp;Mirella Falconi,&nbsp;Vincenzo Stanghellini,&nbsp;Stefano Ratti,&nbsp;Lucia Manzoli,&nbsp;Valerio Carelli,&nbsp;Roberto De Giorgio","doi":"10.1111/joim.70078","DOIUrl":"10.1111/joim.70078","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Chronic intestinal pseudo-obstruction (CIPO) is a severe gastrointestinal motility disorder that may be idiopathic or associated with systemic disease. In idiopathic cases, the pathophysiological mechanisms remain poorly defined. Although mutations in angiogenic factors have been reported in mitochondrial forms of CIPO, their role in non-mitochondrial cases is still unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To investigate genetic and molecular contributors to CIPO, with a specific focus on intestinal microvasculature.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Jejunal samples from patients with CIPO were analysed by whole exome sequencing (WES) and mitochondrial DNA (mtDNA) profiling. Morphometric and immunohistochemical studies assessed collagen remodelling, vascular architecture, neuromuscular integrity and hypoxia. Expression of angiogenic factors, including thymidine phosphorylase (TP) and vascular endothelial growth factor (VEGF), was evaluated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>WES did not identify known CIPO-causing variants, but rare mutations in collagen-related genes were detected in a subset of patients. Tissue analysis revealed higher fibrosis, vascular remodelling with a predominance of very small vessels, thinning of the longitudinal muscle and neuronal loss. TP and VEGF expression were significantly reduced, whereas hypoxia-inducible factor-1α (HIF-1α) was markedly upregulated. mtDNA integrity and copy number were preserved, whereas haplogroup J was overrepresented. Multivariate analysis linked these alterations to a higher frequency of sub-occlusive episodes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Vascular dysfunction and collagen abnormalities emerge as key contributors to neuromuscular degeneration in CIPO. These findings provide novel mechanistic insights into disease pathophysiology and support further exploration of vascular-targeted therapeutic strategies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 5","pages":"587-603"},"PeriodicalIF":9.2,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13061101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147300429","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":"Increased intervals in enzyme replacement therapy for stable type 1 Gaucher disease: A non-inferiority sequential trial emulation","authors":"Maxime Beydon,&nbsp;Jérôme Stirnemann,&nbsp;Karima Yousfi,&nbsp;Samira Zebiche,&nbsp;Dalil Hamroun,&nbsp;Anaïs Brassier,&nbsp;Samia Pichard,&nbsp;Laure Swiader,&nbsp;Thierry Billette de Villemeur,&nbsp;Bénédicte Héron,&nbsp;Florence Dalbies,&nbsp;Bérengère Cador,&nbsp;Anne-Sophie Guemann,&nbsp;Francis Gaches,&nbsp;Bénédicte Hivert,&nbsp;Vanessa Leguy-Seguin,&nbsp;Agathe Masseau,&nbsp;Yves-Marie Pers,&nbsp;Magali Pettazzoni,&nbsp;Soumeya Bekri,&nbsp;Catherine Caillaud,&nbsp;Edouard Le Guillou,&nbsp;Marie Szymanowski,&nbsp;Leonardo Astudillo,&nbsp;Wladimir Mauhin,&nbsp;Yann Nadjar,&nbsp;Christine Serratrice,&nbsp;Marc G. Berger,&nbsp;Fabrice Camou,&nbsp;Nadia Belmatoug,&nbsp;Yann Nguyen,&nbsp;the French Evaluation of Gaucher Disease Treatment Committee","doi":"10.1111/joim.70079","DOIUrl":"10.1111/joim.70079","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To compare the efficacy and safety of extended interval (Q3–4W) enzyme replacement therapy (ERT) versus standard biweekly (Q2W) ERT in clinically stable type 1 Gaucher disease (GD) patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We emulated a target trial with a sequential trial design, using data from the French Gaucher Disease Registry. Eligible patients were treated for ≥2 years biweekly without clinical events. Every 3 months, switchers to Q3–4W were matched to Q2W patients by age, sex, referral center follow-up, disease history (bone events, anemia, thrombocytopenia, splenectomy, and hepatosplenomegaly), and dose of ERT. The primary outcome was a composite of GD-related events (bone events, anemia, and thrombocytopenia). A 10% non-inferiority margin was prespecified. Secondary outcomes were biomarker changes and economic analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among 280 eligible GD patients, 63 switched to Q3–4W and were matched to a total of 215 Q2W patients, followed for an average of 6.3 years. No significant difference in the risk of clinical events was observed between groups (hazard ratio: 0.98 [95% confidence intervals (CI): 0.54–1.51]). During follow-up, absolute risk difference remained below the 10% non-inferiority threshold at all timepoints. Biomarkers remained stable or slightly decreased in the Q3–4W group. The dosing interval extension led to an average reduction of 55 infusions per patient, corresponding to approximately €450,000 saved per patient over 6 years.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In stable GD1 patients, extending ERT administration to every 3–4 weeks was non-inferior to the standard biweekly regimen, supporting personalized spacing strategies that may improve quality of life and reduce healthcare costs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 5","pages":"604-614"},"PeriodicalIF":9.2,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13061099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147315866","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 6","pages":"741-753"},"PeriodicalIF":9.2,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148067649","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 6","pages":"650-669"},"PeriodicalIF":9.2,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148067648","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 6","pages":"670-693"},"PeriodicalIF":9.2,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148064340","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 6","pages":"711-725"},"PeriodicalIF":9.2,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148062934","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 6","pages":""},"PeriodicalIF":9.2,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148099772","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":196,"journal":{"name":"Journal of Internal Medicine","volume":"299 6","pages":"726-740"},"PeriodicalIF":9.2,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148087985","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}