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Genes (Basel). 2025 May 27;16(6):641. doi: 10.3390/genes16060641.

ABSTRACT

Background: Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder due to mutations in the ATM gene. Given the residual kinase activity and the type of ATM mutation, its clinical spectrum varies from a severe classic phenotype to a variant atypical form. Material and methods: This study included 28 patients belonging to four big Bulgarian Muslim pedigrees with tremor and dystonia. Whole-exome sequencing was performed in seven affected individuals from two unrelated pedigrees, followed by Sanger sequencing of the coding sequences and exon-intron borders of the ATM gene. Results: Twenty-four of the affected individuals were homozygous for c.8147T>C (p.Val2716Ala) in ATM, while four of the affected individuals were compound heterozygous. The targeted Sanger sequencing along the ATM gene revealed as a second mutation in three of the patients the splice-site variant c.4909+1G>A and in one patient a synonymous pathogenic variant with a splicing effect, c.3576G>A, p.Lys1192. The age at onset in our group varied between 14 days and 40 years. The main symptoms were dystonia and tremor, more prominent in the upper limbs and the neck, and dystonic dysarthria and dysphagia. The clinical course was very slowly progressive. Brain imaging was normal in the majority of the patients. Conclusion: Clinical features due to mutations in the ATM gene can be very broad. The disease may appear as dystonia, especially of early onset, without frank cerebellar involvement and also normal cerebral imaging. A-T should be considered in all patients with unexplained, even mild movement disorders and elevated α fetoprotein.

PMID:40565533 | DOI:10.3390/genes16060641

Eur J Immunol. 2025 Jun;55(6):e51457. doi: 10.1002/eji.202451457.

ABSTRACT

Gamma delta (γδ) T cells are pivotal in diverse immune responses, encompassing defense against infections, cancer surveillance, and tissue repair. Inborn errors of immunity (IEI) are rare genetic conditions disrupting human immune system development and function, with some impacting γδ T cells. In this review, we focus on IEI leading to a relative increase or decrease of γδ T cells compared to αβ T cells. We discuss how these disorders provide unique insights, in particular concerning the importance of signaling pathways for human αβ versus γδ T cell development, function, and homeostasis. Wherever suitable, we also include data from respective mouse models of IEIs that corroborate patient observations but also illustrate relevant species differences. This comparative approach identifies gaps in knowledge and defines areas for future research. Overall, this review underscores the relevance of IEIs in elucidating the development and function of human γδ T cells with potential implications for diagnosing and treating patients with immune disorders.

PMID:40556329 | DOI:10.1002/eji.202451457

EClinicalMedicine. 2025 Jun 9;84:103271. doi: 10.1016/j.eclinm.2025.103271. eCollection 2025 Jun.

ABSTRACT

BACKGROUND: Wiskott-Aldrich Syndrome (WAS) is characterized by eczema, infections, and severe bleeding, but may also include autoimmunity and malignancy. Subjects with X-linked thrombocytopenia (XLT) can display a mild phenotype, although severe complications may occur at any age. WAS and XLT are caused by mutations of the WAS gene. However, retrospective studies have shown conflicting results about their genotype-phenotype correlation and their relative risk of complications.

METHODS: To evaluate the outcome of patients with WAS or XLT, since January 2004, patients with identified WAS mutations were enrolled in the WAS/XLT IPINet registry at diagnosis and annually evaluated until December 2018 by participating AIEOP-IPINet centers; data were prospectively collected by each participating center throughout a web-based centralized system and then retrieved from the registry for the analysis. This prospective study enrolled 117 patients (according to Zhu criteria, 92 were affected by WAS and 25 by XLT) with appropriate hematological features and documented WAS mutation.

FINDINGS: The median follow-up was 6 years (range 1-30 years), resulting in 1110 patient years. At diagnosis, only the patients with WAS presented invasive infections, such as sepsis, meningitis, cerebral abscesses, herpetic infections, and candida infections, while patients with XLT did not present invasive infections. The most common autoimmune manifestations in patients with WAS were hemolytic anemia (20%) and vasculitis (9.3%), inflammatory bowel disease (5%), arthritis (4%), nephropathy (2%), and coeliac disease (1%). Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) was performed in 71 (61%), autologous hematopoietic stem cell gene therapy (HSC-GT) in 10 (8.5%), splenectomy in 16 (14%) patients, while 26 patients (22%) received none of these therapies. The overall survival at 25-year follow-up was 75% for patients with WAS after HSCT. Considering the cut-off date year 2000, it improved to >80%. Patients with WAS treated by haploidentical HSCT with αβTCRT-/CD19 B-cell depletion or gene therapy showed 100% survival at 5 years. The overall survival rate at the 20-year follow-up of the 25 patients with XLT was 83% but with a cumulative incidence of 100% and 19% of infections and autoimmunity, respectively, at the 15-year follow-up.

INTERPRETATION: The evidence of the heterogeneity of WAS and XLT outcomes could be instrumental to draw updated recommendations for the management of the patients affected by these rare conditions. It would be desirable to expand the tools to estimate the risk of infectious and autoimmune events in patients with XLT and the impact of their treatment, including HSCT over time.

FUNDING: This study was funded by the European Union-Next Generation EU-NRRP M6C2-Investment 2.1 Enhancement and strengthening of biomedical research in the NHS, Ministero della Salute (PNRR-MR1-2022-12376594). A.S., A.A., P.C., F.F., C.M.P., C.F., D.L., G.S., M.D., M.C., P.A., B.A., P.F. are part of the European Reference Network on Rare Primary Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN-RITA, project 739543).

PMID:40547444 | PMC:PMC12179709 | DOI:10.1016/j.eclinm.2025.103271

Immunol Med. 2025 Jun 24:1-12. doi: 10.1080/25785826.2025.2515333. Online ahead of print.

ABSTRACT

Immunoglobulin G replacement therapy prevents infections in patients with antibody deficiencies. Subcutaneous immunoglobulin (SCIg) has typically been administered via infusion pump, but the manual push technique offers a simple, convenient alternative method. The manual push technique is efficacious, well tolerated, quick to administer, offers increased dosing flexibility, and does not rely on a pump. Having various administration options available to patients provides greater treatment satisfaction and feelings of self-empowerment, which may improve compliance. Currently available literature published before 10 February 2022, that reported patient and healthcare professional experience with SCIg administered via manual push, were reviewed. Literature searches were performed using PubMed, Google and ClinicalTrials.gov using key words ‘manual push’, ‘rapid push’, ‘immunoglobulin’, ‘subcutaneous immunoglobulin’, ‘SCIg’, and ‘primary immunodeficiency’. Real-world evidence demonstrates all delivery techniques provide similar efficacy, so treatment administration becomes about patient preference, hospital resources, cost-effectiveness/recovery and clinician attitude. To establish newer administration modalities such as manual push or prefilled syringes, there needs to be patient awareness of these options, then education and finally confidence in recommending these options. Adoption of newer administration modalities will help ensure patients receive the widest range of choice, thus improving compliance and their risk of recurrent and severe infection.

PMID:40552388 | DOI:10.1080/25785826.2025.2515333

Med Princ Pract. 2025 Jun 19:1-23. doi: 10.1159/000547015. Online ahead of print.

ABSTRACT

Vedolizumab (VDZ) is a key therapeutic option for inflammatory bowel disease (IBD) patients, not responding to conventional treatments. An α4β7 integrin antagonist, VDZ primarily prevents T cell migration to the gut by inhibiting the binding of integrins to mucosal vascular address in cellular adhesion molecule. Its gut-selective mechanism of action and safety profile makes it a valuable intervention for treating non-IBD-related diseases, which are difficult to treat and lack standardized guidelines. There is plenty of evidence to suggest that vedolizumab has therapeutic potential beyond its primary indication in IBD, with clinical applications now extending to immune checkpoint inhibitor-associated colitis, chronic pouchitis, gastrointestinal graft-versus-host disease, and acquired immunodeficiency syndrome. This review aimed to analyze the therapeutic value of VDZ for non-IBD-related diseases and provide a reference for treating these patients. It has been observed that long-term follow-up data are lacking, and additional well-designed large-scale studies are still needed to further validate the efficacy and safety of VDZ.

PMID:40545809 | DOI:10.1159/000547015

Ugeskr Laeger. 2025 May 26;187(22):V02250083. doi: 10.61409/V02250083.

ABSTRACT

Primary immunodeficiencies are rare monogenic inborn errors of immunity and can involve any combination of infection, autoimmunity, inflammation, and malignancy. While increased use of whole genome sequencing has vastly improved diagnosis, curative treatment options beyond haematopoietic stem cell transplantation are still lacking behind. In this review, we present and discuss the promising avenues of CRISPR/Cas gene editing of patient stem cells for curing these diseases through homology-directed repair, base- or prime editing and delivery by nanoparticles or viral derivatives. However, technological, regulatory, and economic challenges exist on the road to safe and broad implementation of this technology for personalized medicine in the clinic.

PMID:40539280 | DOI:10.61409/V02250083

BMC Pregnancy Childbirth. 2025 Jun 19;25(1):672. doi: 10.1186/s12884-025-07736-4.

ABSTRACT

BACKGROUND: Understanding determinants of antibiotic use during pregnancy is crucial for optimizing their utilization in clinical practice. We aimed to investigate which individual-level factors are associated with antibiotic use among pregnant women.

METHODS: Population-based cohort study using linked data from the Swedish national health and population registers spanning from 2006 to 2019. Sociodemographic characteristics, medical and obstetric history, lifestyle and healthcare utilization were investigated as independent variables. Any systemic antibiotic use during pregnancy, the primary outcome, was determined from filled prescriptions, with broad-spectrum antibiotics and multiple courses of antibiotics as secondary outcomes. Multiple logistic regression was used to estimate odds ratios (ORs), including all independent variables in the model.

RESULTS: Among 20 variables associated with any systemic antibiotic use during pregnancy, preconception prescription drug use (OR 1.93 [95% CI 1.87-1.98] for > 4 vs. 0-1 unique therapeutic subgroups), chronic renal disease (1.82 [1.73-1.93]) and low maternal age (1.67 [1.61-1.74] for ages < 20 vs. 30-34 years) had the highest odds. Chronic renal disease, immunodeficiency disorders and preconception drug use (> 4 vs. 0-1 therapeutic subgroups) had the highest odds of broad-spectrum antibiotic use and use of multiple antibiotic courses.

CONCLUSIONS: Pre-existing morbidities and low maternal age were most strongly associated with antibiotic use during pregnancy, suggesting a needs-based approach in prescribing. Proactive management of morbidities and infection prevention strategies, particularly targeting young women of reproductive age, could potentially reduce the need for antibiotic treatment in prenatal care.

PMID:40537761 | DOI:10.1186/s12884-025-07736-4

Pediatr Pulmonol. 2025 Jun;60(6):e71174. doi: 10.1002/ppul.71174.

ABSTRACT

Interleukin-6 receptor (IL-6R) deficiency is a rare immunodeficiency marked by impaired IL-6 signaling, affecting the inflammatory response and respiratory health. In this report, pediatric patients with IL-6R deficiency presented with a spectrum of respiratory symptoms, from mild to severe infections, but did not commonly develop early bronchiectasis. Due to the absence of typical inflammatory markers in lung infections, routine imaging is advised to monitor for potential complications, even in the absence of overt clinical signs.

PMID:40536180 | DOI:10.1002/ppul.71174

Clin Exp Immunol. 2025 Jan 21;219(1):uxaf024. doi: 10.1093/cei/uxaf024.

ABSTRACT

Leukocyte adhesion deficiency I (LAD-I) is an autosomal recessive immunodeficiency caused by mutations in the ITGB2 gene, characterized by recurrent severe infections, impaired pus formation, and delayed wound healing. In this study, we describe a late-onset presentation of LAD-I in a 22-year-old male who initially exhibited marked leukocytosis and neonatal omphalitis, followed by recurrent upper respiratory tract infections from 9 months of age. At age 13, the patient developed abdominal and left iliac fossa abscesses, which progressed to a vesicocutaneous fistula after a prolonged febrile episode. Extended catheterization and antibiotic treatment led to the formation of characteristic tin foil-like scarring. Recurrent purulent skin and soft tissue infections led to widespread scarring and pigmentary changes. Next-generation sequencing (NGS) identified a novel homozygous splice-site mutation in ITGB2 (NM_000211.5, c.1225-1G > A, IVS10-1G > A). In silico analysis predicted disruption of the acceptor site, while a minigene assay demonstrated two aberrant splicing events, namely a 12-bp deletion and complete skipping of exon 11 (188 bp). Flow cytometry analysis at age 13 showed CD18 expression reduced to less than 1% across granulocytes, monocytes, and lymphocytes, with concomitant decreases in β2-integrin α subunits (CD11a, CD11b, and CD11c). At 15 years of age, the patient underwent hematopoietic stem cell transplantation (HSCT) from a fully HLA-matched (10/10) heterozygous sister donor following a modified myeloablative conditioning regimen. Although initial chimerism fluctuated, full donor chimerism was ultimately achieved, restoring CD18 expression and normalizing ɑ-integrin levels. This study highlights the therapeutic efficacy of HSCT in correcting the molecular defects associated with LAD-I.

PMID:40531141 | DOI:10.1093/cei/uxaf024

Future Sci OA. 2025 Dec;11(1):2520128. doi: 10.1080/20565623.2025.2520128. Epub 2025 Jun 18.

ABSTRACT

BACKGROUND: This study compares the setup time and steps of two different subcutaneous infusion pumps using a 50 mL prefilled syringe (or PFS).

METHODS: This cross-sectional time and motion assessment followed by a survey gathered patient setup time, number of steps, and surveyed preference for the FREEDOM60^® (“Pump A”; manufactured by KORU Medical Systems, Inc.) and SCIg60^™ (“Pump B”; manufactured by EMED Technologies Corporation) pump for subcutaneous immunoglobulin (SCIg) therapy. Participants were recruited from the Immune Deficiency Foundation (IDF) patient network. Participants provided informed consent, engaged in a hands-on demonstration, and completed a self-administered survey.

RESULTS: 89% reported faster setup times with the Pump A infusion system, resulting in time efficiency improvements. Fast and easy setup, portability, and minimal steps were highly valued and influenced patient satisfaction. Challenges included pump malfunction and complex setup. Patients preferred prefilled syringes due to ease and potential error reduction. Fast setup time was important for arthritis management, reducing stress, work accommodation, and caregiver assistance.

CONCLUSION: A significant majority (78%) of patients preferred Pump A over Pump B. It showed advantages in load/unload setup time, resulting in time savings and increased efficiency for SCIg therapy. Incorporating Pump A may enhance treatment adherence and satisfaction, improving outcomes in primary immunodeficiency (PID) management.

PMID:40530995 | DOI:10.1080/20565623.2025.2520128