Clinical manifestations, disease penetrance, and treatment in individuals with SOCS1 insufficiency: a registry-based and population-based study

The Lancet Rheumatology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Suppressor of cytokine signalling 1 (SOCS1) insufficiency is an inborn error immunity affecting the negative regulation and growth factor signalling. We aimed to enhance understanding clinical manifestations, disease trajectories, penetrance, effect Janus kinase (JAK) inhibition in individuals with SOCS1 insufficiency. This study used data from two independent cohorts: European Society for Immunodeficiencies (ESID) registry UK Biobank. Participants ESID were nine countries (Austria, Belgium, France, Germany, Ireland, Italy, Portugal, Sweden, Ukraine), China, Taiwan, USA. eligible if they had heterozygous, functionally validated variants; participants Biobank included any variant detected cohort or other that was classed as high-impact. Clinical manifestations underlying documented summarised into subgroups, ICD-10 diagnosis codes collected tested relevant autoantibodies their local laboratory. Responses JAK inhibitor treatment assessed by treating physician using a visual analogue scale. Descriptive statistics analysis. People lived experience not involved design. 119 insufficiency: 67 registry, enrolled between Feb 15, 2021, Dec 31, 2023, 52 Of 39 (58%) female, 28 (42%) male, median age years (IQR 15-44, range 2-85). 27 different monoallelic variants identified these participants. 62 (93%) symptomatic five (7%) asymptomatic family members; symptoms, allergy (33 [50%]), inflammatory gastrointestinal (22 [36%]) skin (18 [29%]) autoimmune cytopenia (24 [39%]), lymphoproliferation (23 [37%]) most frequent. Rheumatological systemic lupus erythematosus, Sjögren's disease, rheumatoid arthritis, typical autoantibody profiles. 42 (68%) at least three manifestations. In we found carrying high-impact 29 (56%) 23 (44%) 72 (65-78, 57-86). Only 30 developed potentially related Allergy rheumatological more common than registry. Female predominance (21 [70%] female [30%] male) also among Treatment inhibitors showed promising results 12 (92%) 13 differs genetic lymphoproliferative disorders presence frequent atopic Penetrance incomplete higher females males. targeted therapy patients German Research Foundation (DFG).

Language: Английский

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The same genotype gives rise to a spectrum of disorders

The Lancet Rheumatology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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Genetic variations in NLRP3 and NLRP12 genes in adult-onset patients with autoinflammatory diseases: a comparative study

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 26, 2024

Objectives Cryopyrin-associated periodic syndrome or NLRP3-associated autoinflammatory disease (NLRP3-AID) and NLRP12-AID are both Mendelian disorders with autosomal dominant inheritance. Both diseases rare, primarily reported in the pediatric population, thought to be phenotypically indistinguishable. We provide largest cohort of adult-onset patients compared these gene variant frequency population controls. Methods A adult AIDs were retrospectively studied. All underwent molecular testing for fever panels after extensive negative workups systemic autoimmune other related diseases. Patients divided into Group 1- NLRP3-AID NLRP3 variants (N=15), 2- NLRP12 (N=14) 3- (N=9) variants. Exome sequence data two large control populations including ARIC study used compare distribution frequency. Results 38 Caucasian women accounting 82%. Median age at diagnosis was 41 ± 23 years duration 14 13 years. identified statistically significant differences between groups, notably that gastrointestinal symptoms as well evaluations same significantly more frequent variants, headaches/dizziness less common among patients. Livedo reticularis noted four patients, exclusively carriers. Over 50% Groups 1 2 carry low-frequency disease-associated while remaining rare unprecedently digenic i.e., coexistence NLRP12, which either low frequency/rare. Allele frequencies all our absent lower populations, further strengthening evidence susceptibility SAID phenotypes. Conclusion Our comparative shows share similar clinical phenotypes, yet there them regard neurological symptoms. spectrum high genetic variations genes can contribute individually combination.

Language: Английский

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2024 VCP International Conference: Exploring multi-disciplinary approaches from basic science of valosin containing protein, an AAA+ ATPase protein, to the therapeutic advancement for VCP-associated multisystem proteinopathy

Neurobiology of Disease, Journal Year: 2025, Volume and Issue: unknown, P. 106861 - 106861

Published: March 1, 2025

Valosin-containing protein (VCP/p97) is a ubiquitously expressed AAA+ ATPase associated with numerous protein-protein interactions and critical cellular functions including degradation clearance, mitochondrial homeostasis, DNA repair replication, cell cycle regulation, endoplasmic reticulum-associated degradation, lysosomal autophagy apoptosis. Autosomal-dominant missense mutations in the VCP gene may result VCP-associated multisystem proteinopathy (VCP-MSP), rare degenerative disorder linked to heterogeneous phenotypes inclusion body myopathy (IBM) Paget's disease of bone (PDB) frontotemporal dementia (FTD) or IBMPFD, amyotrophic lateral sclerosis (ALS), Alzheimer's (AD), parkinsonism, Charcot-Marie Tooth (CMT), spastic paraplegia. The complexity VCP-MSP makes collaboration among stakeholders essential necessitates multi-disciplinary approach. 2024 International Conference was hosted at Caltech between February 22 25. Co-organized by Cure Disease Dr. Tsui-Fen Chou, meeting aimed center patient as research partner, harmonize diverse stakeholder engagement, bridge gap basic clinical neuroscience it relates VCP-MSP. Over 100 experts attended, ranging from scientists clinicians advocates. Attendees discussed genetics presentation, molecular mechanisms underlying disease, therapeutic approaches, strategies for future research. conference included three roundtable discussions, 29 scientific presentations, 32 posters, nine caregiver closing discussion forum. following proceedings summarize these sessions, highlighting both identified gaps knowledge significant strides made towards understanding treating diseases.

Language: Английский

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Genetically Transitional Disease and the Road to Personalized Medicine

Genes, Journal Year: 2025, Volume and Issue: 16(4), P. 401 - 401

Published: March 30, 2025

Genetically transitional disease (GTD) is emerging as a new concept in genomic medicine to straddle between the traditional binary classification of monogenic and polygenic disease. Genetic testing result reports molecular laboratories have been predicated on model, which focuses pathogenic likely variants. While variants uncertain significance (VUS) are reported by laboratories, there challenges with regard their clinical application so that these often dismissed ordering physicians. Unlike Mendelian disorders, where genetic high penetrance highly probabilistic, GTD employed highlight impact low-to-moderate effect gene whose influence modified background. The may explain health conditions associated necessary but not sufficient for pathogenesis, lying mid gray zone diseases. Although VUSs reach level pathogenicity based American College Medical Genetics Genomics guidelines, they could be provisionally classified GTD-associated annotate interpret relationship VUS human appropriate implementation patient care research focusing attention individual variability responses various

Language: Английский

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Pharmacotherapeutic strategies to promote regulatory T cell function in autoimmunity

Current Opinion in Immunology, Journal Year: 2025, Volume and Issue: 94, P. 102554 - 102554

Published: April 6, 2025

Autoimmune diseases arise when self-antigen-specific T and B cells escape central peripheral mechanisms of tolerance. One such mechanism is control autoreactivity by regulatory (Tregs), which have an essential role in suppressing autoimmunity. Consequently, there significant interest developing ways to boost or restore the function Tregs order prevent treat autoimmunity, induce tolerance, thus reduce reliance on broadly immunosuppressive agents. Strategies include enhancing numbers and/or directly vivo via adoptive cell therapy. Here, we review recent advances our understanding how pharmacologic approaches can be applied enhance Treg through repurposing established drug therapies application new therapies. Specifically, discuss potential Treg-promoting drugs, including interleukin-2 its derivatives, tumor necrosis factor receptor 2 agonists, as well Treg-preserving tyrosine kinase inhibitors. We co-stimulatory blockade with CTLA-4 immunoglobulin affects tolerogenic environments consider whether lymphodepleting therapies, antithymocyte globulin teplizumab, might needed condition environment for better effects. focus drugs type 1 diabetes draw evidence from transplantation. With multiple pharmacotherapeutic strategies optimize vivo, promise effectively durably autoimmune disease remission.

Language: Английский

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Comprehensive clinical phenotype, genotype and therapy in Yao syndrome

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Sept. 20, 2024

Objective Yao syndrome (YAOS) is formerly called nucleotide-binding oligomerization domain containing 2 ( NOD2) -associated autoinflammatory disease.We report a large cohort of YAOS. Methods We conducted retrospective analysis adult patients with systemic diseases (SAIDs). All underwent testing for periodic fever gene panel. Results A total 194 carried NOD2 variants, 152 were diagnosed YAOS, and 42 had mixed combined variants in other SAID-associated genes. Demographic, clinical molecular data summaried. In sub-group the patients, individual often identified to carry two or more that usually included IVS8 + 158/R702W, 158/L1007fs, 158/V955I, 158/other, NOD2/ SAID Ninety-nine single variants. Taken together, these contribute disease combination individually. Conclusion This largest has provided comprehensive genotyping Variants can give rise spectrum from inflammatory bowel disease.This further raises awareness underdiagnosed medical community.

Language: Английский

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Expanding clinical characteristics and genotypic profiling of Yao syndrome in Chinese patients

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Sept. 3, 2024

Objectives Yao syndrome (YAOS, OMIM# 617321) is a kind of systemic autoinflammatory diseases (SAIDs) linked to the nucleotide-binding oligomerization domain containing 2 ( NOD2 ). Clinical reports YAOS in China are sparse. Herein, we reported largest cohort Chinese patients expand understanding its phenotype, genotype, and therapeutic responses. Methods This study enrolled 15 adult diagnosed with at Peking Union Medical College Hospital from April 2015 May 2024. Whole-exome sequencing was performed on all patients. data, genetic variations, treatment responses were documented compared Caucasian cohort. Results The mean age disease onset 35 ± 17 years old. most common clinical manifestations included recurrent high-grade fever (100%), gastrointestinal symptoms (73.3%), arthralgia/arthritis, fatigue, myalgia, lower extremity swelling (46.7%). All exhibited elevated acute-phase reactants during episodes. 12 heterozygous variants identified, Q902K 4 patients, R471C 3, c.-14C>T, A110T, S127L, R311W, A432V, Y514H, R541P, A661P, K818Q, A886V each found individual 90% responded well glucocorticoids, 55.6% sulfasalazine. 66.7% who received TNF inhibitors achieved complete resolution symptoms. Additionally, one patient favorably canakinumab tocilizumab. Compared cohort, our more balanced gender ratio higher proportion fever, proteinuria/hematuria as frequent leukocytosis, acute phase reactants, anemia. Lower proportions skin rashes, headaches, sicca-like noted Moreover, showed good response inhibitors. Conclusion had pronounced inflammatory Variants A886V, R471C, A432V identified novel YAOS. TNF, IL-6, IL-1 promising options. These findings spectrum, profile, efficacy YAOS, underscoring need for heightened awareness this diverse populations.

Language: Английский

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TNFRSF11A variants contribute to systemic autoinflammatory diseases: A case series of 12 patients

Seminars in Arthritis and Rheumatism, Journal Year: 2024, Volume and Issue: 68, P. 152505 - 152505

Published: July 2, 2024

Language: Английский

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Yao syndrome in a child with C2 deficiency

The Journal of Allergy and Clinical Immunology In Practice, Journal Year: 2024, Volume and Issue: 12(11), P. 3159 - 3162

Published: Aug. 15, 2024

Language: Английский

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